Spanish multidisciplinary clinical practice guidelines for Anderson–Fabry disease in adults. I. Method and recommendations

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I: Método y recomendaciones" ] ] "textoCompleto" => "BackgroundAnderson–Fabry disease or Fabry disease (FD) (OMIM 301500) is a lysosomal storage disease caused by a X-linked inherited disorder in which a mutation in the GLA (Xq22.1) gene produces a total or partial deficit of the α-galactosidase A (α-Gal A) enzyme, which results in impaired degradation of glycosphingolipids in the cell membranes, with the subsequent intracellular accumulation of globotriaosylceramide (GB3) and other complex lipids.<a class="elsevierStyleCrossRef" href="#bib0050">1</a>The gene contains 7 exons, and more than 750 mutations have so far been described, which are distributed among the 7 exons with no predominance of any one area. Most of the mutations are restricted to specific families, with no ethnic predominance.<a class="elsevierStyleCrossRefs" href="#bib0055">2,3</a>FD is considered the second most common lysosomal storage disease after Gaucher's disease. A prevalence among males of between 1/40,000 and 1/117,000 for living newborns has been published, although this figure underestimates the actual prevalence by not considering the disease's involvement in women and the incomplete forms of late onset.<a class="elsevierStyleCrossRefs" href="#bib0055">2,4</a>Hemizygous males with very little or no enzymatic activity present multisystem impairment, known as the classical form of the disease, with symptom onset in childhood or adolescence in the form of acroparesthesia, angiokeratoma, hypohidrosis, intolerance to cold or heat, corneal opacity, hearing loss, gastrointestinal disorders and asthenia. Over time, target organ impairment develops, such as in the kidneys (in the form of proteinuria and renal function impairment), heart (in the form of left ventricular hypertrophy and cardiac conduction disorders) and nervous system central (in the form of strokes). Hemizygous patients who present residual α-Gal A activity can be asymptomatic or present late onset forms with predominant or exclusive impairment of any target organ, which are known as the late-onset renal variant and late-onset cardiac variant.<a class="elsevierStyleCrossRefs" href="#bib0055">2,3</a>Heterozygous women were initially considered only as carriers of the mutation. However, it is clear now that they can experience FD, given that the phenomenon of inactivation of one of the X chromosomes (Lyon effect) can cause them to have a deficit of α-Gal A and present clinical manifestations of varying expression of the disease.<a class="elsevierStyleCrossRefs" href="#bib0055">2,4</a>FD is a major challenge to diagnose because it is a highly heterogeneous disorder clinically and can cause a wide variety of clinical manifestations with different expression between individual carriers of the same mutation and even within the same family. Studies have measured a mean diagnostic delay of 15–20 years from symptom onset for patients with FD.<a class="elsevierStyleCrossRefs" href="#bib0065">4,5</a>This disease does not yet have a curative treatment, but the development of replacement therapies with recombinant enzymes and, very recently, with chaperones that can increase the residual enzymatic activity in a group of “amenable” mutations makes it possible to change the disease's natural history, improving the patients’ quality of life and prognosis.<a class="elsevierStyleCrossRef" href="#bib0070">5</a>The considerable variability in the clinical expression of FD, the difficulties in diagnosing the disease and the current availability of various alternatives for its treatment represent a considerable challenge for practitioners who treat patients with this disease and justify the development of evidence-based clinical practice guidelines that can help in the decision-making process when managing these patients.These clinical practice guidelines are directed to all those health professionals, specifically physicians and nursing staff, who are involved in caring for patients with FD. The target population for these guidelines are adult patients with FD regardless of the medical specialty that cares for them and the care level in which they are treated.Material and methodsThe methodology for this project is based on the 2016 Methodological manual for developing clinical practice guidelines of the Spanish National Health System<a class="elsevierStyleCrossRef" href="#bib0075">6</a> and incorporates the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology in the assessment of the scientific evidence and preparation of the recommendations.<a class="elsevierStyleCrossRef" href="#bib0080">7</a> Consensus was reached among the experts proposed by 9 scientific societies using the Delphi-RAND method.<a class="elsevierStyleCrossRef" href="#bib0085">8</a> The steps followed were adjusted to the PRISMA list<a class="elsevierStyleCrossRef" href="#bib0090">9</a> and are specified in the appendix of the online version (see additional material, Appendix B), along with the references.RecommendationsThe development group designed a map of the healthcare process for FD, structuring the process into 9 steps or chapters. For each chapter, the group specified the potential issues that clinicians and patients could establish on each part of the healthcare process, addressing exclusive aspects in each issue, resulting in 32 PICO (population intervention comparison outcome) items, for which 92 recommendations were drafted.The issues referred to in each chapter and the recommendations on how to act when faced with each issue, along with the strength of their support between parentheses, are shown below.Chapter 1: Screening for an incident familiar case of Fabry diseaseQ.1 What is the effectiveness and yield of family screening when faced with an incident case of FD?<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005">-The recommendation is to perform a complete family tree, which includes at least 3 generations (good practices).</li><li class="elsevierStyleListItem" id="lsti0010">-The recommendation is to offer relatives of a patient newly diagnosed with FD the option of undergoing screening tests and receiving genetic counseling by a qualified physician. Clinical, biochemical and genetic tests should be offered. Counseling should be performed at least before the genetic analysis and after the analysis to notify the recipients of the results and to provide appropriate time to reflect between the first genetic counseling and the blood draw (good practices).</li></ul>Chapter 2: Individual screening for a suspected case of Fabry disease, with no known family historyQ.2 What are the most common symptoms and paraclinical presentation data that would lead to suspected FD in a patient?<ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0015">-The recommendation is to rule out the presence of FD when faced with patients, especially young patients, who have symptoms such as acrodynia, intolerance to cold/heat, anhidrosis and angiokeratoma on the chest or the presence of proteinuria or cornea verticillata (STRONG).</li><li class="elsevierStyleListItem" id="lsti0020">-The recommendation is to rule out the presence of FD in patients (male or female) with cardiac disorders (left ventricular hypertrophy, conduction disorders), renal failure or albuminuria with no other etiological cause, especially if they appear concomitantly or in patients younger than 55 years who have experienced a cryptogenic stroke (STRONG).</li><li class="elsevierStyleListItem" id="lsti0025">-The suggestion is to rule out the presence of the late phenotype of FD in middle-aged men and in women of any age, who, with no previous cardiac or renal impairment, present symptoms suggestive of FD (neuropathic pain, gastrointestinal disorders), even without the presence of characteristic signs (cornea verticillata or angiokeratoma), if no other more prevalent etiology is found to explain the patient's symptoms (WEAK).</li></ul>Chapter 3: Genetic and enzymatic diagnosisQ.3.1.1 What tests should be performed to identify FD in patients with heart, neurological or kidney disease?<ul class="elsevierStyleList" id="lis0015"><li class="elsevierStyleListItem" id="lsti0030">-For men and women with clinical data compatible with FD (acrodynia in childhood, left ventricular hypertrophy, cryptogenic stroke, proteinuria or renal failure not explained by the most common etiologies such as diabetes, hypertension, infection and drugs), the recommendation is to start the diagnostic approach for FD through an analysis of the enzymatic activity of α-Gal A, which can be performed with dried blood spots. If the values are below the reference, the diagnosis should be confirmed in liquid phase (plasma or leukocytes) or directly in liquid phase. In the event of a positive result (enzymatic activity lower than 30% that of healthy controls), perform a genetic study (STRONG).</li><li class="elsevierStyleListItem" id="lsti0035">-For women with clinical data consistent with FD (acrodynia in childhood, left ventricular hypertrophy, cryptogenic stroke, proteinuria or renal failure not explained by the most common etiologies such as diabetes, hypertension, infections and drugs) who present enzymatic activity of α-Gal A above 30% of the minimum level of normality, the recommendation is to determine blood lyso-Gb3 levels. If the levels are high, a genetic study should be performed (STRONG).</li><li class="elsevierStyleListItem" id="lsti0040">-For women with clinical data consistent with FD (acrodynia in childhood, left ventricular hypertrophy, cryptogenic stroke, proteinuria or renal failure not explained by the most common etiologies such as diabetes, hypertension, infections and drugs) and a family history of FD or high suspicion, the suggestion is to perform a genetic study even though the enzymatic activity of α-Gal A and lyso-Gb3 levels are normal (WEAK).</li></ul>Q.3.1.2 What tests and criteria should be employed for the diagnostic confirmation of FD?<ul class="elsevierStyleList" id="lis0020"><li class="elsevierStyleListItem" id="lsti0045">-The recommendation is to use the following diagnostic criteria for FD, both for men and for women:<ul class="elsevierStyleList" id="lis0025"><li class="elsevierStyleListItem" id="lsti0050">α-Gal A enzymatic activity in liquid phase lower than 5% of the mean reference value</li><li class="elsevierStyleListItem" id="lsti0055">… AND the presence of a pathogenic variant in the GLA gene</li><li class="elsevierStyleListItem" id="lsti0060">… AND at least one of the following criteria:</li></ul></li></ul>The presence of 1 or more characteristic signs of the disease (neuropathic pain, cornea verticillata, angiokeratoma)Presence of a family member with a definitive diagnosis of classical FD carrying the same GLA gene variantPatients who, meeting the first 2 criteria, present some of the characteristic signs of FD would have a classical form of the disease, while those with target organ impairment (kidney, heart or central nervous system) who do not present characteristic signs of the disease but who meet the other criteria would present a nonclassical form of FD.Not meeting the criterion of enzymatic activity lower than 5% does not rule out the presence of FD, especially in women (GOOD PRACTICES).Q.3.2.1 In patients with a probable diagnosis of FD, what is the yield of a histological study of deposits for men/women?<ul class="elsevierStyleList" id="lis0030"><li class="elsevierStyleListItem" id="lsti0065">-The recommendation is to not routinely perform histological studies for the diagnosis of FD (STRONG).</li><li class="elsevierStyleListItem" id="lsti0070">-The suggestion is to perform a biopsy of the affected organ for a histological study with electron microscopy in cases of FD of undetermined diagnosis after an enzymatic and genetic study, especially in cases in which a second disease is suspected with which a differential diagnosis needs to be established (WEAK).</li></ul>Q.3.2.2 In what clinical situations is it necessary to confirm the tissue deposit of Gb3 through biopsy for the diagnostic confirmation?<ul class="elsevierStyleList" id="lis0035"><li class="elsevierStyleListItem" id="lsti0075">-The recommendation is to perform a biopsy to determine tissue deposits in patients with symptoms suggestive of FD (men or women) with an enzymatic activity for α-Gal A ≤5% of the reference value in leukocytes, with 1 or more symptoms or signs characteristic of the disease (neuropathic pain, cornea verticillata or angiokeratoma) or high plasma Lyso-Gb3 levels or relatives with a confirmed diagnosis of FD who have the same genetic variant, because the diagnosis in these cases is certain (STRONG).</li></ul>Q.3.3 What is the diagnostic value for FD of detecting Gb3 in urine or blood in men/women, regardless of the detected enzymatic activity and genetic study?<ul class="elsevierStyleList" id="lis0040"><li class="elsevierStyleListItem" id="lsti0080">-The recommendation is to not measure urine or plasma Gb3 levels for the diagnosis of FD or as a marker of severity, because Gb3 levels can be normal in patients with FD and can be high in other diseases (STRONG).</li></ul>Q.3.4 What is the value for FD of detecting Lyso-Gb3 in urine or blood in men/women, regardless of the detected enzymatic activity and genetic study?<ul class="elsevierStyleList" id="lis0045"><li class="elsevierStyleListItem" id="lsti0085">-The suggestion is to determine the plasma Lyso-Gb3 levels for the diagnosis of FD both for men and for women (WEAK).</li><li class="elsevierStyleListItem" id="lsti0090">-The suggestion is to use plasma Lyso-Gb3 levels as a marker of severity of FD both for men and for women (WEAK).</li></ul>Chapter 4: Genotype/phenotype correlationQ.4.1 When faced with the isolated identification of a genetic variant of GLA, which is its pathogenic meaning and diagnostic value in FD?<ul class="elsevierStyleList" id="lis0050"><li class="elsevierStyleListItem" id="lsti0095">-The recommendation is to not perform the diagnosis of FD based on the isolated identification of a genetic variant of GLA. In each case, we need to consider whether the variant is already identified as pathogenic, as well as the symptoms present and the other diagnostic criteria (STRONG).</li><li class="elsevierStyleListItem" id="lsti0100">-The recommendation is to perform a stepped genetic diagnosis, starting with the search for known genetic variants in the family. If this information is not available, clinicians should start with sequencing techniques followed by other more advanced techniques to rule out duplications if necessary (STRONG).</li></ul>Q.4.2 Is the presence of a certain genetic disorder associated preferentially with SPECIFIC PHENOTYPES (classical, late, renal, cardiac, neurological)?<ul class="elsevierStyleList" id="lis0055"><li class="elsevierStyleListItem" id="lsti0105">-The recommendation is to determine the genotype in patients with FD both for men and women, because it is essential for the diagnosis and can indicate future organ impairment and thereby guide the therapeutic decision (STRONG).</li><li class="elsevierStyleListItem" id="lsti0110">-The recommendation is to provide information on the phenotypic expression of each genetic variant in each patient to international registries, given that our understanding of the correlation between genetic variant/phenotype and natural history is currently insufficient and requires more data on these variants (STRONG).</li><li class="elsevierStyleListItem" id="lsti0115">-The suggestion is to consider reading the residual activity of enzyme α-Gal A in liquid phase, because the phenotypic expression is determined by the residual activity. Its reading can therefore provide guidance as to the severity of the manifestations of the disease (WEAK).</li></ul>Q.4.3 Is there a threshold of residual enzymatic activity that is correlated with the classical phenotype of FD?<ul class="elsevierStyleList" id="lis0060"><li class="elsevierStyleListItem" id="lsti0120">-Until a threshold has been established for the enzymatic activity of α-gal A below which FD manifests with its classical phenotype, the suggestion is to not use residual enzymatic activity values to identify the classical form of the disease, either in men or women (WEAK).</li></ul>Chapter 5: Clinical characterization. Target organ assessmentQ.5.1 What assessment of signs and symptoms of specific organ impairment should be performed for patients with FD?<ul class="elsevierStyleList" id="lis0065"><li class="elsevierStyleListItem" id="lsti0125">-For all patients with FD, the recommendation is to assess their possible auditory (audiometry), vestibular and gastrointestinal impairment (intestinal rhythm disorders, abdominal pain), as well as manifestations of neuropathic pain and cardiac, renal and neurological impairment, regardless of their late or classical phenotype (STRONG).</li><li class="elsevierStyleListItem" id="lsti0130">-For patients with late phenotypes (renal, cardiac or neurological), the suggestion is to assess the impairment of the other target organs that affect the vital prognosis (WEAK).</li><li class="elsevierStyleListItem" id="lsti0135">-The recommendation is to perform an annual follow-up of the cardiac, neurological or renal impairment, to monitor the impairment and adopt appropriate therapeutic decisions. Renal monitoring should be performed using a standardized formula for calculating the glomerular filtration rate (Chronic Kidney Disease Epidemiology Collaboration equation) and albuminuria quantification (STRONG).</li><li class="elsevierStyleListItem" id="lsti0140">-For patients with FD, the recommendation is to systematically perform a neurological examination that includes a pain assessment using specific questionnaires (Brief Pain Inventory, McGill Pain Questionnaire) and an examination of tactile and thermal sensitivity. A neuroimaging study should also be performed, preferably cranial magnetic resonance imaging (MRI), to identify subcortical white matter lesions, lacunar and cortical infarctions, small hemorrhages and vertebrobasilar dolichoectasia. The risk of depression and suicide should also be routinely assessed (STRONG).</li><li class="elsevierStyleListItem" id="lsti0145">-For patients with FD, the suggestion is to perform sensitive tests to identify cognitive impairment (WEAK).</li><li class="elsevierStyleListItem" id="lsti0150">-For patients with FD, the recommendation is to not rule out the presence of neuropathic impairment even when the electroneurography results are normal (STRONG).</li><li class="elsevierStyleListItem" id="lsti0155">-For patients with FD and oculomotor disorders, imbalance or lower cranial nerves disorders, the suggestion is to rule out the presence of a Chiari malformation (WEAK).</li><li class="elsevierStyleListItem" id="lsti0160">-For patients who are treated with drugs that have amphiphilic properties such as amiodarone and chloroquine that can cause corneal deposits, the suggestion is that an examination with confocal laser scanning microscopy can help distinguish those deposits from FD deposits resulting from cornea verticillata (WEAK).</li></ul>Q 5.2 For patients with FD, what tests should be performed to confirm that the signs and symptoms of each organ impairment are due to this disease?<ul class="elsevierStyleList" id="lis0070"><li class="elsevierStyleListItem" id="lsti0165">-The suggestion is to perform an echocardiogram as an initial test to detect cardiac impairment in FD. A conventional echocardiogram might not be useful for assessing patients in early phases of the disease when there is still no left ventricular hypertrophy. The suggestion is to use the following techniques: myocardial deformation rate (strain and strain rate) and myocardial signal tracking (speckle-tracking echocardiography) (WEAK).</li><li class="elsevierStyleListItem" id="lsti0170">-The recommendation is to perform cardiac MRI to assess the cardiac impairment in FD, even when the results of the echocardiography are normal (STRONG).</li><li class="elsevierStyleListItem" id="lsti0175">-The suggestion is to use cardiac MRI (especially the T1 relaxation time) as a diagnostic test to determine whether the left ventricular hypertrophy is due to FD and to assess the cardiac response after treatment (WEAK).</li><li class="elsevierStyleListItem" id="lsti0180">-The suggestion is that measuring the diameter of the basilar artery using MRI with a cutoff of 2.67 mm can be useful for identifying brain impairment in FD (WEAK).</li><li class="elsevierStyleListItem" id="lsti0185">-The suggestion is that hippocampal atrophy identified using MRI could be useful as a marker of brain impairment in patients with FD (WEAK).</li><li class="elsevierStyleListItem" id="lsti0190">-The suggestion is that the FabryScan screening tool could be useful for identifying pain caused by FD (WEAK).</li><li class="elsevierStyleListItem" id="lsti0195">-For patients with FD, the suggestion is that a study using CO2 laser-evoked potentials could be useful for identifying small fiber neuropathic impairment (WEAK).</li><li class="elsevierStyleListItem" id="lsti0200">-For patients with FD, the recommendation is to perform an ophthalmic exam that includes a slit-lamp examination to identify the presence of corneal abnormalities (cornea verticillata) (STRONG).</li><li class="elsevierStyleListItem" id="lsti0205">-The recommendation is to attribute organ impairment (neurological, cardiac or renal) to FD in those patients with a diagnosis based on an early compatible clinical presentation, low (<15%) or no activity of the α-Gal A enzyme in leukocytes and genetic confirmation (STRONG).</li><li class="elsevierStyleListItem" id="lsti0210">-The recommendation is to rule out other common causes of organ impairment in women with the classical phenotype (early impairment and family with this impairment) and in male patients with the non-classical phenotype, by late impairment (renal, cardiac or neurological before attributing the symptoms to FD (STRONG).</li><li class="elsevierStyleListItem" id="lsti0215">-The suggestion for women with the non-classical phenotype and preserved α-Gal A activity is to individually assess whether the organ impairment is attributable to FD, either by studying the Gb3 deposits in a biopsy or by measuring plasma Lyso-Gb3 levels with a concentration 1.3nmol/L, provided the reading is guaranteed to be performed with mass spectrometry (WEAK).</li></ul>Q.5.3 For patients diagnosed with FD, can renal, cardiac or cerebral impairment predict their vital prognosis?<ul class="elsevierStyleList" id="lis0075"><li class="elsevierStyleListItem" id="lsti0220">-The recommendation is to assess and conduct follow-up of cardiac, renal and neurovascular organ impairment for patients with FD, given that it is a determinant of the patients’ early mortality, with a view to making decisions corresponding to the severity of their impairment (STRONG).</li><li class="elsevierStyleListItem" id="lsti0225">-The recommendation is to perform a proper assessment of the heart disease burden to establish a prognosis, because cardiac disorders represent the main cause of mortality for patients with FD (STRONG).</li><li class="elsevierStyleListItem" id="lsti0230">-The suggestion is that the identification of white matter lesions by MRI in patients with FD represents a greater risk of having a classical form of the disease and therefore a poorer prognosis (WEAK).</li></ul>Q.5.4 For patients with FD, is there a severity scale with sufficient sensitivity and specificity to predict the patient's vital prognosis or outcome or the therapy's benefits?<ul class="elsevierStyleList" id="lis0080"><li class="elsevierStyleListItem" id="lsti0235">-The reviewed evidence does not allow for a recommendation as to the use of the available instruments for purposes of predicting the disease prognosis. The suggestion is to use the instruments to assess the disease progression and the effects of the specific treatment, as much as possible by independent observers (WEAK).</li></ul>Chapter 6: Specific treatment for Fabry diseaseQ.6.1.1 For patients diagnosed with FD with organ impairment in the initial/intermediate/advanced stages, does enzyme replacement therapy (ERT) improve the outcome of the organ impairment, survival or quality of life?<ul class="elsevierStyleList" id="lis0085"><li class="elsevierStyleListItem" id="lsti0240">-When faced with the first symptoms of FD or signs of visceral impairment (albuminuria), the recommendation is to administer ERT at standard dosages (STRONG).</li><li class="elsevierStyleListItem" id="lsti0245">-For patients with FD with renal impairment (proteinuria >1g, glomerular filtration rate <60mL/min/1.73m2), the recommendation is to start ERT (STRONG).</li><li class="elsevierStyleListItem" id="lsti0250">-For patients with FD-related gastrointestinal symptoms that affect basic activities of daily life, the suggestion is to use ERT (WEAK).</li><li class="elsevierStyleListItem" id="lsti0255">-For patients with FD, the suggestion is to use ERT to decrease cerebrovascular complications and pain (WEAK).</li><li class="elsevierStyleListItem" id="lsti0260">-For patients with FD, the suggestion is to maintain long-term ERT to help reduce neuropathic pain (WEAK).</li><li class="elsevierStyleListItem" id="lsti0265">-For patients with FD, the suggestion is to maintain ERT even if the neuropathic pain does not decrease within the first 6 months of therapy (WEAK).</li><li class="elsevierStyleListItem" id="lsti0270">-The suggestion is that ERT does not prevent the onset of pain in patients with FD who do not have pain but can make the pain milder if it appears (WEAK).</li><li class="elsevierStyleListItem" id="lsti0275">-The suggestion is that ERT at a dosage of 1mg/kg every 2 weeks can improve baroreceptor function and orthostatic control in patients with FD (WEAK).</li><li class="elsevierStyleListItem" id="lsti0280">-For patients with FD with mild to moderate sensorineural hearing loss, the suggestion is that ERT can improve or stabilize these hearing disorders (WEAK).</li><li class="elsevierStyleListItem" id="lsti0285">-The recommendation is to start ERT in the earliest phases of cardiac impairment, because it has been observed that the treatment appears to be more effective in these initial phases in preventing the progression of heart disease (STRONG).</li><li class="elsevierStyleListItem" id="lsti0290">-For patients with FD with advanced cardiac impairment (pronounced myocardial fibrosis), the suggestion is to individually consider the start of ERT (WEAK).</li></ul>Q.6.1.2 For patients with confirmed FD in similar clinical situations, does therapy with agalsidase α have the same clinical effectiveness as therapy with agalsidase β (at the recommended dosages for each drug) for stopping the disease progression and organ impairment or improving the quality of life and vital prognosis?<ul class="elsevierStyleList" id="lis0090"><li class="elsevierStyleListItem" id="lsti0295">-The suggestion is that there is insufficient information to determine whether there are differences in efficacy between therapy with agalsidase α and therapy with agalsidase β (WEAK).</li></ul>Q.6.1.3 What dosage and administration regimen for ERT shows the greatest effectiveness against progression of each organ impairment?<ul class="elsevierStyleList" id="lis0095"><li class="elsevierStyleListItem" id="lsti0300">-For patients with FD treated with agalsidase β, the recommendation is to use a dosage of 1mg/kg every 2 weeks. The suggestion is that lower dosages of agalsidase every 2 weeks might be insufficient to reduce left ventricular hypertrophy and prevent disease progression (STRONG).</li><li class="elsevierStyleListItem" id="lsti0305">-When using agalsidase alpha to control neuropathic pain in FD, the suggestion is to administer the typically recommended dosage of 0.2mg/kg every 2 weeks, because there is no difference in the results using other dosages (WEAK).</li></ul>Q.6.1.4 For what level of enzyme deficiency has ERT shown a clinical benefit?<ul class="elsevierStyleList" id="lis0100"><li class="elsevierStyleListItem" id="lsti0310">-For patients with confirmed FD, a level of residual enzymatic activity at which ERT is beneficial has not been determined; the recommendation is therefore to no use baseline α-gal A activity levels when deciding on the treatment (STRONG).</li></ul>Q.6.1.5 For pregnant women, does ERT have a clearly favorable damage/benefit ratio for the mother and/or fetus?<ul class="elsevierStyleList" id="lis0105"><li class="elsevierStyleListItem" id="lsti0315">-The suggestion is to maintain ERT for pregnant women for whom discontinuing the therapy entails a risk of severe complications (WEAK).</li></ul>Q.6.2 When is the most ideal time to start ERT in terms of the clinical benefit for organ impairment/survival/quality of life, according to the phenotype?<ul class="elsevierStyleList" id="lis0110"><li class="elsevierStyleListItem" id="lsti0320">-When faced with the first FD symptoms or signs of visceral impairment (pathological albuminuria), the recommendation is to administer ERT at standard dosages, taking into account each patient's individual circumstances (STRONG).</li></ul>Q.6.3 For patients with FD undergoing ERT, what is the course of action when faced with the development of antiagalsidase antibodies?<ul class="elsevierStyleList" id="lis0115"><li class="elsevierStyleListItem" id="lsti0325">-When faced with the development of antiagalsidase β IgG antibodies, the recommendation is to maintain the dosage of 1mg/kg every 2 weeks because it is a better option than changing from one agalsidase to another or reducing its dosage (STRONG).</li><li class="elsevierStyleListItem" id="lsti0330">-When faced with significant allergic reactions related to the infusions of recombinant enzymes, the suggestion is that desensitization regimens based on dosage reduction and reducing infusion rates, along with premedication with various combinations of drugs (corticosteroids, antihistamines, nonsteroidal anti-inflammatory drugs or montelukast), can be safe and allow the therapy to be maintained (WEAK).</li><li class="elsevierStyleListItem" id="lsti0335">-The recommendation is that desensitization treatments should always be performed under strict monitoring and medical supervision (STRONG).</li><li class="elsevierStyleListItem" id="lsti0340">-When faced with mild to moderate reactions during the recombinant enzyme infusion sessions, the suggestion is that the session can be maintained, decreasing the infusion rate and administering treatment with antihistamines or low-dose corticosteroids, if necessary (WEAK).</li><li class="elsevierStyleListItem" id="lsti0345">-The suggestion is that changing an agalsidase for another can be an option in the presence of treatment-related allergic reactions (WEAK).</li></ul>Q.6.4 What is the value of measuring Gb3/lyso-Gb3 levels for monitoring treatment effectiveness?<ul class="elsevierStyleList" id="lis0120"><li class="elsevierStyleListItem" id="lsti0350">-The suggestion is to not base the follow-up of the response to ERT exclusively on Gb3 or lyso-Gb3 measurements (WEAK).</li></ul>Q.6.5 At what point of advanced organ impairment does the patient not benefit from ERT? Are there treatment failure criteria?<ul class="elsevierStyleList" id="lis0125"><li class="elsevierStyleListItem" id="lsti0355">-The recommendation is to discontinue or not start ERT in the following cases:<ul class="elsevierStyleList" id="lis0130"><li class="elsevierStyleListItem" id="lsti0360">Administration difficulties (therapeutic noncompliance or others).</li><li class="elsevierStyleListItem" id="lsti0365">Persistent reactions, after an anaphylactic reaction or a severe reaction to the infusion that does not respond to prophylaxis.</li><li class="elsevierStyleListItem" id="lsti0370">In the final stages of FD (cardiac with no transplantation option), neurological and when faced with comorbidities with a short life expectancy (STRONG).</li></ul></li></ul>Q.6.6 Has therapy with chaperones or other specific drugs for FD been shown to be effective in combination with or as an alternative to ERT?<ul class="elsevierStyleList" id="lis0135"><li class="elsevierStyleListItem" id="lsti0375">-The suggestion for patients with confirmed FD and pathogenic genetic variants amenable to treatment with the chaperone migalastat is to assess this alternative at a dosage of 150mg every 48h against ERT, providing information on the effects of the 2 treatments and their correct follow-up. The suggestion is that Migalastat can be an alternative for patients with amenable genetic variants who do not want to undergo ERT or for whom ERT has been shown ineffective (WEAK).</li><li class="elsevierStyleListItem" id="lsti0380">-The recommendation is to not use the chaperone migalastat in combined therapy with ERT due to the lack of studies that have evaluated this combination (STRONG).</li></ul>Chapter 7: Specific adjuvant therapy of the organ disorders of Fabry diseaseQ.7 Which adjuvant therapy has a beneficial effect on improving symptoms and quality of life or preventing the specific organ complications of patients with FD?<ul class="elsevierStyleList" id="lis0140"><li class="elsevierStyleListItem" id="lsti0385">-The suggestion is that local treatment with laser can be useful for angiokeratomas in FD (WEAK).</li><li class="elsevierStyleListItem" id="lsti0390">-The recommendation is to not use alternative medicine therapies as treatment for FD (STRONG).</li><li class="elsevierStyleListItem" id="lsti0395">-The recommendation is to treat the various cardiac manifestations of FD following the current good practice standards (STRONG).</li><li class="elsevierStyleListItem" id="lsti0400">-The recommendation is to use oral anticoagulation for patients with atrial fibrillation and hypertrophic heart disease (STRONG).</li><li class="elsevierStyleListItem" id="lsti0405">-The suggestion is to use an implantable cardioverter defibrillator as primary prevention for sudden death in FD with myocardial fibrosis documented by MRI and ventricular arrhythmias (WEAK).</li><li class="elsevierStyleListItem" id="lsti0410">-The recommendation is to use angiotensin-converting enzyme inhibitors or angiotensin II receptor antagonist II along with ERT for patients with proteinuria who do not have advanced impairment of the glomerular filtration rate, following the current good practice standards (STRONG).</li><li class="elsevierStyleListItem" id="lsti0415">-For patients with FD (men and women), the recommendation is to control cardiovascular risk factors (arterial hypertension, diabetes mellitus, dyslipidemia and tobacco use) and to use anticoagulation in case of atrial fibrillation to decrease cerebrovascular complications following the same regimens used in the general population (STRONG).</li><li class="elsevierStyleListItem" id="lsti0420">-For patients with FD who have had a stroke, the recommendation is to use secondary prevention measures: smoking cessation, physical activity, antiplatelet therapy or anticoagulant therapy, statin treatment and blood pressure and blood glucose control, as with patients without FD (STRONG).</li><li class="elsevierStyleListItem" id="lsti0425">-For treating chronic pain in patients with FD, the suggestion is to use the following first-line drugs: carbamazepine, gabapentin, phenytoin, pregabalin, tricyclic antidepressants or serotonin reuptake inhibitors (duloxetine or venlafaxine), adjusting the dosage according to tolerance and pain control (WEAK).</li><li class="elsevierStyleListItem" id="lsti0430">-To treat pain crises in patients with FD, the suggestion is to use tramadol, morphine, oxycodone, ibuprofen, diclofenac or intravenous lidocaine (WEAK).</li><li class="elsevierStyleListItem" id="lsti0435">-To treat chronic neuropathic pain in patients with FD, the suggestion is to not initially use morphine or its derivatives to avoid their adverse effects and risk of dependence (WEAK).</li></ul>Chapter 8: Specific treatment in conditions of multimorbidityQ.8.1 Is the effect of ERT or that of chaperone therapy affected by the concomitant use of analgesics, antiepileptics, antiplatelets, hypotensive drugs or other drugs?<ul class="elsevierStyleList" id="lis0145"><li class="elsevierStyleListItem" id="lsti0440">-For patients with FD who are undergoing ERT or chaperone therapy, the suggestion is to follow the general regimens for treating chronic kidney, heart and cerebrovascular disease, as well as for the use of analgesics, according to the standards of the clinical guidelines for controlling such complications (WEAK).</li></ul>P.8.2 Are the effects or dosages of ERT and chaperone therapy changed by gastrointestinal or renal impairment?<ul class="elsevierStyleList" id="lis0150"><li class="elsevierStyleListItem" id="lsti0445">-The recommendation is to not change the ERT or chaperone therapy due to the degree of target organ impairment. The datasheet for Migalastat rules out its use if the glomerular filtration rate is <30mL/min (STRONG).</li><li class="elsevierStyleListItem" id="lsti0450">-For patients with advanced chronic kidney disease undergoing renal replacement therapy who were undergoing ERT, the recommendation is to perform the ERT during the dialysis sessions (STRONG).</li></ul>Chapter 9: Support measures, disease management and care coordinationQ.9.1 What are the healthcare preferences of patients with FD regarding their quality of life and functionality?<ul class="elsevierStyleList" id="lis0155"><li class="elsevierStyleListItem" id="lsti0455">-The recommendation is to evaluate with the patients their treatment modality (ERT or chaperone therapy, if amenable) and available administration preferences (e.g., home infusions), as well as the discomfort threshold, safety, long-term follow-up requirements and complications they are willing to tolerate before considering a change in therapy (STRONG).</li><li class="elsevierStyleListItem" id="lsti0460">-The recommendation is to provide patients with FD information on patient associations and patient guidelines (STRONG).</li></ul>Q.9.2 What is the disease burden and care time for patients with FD as they age?<ul class="elsevierStyleList" id="lis0160"><li class="elsevierStyleListItem" id="lsti0465">-The recommendation is to evaluate the disease burden of patients with FD with them and their family (STRONG).</li><li class="elsevierStyleListItem" id="lsti0470">-For patients with FD, the recommendation is to assess the impact of their symptoms on their school performance, employment status, their feelings as to their physical and emotional health, and the repercussion on their social life and financial situation (STRONG).</li><li class="elsevierStyleListItem" id="lsti0475">-The recommendation is to perform a structured assessment of the quality of life and disease severity of patients with FD once the diagnosis has been confirmed. The assessment should use validated scales, such as the Short Form 36 health questionnaire and the Mainz Severity Score Index (MSSI), to have objective criteria for the progression of the effects on the patients’ daily life (STRONG).</li><li class="elsevierStyleListItem" id="lsti0480">-When ERT is performed, the recommendation is to adapt the administration regimen to facilitate the patient's activity, with proven measures such as home administration and during dialysis sessions (STRONG).</li></ul>Q.9.3 Do adolescents with FD have school performance issues?<ul class="elsevierStyleList" id="lis0165"><li class="elsevierStyleListItem" id="lsti0485">-The suggestion is that ERT at a dosage of 1mg/kg every 2 weeks can reduce the school absenteeism of patients with FD (WEAK).</li><li class="elsevierStyleListItem" id="lsti0490">-For adolescents with FD, the recommendation is to perform audiometry to identify hearing problems that can affect their school performance (STRONG).</li></ul>Q.9.4 Does FD functionally impair work activities and quality of life?<ul class="elsevierStyleList" id="lis0170"><li class="elsevierStyleListItem" id="lsti0495">-The suggestion is to periodically assess the health-related quality of life of patients with FD, including how the disease affects work and social activities (WEAK).</li></ul>CorollaryThe recommendations presented in these clinical practice guidelines have been obtained after systematically reviewing and assessing (with a rigorous and reproducible methodology) the best scientific evidence currently available on FD, taking into account the risk-benefit balance, the patients’ values and preferences and the organizational aspects. Research in the field of lysosomal storage diseases in general, and in FD in particular, is in full swing. We therefore expect that new diagnostic and therapeutic approaches will quickly become available. These clinical practice guidelines are therefore created with the commitment to keep them in use and regularly updated as needed based on new evidence that can arise in the management of this disease.FundingThe Enebro Foundation acted as sponsor for developing these guidelines, using their own funds and a grant from Sanofi-Genzyme, which was accepted with the explicit commitment by the sponsors to respect the guidelines authors’ independence and autonomy. In this respect, the authors followed a protocol by which the sponsor abstained from directly intervening or interacting with the authors and experts of the guidelines, who were coordinated at all times by the organization arranged by the Enebro Foundation.Conflicts of interestC. Alonso-Ortiz del Río, M. Barcos Martínez and E. Briones Pérez de la Blanca declare having received external aid related to the implementation of the study in the form of research funds from the Enebro Foundation.E.J. Calderón Sandubete, M. López Mendoza, C. Márquez Infante and R. Santamaría Olmo declare that they (1) have received external aid related to the implementation of the study in the form of research funds from the Enebro Foundation and (2) have received the following contributions from Sanofi-Genzyme, Amicus Therapeutics and Shire in the form of aid for attending congresses unrelated to the implementation of the study.I. Marín-León declares that they (1) have received external aid related to the implementation of the study in the form of research funds from the Enebro Foundation and (2) have received the following contributions from Sanofi-Genzyme, in the form of aid for attending congresses unrelated to the implementation of the study." "textoCompletoSecciones" => array:1 [ "secciones" => array:11 [ 0 => array:3 [ "identificador" => "xres1183873" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1104295" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1183874" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1104296" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Background" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Material and methods" ] 6 => array:3 [ "identificador" => "sec0015" "titulo" => "Recommendations" "secciones" => array:9 [ 0 => array:2 [ "identificador" => "sec0020" "titulo" => "Chapter 1: Screening for an incident familiar case of Fabry disease" ] 1 => array:2 [ "identificador" => "sec0025" "titulo" => "Chapter 2: Individual screening for a suspected case of Fabry disease, with no known family history" ] 2 => array:2 [ "identificador" => "sec0030" "titulo" => "Chapter 3: Genetic and enzymatic diagnosis" ] 3 => array:2 [ "identificador" => "sec0035" "titulo" => "Chapter 4: Genotype/phenotype correlation" ] 4 => array:2 [ "identificador" => "sec0040" "titulo" => "Chapter 5: Clinical characterization. Target organ assessment" ] 5 => array:2 [ "identificador" => "sec0045" "titulo" => "Chapter 6: Specific treatment for Fabry disease" ] 6 => array:2 [ "identificador" => "sec0050" "titulo" => "Chapter 7: Specific adjuvant therapy of the organ disorders of Fabry disease" ] 7 => array:2 [ "identificador" => "sec0055" "titulo" => "Chapter 8: Specific treatment in conditions of multimorbidity" ] 8 => array:2 [ "identificador" => "sec0060" "titulo" => "Chapter 9: Support measures, disease management and care coordination" ] ] ] 7 => array:2 [ "identificador" => "sec0065" "titulo" => "Corollary" ] 8 => array:2 [ "identificador" => "sec0070" "titulo" => "Funding" ] 9 => array:2 [ "identificador" => "sec0075" "titulo" => "Conflicts of interest" ] 10 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2018-07-30" "fechaAceptado" => "2018-09-28" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1104295" "palabras" => array:6 [ 0 => "Clinical guidelines" 1 => "Evidence-based" 2 => "Fabry disease" 3 => "Diagnosis" 4 => "Screening" 5 => "Treatment" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1104296" "palabras" => array:6 [ 0 => "Guía clínica" 1 => "Basada en evidencia" 2 => "Fabry" 3 => "Diagnóstico" 4 => "Cribado" 5 => "Tratamiento" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "Anderson–Fabry disease is a severe progressive multisystem condition of genetic origin that affects men and women, reducing their life expectancy and quality of life. The considerable variability in its clinical expression, the difficulties in diagnosing the condition and the current availability of several alternatives for its treatment represent a considerable challenge that justifies the development of evidence-based clinical practice guidelines that can help health professionals in the decision-making process for managing these patients. To develop these guidelines, we conducted a systematic search of the main reference databases using strategies adapted to each of the 32 clinical questions considered. We prepared documents to synthesize the evidence and assess its quality for each of the questions. 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La gran variabilidad en su expresión clínica, las dificultades para su diagnóstico y la disponibilidad actual de varias alternativas para su tratamiento suponen un gran reto que justifica la realización de una guía de práctica clínica basada en la evidencia que pueda ayudar a los profesionales sanitarios en la toma de decisiones en el manejo de estos pacientes. Para elaborarla se ha realizado una búsqueda sistemática en las principales bases de datos bibliográficas mediante estrategias adaptadas a cada una de las 32 preguntas clínicas consideradas. Se confeccionaron fichas para la síntesis y evaluación de la calidad de las evidencias para cada una de las preguntas. La metodología empleada se basa en el Manual metodológico español para la elaboración de guías de práctica clínica e incorpora en la evaluación de la evidencia científica y en la elaboración de las recomendaciones la metodología GRADE, considerando la calidad de la evidencia, el balance entre beneficios y riesgos, valores y preferencias de los pacientes, equidad y uso de recursos. Para la elaboración definitiva de las recomendaciones se llevó a cabo un proceso de consenso estructurado basado en la metodología Delphi-RAND en 2 rondas, con un panel de expertos propuesto por diferentes sociedades científicas, centros de investigación y asociaciones de pacientes. Finalmente, se han elaborado 92 recomendaciones específicas para el manejo de la enfermedad de Fabry." ] ] "NotaPie" => array:2 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Calderón Sandubete EJ, Briones Pérez de la Blanca E, Alonso-Ortiz del Río C, Santamaría Olmo R, López Mendoza M, Barcos Martínez M, et al. Guía de práctica clínica multidisciplinar española sobre la enfermedad de Anderson-Fabry en adultos. I: Método y recomendaciones. Rev Clin Esp. 2019;219:200–207." ] 1 => array:3 [ "etiqueta" => "◊" "nota" => "The authors of the Fabry Disease Guidelines group are listed in <a class="elsevierStyleCrossRef" href="#sec0085">Appendix A</a>." "identificador" => "fn1" ] ] "apendice" => array:1 [ 0 => array:1 [ "seccion" => array:2 [ 0 => array:4 [ "apendice" => "Manuel Posada de la Paz (Rare Diseases Research Institute, Health Institute Carlos III-IIER-ISCIII); Pilar Giraldo Castellano (Biomedical Research Center in Network, CIBERER-EF); Juan Ramón Gimeno Blanes (Spanish Society of Cardiology, SEC); Encarnación Guillén Navarro (Spanish Society of Clinical Genetics and Dysmorphology, SEGCD); Mónica López Rodríguez (Spanish Society of Internal Medicine, SEMI); Alberto Ortiz Arduán (Spanish Society of Nephrology, SENEFRO); Jaime Díaz Guzmán (Spanish Society of Neurology, SEN); Paz Latre Martínez (Spanish Society of Family and Community Medicine, SEMFYC); Jordi Cruz Villalba (Spanish Federation of Rare Diseases, FEDER); José María Carrión Pérez, Documentalist." 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Special article

Spanish multidisciplinary clinical practice guidelines for Anderson–Fabry disease in adults. I. Method and recommendations

Guía de práctica clínica multidisciplinar española sobre la enfermedad de Anderson-Fabry en adultos. I: Método y recomendaciones

E.J. Calderón Sandubetea,b,c,d, E. Briones Pérez de la Blancac,e, C. Alonso-Ortiz del Ríof, R. Santamaría Olmog, M. López Mendozah, M. Barcos Martínezi, C. Márquez Infantej, I. Marín-Leónk,

Corresponding author

gpcfabry@gmail.com

Corresponding author.

, Fabry Disease Guidelines Group ◊

a Servicio de Medicina Interna, Hospital Universitario Virgen del Rocío, Sevilla, Spain

b Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío, Consejo Superior de Investigaciones Científicas, Universidad de Sevilla, Sevilla, Spain

c Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), Spain

d Departamento de Medicina, Universidad de Sevilla, Sevilla, Spain

e Unidad de Salud Pública, Sevilla, Spain

f Servicio de Medicina Interna, Hospital Universitario Virgen de Valme, Sevilla, Spain

g Unidad de Nefrología, Hospital Universitario Reina Sofía, Córdoba, Spain

h Unidad de Nefrología, Hospital Universitario Virgen del Rocío, Sevilla, Spain

i Unidad de Análisis Clínico, Hospital Universitario Reina Sofía, Córdoba, Spain

j Unidad de Neurología y Neurofisiología, Hospital Universitario Virgen del Rocío, Sevilla, Spain

k Fundación Enebro, Sevilla, Spain

The Authors of the Fabry Disease Guidelines Group , Manuel Posada de la Pazaa, Pilar Giraldo Castellanoab, Juan Ramón Gimeno Blanesac, Encarnación Guillén Navarroad, Mónica López Rodríguezae, Alberto Ortiz Arduánaf, Jaime Díaz Guzmánag, Paz Latre Martínezah, Jordi Cruz Villalbaai, José María Carrión Pérezaj

aa Rare Diseases Research Institute, Health Institute Carlos III-IIER-ISCIII

ab Biomedical Research Center in Network, CIBERER-EF

ac Spanish Society of Cardiology, SEC

ad Spanish Society of Clinical Genetics and Dysmorphology, SEGCD

ae Spanish Society of Internal Medicine, SEMI

af Spanish Society of Nephrology, SENEFRO

ag Spanish Society of Neurology, SEN

ah Spanish Society of Family and Community Medicine, SEMFYC

ai Spanish Federation of Rare Diseases, FEDER)

aj Documentalist

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        "titulo" => "Gu&#237;a de pr&#225;ctica cl&#237;nica multidisciplinar espa&#241;ola sobre la enfermedad de Anderson-Fabry en adultos&#46; I&#58; M&#233;todo y recomendaciones"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Background</span><p id="par0005" class="elsevierStylePara elsevierViewall">Anderson&#8211;Fabry disease or Fabry disease &#40;FD&#41; &#40;OMIM 301500&#41; is a lysosomal storage disease caused by a X-linked inherited disorder in which a mutation in the <span class="elsevierStyleItalic">GLA</span> &#40;Xq22&#46;1&#41; gene produces a total or partial deficit of the &#945;-galactosidase A &#40;&#945;-Gal A&#41; enzyme&#44; which results in impaired degradation of glycosphingolipids in the cell membranes&#44; with the subsequent intracellular accumulation of globotriaosylceramide &#40;GB3&#41; and other complex lipids&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">1</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">The gene contains 7 exons&#44; and more than 750 mutations have so far been described&#44; which are distributed among the 7 exons with no predominance of any one area&#46; Most of the mutations are restricted to specific families&#44; with no ethnic predominance&#46;<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">2&#44;3</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">FD is considered the second most common lysosomal storage disease after Gaucher&#39;s disease&#46; A prevalence among males of between 1&#47;40&#44;000 and 1&#47;117&#44;000 for living newborns has been published&#44; although this figure underestimates the actual prevalence by not considering the disease&#39;s involvement in women and the incomplete forms of late onset&#46;<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">2&#44;4</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Hemizygous males with very little or no enzymatic activity present multisystem impairment&#44; known as the classical form of the disease&#44; with symptom onset in childhood or adolescence in the form of acroparesthesia&#44; angiokeratoma&#44; hypohidrosis&#44; intolerance to cold or heat&#44; corneal opacity&#44; hearing loss&#44; gastrointestinal disorders and asthenia&#46; Over time&#44; target organ impairment develops&#44; such as in the kidneys &#40;in the form of proteinuria and renal function impairment&#41;&#44; heart &#40;in the form of left ventricular hypertrophy and cardiac conduction disorders&#41; and nervous system central &#40;in the form of strokes&#41;&#46; Hemizygous patients who present residual &#945;-Gal A activity can be asymptomatic or present late onset forms with predominant or exclusive impairment of any target organ&#44; which are known as the late-onset renal variant and late-onset cardiac variant&#46;<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">2&#44;3</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">Heterozygous women were initially considered only as carriers of the mutation&#46; However&#44; it is clear now that they can experience FD&#44; given that the phenomenon of inactivation of one of the X chromosomes &#40;Lyon effect&#41; can cause them to have a deficit of &#945;-Gal A and present clinical manifestations of varying expression of the disease&#46;<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">2&#44;4</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">FD is a major challenge to diagnose because it is a highly heterogeneous disorder clinically and can cause a wide variety of clinical manifestations with different expression between individual carriers of the same mutation and even within the same family&#46; Studies have measured a mean diagnostic delay of 15&#8211;20 years from symptom onset for patients with FD&#46;<a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">4&#44;5</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">This disease does not yet have a curative treatment&#44; but the development of replacement therapies with recombinant enzymes and&#44; very recently&#44; with chaperones that can increase the residual enzymatic activity in a group of &#8220;amenable&#8221; mutations makes it possible to change the disease&#39;s natural history&#44; improving the patients&#8217; quality of life and prognosis&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">5</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">The considerable variability in the clinical expression of FD&#44; the difficulties in diagnosing the disease and the current availability of various alternatives for its treatment represent a considerable challenge for practitioners who treat patients with this disease and justify the development of evidence-based clinical practice guidelines that can help in the decision-making process when managing these patients&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">These clinical practice guidelines are directed to all those health professionals&#44; specifically physicians and nursing staff&#44; who are involved in caring for patients with FD&#46; The target population for these guidelines are adult patients with FD regardless of the medical specialty that cares for them and the care level in which they are treated&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Material and methods</span><p id="par0050" class="elsevierStylePara elsevierViewall">The methodology for this project is based on the 2016 <span class="elsevierStyleItalic">Methodological manual for developing clinical practice guidelines of the Spanish National Health</span> System<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">6</span></a> and incorporates the Grading of Recommendations Assessment&#44; Development and Evaluation &#40;GRADE&#41; methodology in the assessment of the scientific evidence and preparation of the recommendations&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">7</span></a> Consensus was reached among the experts proposed by 9 scientific societies using the Delphi-RAND method&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">8</span></a> The steps followed were adjusted to the PRISMA list<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">9</span></a> and are specified in the appendix of the online version &#40;see additional material&#44; Appendix B&#41;&#44; along with the references&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Recommendations</span><p id="par0055" class="elsevierStylePara elsevierViewall">The development group designed a map of the healthcare process for FD&#44; structuring the process into 9 steps or chapters&#46; For each chapter&#44; the group specified the potential issues that clinicians and patients could establish on each part of the healthcare process&#44; addressing exclusive aspects in each issue&#44; resulting in 32 PICO &#40;population intervention comparison outcome&#41; items&#44; for which 92 recommendations were drafted&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">The issues referred to in each chapter and the recommendations on how to act when faced with each issue&#44; along with the strength of their support between parentheses&#44; are shown below&#46;</p><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Chapter 1&#58; Screening for an incident familiar case of Fabry disease</span><p id="par0065" class="elsevierStylePara elsevierViewall">Q&#46;1 What is the effectiveness and yield of family screening when faced with an incident case of FD&#63;<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">-</span><p id="par0070" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">recommendation</span> is to perform a complete family tree&#44; which includes at least 3 generations &#40;<span class="elsevierStyleItalic">good practices</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">-</span><p id="par0075" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">recommendation</span> is to offer relatives of a patient newly diagnosed with FD the option of undergoing screening tests and receiving genetic counseling by a qualified physician&#46; Clinical&#44; biochemical and genetic tests should be offered&#46; Counseling should be performed at least before the genetic analysis and after the analysis to notify the recipients of the results and to provide appropriate time to reflect between the first genetic counseling and the blood draw &#40;<span class="elsevierStyleItalic">good practices</span>&#41;&#46;</p></li></ul></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Chapter 2&#58; Individual screening for a suspected case of Fabry disease&#44; with no known family history</span><p id="par0080" class="elsevierStylePara elsevierViewall">Q&#46;2 What are the most common symptoms and paraclinical presentation data that would lead to suspected FD in a patient&#63;<ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">-</span><p id="par0085" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">recommendation</span> is to rule out the presence of FD when faced with patients&#44; especially young patients&#44; who have symptoms such as acrodynia&#44; intolerance to cold&#47;heat&#44; anhidrosis and angiokeratoma on the chest or the presence of proteinuria or cornea verticillata &#40;<span class="elsevierStyleItalic">STRONG</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">-</span><p id="par0090" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">recommendation</span> is to rule out the presence of FD in patients &#40;male or female&#41; with cardiac disorders &#40;left ventricular hypertrophy&#44; conduction disorders&#41;&#44; renal failure or albuminuria with no other etiological cause&#44; especially if they appear concomitantly or in patients younger than 55 years who have experienced a cryptogenic stroke &#40;<span class="elsevierStyleItalic">STRONG</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0025"><span class="elsevierStyleLabel">-</span><p id="par0095" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">suggestion</span> is to rule out the presence of the late phenotype of FD in middle-aged men and in women of any age&#44; who&#44; with no previous cardiac or renal impairment&#44; present symptoms suggestive of FD &#40;neuropathic pain&#44; gastrointestinal disorders&#41;&#44; even without the presence of characteristic signs &#40;cornea verticillata or angiokeratoma&#41;&#44; if no other more prevalent etiology is found to explain the patient&#39;s symptoms &#40;<span class="elsevierStyleItalic">WEAK</span>&#41;&#46;</p></li></ul></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Chapter 3&#58; Genetic and enzymatic diagnosis</span><p id="par0100" class="elsevierStylePara elsevierViewall">Q&#46;3&#46;1&#46;1 What tests should be performed to identify FD in patients with heart&#44; neurological or kidney disease&#63;<ul class="elsevierStyleList" id="lis0015"><li class="elsevierStyleListItem" id="lsti0030"><span class="elsevierStyleLabel">-</span><p id="par0105" class="elsevierStylePara elsevierViewall">For men and women with clinical data compatible with FD &#40;acrodynia in childhood&#44; left ventricular hypertrophy&#44; cryptogenic stroke&#44; proteinuria or renal failure not explained by the most common etiologies such as diabetes&#44; hypertension&#44; infection and drugs&#41;&#44; the <span class="elsevierStyleItalic">recommendation</span> is to start the diagnostic approach for FD through an analysis of the enzymatic activity of &#945;-Gal A&#44; which can be performed with dried blood spots&#46; If the values are below the reference&#44; the diagnosis should be confirmed in liquid phase &#40;plasma or leukocytes&#41; or directly in liquid phase&#46; In the event of a positive result &#40;enzymatic activity lower than 30&#37; that of healthy controls&#41;&#44; perform a genetic study &#40;<span class="elsevierStyleItalic">STRONG</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0035"><span class="elsevierStyleLabel">-</span><p id="par0110" class="elsevierStylePara elsevierViewall">For women with clinical data consistent with FD &#40;acrodynia in childhood&#44; left ventricular hypertrophy&#44; cryptogenic stroke&#44; proteinuria or renal failure not explained by the most common etiologies such as diabetes&#44; hypertension&#44; infections and drugs&#41; who present enzymatic activity of &#945;-Gal A above 30&#37; of the minimum level of normality&#44; the <span class="elsevierStyleItalic">recommendation</span> is to determine blood lyso-Gb3 levels&#46; If the levels are high&#44; a genetic study should be performed &#40;STRONG&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0040"><span class="elsevierStyleLabel">-</span><p id="par0115" class="elsevierStylePara elsevierViewall">For women with clinical data consistent with FD &#40;acrodynia in childhood&#44; left ventricular hypertrophy&#44; cryptogenic stroke&#44; proteinuria or renal failure not explained by the most common etiologies such as diabetes&#44; hypertension&#44; infections and drugs&#41; and a family history of FD or high suspicion&#44; the <span class="elsevierStyleItalic">suggestion</span> is to perform a genetic study even though the enzymatic activity of &#945;-Gal A and lyso-Gb3 levels are normal &#40;<span class="elsevierStyleItalic">WEAK</span>&#41;&#46;</p></li></ul></p><p id="par0120" class="elsevierStylePara elsevierViewall">Q&#46;3&#46;1&#46;2 What tests and criteria should be employed for the diagnostic confirmation of FD&#63;<ul class="elsevierStyleList" id="lis0020"><li class="elsevierStyleListItem" id="lsti0045"><span class="elsevierStyleLabel">-</span><p id="par0125" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">recommendation</span> is to use the following diagnostic criteria for FD&#44; both for men and for women&#58;<ul class="elsevierStyleList" id="lis0025"><li class="elsevierStyleListItem" id="lsti0050"><p id="par0130" class="elsevierStylePara elsevierViewall">&#945;-Gal A enzymatic activity in liquid phase lower than 5&#37; of the mean reference value</p></li><li class="elsevierStyleListItem" id="lsti0055"><p id="par0135" class="elsevierStylePara elsevierViewall">&#8230; AND the presence of a pathogenic variant in the <span class="elsevierStyleItalic">GLA</span> gene</p></li><li class="elsevierStyleListItem" id="lsti0060"><p id="par0140" class="elsevierStylePara elsevierViewall">&#8230; AND at least one of the following criteria&#58;</p></li></ul></p></li></ul></p><p id="par0145" class="elsevierStylePara elsevierViewall">The presence of 1 or more characteristic signs of the disease &#40;neuropathic pain&#44; cornea verticillata&#44; angiokeratoma&#41;</p><p id="par0150" class="elsevierStylePara elsevierViewall">Presence of a family member with a definitive diagnosis of classical FD carrying the same <span class="elsevierStyleItalic">GLA</span> gene variant</p><p id="par0155" class="elsevierStylePara elsevierViewall">Patients who&#44; meeting the first 2 criteria&#44; present some of the characteristic signs of FD would have a classical form of the disease&#44; while those with target organ impairment &#40;kidney&#44; heart or central nervous system&#41; who do not present characteristic signs of the disease but who meet the other criteria would present a nonclassical form of FD&#46;</p><p id="par0160" class="elsevierStylePara elsevierViewall">Not meeting the criterion of enzymatic activity lower than 5&#37; does not rule out the presence of FD&#44; especially in women &#40;<span class="elsevierStyleItalic">GOOD PRACTICES</span>&#41;&#46;</p><p id="par0165" class="elsevierStylePara elsevierViewall">Q&#46;3&#46;2&#46;1 In patients with a probable diagnosis of FD&#44; what is the yield of a histological study of deposits for men&#47;women&#63;<ul class="elsevierStyleList" id="lis0030"><li class="elsevierStyleListItem" id="lsti0065"><span class="elsevierStyleLabel">-</span><p id="par0170" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">recommendation</span> is to not routinely perform histological studies for the diagnosis of FD &#40;<span class="elsevierStyleItalic">STRONG</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0070"><span class="elsevierStyleLabel">-</span><p id="par0175" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">suggestion</span> is to perform a biopsy of the affected organ for a histological study with electron microscopy in cases of FD of undetermined diagnosis after an enzymatic and genetic study&#44; especially in cases in which a second disease is suspected with which a differential diagnosis needs to be established &#40;<span class="elsevierStyleItalic">WEAK</span>&#41;&#46;</p></li></ul></p><p id="par0180" class="elsevierStylePara elsevierViewall">Q&#46;3&#46;2&#46;2 In what clinical situations is it necessary to confirm the tissue deposit of Gb3 through biopsy for the diagnostic confirmation&#63;<ul class="elsevierStyleList" id="lis0035"><li class="elsevierStyleListItem" id="lsti0075"><span class="elsevierStyleLabel">-</span><p id="par0185" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">recommendation</span> is to perform a biopsy to determine tissue deposits in patients with symptoms suggestive of FD &#40;men or women&#41; with an enzymatic activity for &#945;-Gal A &#8804;5&#37; of the reference value in leukocytes&#44; with 1 or more symptoms or signs characteristic of the disease &#40;neuropathic pain&#44; cornea verticillata or angiokeratoma&#41; or high plasma Lyso-Gb3 levels or relatives with a confirmed diagnosis of FD who have the same genetic variant&#44; because the diagnosis in these cases is certain &#40;<span class="elsevierStyleItalic">STRONG</span>&#41;&#46;</p></li></ul></p><p id="par0190" class="elsevierStylePara elsevierViewall">Q&#46;3&#46;3 What is the diagnostic value for FD of detecting Gb3 in urine or blood in men&#47;women&#44; regardless of the detected enzymatic activity and genetic study&#63;<ul class="elsevierStyleList" id="lis0040"><li class="elsevierStyleListItem" id="lsti0080"><span class="elsevierStyleLabel">-</span><p id="par0195" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">recommendation</span> is to not measure urine or plasma Gb3 levels for the diagnosis of FD or as a marker of severity&#44; because Gb3 levels can be normal in patients with FD and can be high in other diseases &#40;<span class="elsevierStyleItalic">STRONG</span>&#41;&#46;</p></li></ul></p><p id="par0200" class="elsevierStylePara elsevierViewall">Q&#46;3&#46;4 What is the value for FD of detecting Lyso-Gb3 in urine or blood in men&#47;women&#44; regardless of the detected enzymatic activity and genetic study&#63;<ul class="elsevierStyleList" id="lis0045"><li class="elsevierStyleListItem" id="lsti0085"><span class="elsevierStyleLabel">-</span><p id="par0205" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">suggestion</span> is to determine the plasma Lyso-Gb3 levels for the diagnosis of FD both for men and for women &#40;<span class="elsevierStyleItalic">WEAK</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0090"><span class="elsevierStyleLabel">-</span><p id="par0210" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">suggestion</span> is to use plasma Lyso-Gb3 levels as a marker of severity of FD both for men and for women &#40;<span class="elsevierStyleItalic">WEAK</span>&#41;&#46;</p></li></ul></p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Chapter 4&#58; Genotype&#47;phenotype correlation</span><p id="par0215" class="elsevierStylePara elsevierViewall">Q&#46;4&#46;1 When faced with the isolated identification of a genetic variant of <span class="elsevierStyleItalic">GLA</span>&#44; which is its pathogenic meaning and diagnostic value in FD&#63;<ul class="elsevierStyleList" id="lis0050"><li class="elsevierStyleListItem" id="lsti0095"><span class="elsevierStyleLabel">-</span><p id="par0220" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">recommendation</span> is to not perform the diagnosis of FD based on the isolated identification of a genetic variant of <span class="elsevierStyleItalic">GLA</span>&#46; In each case&#44; we need to consider whether the variant is already identified as pathogenic&#44; as well as the symptoms present and the other diagnostic criteria &#40;<span class="elsevierStyleItalic">STRONG</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0100"><span class="elsevierStyleLabel">-</span><p id="par0225" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">recommendation</span> is to perform a stepped genetic diagnosis&#44; starting with the search for known genetic variants in the family&#46; If this information is not available&#44; clinicians should start with sequencing techniques followed by other more advanced techniques to rule out duplications if necessary &#40;<span class="elsevierStyleItalic">STRONG</span>&#41;&#46;</p></li></ul></p><p id="par0230" class="elsevierStylePara elsevierViewall">Q&#46;4&#46;2 Is the presence of a certain genetic disorder associated preferentially with SPECIFIC PHENOTYPES &#40;classical&#44; late&#44; renal&#44; cardiac&#44; neurological&#41;&#63;<ul class="elsevierStyleList" id="lis0055"><li class="elsevierStyleListItem" id="lsti0105"><span class="elsevierStyleLabel">-</span><p id="par0235" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">recommendation</span> is to determine the genotype in patients with FD both for men and women&#44; because it is essential for the diagnosis and can indicate future organ impairment and thereby guide the therapeutic decision &#40;<span class="elsevierStyleItalic">STRONG</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0110"><span class="elsevierStyleLabel">-</span><p id="par0240" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">recommendation</span> is to provide information on the phenotypic expression of each genetic variant in each patient to international registries&#44; given that our understanding of the correlation between genetic variant&#47;phenotype and natural history is currently insufficient and requires more data on these variants &#40;<span class="elsevierStyleItalic">STRONG</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0115"><span class="elsevierStyleLabel">-</span><p id="par0245" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">suggestion</span> is to consider reading the residual activity of enzyme &#945;-Gal A in liquid phase&#44; because the phenotypic expression is determined by the residual activity&#46; Its reading can therefore provide guidance as to the severity of the manifestations of the disease &#40;<span class="elsevierStyleItalic">WEAK</span>&#41;&#46;</p></li></ul></p><p id="par0250" class="elsevierStylePara elsevierViewall">Q&#46;4&#46;3 Is there a threshold of residual enzymatic activity that is correlated with the classical phenotype of FD&#63;<ul class="elsevierStyleList" id="lis0060"><li class="elsevierStyleListItem" id="lsti0120"><span class="elsevierStyleLabel">-</span><p id="par0255" class="elsevierStylePara elsevierViewall">Until a threshold has been established for the enzymatic activity of &#945;-gal A below which FD manifests with its classical phenotype&#44; the <span class="elsevierStyleItalic">suggestion</span> is to not use residual enzymatic activity values to identify the classical form of the disease&#44; either in men or women &#40;<span class="elsevierStyleItalic">WEAK</span>&#41;&#46;</p></li></ul></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Chapter 5&#58; Clinical characterization&#46; Target organ assessment</span><p id="par0260" class="elsevierStylePara elsevierViewall">Q&#46;5&#46;1 What assessment of signs and symptoms of specific organ impairment should be performed for patients with FD&#63;<ul class="elsevierStyleList" id="lis0065"><li class="elsevierStyleListItem" id="lsti0125"><span class="elsevierStyleLabel">-</span><p id="par0265" class="elsevierStylePara elsevierViewall">For all patients with FD&#44; the <span class="elsevierStyleItalic">recommendation</span> is to assess their possible auditory &#40;audiometry&#41;&#44; vestibular and gastrointestinal impairment &#40;intestinal rhythm disorders&#44; abdominal pain&#41;&#44; as well as manifestations of neuropathic pain and cardiac&#44; renal and neurological impairment&#44; regardless of their late or classical phenotype &#40;<span class="elsevierStyleItalic">STRONG</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0130"><span class="elsevierStyleLabel">-</span><p id="par0270" class="elsevierStylePara elsevierViewall">For patients with late phenotypes &#40;renal&#44; cardiac or neurological&#41;&#44; the <span class="elsevierStyleItalic">suggestion</span> is to assess the impairment of the other target organs that affect the vital prognosis &#40;<span class="elsevierStyleItalic">WEAK</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0135"><span class="elsevierStyleLabel">-</span><p id="par0275" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">recommendation</span> is to perform an annual follow-up of the cardiac&#44; neurological or renal impairment&#44; to monitor the impairment and adopt appropriate therapeutic decisions&#46; Renal monitoring should be performed using a standardized formula for calculating the glomerular filtration rate &#40;Chronic Kidney Disease Epidemiology Collaboration equation&#41; and albuminuria quantification &#40;<span class="elsevierStyleItalic">STRONG</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0140"><span class="elsevierStyleLabel">-</span><p id="par0280" class="elsevierStylePara elsevierViewall">For patients with FD&#44; the <span class="elsevierStyleItalic">recommendation</span> is to systematically perform a neurological examination that includes a pain assessment using specific questionnaires &#40;Brief Pain Inventory&#44; McGill Pain Questionnaire&#41; and an examination of tactile and thermal sensitivity&#46; A neuroimaging study should also be performed&#44; preferably cranial magnetic resonance imaging &#40;MRI&#41;&#44; to identify subcortical white matter lesions&#44; lacunar and cortical infarctions&#44; small hemorrhages and vertebrobasilar dolichoectasia&#46; The risk of depression and suicide should also be routinely assessed &#40;<span class="elsevierStyleItalic">STRONG</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0145"><span class="elsevierStyleLabel">-</span><p id="par0285" class="elsevierStylePara elsevierViewall">For patients with FD&#44; the <span class="elsevierStyleItalic">suggestion</span> is to perform sensitive tests to identify cognitive impairment &#40;<span class="elsevierStyleItalic">WEAK</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0150"><span class="elsevierStyleLabel">-</span><p id="par0290" class="elsevierStylePara elsevierViewall">For patients with FD&#44; the <span class="elsevierStyleItalic">recommendation</span> is to not rule out the presence of neuropathic impairment even when the electroneurography results are normal &#40;<span class="elsevierStyleItalic">STRONG</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0155"><span class="elsevierStyleLabel">-</span><p id="par0295" class="elsevierStylePara elsevierViewall">For patients with FD and oculomotor disorders&#44; imbalance or lower cranial nerves disorders&#44; the <span class="elsevierStyleItalic">suggestion</span> is to rule out the presence of a Chiari malformation &#40;<span class="elsevierStyleItalic">WEAK</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0160"><span class="elsevierStyleLabel">-</span><p id="par0300" class="elsevierStylePara elsevierViewall">For patients who are treated with drugs that have amphiphilic properties such as amiodarone and chloroquine that can cause corneal deposits&#44; the <span class="elsevierStyleItalic">suggestion</span> is that an examination with confocal laser scanning microscopy can help distinguish those deposits from FD deposits resulting from cornea verticillata &#40;<span class="elsevierStyleItalic">WEAK</span>&#41;&#46;</p></li></ul></p><p id="par0305" class="elsevierStylePara elsevierViewall">Q 5&#46;2 For patients with FD&#44; what tests should be performed to confirm that the signs and symptoms of each organ impairment are due to this disease&#63;<ul class="elsevierStyleList" id="lis0070"><li class="elsevierStyleListItem" id="lsti0165"><span class="elsevierStyleLabel">-</span><p id="par0310" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">suggestion</span> is to perform an echocardiogram as an initial test to detect cardiac impairment in FD&#46; A conventional echocardiogram might not be useful for assessing patients in early phases of the disease when there is still no left ventricular hypertrophy&#46; The <span class="elsevierStyleItalic">suggestion</span> is to use the following techniques&#58; myocardial deformation rate &#40;strain and strain rate&#41; and myocardial signal tracking &#40;speckle-tracking echocardiography&#41; &#40;<span class="elsevierStyleItalic">WEAK</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0170"><span class="elsevierStyleLabel">-</span><p id="par0315" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">recommendation</span> is to perform cardiac MRI to assess the cardiac impairment in FD&#44; even when the results of the echocardiography are normal &#40;<span class="elsevierStyleItalic">STRONG</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0175"><span class="elsevierStyleLabel">-</span><p id="par0320" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">suggestion</span> is to use cardiac MRI &#40;especially the T1 relaxation time&#41; as a diagnostic test to determine whether the left ventricular hypertrophy is due to FD and to assess the cardiac response after treatment &#40;<span class="elsevierStyleItalic">WEAK</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0180"><span class="elsevierStyleLabel">-</span><p id="par0325" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">suggestion</span> is that measuring the diameter of the basilar artery using MRI with a cutoff of 2&#46;67 mm can be useful for identifying brain impairment in FD &#40;<span class="elsevierStyleItalic">WEAK</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0185"><span class="elsevierStyleLabel">-</span><p id="par0330" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">suggestion</span> is that hippocampal atrophy identified using MRI could be useful as a marker of brain impairment in patients with FD &#40;<span class="elsevierStyleItalic">WEAK</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0190"><span class="elsevierStyleLabel">-</span><p id="par0335" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">suggestion</span> is that the FabryScan screening tool could be useful for identifying pain caused by FD &#40;<span class="elsevierStyleItalic">WEAK</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0195"><span class="elsevierStyleLabel">-</span><p id="par0340" class="elsevierStylePara elsevierViewall">For patients with FD&#44; the <span class="elsevierStyleItalic">suggestion</span> is that a study using CO<span class="elsevierStyleInf">2</span> laser-evoked potentials could be useful for identifying small fiber neuropathic impairment &#40;<span class="elsevierStyleItalic">WEAK</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0200"><span class="elsevierStyleLabel">-</span><p id="par0345" class="elsevierStylePara elsevierViewall">For patients with FD&#44; the <span class="elsevierStyleItalic">recommendation</span> is to perform an ophthalmic exam that includes a slit-lamp examination to identify the presence of corneal abnormalities &#40;cornea verticillata&#41; &#40;<span class="elsevierStyleItalic">STRONG</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0205"><span class="elsevierStyleLabel">-</span><p id="par0350" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">recommendation</span> is to attribute organ impairment &#40;neurological&#44; cardiac or renal&#41; to FD in those patients with a diagnosis based on an early compatible clinical presentation&#44; low &#40;&#60;15&#37;&#41; or no activity of the &#945;-Gal A enzyme in leukocytes and genetic confirmation &#40;<span class="elsevierStyleItalic">STRONG</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0210"><span class="elsevierStyleLabel">-</span><p id="par0355" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">recommendation</span> is to rule out other common causes of organ impairment in women with the classical phenotype &#40;early impairment and family with this impairment&#41; and in male patients with the non-classical phenotype&#44; by late impairment &#40;renal&#44; cardiac or neurological before attributing the symptoms to FD &#40;<span class="elsevierStyleItalic">STRONG</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0215"><span class="elsevierStyleLabel">-</span><p id="par0360" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">suggestion</span> for women with the non-classical phenotype and preserved &#945;-Gal A activity is to individually assess whether the organ impairment is attributable to FD&#44; either by studying the Gb3 deposits in a biopsy or by measuring plasma Lyso-Gb3 levels with a concentration 1&#46;3<span class="elsevierStyleHsp" style=""></span>nmol&#47;L&#44; provided the reading is guaranteed to be performed with mass spectrometry &#40;<span class="elsevierStyleItalic">WEAK</span>&#41;&#46;</p></li></ul></p><p id="par0365" class="elsevierStylePara elsevierViewall">Q&#46;5&#46;3 For patients diagnosed with FD&#44; can renal&#44; cardiac or cerebral impairment predict their vital prognosis&#63;<ul class="elsevierStyleList" id="lis0075"><li class="elsevierStyleListItem" id="lsti0220"><span class="elsevierStyleLabel">-</span><p id="par0370" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">recommendation</span> is to assess and conduct follow-up of cardiac&#44; renal and neurovascular organ impairment for patients with FD&#44; given that it is a determinant of the patients&#8217; early mortality&#44; with a view to making decisions corresponding to the severity of their impairment &#40;<span class="elsevierStyleItalic">STRONG</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0225"><span class="elsevierStyleLabel">-</span><p id="par0375" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">recommendation</span> is to perform a proper assessment of the heart disease burden to establish a prognosis&#44; because cardiac disorders represent the main cause of mortality for patients with FD &#40;<span class="elsevierStyleItalic">STRONG</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0230"><span class="elsevierStyleLabel">-</span><p id="par0380" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">suggestion</span> is that the identification of white matter lesions by MRI in patients with FD represents a greater risk of having a classical form of the disease and therefore a poorer prognosis &#40;<span class="elsevierStyleItalic">WEAK</span>&#41;&#46;</p></li></ul></p><p id="par0385" class="elsevierStylePara elsevierViewall">Q&#46;5&#46;4 For patients with FD&#44; is there a severity scale with sufficient sensitivity and specificity to predict the patient&#39;s vital prognosis or outcome or the therapy&#39;s benefits&#63;<ul class="elsevierStyleList" id="lis0080"><li class="elsevierStyleListItem" id="lsti0235"><span class="elsevierStyleLabel">-</span><p id="par0390" class="elsevierStylePara elsevierViewall">The reviewed evidence does not allow for a recommendation as to the use of the available instruments for purposes of predicting the disease prognosis&#46; The <span class="elsevierStyleItalic">suggestion</span> is to use the instruments to assess the disease progression and the effects of the specific treatment&#44; as much as possible by independent observers &#40;<span class="elsevierStyleItalic">WEAK</span>&#41;&#46;</p></li></ul></p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Chapter 6&#58; Specific treatment for Fabry disease</span><p id="par0395" class="elsevierStylePara elsevierViewall">Q&#46;6&#46;1&#46;1 For patients diagnosed with FD with organ impairment in the initial&#47;intermediate&#47;advanced stages&#44; does enzyme replacement therapy &#40;ERT&#41; improve the outcome of the organ impairment&#44; survival or quality of life&#63;<ul class="elsevierStyleList" id="lis0085"><li class="elsevierStyleListItem" id="lsti0240"><span class="elsevierStyleLabel">-</span><p id="par0400" class="elsevierStylePara elsevierViewall">When faced with the first symptoms of FD or signs of visceral impairment &#40;albuminuria&#41;&#44; the <span class="elsevierStyleItalic">recommendation</span> is to administer ERT at standard dosages &#40;<span class="elsevierStyleItalic">STRONG</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0245"><span class="elsevierStyleLabel">-</span><p id="par0405" class="elsevierStylePara elsevierViewall">For patients with FD with renal impairment &#40;proteinuria &#62;1<span class="elsevierStyleHsp" style=""></span>g&#44; glomerular filtration rate &#60;60<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#41;&#44; the <span class="elsevierStyleItalic">recommendation</span> is to start ERT &#40;<span class="elsevierStyleItalic">STRONG</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0250"><span class="elsevierStyleLabel">-</span><p id="par0410" class="elsevierStylePara elsevierViewall">For patients with FD-related gastrointestinal symptoms that affect basic activities of daily life&#44; the <span class="elsevierStyleItalic">suggestion</span> is to use ERT &#40;<span class="elsevierStyleItalic">WEAK</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0255"><span class="elsevierStyleLabel">-</span><p id="par0415" class="elsevierStylePara elsevierViewall">For patients with FD&#44; the <span class="elsevierStyleItalic">suggestion</span> is to use ERT to decrease cerebrovascular complications and pain &#40;<span class="elsevierStyleItalic">WEAK</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0260"><span class="elsevierStyleLabel">-</span><p id="par0420" class="elsevierStylePara elsevierViewall">For patients with FD&#44; the <span class="elsevierStyleItalic">suggestion</span> is to maintain long-term ERT to help reduce neuropathic pain &#40;<span class="elsevierStyleItalic">WEAK</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0265"><span class="elsevierStyleLabel">-</span><p id="par0425" class="elsevierStylePara elsevierViewall">For patients with FD&#44; the <span class="elsevierStyleItalic">suggestion</span> is to maintain ERT even if the neuropathic pain does not decrease within the first 6 months of therapy &#40;<span class="elsevierStyleItalic">WEAK</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0270"><span class="elsevierStyleLabel">-</span><p id="par0430" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">suggestion</span> is that ERT does not prevent the onset of pain in patients with FD who do not have pain but can make the pain milder if it appears &#40;<span class="elsevierStyleItalic">WEAK</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0275"><span class="elsevierStyleLabel">-</span><p id="par0435" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">suggestion</span> is that ERT at a dosage of 1<span class="elsevierStyleHsp" style=""></span>mg&#47;kg every 2 weeks can improve baroreceptor function and orthostatic control in patients with FD &#40;<span class="elsevierStyleItalic">WEAK</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0280"><span class="elsevierStyleLabel">-</span><p id="par0440" class="elsevierStylePara elsevierViewall">For patients with FD with mild to moderate sensorineural hearing loss&#44; the <span class="elsevierStyleItalic">suggestion</span> is that ERT can improve or stabilize these hearing disorders &#40;<span class="elsevierStyleItalic">WEAK</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0285"><span class="elsevierStyleLabel">-</span><p id="par0445" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">recommendation</span> is to start ERT in the earliest phases of cardiac impairment&#44; because it has been observed that the treatment appears to be more effective in these initial phases in preventing the progression of heart disease &#40;<span class="elsevierStyleItalic">STRONG</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0290"><span class="elsevierStyleLabel">-</span><p id="par0450" class="elsevierStylePara elsevierViewall">For patients with FD with advanced cardiac impairment &#40;pronounced myocardial fibrosis&#41;&#44; the <span class="elsevierStyleItalic">suggestion</span> is to individually consider the start of ERT &#40;<span class="elsevierStyleItalic">WEAK</span>&#41;&#46;</p></li></ul></p><p id="par0455" class="elsevierStylePara elsevierViewall">Q&#46;6&#46;1&#46;2 For patients with confirmed FD in similar clinical situations&#44; does therapy with agalsidase &#945; have the same clinical effectiveness as therapy with agalsidase &#946; &#40;at the recommended dosages for each drug&#41; for stopping the disease progression and organ impairment or improving the quality of life and vital prognosis&#63;<ul class="elsevierStyleList" id="lis0090"><li class="elsevierStyleListItem" id="lsti0295"><span class="elsevierStyleLabel">-</span><p id="par0460" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">suggestion</span> is that there is insufficient information to determine whether there are differences in efficacy between therapy with agalsidase &#945; and therapy with agalsidase &#946; &#40;<span class="elsevierStyleItalic">WEAK</span>&#41;&#46;</p></li></ul></p><p id="par0465" class="elsevierStylePara elsevierViewall">Q&#46;6&#46;1&#46;3 What dosage and administration regimen for ERT shows the greatest effectiveness against progression of each organ impairment&#63;<ul class="elsevierStyleList" id="lis0095"><li class="elsevierStyleListItem" id="lsti0300"><span class="elsevierStyleLabel">-</span><p id="par0470" class="elsevierStylePara elsevierViewall">For patients with FD treated with agalsidase &#946;&#44; the <span class="elsevierStyleItalic">recommendation</span> is to use a dosage of 1<span class="elsevierStyleHsp" style=""></span>mg&#47;kg every 2 weeks&#46; The <span class="elsevierStyleItalic">suggestion</span> is that lower dosages of agalsidase every 2 weeks might be insufficient to reduce left ventricular hypertrophy and prevent disease progression &#40;<span class="elsevierStyleItalic">STRONG</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0305"><span class="elsevierStyleLabel">-</span><p id="par0475" class="elsevierStylePara elsevierViewall">When using agalsidase alpha to control neuropathic pain in FD&#44; the <span class="elsevierStyleItalic">suggestion</span> is to administer the typically recommended dosage of 0&#46;2<span class="elsevierStyleHsp" style=""></span>mg&#47;kg every 2 weeks&#44; because there is no difference in the results using other dosages &#40;<span class="elsevierStyleItalic">WEAK</span>&#41;&#46;</p></li></ul></p><p id="par0480" class="elsevierStylePara elsevierViewall">Q&#46;6&#46;1&#46;4 For what level of enzyme deficiency has ERT shown a clinical benefit&#63;<ul class="elsevierStyleList" id="lis0100"><li class="elsevierStyleListItem" id="lsti0310"><span class="elsevierStyleLabel">-</span><p id="par0485" class="elsevierStylePara elsevierViewall">For patients with confirmed FD&#44; a level of residual enzymatic activity at which ERT is beneficial has not been determined&#59; the <span class="elsevierStyleItalic">recommendation</span> is therefore to no use baseline &#945;-gal A activity levels when deciding on the treatment &#40;<span class="elsevierStyleItalic">STRONG</span>&#41;&#46;</p></li></ul></p><p id="par0490" class="elsevierStylePara elsevierViewall">Q&#46;6&#46;1&#46;5 For pregnant women&#44; does ERT have a clearly favorable damage&#47;benefit ratio for the mother and&#47;or fetus&#63;<ul class="elsevierStyleList" id="lis0105"><li class="elsevierStyleListItem" id="lsti0315"><span class="elsevierStyleLabel">-</span><p id="par0495" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">suggestion</span> is to maintain ERT for pregnant women for whom discontinuing the therapy entails a risk of severe complications &#40;<span class="elsevierStyleItalic">WEAK</span>&#41;&#46;</p></li></ul></p><p id="par0500" class="elsevierStylePara elsevierViewall">Q&#46;6&#46;2 When is the most ideal time to start ERT in terms of the clinical benefit for organ impairment&#47;survival&#47;quality of life&#44; according to the phenotype&#63;<ul class="elsevierStyleList" id="lis0110"><li class="elsevierStyleListItem" id="lsti0320"><span class="elsevierStyleLabel">-</span><p id="par0505" class="elsevierStylePara elsevierViewall">When faced with the first FD symptoms or signs of visceral impairment &#40;pathological albuminuria&#41;&#44; the <span class="elsevierStyleItalic">recommendation</span> is to administer ERT at standard dosages&#44; taking into account each patient&#39;s individual circumstances &#40;<span class="elsevierStyleItalic">STRONG</span>&#41;&#46;</p></li></ul></p><p id="par0510" class="elsevierStylePara elsevierViewall">Q&#46;6&#46;3 For patients with FD undergoing ERT&#44; what is the course of action when faced with the development of antiagalsidase antibodies&#63;<ul class="elsevierStyleList" id="lis0115"><li class="elsevierStyleListItem" id="lsti0325"><span class="elsevierStyleLabel">-</span><p id="par0515" class="elsevierStylePara elsevierViewall">When faced with the development of antiagalsidase &#946; IgG antibodies&#44; the <span class="elsevierStyleItalic">recommendation</span> is to maintain the dosage of 1<span class="elsevierStyleHsp" style=""></span>mg&#47;kg every 2 weeks because it is a better option than changing from one agalsidase to another or reducing its dosage &#40;<span class="elsevierStyleItalic">STRONG</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0330"><span class="elsevierStyleLabel">-</span><p id="par0520" class="elsevierStylePara elsevierViewall">When faced with significant allergic reactions related to the infusions of recombinant enzymes&#44; the <span class="elsevierStyleItalic">suggestion</span> is that desensitization regimens based on dosage reduction and reducing infusion rates&#44; along with premedication with various combinations of drugs &#40;corticosteroids&#44; antihistamines&#44; nonsteroidal anti-inflammatory drugs or montelukast&#41;&#44; can be safe and allow the therapy to be maintained &#40;<span class="elsevierStyleItalic">WEAK</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0335"><span class="elsevierStyleLabel">-</span><p id="par0525" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">recommendation</span> is that desensitization treatments should always be performed under strict monitoring and medical supervision &#40;<span class="elsevierStyleItalic">STRONG</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0340"><span class="elsevierStyleLabel">-</span><p id="par0530" class="elsevierStylePara elsevierViewall">When faced with mild to moderate reactions during the recombinant enzyme infusion sessions&#44; the <span class="elsevierStyleItalic">suggestion</span> is that the session can be maintained&#44; decreasing the infusion rate and administering treatment with antihistamines or low-dose corticosteroids&#44; if necessary &#40;<span class="elsevierStyleItalic">WEAK</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0345"><span class="elsevierStyleLabel">-</span><p id="par0535" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">suggestion</span> is that changing an agalsidase for another can be an option in the presence of treatment-related allergic reactions &#40;<span class="elsevierStyleItalic">WEAK</span>&#41;&#46;</p></li></ul></p><p id="par0540" class="elsevierStylePara elsevierViewall">Q&#46;6&#46;4 What is the value of measuring Gb3&#47;lyso-Gb3 levels for monitoring treatment effectiveness&#63;<ul class="elsevierStyleList" id="lis0120"><li class="elsevierStyleListItem" id="lsti0350"><span class="elsevierStyleLabel">-</span><p id="par0545" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">suggestion</span> is to not base the follow-up of the response to ERT exclusively on Gb3 or lyso-Gb3 measurements &#40;<span class="elsevierStyleItalic">WEAK</span>&#41;&#46;</p></li></ul></p><p id="par0550" class="elsevierStylePara elsevierViewall">Q&#46;6&#46;5 At what point of advanced organ impairment does the patient not benefit from ERT&#63; Are there treatment failure criteria&#63;<ul class="elsevierStyleList" id="lis0125"><li class="elsevierStyleListItem" id="lsti0355"><span class="elsevierStyleLabel">-</span><p id="par0555" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">recommendation</span> is to discontinue or not start ERT in the following cases&#58;<ul class="elsevierStyleList" id="lis0130"><li class="elsevierStyleListItem" id="lsti0360"><p id="par0560" class="elsevierStylePara elsevierViewall">Administration difficulties &#40;therapeutic noncompliance or others&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0365"><p id="par0565" class="elsevierStylePara elsevierViewall">Persistent reactions&#44; after an anaphylactic reaction or a severe reaction to the infusion that does not respond to prophylaxis&#46;</p></li><li class="elsevierStyleListItem" id="lsti0370"><p id="par0570" class="elsevierStylePara elsevierViewall">In the final stages of FD &#40;cardiac with no transplantation option&#41;&#44; neurological and when faced with comorbidities with a short life expectancy &#40;<span class="elsevierStyleItalic">STRONG</span>&#41;&#46;</p></li></ul></p></li></ul></p><p id="par0575" class="elsevierStylePara elsevierViewall">Q&#46;6&#46;6 Has therapy with chaperones or other specific drugs for FD been shown to be effective in combination with or as an alternative to ERT&#63;<ul class="elsevierStyleList" id="lis0135"><li class="elsevierStyleListItem" id="lsti0375"><span class="elsevierStyleLabel">-</span><p id="par0580" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">suggestion</span> for patients with confirmed FD and pathogenic genetic variants amenable to treatment with the chaperone migalastat is to assess this alternative at a dosage of 150<span class="elsevierStyleHsp" style=""></span>mg every 48<span class="elsevierStyleHsp" style=""></span>h against ERT&#44; providing information on the effects of the 2 treatments and their correct follow-up&#46; The <span class="elsevierStyleItalic">suggestion</span> is that Migalastat can be an alternative for patients with amenable genetic variants who do not want to undergo ERT or for whom ERT has been shown ineffective &#40;<span class="elsevierStyleItalic">WEAK</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0380"><span class="elsevierStyleLabel">-</span><p id="par0585" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">recommendation</span> is to not use the chaperone migalastat in combined therapy with ERT due to the lack of studies that have evaluated this combination &#40;<span class="elsevierStyleItalic">STRONG</span>&#41;&#46;</p></li></ul></p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Chapter 7&#58; Specific adjuvant therapy of the organ disorders of Fabry disease</span><p id="par0590" class="elsevierStylePara elsevierViewall">Q&#46;7 Which adjuvant therapy has a beneficial effect on improving symptoms and quality of life or preventing the specific organ complications of patients with FD&#63;<ul class="elsevierStyleList" id="lis0140"><li class="elsevierStyleListItem" id="lsti0385"><span class="elsevierStyleLabel">-</span><p id="par0595" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">suggestion</span> is that local treatment with laser can be useful for angiokeratomas in FD &#40;<span class="elsevierStyleItalic">WEAK</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0390"><span class="elsevierStyleLabel">-</span><p id="par0600" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">recommendation</span> is to not use alternative medicine therapies as treatment for FD &#40;<span class="elsevierStyleItalic">STRONG</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0395"><span class="elsevierStyleLabel">-</span><p id="par0605" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">recommendation</span> is to treat the various cardiac manifestations of FD following the current good practice standards &#40;<span class="elsevierStyleItalic">STRONG</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0400"><span class="elsevierStyleLabel">-</span><p id="par0610" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">recommendation</span> is to use oral anticoagulation for patients with atrial fibrillation and hypertrophic heart disease &#40;<span class="elsevierStyleItalic">STRONG</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0405"><span class="elsevierStyleLabel">-</span><p id="par0615" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">suggestion</span> is to use an implantable cardioverter defibrillator as primary prevention for sudden death in FD with myocardial fibrosis documented by MRI and ventricular arrhythmias &#40;<span class="elsevierStyleItalic">WEAK</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0410"><span class="elsevierStyleLabel">-</span><p id="par0620" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">recommendation</span> is to use angiotensin-converting enzyme inhibitors or angiotensin II receptor antagonist II along with ERT for patients with proteinuria who do not have advanced impairment of the glomerular filtration rate&#44; following the current good practice standards &#40;<span class="elsevierStyleItalic">STRONG</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0415"><span class="elsevierStyleLabel">-</span><p id="par0625" class="elsevierStylePara elsevierViewall">For patients with FD &#40;men and women&#41;&#44; the <span class="elsevierStyleItalic">recommendation</span> is to control cardiovascular risk factors &#40;arterial hypertension&#44; diabetes mellitus&#44; dyslipidemia and tobacco use&#41; and to use anticoagulation in case of atrial fibrillation to decrease cerebrovascular complications following the same regimens used in the general population &#40;<span class="elsevierStyleItalic">STRONG</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0420"><span class="elsevierStyleLabel">-</span><p id="par0630" class="elsevierStylePara elsevierViewall">For patients with FD who have had a stroke&#44; the <span class="elsevierStyleItalic">recommendation</span> is to use secondary prevention measures&#58; smoking cessation&#44; physical activity&#44; antiplatelet therapy or anticoagulant therapy&#44; statin treatment and blood pressure and blood glucose control&#44; as with patients without FD &#40;<span class="elsevierStyleItalic">STRONG</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0425"><span class="elsevierStyleLabel">-</span><p id="par0635" class="elsevierStylePara elsevierViewall">For treating chronic pain in patients with FD&#44; the <span class="elsevierStyleItalic">suggestion</span> is to use the following first-line drugs&#58; carbamazepine&#44; gabapentin&#44; phenytoin&#44; pregabalin&#44; tricyclic antidepressants or serotonin reuptake inhibitors &#40;duloxetine or venlafaxine&#41;&#44; adjusting the dosage according to tolerance and pain control &#40;<span class="elsevierStyleItalic">WEAK</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0430"><span class="elsevierStyleLabel">-</span><p id="par0640" class="elsevierStylePara elsevierViewall">To treat pain crises in patients with FD&#44; the <span class="elsevierStyleItalic">suggestion</span> is to use tramadol&#44; morphine&#44; oxycodone&#44; ibuprofen&#44; diclofenac or intravenous lidocaine &#40;<span class="elsevierStyleItalic">WEAK</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0435"><span class="elsevierStyleLabel">-</span><p id="par0645" class="elsevierStylePara elsevierViewall">To treat chronic neuropathic pain in patients with FD&#44; the <span class="elsevierStyleItalic">suggestion</span> is to not initially use morphine or its derivatives to avoid their adverse effects and risk of dependence &#40;<span class="elsevierStyleItalic">WEAK</span>&#41;&#46;</p></li></ul></p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Chapter 8&#58; Specific treatment in conditions of multimorbidity</span><p id="par0650" class="elsevierStylePara elsevierViewall">Q&#46;8&#46;1 Is the effect of ERT or that of chaperone therapy affected by the concomitant use of analgesics&#44; antiepileptics&#44; antiplatelets&#44; hypotensive drugs or other drugs&#63;<ul class="elsevierStyleList" id="lis0145"><li class="elsevierStyleListItem" id="lsti0440"><span class="elsevierStyleLabel">-</span><p id="par0655" class="elsevierStylePara elsevierViewall">For patients with FD who are undergoing ERT or chaperone therapy&#44; the <span class="elsevierStyleItalic">suggestion</span> is to follow the general regimens for treating chronic kidney&#44; heart and cerebrovascular disease&#44; as well as for the use of analgesics&#44; according to the standards of the clinical guidelines for controlling such complications &#40;<span class="elsevierStyleItalic">WEAK</span>&#41;&#46;</p></li></ul></p><p id="par0660" class="elsevierStylePara elsevierViewall">P&#46;8&#46;2 Are the effects or dosages of ERT and chaperone therapy changed by gastrointestinal or renal impairment&#63;<ul class="elsevierStyleList" id="lis0150"><li class="elsevierStyleListItem" id="lsti0445"><span class="elsevierStyleLabel">-</span><p id="par0665" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">recommendation</span> is to not change the ERT or chaperone therapy due to the degree of target organ impairment&#46; The datasheet for Migalastat rules out its use if the glomerular filtration rate is &#60;30<span class="elsevierStyleHsp" style=""></span>mL&#47;min &#40;<span class="elsevierStyleItalic">STRONG</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0450"><span class="elsevierStyleLabel">-</span><p id="par0670" class="elsevierStylePara elsevierViewall">For patients with advanced chronic kidney disease undergoing renal replacement therapy who were undergoing ERT&#44; the <span class="elsevierStyleItalic">recommendation</span> is to perform the ERT during the dialysis sessions &#40;<span class="elsevierStyleItalic">STRONG</span>&#41;&#46;</p></li></ul></p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Chapter 9&#58; Support measures&#44; disease management and care coordination</span><p id="par0675" class="elsevierStylePara elsevierViewall">Q&#46;9&#46;1 What are the healthcare preferences of patients with FD regarding their quality of life and functionality&#63;<ul class="elsevierStyleList" id="lis0155"><li class="elsevierStyleListItem" id="lsti0455"><span class="elsevierStyleLabel">-</span><p id="par0680" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">recommendation</span> is to evaluate with the patients their treatment modality &#40;ERT or chaperone therapy&#44; if amenable&#41; and available administration preferences &#40;e&#46;g&#46;&#44; home infusions&#41;&#44; as well as the discomfort threshold&#44; safety&#44; long-term follow-up requirements and complications they are willing to tolerate before considering a change in therapy &#40;<span class="elsevierStyleItalic">STRONG</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0460"><span class="elsevierStyleLabel">-</span><p id="par0685" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">recommendation</span> is to provide patients with FD information on patient associations and patient guidelines &#40;<span class="elsevierStyleItalic">STRONG</span>&#41;&#46;</p></li></ul></p><p id="par0690" class="elsevierStylePara elsevierViewall">Q&#46;9&#46;2 What is the disease burden and care time for patients with FD as they age&#63;<ul class="elsevierStyleList" id="lis0160"><li class="elsevierStyleListItem" id="lsti0465"><span class="elsevierStyleLabel">-</span><p id="par0695" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">recommendation</span> is to evaluate the disease burden of patients with FD with them and their family &#40;<span class="elsevierStyleItalic">STRONG</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0470"><span class="elsevierStyleLabel">-</span><p id="par0700" class="elsevierStylePara elsevierViewall">For patients with FD&#44; the <span class="elsevierStyleItalic">recommendation</span> is to assess the impact of their symptoms on their school performance&#44; employment status&#44; their feelings as to their physical and emotional health&#44; and the repercussion on their social life and financial situation &#40;<span class="elsevierStyleItalic">STRONG</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0475"><span class="elsevierStyleLabel">-</span><p id="par0705" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">recommendation</span> is to perform a structured assessment of the quality of life and disease severity of patients with FD once the diagnosis has been confirmed&#46; The assessment should use validated scales&#44; such as the Short Form 36 health questionnaire and the Mainz Severity Score Index &#40;MSSI&#41;&#44; to have objective criteria for the progression of the effects on the patients&#8217; daily life &#40;<span class="elsevierStyleItalic">STRONG</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0480"><span class="elsevierStyleLabel">-</span><p id="par0710" class="elsevierStylePara elsevierViewall">When ERT is performed&#44; the <span class="elsevierStyleItalic">recommendation</span> is to adapt the administration regimen to facilitate the patient&#39;s activity&#44; with proven measures such as home administration and during dialysis sessions &#40;<span class="elsevierStyleItalic">STRONG</span>&#41;&#46;</p></li></ul></p><p id="par0715" class="elsevierStylePara elsevierViewall">Q&#46;9&#46;3 Do adolescents with FD have school performance issues&#63;<ul class="elsevierStyleList" id="lis0165"><li class="elsevierStyleListItem" id="lsti0485"><span class="elsevierStyleLabel">-</span><p id="par0720" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">suggestion</span> is that ERT at a dosage of 1<span class="elsevierStyleHsp" style=""></span>mg&#47;kg every 2 weeks can reduce the school absenteeism of patients with FD &#40;<span class="elsevierStyleItalic">WEAK</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0490"><span class="elsevierStyleLabel">-</span><p id="par0725" class="elsevierStylePara elsevierViewall">For adolescents with FD&#44; the <span class="elsevierStyleItalic">recommendation</span> is to perform audiometry to identify hearing problems that can affect their school performance &#40;<span class="elsevierStyleItalic">STRONG</span>&#41;&#46;</p></li></ul></p><p id="par0730" class="elsevierStylePara elsevierViewall">Q&#46;9&#46;4 Does FD functionally impair work activities and quality of life&#63;<ul class="elsevierStyleList" id="lis0170"><li class="elsevierStyleListItem" id="lsti0495"><span class="elsevierStyleLabel">-</span><p id="par0735" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">suggestion</span> is to periodically assess the health-related quality of life of patients with FD&#44; including how the disease affects work and social activities &#40;<span class="elsevierStyleItalic">WEAK</span>&#41;&#46;</p></li></ul></p></span></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Corollary</span><p id="par0740" class="elsevierStylePara elsevierViewall">The recommendations presented in these clinical practice guidelines have been obtained after systematically reviewing and assessing &#40;with a rigorous and reproducible methodology&#41; the best scientific evidence currently available on FD&#44; taking into account the risk-benefit balance&#44; the patients&#8217; values and preferences and the organizational aspects&#46; Research in the field of lysosomal storage diseases in general&#44; and in FD in particular&#44; is in full swing&#46; We therefore expect that new diagnostic and therapeutic approaches will quickly become available&#46; These clinical practice guidelines are therefore created with the commitment to keep them in use and regularly updated as needed based on new evidence that can arise in the management of this disease&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Funding</span><p id="par0745" class="elsevierStylePara elsevierViewall">The Enebro Foundation acted as sponsor for developing these guidelines&#44; using their own funds and a grant from Sanofi-Genzyme&#44; which was accepted with the explicit commitment by the sponsors to respect the guidelines authors&#8217; independence and autonomy&#46; In this respect&#44; the authors followed a protocol by which the sponsor abstained from directly intervening or interacting with the authors and experts of the guidelines&#44; who were coordinated at all times by the organization arranged by the Enebro Foundation&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Conflicts of interest</span><p id="par0750" class="elsevierStylePara elsevierViewall">C&#46; Alonso-Ortiz del R&#237;o&#44; M&#46; Barcos Mart&#237;nez and E&#46; Briones P&#233;rez de la Blanca declare having received external aid related to the implementation of the study in the form of research funds from the Enebro Foundation&#46;</p><p id="par0755" class="elsevierStylePara elsevierViewall">E&#46;J&#46; Calder&#243;n Sandubete&#44; M&#46; L&#243;pez Mendoza&#44; C&#46; M&#225;rquez Infante and R&#46; Santamar&#237;a Olmo declare that they &#40;1&#41; have received external aid related to the implementation of the study in the form of research funds from the Enebro Foundation and &#40;2&#41; have received the following contributions from Sanofi-Genzyme&#44; Amicus Therapeutics and Shire in the form of aid for attending congresses unrelated to the implementation of the study&#46;</p><p id="par0760" class="elsevierStylePara elsevierViewall">I&#46; Mar&#237;n-Le&#243;n declares that they &#40;1&#41; have received external aid related to the implementation of the study in the form of research funds from the Enebro Foundation and &#40;2&#41; have received the following contributions from Sanofi-Genzyme&#44; in the form of aid for attending congresses unrelated to the implementation of the study&#46;</p></span></span>"
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              "titulo" => "Chapter 1&#58; Screening for an incident familiar case of Fabry disease"
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              "titulo" => "Chapter 8&#58; Specific treatment in conditions of multimorbidity"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Anderson&#8211;Fabry disease is a severe progressive multisystem condition of genetic origin that affects men and women&#44; reducing their life expectancy and quality of life&#46; The considerable variability in its clinical expression&#44; the difficulties in diagnosing the condition and the current availability of several alternatives for its treatment represent a considerable challenge that justifies the development of evidence-based clinical practice guidelines that can help health professionals in the decision-making process for managing these patients&#46; To develop these guidelines&#44; we conducted a systematic search of the main reference databases using strategies adapted to each of the 32 clinical questions considered&#46; We prepared documents to synthesize the evidence and assess its quality for each of the questions&#46; The methodology employed is based on the Spanish methodology manual for preparing clinical practice guidelines&#44; incorporating the GRADE methodology in the assessment of the scientific evidence and the preparation of the recommendations&#44; considering the quality of the evidence&#44; the risk-benefit balance&#44; patient values and preferences&#44; equity and use of resources&#46; For the definitive preparation of the recommendations&#44; we conducted a structured consensus process based on the Delphi-RAND methodology in 2 rounds&#44; with an expert panel proposed by various scientific societies&#44; research centers and patient associations&#46; Ultimately&#44; we developed 92 specific recommendations for managing Fabry disease&#46;</p></span>"
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        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">La enfermedad de Anderson-Fabry es una afecci&#243;n multisist&#233;mica progresiva y grave de origen gen&#233;tico que afecta tanto a hombres como a mujeres y que reduce sus expectativas y calidad de vida&#46; La gran variabilidad en su expresi&#243;n cl&#237;nica&#44; las dificultades para su diagn&#243;stico y la disponibilidad actual de varias alternativas para su tratamiento suponen un gran reto que justifica la realizaci&#243;n de una gu&#237;a de pr&#225;ctica cl&#237;nica basada en la evidencia que pueda ayudar a los profesionales sanitarios en la toma de decisiones en el manejo de estos pacientes&#46; Para elaborarla se ha realizado una b&#250;squeda sistem&#225;tica en las principales bases de datos bibliogr&#225;ficas mediante estrategias adaptadas a cada una de las 32 preguntas cl&#237;nicas consideradas&#46; Se confeccionaron fichas para la s&#237;ntesis y evaluaci&#243;n de la calidad de las evidencias para cada una de las preguntas&#46; La metodolog&#237;a empleada se basa en el <span class="elsevierStyleItalic">Manual metodol&#243;gico espa&#241;ol para la elaboraci&#243;n de gu&#237;as de pr&#225;ctica cl&#237;nica</span> e incorpora en la evaluaci&#243;n de la evidencia cient&#237;fica y en la elaboraci&#243;n de las recomendaciones la metodolog&#237;a GRADE&#44; considerando la calidad de la evidencia&#44; el balance entre beneficios y riesgos&#44; valores y preferencias de los pacientes&#44; equidad y uso de recursos&#46; Para la elaboraci&#243;n definitiva de las recomendaciones se llev&#243; a cabo un proceso de consenso estructurado basado en la metodolog&#237;a Delphi-RAND en 2 rondas&#44; con un panel de expertos propuesto por diferentes sociedades cient&#237;ficas&#44; centros de investigaci&#243;n y asociaciones de pacientes&#46; Finalmente&#44; se han elaborado 92 recomendaciones espec&#237;ficas para el manejo de la enfermedad de Fabry&#46;</p></span>"
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            "apendice" => "<p id="par0765" class="elsevierStylePara elsevierViewall">Manuel Posada de la Paz &#40;Rare Diseases Research Institute&#44; Health Institute Carlos III-IIER-ISCIII&#41;&#59; Pilar Giraldo Castellano &#40;Biomedical Research Center in Network&#44; CIBERER-EF&#41;&#59; Juan Ram&#243;n Gimeno Blanes &#40;Spanish Society of Cardiology&#44; SEC&#41;&#59; Encarnaci&#243;n Guill&#233;n Navarro &#40;Spanish Society of Clinical Genetics and Dysmorphology&#44; SEGCD&#41;&#59; M&#243;nica L&#243;pez Rodr&#237;guez &#40;Spanish Society of Internal Medicine&#44; SEMI&#41;&#59; Alberto Ortiz Ardu&#225;n &#40;Spanish Society of Nephrology&#44; SENEFRO&#41;&#59; Jaime D&#237;az Guzm&#225;n &#40;Spanish Society of Neurology&#44; SEN&#41;&#59; Paz Latre Mart&#237;nez &#40;Spanish Society of Family and Community Medicine&#44; SEMFYC&#41;&#59; Jordi Cruz Villalba &#40;Spanish Federation of Rare Diseases&#44; FEDER&#41;&#59; Jos&#233; Mar&#237;a Carri&#243;n P&#233;rez&#44; Documentalist&#46;</p>"
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Article information

ISSN: 22548874
Original language: English

DOI:10.1016/j.rceng.2019.02.001

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