Acid sphingomyelinase deficiency (ASMD), previously known as Niemann-Pick A or B (or simply NPD), is an extremely rare lysosomal disease that is characterised by the accumulation of sphingomyelinase, mainly in hepatocytes and reticuloendothelial system cells.1 The most frequently affected organs are the liver, spleen, lungs, bone marrow, and lymph nodes, as well as the central nervous system in more severe cases.2,3

ASMD is a disease that remains largely unknown, that presents a wide range of different and non-specific symptoms, making it difficult to diagnosis and often resulting in a delayed diagnosis that can take many years.4,5 Although the clinical presentation is non-specific, ASMD may be suspected in patients with hepatosplenomegaly, thrombocytopenia, interstitial lung disease, hyperlipidaemia, delayed development, and/or a cherry-red spot on the ocular fundus (particularly in pediatric patients). Diagnosis can be confirmed by means of biochemical and genetic techniques. The gold standard diagnostic technique is to measure enzyme acid sphingomyelinase activity in dried blood spots that can be performed in peripheral blood lymphocytes or in cultured skin fibroblasts.6 Following a positive enzymatic diagnosis it is recommended to complement this confirmation with a genetic study to detect pathogenic mutations of the SMPD1 gene.6,7

The progression of the disease varies from the fast-progressing and fatal forms presenting in children to the chronic, slower progressing form presenting in adults.8 ASMD has different phenotypes: ASMD type A, infantile neurovisceral; ASMD type B, chronic visceral; and ASMD type A/B, chronic neurovisceral.9 Types A and A/B are associated with neurological involvement. Type A has a highly uniform natural history, characterised by hepatosplenomegaly at 2 to 4 months old and progressive neurodegeneration starting in the first months of life and an expected survival of less than 3 years.9 The most common form of the disease is ASMD type B and does not present with neurological involvement (or if it does it is very mild); it is the most variable form of the disease, both in terms of clinical presentation and life expectancy, which can reach 70 years or result in premature death due to related complications. The visceral manifestations are clearly predominant in this phenotype.9

Studies on ASMD prevalence are few and provide varied data (between 0.3 and 0.6 cases per every 100,000 or 250,000 live births).10–14 Recently, consensus clinical guidelines for the management of ASMD have presented a prevalence of approximately 1 out of 100,000 or 1,000,000 births.1 To date, no epidemiological studies have been carried out in patients with this disease in Spain. Therefore, the main objective of the present study was to determine the estimated prevalence of patients diagnosed with ASMD (types A/B and B) in Spain.

This is the first epidemiological study of ASMD in Spain and reports an estimated prevalence of 0.7 cases per 1,000,000 inhabitants, that is higher in the paediatric population (1.2) than in adult population (0.6). Previous studies carried out in different countries (Czech Republic, The Netherlands, Portugal, and United Arab Emirates) have shown prevalence rates of ASMD types A and B at birth of between 0.3 and 0.6 cases for every 100,000 live births.11–14 However, a prior study from Australia reported a rate of 1 in every 248,000 live births.10 In our study, the prevalence of ASMD types A/B and B measured in paediatric and adult populations is below that reported in previously published studies.4 In our opinion, methodological disparities in determining the prevalence might explain these discrepancies. On the one hand, previous studies evaluated prevalence at birth; thus, calculations were made based on the total number of diagnosed cases that were born during a certain time frame with respect to the total number of births in that same period. Furthermore, these studies determined the combined prevalence of ASMD types A and B, unlike our study which considered types A/B and B. In any case, all estimated prevalence rates, those from both the literature11–14 and our study, were based on suspected cases that were referred by specialists for the biochemical and/or molecular confirmation, and not based on screening studies of the general population. The only available screening study was carried out in Chile on 1,691 healthy individuals, where one of the pathogenic variants of ASMD (p.Ala359Asp) was identified.16 That study reported a disease incidence of 1 case per 44,960 individuals. Given the limited available information, it is considered that ASMD is highly underdiagnosed in routine clinical practice, especially in cases of ASMD type B where the diagnosis may not be easily evident.

In that regard, the clinical manifestations of ASMD may overlap with other lysosomal storage disorders such as Gaucher’s disease.10 Hepatosplenomegaly is one of the most common clinical manifestations used for identification.17 The presence of interstitial lung disease and dyslipidaemia may help differentiate ASMD from other pathologies such as hematologic malignancies that can also present with hepatosplenomegaly and pancytopenia.10 Nevertheless, definitive diagnostic confirmation of ASMD is achieved using biochemical and/or genetic testing.18,19 In our study, the specialists identified splenomegaly, hepatomegaly, interstitial lung disease, and thrombocytopenia as the primary symptoms that lead to diagnosis. It is also important to highlight that the specialists associated the severity of lung and liver involvement as main factors for determining prognosis and the course of the disease. As described in prior studies, there is an important delay between the initial onset of symptoms and a definitive diagnosis of the disease (approximately 5 on average).20 In our study, the diagnostic delay was slightly lower (2.5 years). With regards to patients with ASMD, it must be stated that most of them in our study were adults (70.6%). By contrast, other studies have reported similar data or a majority of paediatric patients.20,21 For example, in one multinational, multicentre, cross-sectional survey study with data from 59 patients with ASMD type B, 50.8% of patients were paediatric.20 However, one study with data from 64 cases of ASMD type B showed that the percent of paediatric patients (57.8%) was slightly higher than that of adults (42.2%).21

In Spain, the PREDIGA project is currently being carried out with the aim of identifying undiagnosed patients with ASMD disease and Gaucher’s disease who could benefit from effective treatments.22 The project also involves a country-wide education program aimed at improving the knowledge on these diseases and the dissemination of diagnostic algorithms. During the first year of the educational project, with the participation of 52 healthcare professionals from 34 hospitals in Spain, 166 patients with diagnostic criteria were reviewed and diagnostic confirmation of ASMD was achieved in two of them.

On the other hand, ASMD is associated with a significant physical, emotional, psychosocial, and economic burden on patients and caregivers.23,24 Previous studies have revealed that patients with chronic diseases require outpatient care that includes physical therapy or home medical care. In addition, it has been reported that the use of healthcare services by patients with ASMD is extensive and may include laboratory testing (liver enzymes and lipid panels), pulmonary function testing, histopathology, ultrasound/X-rays, and pharmacological prophylactic and symptomatic treatments. They also require medical services such as oxygen therapy, physical therapy, and organ transplant.25,26 In our study, the most commonly used healthcare resources were laboratory tests and Primary Care consultations. For patient follow-up, specialists mainly used medical consultations, blood tests, ultrasounds, pulmonary diffusion tests, and chest X-rays.

The main limitation of the present study is the subjective nature of the data, which are provided as aggregated data from the specialists’ experience, i.e. without including data from medical charts. Also, data may be influenced by a recall bias. Despite that, ecological studies are part of epidemiological observational designs and are used as hypothesis generators as they are easy to carry out, quick, low-cost, and relatively easy to analyse.27 Another study limitation may derive from the 23.8% of patients with ASMD, whose diagnosis could not confirmed via genetic testing due to the closure of the database. Yet, algorithms used in clinical practice allow for an ASMD diagnosis to be established based on family history, clinical presentation highly suggestive of the disease, or histological studies. Overall, our results provide a first step of information on the epidemiology of the disease in Spain, as well as the sociodemographic and clinical profile of these patients and the burden of disease on the healthcare system.

This first study of ASMD carried out in Spain presents an estimated prevalence of patients with ASMD type A/B and B of 0.7 per 1,000,000 inhabitants, which is higher in paediatric population (1.2) than in adult population (0.6). Given the scarce epidemiological studies on this disease, it is considered to be underdiagnosed in routine clinical practice. More studies are needed with a larger number of participants and, even, screening studies in healthy population to establish a value as close to reality as possible.

This study was financed by Sanofi Spain. Assistance in the writing of the manuscript was provided by Evidenze Health España S.L.U., which was hired by Sanofi Spain. Sanofi Spain had no direct relationship with the authors. None of the authors received direct financing from the industry.