What Is Acid Sphingomyelinase Deficiency?

Introduction

Sphingomyelin is a type of lipid found in mammalian cell membranes. This sphingolipid is involved in different cellular processes and functions, which is why it is essential for the proper functioning of our cells. For example, membrane sphingomyelin is involved in protein sorting, ion channel functioning, and endocytosis (which is the process by which molecules are brought into the cell).¹ Sphingomyelin can be hydrolysed, giving rise to ceramide, which is essential for cell regulation.² This hydrolysis is mediated via a synthesis pathway by the enzyme acid sphingomyelinase.³ Problems in the activity of acid sphingomyelinase can give rise to lower ceramide levels and the accumulation of sphingomyelin, leading to cell regulation problems.  In the next sections, acid sphingomyelinase deficiency, its causes, its symptoms, and the treatments available will be further explored. 

Overview of acid sphingomyelinase deficiency

Acid sphingomyelinase deficiency (ASMD) is a lysosomal storage disease characterised by, as stated, a deficient activity of the enzyme acid sphingomyelinase. This disease gives rise to the accumulation of lipids, mainly sphingomyelin, in various organs. The main characteristics of this are foam cell infiltration in different tissues and lipid storage. ASMD is a type of Niemman-Pick disease and can be presented in two different forms: ASMD A and B. These forms are different, with ASMD A considered more fatal. Furthermore, while ASMD A is characterised by an early age of onset and severe central nervous system impairment, ASMD B has an irregular age of onset, a slower progressive apparition of symptoms, and does not affect the nervous system (no neurological involvement), or at least to a lesser extent.⁴ The worldwide incidence of ASMD is estimated to be between 0.4 and 0.6 per 100,000 births. However, this value might be underestimated.⁵

Causes

ASMD occurs due to a mutation on the SMPD1 gene, which is located on the short arm of chromosome 11 (11p.54). This gene encodes for the enzyme acid sphingomyelinase. Hence, a mutation in this gene leads to deficient sphingomyelinase activity. A range of mutations have been linked to ASMD, including missense, nonsense, and intronic variants.6 In fact, more than 200 variants within this gene have been described in patients affected by ASMD.4 However, currently, only 3 large alterations (e.g. deletions/duplications) have been identified.⁷ These mutations are inherited through autosomes recessively... This means that for an individual to suffer from ASMD, the person must have two copies of the mutated gene (one from each parent). If an individual has only one copy of the mutated gene, the person would be a carrier for the disease but will not suffer from it. In this way, the risk for two carriers to have a child with ASMD will be 25%, as the child would only have 1 in 4 chances of inheriting both mutated genes.

Symptoms 

Symptoms of ASMD are varied. ASMD A is characterised by more severe symptoms affecting many different organs. In contrast, ASMD B is a chronic progressive form that affects fewer organs and produces milder symptoms.

 The symptoms of ASMD include the following:^4,6,8 

• Swelling of both the spleen and liver (hepatosplenomegaly). This is caused by the accumulation of sphingomyelin in hepatocytes and Kupffer cells. It can lead to fatality due to liver failure.
• Swelling of the spleen (splenomegaly) as a result of the infiltration of lipid-laden macrophages. This is associated with abdominal pain and splenic infarctions, which are characterised by the immune-mediated destruction of haematologic cells such as white blood cells. 
• Lung dysfunction with oxygen dependence - ranging from none to severe
• Low bone density 

ASMD A is the most severe form of the disease. Children with this form of the disease do not tend to live for longer than 3 years.

 The symptoms of ASMD A include:⁷,⁹ 

• Rapid and progressive neurodegeneration 
• Hypotonia - decreased muscle tone that leads to floppiness 
• Cherry-red spot in the macula 
• Feeding difficulties 
• Nausea and vomiting 
• Constipation 
• Fluid accumulation in the abdomen 

Whereas ASMD B symptoms include:⁷

• Neurological manifestations: some reports have suggested that ASMD B can have neurological manifestations such as ataxia, motor delay, and learning difficulties
• Reddish-brown hallow surrounding the macula
• Decreased levels of HDL and increased levels of LDL, VLDL, and triglycerides
• Growth restriction due to delayed onset of puberty and bone age
• Bruises and joint and limb pain 
• Bleeding and bone fractures 
• Headache 

Diagnosis 

After clinical suspicion of ASMD, the activity of acid sphingomyelinase is measured; this can be done using either leukocytes, dried blood spots, or cultured skin fibroblasts. If the activity is 10-15% lower than in healthy control individuals, it is considered to be deficient.⁴ Then, it is highly recommended to analyse the gene SMPD1 through gene sequencing to confirm the diagnosis. It is the only reliable method for carrier identification within family members, and it is the preferred method for prenatal diagnosis.⁷ If, through the molecular analysis of SMPD1, two pathogenic variants are identified, ASMD is diagnosed.

Treatment and management

Unfortunately, there are no approved specific therapies for ASMD, being this disease is considered to be non-curable. However, there are some therapeutic approaches that can allow doctors to manage the symptoms of patients and address any complications that may arise. Management of ASMD is based on therapies, supportive care, and palliation focused on, as mentioned, alleviating symptoms. In this way, for example, patients with progressive pulmonary disease might need chronic oxygen therapy, and those with cytopenia may require multiple blood transfusions. Unfortunately, there is no treatment for either low bone density or hepatosplenomegaly. Furthermore, it is worth mentioning that psychological support for both patients and their relatives is essential; even though there is a lack of data due to the rarity of this disease, ASMD is thought to have a high psychosocial impact on patients (mainly due to factors such as social isolation linked, in juvenile patients, to peer rejection, and in adults, to lack of energy and chronic fatigue).⁶

Enzyme replacement therapy (ERT) is a type of therapy based on replacing a deficient enzyme (in this case, acid sphingomyelinase) using, for example, recombinant human enzyme preparations, which are usually given by intravenous infusion.¹⁰ In reference to ASMD, ERT seems to be able to slow non-CNS manifestations of the disease. Olipudase alfa is an ERT that replaces acid sphingomyelinase. Studies have shown that this therapy is safe and effective for improving the outcomes of ASMD patients.⁵ Currently, a few clinical trials testing Olipudase alfa are being conducted. From these, one is in phase 2 and the other one in phase 2/3.⁴

In reference to potential therapies to treat ASMD, some experimental approaches include bone marrow transplantation, total lavage of lungs, and amniotic cell transplant. However, they all have a high risk of complications and a low benefit/risk ratio.⁶ Thus, further research is needed to find a safe and effective treatment to cure ASMD.

Conclusion

Acid sphingomyelinase deficiency (ASMD) is a disease characterised by the deficient activity of the enzyme that converts sphingomyelin to ceramide. The deficiency of this enzyme leads to sphingomyelin accumulation, giving rise to many symptoms which differ between the two types of ASMD: ASMD A and B. The cause of ASMD has been determined to be genetic; its development is due to a mutation in the gene that encodes for acid sphingomyelinase, SMPD1, which is analysed in order to make a diagnosis. Unfortunately, currently, there is no cure for ASMD. However, there are various therapeutic approaches based on managing the symptoms of ASMD. Through further research, we will hopefully be able to find a safe and effective treatment.