Acid sphingomyelinase deficiency is a genetic disorder caused by a deficiency of the enzyme acid sphingomyelinase. It leads to the accumulation of sphingomyelin— a type of lipid (fat) in the cells, leading to liver, spleen, lung and in some cases, central nervous system disorders. It may affect all populations irrespective of gender, and the incidence is estimated to be 1 in 250,000 individuals in the general population. Understanding the clinical features and symptoms of this disease can help in early diagnosis and effective symptomatic management.

Introduction

Acid sphingomyelinase is the enzyme required to break down sphingomyelin, a type of body fat. Due to the deficiency of this enzyme, sphingomyelin accumulates in the cells and tissues of the body, causing multiple organ failures.

The first reported case of this rare disorder was found in an infant by Albert Niemann, in 1914 and was differentiated from Gaucher disease by Ludwig Pick. It later became known as Niemann–Pick disease. Over the years, many studies were conducted on this disorder, which led to the classification into two groups —acid sphingomyelinase deficiency (ASMD), comprising the ASMD A and B, and Niemann–Pick type C (NPC).¹

ASMD is caused by a genetic mutation in the gene SMPD1 which codes for the enzyme acid sphingomyelinase. Type C is caused by a mutation in NPC1 and NPC2 genes. It is inherited in an autosomal recessive pattern—both copies of genes must be mutated for the disease to occur.²

Autosomal recessive inheritance pattern

Pathophysiology

Sphingomyelin is a lipid found in cell membranes. Acid sphingomyelinase is the enzyme that helps in cell membrane turnover and degradation, thus maintaining cellular balance. In patients with this enzyme deficiency, there is an accumulation of sphingomyelin in the cells, predominantly in cells called macrophages resulting in the formation of lipid-loaded cells called foam cells.

It usually affects the lungs, spleen, bone marrow, lymph nodes and liver, and although rare, they can be found in the small and large intestines. Eventually, these cells lose their function and die, causing various problems.³

Niemann-Pick disease type C is not caused by the deficiency of acid sphingomyelinase but by the defective transport and mobilisation of cholesterol and sterols from the cells. As a result, there is excessive build-up of cholesterol resulting in tissue damage and organ failure.²

Clinical features and symptoms

Acid sphingomyelinase deficiency (ASMD) manifests itself as a multiorgan disease. Type A is more fatal and is typically characterised by the occurrence in early infancy. Generally, type A patients show involvement of the spleen, liver, lungs and central nervous system(CNS). Type B patients also have involvement of the spleen, liver and lungs with little or no CNS involvement. Type B shows slow progression,, and the symptoms are milder.

Niemann-Pick disease type A (ASMD Type A)

Onset in infancy

• ASMD type A usually occurs in early infancy, and the affected patients fail to thrive even in the first year of life
• Most patients do not survive beyond 2 to 3 years of life⁴

Severe neurodegeneration

• ASMD type A is characterised by central nervous system involvement and is rapid and progressive
• Neurodegeneration results in weakness of the muscle, developmental delay and reduced coordination³

Hepatosplenomegaly 

• This is characterised by enlargement of the liver and spleen with yellowing of the skin and whites of the eyes (jaundice)
• Hepatosplenomegaly can be mild to severe
• Usually associated with hepatic fibrosis and increased levels of transaminases— a liver enzyme that helps in a reaction between an amino acid and an α-keto acid.
• Liver disease may be fatal and lead to liver failure
• Enlarged liver and spleen result in abdominal pain, constipation and discomfort³

Pulmonary issues 

• Lungs are frequently involved with breathing difficulties 
• Respiratory infections may occur secondary to aspiration⁵

Developmental delay

• ASMD type A is characterised by rapidly progressing neurodegeneration and hence muscle weakness
• Hence, the patient shows developmental delay and failure to attain milestones
• Reduced coordination and movements are evident in 6 to 15 months of age
• Most of the patients do not develop the ability to sit independently
• Infants show very minimal interaction, especially after 6 months⁴

Hypotonia (reduced muscle tone)

• Patients show the generalised weakness of muscles and loss of control over the muscles
• Even though hypotonia will be evident within the first few months, development usually progresses up to 6 months of age and shows a decrease in the following months⁴

Eye involvement

Infants affected with ASMD type A usually show a cherry-red spot in the macula of the eye.³

Cherry red spot

Feeding difficulties

• Due to the muscle weakness, weak sucking and compression of the stomach (because of hepatosplenomegaly), there will be feeding difficulties in infants
• By 2 to 3 years, it may become severe and cause an inability to consume sufficient calories to survive⁴

Niemann-Pick disease type B (ASMD Type B)

Onset in childhood or adulthood

• The symptoms begin to appear in early childhood, teens or, in some cases, adulthood
• The disease progression is slow and variable 
• Patients may have a normal lifespan if there are fewer complications involved⁵

Chronic and less severe neurodegeneration

• Neurodegeneration is slowly progressing, does not involve the brain and is often milder than type A
• Associated with impaired coordination, learning difficulties and delayed motor functions⁴
• Neurological symptoms can be variable, from mild hypotonia or hyporeflexia—reduced reflexes, increased sensitivity to touch, slurred speech due to loss of motor function⁵

Hepatosplenomegaly

• Associated with liver and spleen enlargement
• Usually, hepatosplenomegaly is noticed in early childhood. Sometimes in patients with mild symptoms, the diagnosis may get delayed into the 6th decade of life
• The increased size of the spleen can be up to ten times the normal size and in some patients it can be fatal, resulting in splenic rupture
• Shows signs of liver cirrhosis and liver failure with elevated serum triglycerides and LDL-cholesterol, and low HDL-cholesterol⁴

Pulmonary issues 

• Lungs are frequently involved with breathing difficulties and decreased oxygen diffusion
• Associated with interstitial lung disease and lung infections⁴

Eye involvement

• Associated with clouding of the cornea and a reddish brown halo surrounding the macula of the eye
• Rarely, a cherry red spot may be seen⁴

Cardiac problems

• Patients often present with coronary artery or valvular heart diseases⁴

Growth retardation

• Children often show growth restriction and delayed bone age
• Delay in the onset of puberty is quite common among patients⁴

Reduced blood cell count

• Patients show thrombocytopenia—decreased platelet count and leucopenia— decreased leukocytes
• It typically worsens over time, leading to increased chances of bleeding, hemorrhage and risk of infections⁴

Bone abnormalities 

• Patients show osteopenia—reduced bone density, thus increasing the chances of bone fractures
• Also associated with bone and joint pain
• Delayed bone maturation and growth restriction can also be seen¹

Other common symptoms

Both types show hepatosplenomegaly leading to stomach compression. Hence, the patients experience abdominal pain and discomfort. The patients also show symptoms like fatigue and generalised weakness of muscles. Other symptoms include poor sleep, irritability, headache, rapid uncontrolled eye movements, intellectual disability, recurrent ear infections, etc.¹

Diagnosis

• Early diagnosis involves clinical evaluation and a thorough medical history
• The common laboratory tests are the detection of biallelic pathogenic variants in SMPD1 by molecular genetic testing, bone marrow examination and enzymatic evaluation
• A residual acid sphingomyelinase enzyme activity that is less than 10% shows positive results
• Imaging studies like MRI, ultrasound, chest x-rays, etc. help diagnose hepatosplenomegaly and the involvement of the lungs
• Early diagnosis is the key to improving the affected individual's quality of life⁶

Management and treatment

Treatment involves a multidisciplinary approach including paediatricians (for children), neurologists, hepatologists, cardiologists, and ophthalmologists. Currently, there are no disease-specific treatments for ASMD, but involve symptomatic treatments, proper nutrition, and physical therapy. However, research is ongoing in this field and potential future therapies for the management of acid sphingomyelinase deficiency are being developed. An enzyme replacement therapy with a recombinant human ASM (olipudase alfa) is at clinical development stage.⁵

Living with ASMD

Each person's experience with ASMD may be different. As the symptoms progress, it may impact the emotional status and mental health of the individual. Patients or caretakers can track their symptoms and keep a note of them. Discuss the findings with the healthcare practitioners and stick to the symptom management plan advised by the healthcare team. Always try to maintain an active life with adequate nutrition. There are many support networks and resources like npuk and the National Organisation for Rare Disorders (NORD) that can help and support patients through their journey.

Summary

Acid sphingomyelinase deficiency is a type of genetic disorder that affects mainly the organs like the liver, spleen, lungs, and central nervous system and also manifests heart, bone, muscle and haematological symptoms. There are basically two types of ASMD. Type A, which occurs in early infancy associated with fatal symptoms and feeding difficulties, and type B which has a later onset in life with milder symptoms. The important clinical features involve hepatosplenomegaly, reduced tone and strength of muscles, lung diseases and infections, heart diseases, nerve degeneration, delayed development, bone and joint pain. Even though the current treatment strategies are symptomatic, ongoing research in this field is promising. Awareness and early intervention are crucial for the management and well-being of the affected individuals.