Acid Sphingomyelinase Deficiency (ASM disease) is an inherited and progressive genetic disorder, also known by its historical names Niemann-Pick disease type A, A/B, and B. The condition results from the harmful accumulation of a fatty substance, sphingomyelin, within cells and organs like the liver, spleen, and lungs. This buildup disrupts cellular function, leading to organ damage over time. The severity and age of onset vary, with symptoms appearing from early infancy to adulthood.
The Genetic Basis of ASM Disease
ASM disease is caused by mutations in the SMPD1 gene, which provides instructions for producing the enzyme acid sphingomyelinase (ASM). This enzyme works within cellular compartments called lysosomes to break down the fatty substance sphingomyelin. When mutations occur in the SMPD1 gene, the body produces an insufficient or non-functional ASM enzyme.
This deficiency prevents the breakdown of sphingomyelin, causing it to accumulate and lead to cell damage and organ dysfunction. The disease is inherited in an autosomal recessive pattern, meaning an affected person must inherit a mutated copy of the SMPD1 gene from each parent.
Classifications and Associated Symptoms
The clinical presentation of ASM disease exists on a spectrum and is categorized into three main types based on the age of onset and severity of symptoms. The different types are distinguished by the level of neurological involvement and the rate of disease progression. This classification helps in understanding the potential course of the condition for affected individuals.
The most severe form is type A, or the infantile neurovisceral form. Symptoms manifest within the first few months of life, with a prominent early sign being a significantly enlarged liver and spleen, a condition called hepatosplenomegaly. Infants with type A experience a rapid decline in neurological function and fail to reach developmental milestones. A finding in nearly all children with this form is a cherry-red spot on the macula of the retina. Most children with untreated type A succumb to the disease by age three due to respiratory failure.
A less severe variant is type B, the chronic visceral form, which involves little to no neurological impairment. Symptoms can emerge from childhood to adulthood and are related to organ dysfunction outside of the central nervous system. Individuals with type B have progressive hepatosplenomegaly, which can lead to liver problems, and low platelet counts, known as thrombocytopenia. Lung involvement is common, with sphingomyelin accumulation causing interstitial lung disease and respiratory complications.
An intermediate form, type A/B, presents with a mix of symptoms that fall between the severity of types A and B. These individuals survive past early childhood but experience progressive neurological symptoms alongside the visceral organ involvement seen in type B. The rate of progression and the specific combination of symptoms can vary widely.
Diagnostic Procedures
The initial step in diagnosing ASM disease involves a blood test to measure the activity of the acid sphingomyelinase enzyme, which can be done using peripheral white blood cells or cultured skin cells. An individual with any form of ASM disease will show markedly deficient ASM enzyme activity. This biochemical test is a strong indicator of the disorder, with activity often less than 5% of normal levels in severe cases.
While enzyme analysis is highly suggestive, a definitive diagnosis requires molecular genetic testing of the SMPD1 gene. This testing identifies the specific disease-causing mutations, confirming the diagnosis and helping to predict disease severity. Identifying the mutations is also valuable for genetic counseling and for testing at-risk family members. The presence of characteristic lipid-laden foam cells in a bone marrow sample can support a diagnosis, but it is not definitive on its own as these cells can be present in other related disorders.
Management and Therapeutic Approaches
The primary treatment for the non-neurological symptoms of ASM disease is enzyme replacement therapy (ERT). The approved therapy, olipudase alfa, provides a functional, manufactured version of the ASM enzyme that the patient’s body cannot produce sufficiently. This therapy works to break down the accumulated sphingomyelin in organs like the spleen, liver, and lungs, which can help reduce their size and improve function. ERT is administered intravenously and is a long-term treatment. The therapy does not address the neurological symptoms associated with severe forms of the disease because the replacement enzyme cannot effectively cross the blood-brain barrier.
Beyond ERT, management of ASM disease focuses on supportive care tailored to specific symptoms. This can include blood transfusions to address low platelet counts, respiratory support for patients with significant lung disease, and regular monitoring of liver function and spleen size. For individuals with the severe infantile form, care is focused on managing symptoms to provide comfort.