Niemann-Pick Disease

Lysosomal storage diseases are characterized by inherited deficiencies of one or more lysosomal enzymes involved in the degradation of lipids and their products. Niemann-Pick disease (NPD) is a lysosomal storage disease caused by acid sphingomyelinase deficiency (ASMD), which catalyzes the hydrolysis of sphingomyelin (SM) to ceramide and phosphocholine. As a result, SM and its precursor lipids begin to accumulate in lysosomes, mainly in macrophages. These lipid-laden macrophages deposit in the liver, spleen, lungs, and brain causing hepatosplenomegaly, cytopenias, lung disease, and neurologic symptoms.Traditionally, NPD is classified into four subtypes: type A, B, C, and E. Type A is known as infantile neurovisceral form with very low acid sphingomyelinase (ASM) activity and is usually fatal before the age of three. It affects younger children and results in neurological deficits and impaired growth. Type B is less severe and is characterized by variable visceral symptoms and minimal neurological involvement. The most common visceral symptoms in these phenotypes include hepatosplenomegaly, thrombocytopenia, and interstitial lung disease. Niemann-Pick disease type C (NPC) has a heterogeneous clinical presentation and includes systemic, neurologic, and psychiatric involvement. It usually affects adults but can occur during any phase of life. Early-onset NPC manifests as infantile jaundice, hepatosplenomegaly, or isolated splenomegaly, and usually, these symptoms precede neurological involvement. In about 50% of adult patients, NPC can manifest without or minimal hepatosplenomegaly, so the presence of isolated splenomegaly in patients with neurological or psychiatric illnesses favors NPC. Type E is a less common variant of NPD that develops in adulthood. The most common neurologic manifestations of NPD include cognitive or motor developmental delay in childhood-onset cases, vertical supranuclear gaze palsy, ataxia, dysarthria, dysphagia, and dystonia.