Niemann-Pick disease type A

Niemann-Pick disease type A (NPD-A) is a severe pathology, with an autosomal recessive inheritance pattern and very rare. Its prevalence is less than 1 case per 1,000,000 people. NPD-A causes an accumulation of certain lipids in lysosomes due to defects in the SMPD1 gene.

Niemann-Pick disease type A and type B (less severe) are caused by pathogenic variants in the SMPD1 gene that produces the lysosomal enzyme sphingomyelin phosphodiesterase 1 or acid sphingomyelinase (ASM). This enzyme is essential for the breakdown of sphingomyelin into ceramide and certain mutations in this gene can reduce the activity of the enzyme causing an accumulation of ceramide in the lysosomes. Some cells with sphingomyelin accumulations become enlarged, especially in the liver, spleen, lungs and brain, where they cause tissue damage and inflammation.

NPD is classified into four subtypes:

• NPD type A is the most severe and results in very low sphingomyelinase activity. It affects younger children and causes neurological deficits and growth disturbances. Patients present with hepatosplenomegaly (enlarged liver and spleen), recurrent lung infections and thrombocytopenia or reduced platelet counts. Typical neurological symptoms of early onset Niemann-Pick disease include vertical supranuclear gaze palsy, ataxia or loss of muscle coordination, slurred speech, difficulty swallowing, and involuntary muscle twitching.
• NPD type B is less severe and may produce hepatosplenomegaly, thrombocytopenia and interstitial lung disease. Neurological involvement is minimal.
• NPD type C has a heterogeneous clinical presentation and includes systemic, neurological and psychiatric involvement. It usually manifests in adulthood, but may appear earlier. Unlike NPD-A and NPD-B, it is caused by pathogenic variants in the NPC1 gene.
• NPD type E is the least common and develops in adults.

There is no cure for NPD-A and most of these children do not survive beyond the third year of life. Management of these patients focuses on symptom relief.