Genetics of Niemann-Pick Disease 

Niemann-Pick disease (NPD) is a lipid storage disorder that results from the deficiency of a lysosomal enzyme, acid sphingomyelinase. The original description of Niemann-Pick disease referred to what is currently termed Niemann-Pick disease type A, which is a fatal disorder of early childhood characterized by failure to thrive, hepatosplenomegaly, and a rapidly progressive neurodegenerative course that leads to death by age 2-3 years.

Since this original description, other forms of Niemann-Pick disease have been described. Niemann-Pick type B is a milder, nonneuronopathic form with later onset and longer survival, sometimes into adulthood. Niemann-Pick type C, a rarer form that results from defects in cholesterol metabolism, is discussed elsewhere (see Lipid Storage Disorders). Both Niemann-Pick disease types A and B are inherited as autosomal recessive traits.

Niemann-Pick disease types A and B result from the deficient activity of sphingomyelinase, a lysosomal enzyme encoded by the SMPD1 gene located on chromosome bands 11p15.1-p15.4.^{[1, 2]} The enzymatic defect results in pathologic accumulation of sphingomyelin (which is a ceramide phospholipid) and other lipids in the monocyte-macrophage system, the primary site of pathology in patients with Niemann-Pick disease. Additional progressive deposition of sphingomyelin in the CNS results in the neurodegenerative course observed in type A, which shares systemic disease manifestations with type B. Severity of systemic involvement varies in affected individuals. Systemic involvement includes progressive lung disease, hepatosplenomegaly, short stature, and pancytopenia.^[3]

Individuals with Niemann-Pick disease types A and B typically have less than 10% residual acid sphingomyelinase enzyme activity. The complete sphingomyelinase genomic region has been isolated and sequenced. Three common mutations (L302P, 1bp del fsP330, R496L) account for approximately 90% of Niemann-Pock disease type A alleles in the Ashkenazi Jewish population. The deltaR608 mutation is a common mutation that causes Niemann-Pick disease type B.

Frequency

International

Niemann-Pick disease is a rare disorder that occurs in all races,^{[4, 5]} although Niemann-Pick disease type A is more common in persons of Ashkenazi Jewish descent.

Mortality/Morbidity

Patients with Niemann-Pick type A develop progressive failure to thrive, sphingomyelin accumulation, liver dysfunction, and neurodegeration beginning at age 6 months and ending with death by age 3 years. Patients with Niemann-Pick type B develop extensive involvement of the spleen, liver and lungs, but remain free of neurological manifestations; these patients often survive into adulthood.

Race

Niemann-Pick disease types A and B occur in all races, although type A disease occurs more frequently in individuals of Ashkenazi Jewish descent, in whom the carrier frequency is approximately 1 in 80. Guidelines for carrier screening in individuals of Ashkenazi Jewish descent have been established.^[6] Niemann-Pick disease type B occurs worldwide but has a higher frequency in the Maghreb region of North Africa and Saudi Arabia and in individuals of Turkish descent.^[7]

Sex

Niemann-Pick disease types A and B are autosomal recessive disorders, equally affecting males and females.

Age

Patients with Niemann-Pick Type A disease develop symptoms as early as age 6 months and die by age 3 years. In contrast, patients with type B disease survive to adulthood, although most present in childhood with hepatosplenomegaly.