Review Question - QID 105416

The patient has Niemann-Pick disease, a lysosomal storage disease characterized by a deficiency of sphingomyelinase. Splenomegaly is typical of Niemann-Pick disease.

Niemann-Pick results from a deficiency in the lysosomal enzyme sphingomyelinase, whereby sphingomyelin accumulates in reticuloendothelial and parenchymal cells. The disease presents with failure to thrive and neurologic symptoms from demyelination including hypotonia. Niemann-Pick type A is fatal in infancy while type B is a non-neuronopathic form seen in adults. Inheritance is autosomal recessive. Both Tay-Sachs disease and Niemann-Pick are well-known for its "cherry-red" macular spots seen on ophthalmologic exam, however Tay-Sach does not present with hepatosplenomegaly or cervical lymphadenopathy.

Wraith discusses the presentation of the lysosomal storage disorders: "Lysosomal storage disorders (LSDs) are present from conception and produce a clinical phenotype that evolves with time. The introduction of new therapies has made early diagnosis a priority. Loss of a previously acquired skill (regression) is very characteristic of this group of disorders."

Vazquez et al. present a pathophysiologic mechanism for the damage seen in Niemann-Pick disease type C: "Recent evidence strongly suggests that mitochondrial dysfunction plays an important role in NPC pathogenesis and that mitochondria could be a significant source of oxidative stress in this disease. In this context, the accumulation of vitamin E in the late endosomal/lysosomal compartments in NPC could lead to a potential decrease of its bioavailability and could be another possible cause of oxidative damage."

Illustration A shows the "cherry-red macula" classically seen on fundoscopic exam in patients with Niemann-Pick disease and Tay-Sachs disease due to accumulation of lipids in the retina.

Incorrect answers:
Answer 2: Macrophages with a "tissue paper" appearance are characteristic of Gaucher's disease, a deficiency of beta-glucosidase.
Answer 3: A normal spleen and accumulation of GM2 ganglioside are seen in Tay-Sachs disease, a deficiency of hexosaminidase A.
Answer 4-5: Angiokeratomas are seen in Fabry's disease, an X-linked recessive deficiency of alpha-galactosidase A (also known as ceramide trihexosidase).
(Note: Do not confuse Fabry's disease with Farber's disease (a deficiency of ceramidase) that presents at age 1 with granulomatous nodules on joints and vocal cords.)