An 18-month-old boy is being evaluated for neurologic regression. He had a normal neonatal course and early development until age 5 months. The boy subsequently experienced gradual regression of developmental milestones, and now has inability to sit with support, poor head control, and loss of a social smile. Weight and height are below the 5^th percentile. Physical examination shows an enlarged liver and spleen, diminished deep tendon reflexes in all limbs, and hypotonia. Funduscopic findings are shown in the exhibit.

This patient most likely has an accumulation of which of the following substrates?

Question

An 18-month-old boy is being evaluated for neurologic regression. He had a normal neonatal course and early development until age 5 months. The boy subsequently experienced gradual regression of developmental milestones, and now has inability to sit with support, poor head control, and loss of a social smile. Weight and height are below the 5^th percentile. Physical examination shows an enlarged liver and spleen, diminished deep tendon reflexes in all limbs, and hypotonia. Funduscopic findings are shown in the exhibit.

This patient most likely has an accumulation of which of the following substrates?

Quizplus · Accepted Answer

11ec160b_36cd_c98c_9249_7b551ec7c60c_MD0001_00 Niemann-Pick disease is an autosomal recessive disorder common among Ashkenazi Jews and is characterized by sphingomyelinase deficiency. Sphingomyelinase is responsible for the breakdown of sphingomyelin, a lipid constituent of cell membranes. In Niemann-Pick disease, sphingomyelin accumulation within lysosomes results in cells that appear enlarged, foamy, and vacuolated on electron microscopy. These lipid-laden foam cells accumulate in the liver and spleen and cause hepatosplenomegaly. Progressive neuronal accumulation is responsible for hypotonia and neurologic degeneration (eg, failure to progress developmentally, loss of milestones). Retinal accumulation leads to a cherry-red macular spot. This patient is presenting with the classic infantile type A variant that results in hepatosplenomegaly, progressive neurologic deterioration, and death by age 3 years. (Choice A) In patients with metachromatic leukodystrophy, central nervous system accumulation of cerebroside sulfate is caused by arylsulfatase A deficiency. Central and peripheral demyelination leads to peripheral neuropathy and ataxia. (Choice B) In Krabbe disease, galactocerebrosidase deficiency causes accumulation of galactocerebroside and psychosine. Infants have developmental delay and/or regression, axial hypotonia, limb stiffness, optic atrophy, and seizures. (Choice C) In Fabry disease, ?-galactosidase A deficiency causes globotriaosylceramide (ceramide trihexoside) accumulation. Clinical manifestations begin in childhood with neuropathic pain and dermatologic pathology (eg, telangiectasias, angiokeratomas). (Choice D) Glucocerebroside accumulation occurs in Gaucher disease, an autosomal recessive disorder of ?-glucocerebrosidase deficiency. Patients typically have hepatosplenomegaly, pancytopenia, and skeletal problems. (Choice E) Patients with Tay-Sachs disease are deficient in ?-hexosaminidase A, which leads to GM2 accumulation in neurons. Neurologic regression and cherry-red macular spots are classic symptoms (similar to Niemann-Pick disease), but hepatosplenomegaly is absent. Educational objective: In Niemann-Pick disease, sphingomyelinase deficiency causes accumulation of the lipid sphingomyelin. Clinical features include hepatosplenomegaly, neurologic regression, and a cherry-red macular spot in infancy.

An 18-Month-Old Boy Is Being Evaluated for Neurologic Regression