Clinical Scenario:
A 2-year-old boy is brought with progressive developmental regression that began at 15 months of age. He initially developed normally but subsequently lost acquired motor and language skills. Examination reveals generalized hypotonia, hepatosplenomegaly, and a cherry-red spot on fundoscopy. He also has an exaggerated startle response to sudden sounds. Which of the following is the most likely diagnosis?
A. Tay-Sachs disease
B. Niemann-Pick disease type A
C. Krabbe disease
D. Metachromatic leukodystrophy
E. Rett syndrome
Correct answer & Explanation:
Correct answer: B
Explanation:
Niemann-Pick disease type A is an autosomal recessive lysosomal storage disorder caused by deficiency of acid sphingomyelinase, resulting in the accumulation of sphingomyelin within macrophages and other cells.
The characteristic clinical features in this child are:
Progressive developmental regression: Initially normal development followed by loss of acquired motor and language skills due to progressive neurodegeneration.
Hepatosplenomegaly: Accumulation of sphingomyelin in the reticuloendothelial system causes enlargement of the liver and spleen.
Cherry-red spot: Lipid accumulation in retinal ganglion cells produces a pale surrounding retina with a relatively preserved red fovea.
Generalized hypotonia: Progressive neurological involvement leads to worsening muscle tone and motor function.
Niemann-Pick disease type A typically presents in infancy and has a rapidly progressive course, with severe neurological deterioration and death usually by 2–3 years of age.
Why the other options are incorrect
A. Tay-Sachs disease: Causes developmental regression, hypotonia, a cherry-red spot, and an exaggerated startle response. However, significant hepatosplenomegaly is not typical of classic Tay-Sachs disease.
C. Krabbe disease: Causes progressive neurological deterioration, irritability, hypotonia, and later spasticity. A cherry-red spot and prominent hepatosplenomegaly are not characteristic.
D. Metachromatic leukodystrophy: Causes progressive motor and cognitive regression, hypotonia, and white-matter disease. Hepatosplenomegaly and a cherry-red spot are not typical findings.
E. Rett syndrome: Usually affects girls and is associated with developmental regression, loss of purposeful hand movements, and stereotypic hand movements. Hepatosplenomegaly and a cherry-red spot are not characteristic.
Clinical pearl
Developmental regression + hepatosplenomegaly + cherry-red spot = Niemann-Pick disease type A should be strongly suspected.
An exaggerated startle response is classically associated with Tay-Sachs disease, but the presence of marked hepatosplenomegaly in this stem favors Niemann-Pick disease type A.
Reference
Wasserstein MP, Schuchman EH. Acid Sphingomyelinase Deficiency. 2006 Dec 7 [Updated 2023 Apr 27]. In: Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2026.
Full reference: GeneReviews® — Acid Sphingomyelinase Deficiency
You can also practice another MCQ on Ataxia.
