A 6-month-old boy is brought to the pediatrician by his parents for a routine visit. His parents report that he is feeding and stooling well and they have just started experimenting with solid foods. His parents are concerned because a few weeks ago he started rolling from back to front in addition to front to back, but he now struggles when placed on his back. The patient was noted to be developmentally appropriate for his age at his last visit 2 months ago. On physical exam, the patient seems well-nourished and has no dysmorphic features. His temperature is 98.6°F (37°C), blood pressure is 77/49 mmHg, pulse is 112/min, and respirations are 24/min. In the examination room, he is able to roll from front to back but cannot roll from back to front. He is not able to sit without support and makes no attempt at bouncing when supported in a standing position. The patient’s abdomen is non-tender and soft without hepatosplenomegaly. His patellar reflexes are 4+ bilaterally. He is found to have the ocular finding seen in Figure A. Accumulation of which of the following would most likely be found in this patient’s cells?
Sphingomyelin
Glucocerebroside
GM2-ganglioside
Galactocerebroside
GM2-ganglioside
This 6-month-old boy who presents with developmental regression, a “cherry-red” macula, and hyperreflexia most likely has a diagnosis of Tay-Sachs disease. Tay-Sachs disease is caused by a deficiency of beta-hexosaminidase A that results in the accumulation of GM2-ganglioside.

Tay-Sachs disease is a genetic disorder caused by an autosomal recessive deficiency of the beta-hexosaminidase A enzyme. This disease presents in infants aged 2-6 months with progressive neurodegeneration, hypotonia, feeding difficulties, and a “cherry red” spot on the macula. Tay-Sachs disease shares many features with Niemann-Pick disease; however, Niemann-Pick disease presents with the additional findings of hepatosplenomegaly and hyporeflexia whereas Tay-Sachs presents with hyperreflexia without hepatosplenomegaly. Both diseases are more common in the Ashkenazi Jewish population. There is no curative treatment for this disease so treatment is generally supportive.

Solovyeva et al. review the evidence regarding the diagnosis and treatment of Tay-Sachs disease. They discuss how this disease normally presents with muscle weakness, ataxia, speech, and mental disorders. They recommend considering novel treatments such as substrate reduction therapy.

Figure/Illustration A is a fundoscopic exam demonstrating a “cherry-red” spot on the macula (blue circle). This finding is seen in both Tay-Sachs disease and Niemann-Pick disease.

Incorrect Answers:
Answer A: Cerebroside sulfate accumulates in metachromic leukodystrophy, which is caused by an autosomal recessive deficiency in arylsufatase A. This disease presents with optic atrophy and seizures in childhood. Patients will later develop dementia, psychiatric disease, and neuropathy. There is no cure so treatment is supportive.

Answer B: Galactocerebroside accumulates in Krabbe disease, which is caused by an autosomal recessive deficiency in galactocerebrosidase. Krabbe disease presents in early infancy with developmental regression, hypotonia, and areflexia. Treatment is supportive with musculoskeletal bracing as needed.

Answer C: Glucocerebroside accumulates in Gaucher disease, which is caused by an autosomal recessive deficiency in glucocerebrosidase. Gaucher disease presents with pancytopenia and hepatosplenomegaly. “Gaucher cells,” or lipid-laden macrophages resembling crumpled tissue paper, can be seen on histology. Treatment is with enzyme replacement therapy.

Answer E: Sphingomyelin accumulates in Niemann-Pick disease, an autosomal recessive sphingolipidosis caused by a deficiency in sphingomyelinase. Niemann-Pick disease presents with many of the same features as Tay-Sachs disease but has additional findings of hyporeflexia and hepatosplenomegaly.

Bullet Summary:
Tay-Sachs disease is caused by a deficiency of beta-hexosaminidase A resulting in the accumulation of GM2-ganglioside.