GM1 gangliosidosis, and Krabbe disease

A young Jewish couple brings in their 6-month-old baby to a pediatrician because they are concerned about the baby’s deteriorating movement. On physical exam, the pediatrician finds an exaggerated startle response, visual deterioration, macular cherry-red spots, and generalized muscle weakness, but no organomegaly or hearing impairment. A blood sample is taken and sent off to assess the activity of several enzymes. Which of the following enzymes is most likely to be defective in this patient?
Arylsulfatase A
B-glucocerebrosidase
Hexosaminidase A
Iduronidate sulfatase
Sphingomyelinase
Correct answer
Hexosaminidase A
Feedback
correct answer: C
Given the patient’s ethnicity (Ashkenazi Jews have greatest prevalence of disease), rapid onset of neurologic defects, and macular cherry-red spots, the most likely diagnosis is Tay-Sachs disease (GM2 gangliosidosis). Tay-Sachs results from a deficiency in hexosaminidase A that causes accumulation of GM2 gangliosides.
Niemann-Pick disease (type A most common) also presents with cherry-red spots, as well as severe hearing impairment/deafness and hepatosplenomegaly. Niemann-Pick disease results from a deficiency in sphingomyelinase that causes accumulation of sphingomyelin.

Cherry-red spots are also found in mucolipidosis type I, GM1 gangliosidosis, and Krabbe disease.

Metachromatic leukodystrophy typically presents early in life with progressive deterioration of motor and neurocognitive function-- specifically ataxia and dementia. It occurs due to deficiency of arylsulfatase A that results in accumulation of cerebroside sulfate.

Gaucher disease (Type I most common) typically presents with organomegaly, pancytopenia, and skeletal disease. It occurs due to deficiency of B-glucocerebrosidase that results in accumulation of glucocerebroside. It is also the most common lysosomal storage disease and prevalent in those of Ashkenazi Jewish descent.

Hunter syndrome is a mucopolysaccharidosis typically presents with organomegaly, dysostosis multiplex (defects in ossificiation), and neurocognitive degeneration with progressive mental retardation. It is caused by deficiency of iduronidate sulfatase that results in accumulation of mucopolysaccarides such as heparan sulfate and dermatan sulfate.