MEDizzy - A 6-month-old baby of Ashkenazi Jewish background is brought

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Child Psychiatry

A 6-month-old baby of Ashkenazi Jewish background is brought for evaluation of seizures. He has prominent startle response and developmental delay. He had reached some early developmental milestones but then began to regress. It is also noticed that he is macrocephalic and spastic, but there is no visceromegaly. A cherry-red spot is seen on ophthalmologic examination. There is suspicion for a GM2 gangliosidosis. Which of the following is correct regarding this patient’s condition?

ExplanationThe patient has a GM2 gangliosidosis, more specifically Tay–Sachs disease caused by hexosaminidase A deficiency. The patient in question 77 has another GM2 gangliosidosis, more specifically Sandhoff’s disease caused by deficiency of hexosaminidase A and B. β-Galactosidase deficiency causes GM1 but not GM2 gangliosidosis. Sphingomyelinase deficiency causes Niemann–Pick types A and B. GM2 gangliosidosis is caused by deficiency of hexosaminidase A in Tay–Sachs disease or hexosaminidase A and B in Sandhoff’s disease. These isoenzymes are made of subunits, with hexosaminidase A containing alpha–beta, and hexosaminidase B containing beta–beta. Mutations in the HEXA gene disrupt alpha subunits only, giving rise to Tay–Sachs disease, whereas HEXB mutations disrupt the beta subunit, resulting in deficiency of both hexosaminidases A and B. Both are rare autosomal recessive diseases, occurring in approximately 1:320,000 newborns in the United States’ general population. Tay–Sachs disease or infantile GM2 gangliosidosis is more common in Ashkenazi Jews, with heterogeneous carrier rates as high as 1:25 to 30 people, though carrier screening has reduced the incidence of Tay–Sachs disease in Ashkenazi populations by 90%. Other populations with higher incidence of Tay–Sachs disease include some French–Canadian families in Quebec, some Amish populations, and Cajun populations in Louisiana, though the disease may also occur in other populations with less frequency. In Tay–Sachs disease, the CNS is the only affected system, differentiating it from Sandhoff’s disease which affects both the CNS and the viscera, resulting in hepatosplenomegaly. Onset is between 3 and 6 months of age, with increased startle response and subsequent motor regression, spasticity, blindness with optic atrophy, and seizures. There is a delay in reaching developmental milestones, with subsequent developmental regression. A cherryred spot in the macula is commonly seen, and these patients have macrocephaly. Progression to severe intellectual disability occurs, and most children die by the age of 5 years. The diagnosis is suspected in patients with psychomotor retardation and a cherryred spot and is confirmed with the detection of hexosaminidase A deficiency with normal activity of hexosaminidase B. Targeted mutation analysis or gene sequencing of the HEXA gene to detect specific mutations may be helpful to identify asymptomatic carriers in the family and to differentiate between disease-causing mutations and so-called pseudodeficiency alleles that result in decreased hexosaminidase A activity in the laboratory but do not cause disease. Treatment of Tay–Sachs disease is supportive. Sandhoff’s disease occurs from combined deficiency of hexosaminidase A and B. The clinical features are similar to those seen in Tay–Sachs disease; however, as mentioned, in Tay–Sachs disease, the CNS is the only system involved, whereas in Sandhoff’s disease, the GM2 gangliosides accumulate in the brain and the viscera, causing hepatosplenomegaly. The diagnosis is based on these clinical features and confirmed with analysis of the enzymatic activity of the enzymes involved. Sandhoff’s disease rarely occurs in Ashkenazi Jewish populations.