An 8-month-old girl is brought to the office due to irritability and regression of motor skills. The patient's birth was unremarkable and her development had appeared normal, but she can no longer sit or roll over. Her parents have also noticed that she startles easily at loud noises. Head circumference measurement is consistent with macrocephaly. Bilateral funduscopic evaluation shows a bright red fovea centralis that is surrounded by a contrasting white macula. Peripheral vision is decreased. Abdominal examination is normal. Accumulation of which of the following metabolites is most likely present in this patient's tissues?
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This patient's loss of motor skills, excessive startle response, and ophthalmic findings are most likely due to Tay-Sachs disease, an autosomal recessive neurodegenerative disorder commonly seen in the Ashkenazi Jewish population. Tay-Sachs is caused by β-hexosaminidase A deficiency, which results in lysosomal accumulation of GM2 ganglioside, a glycolipid component of cell membranes.
Infants with Tay-Sachs disease typically develop normally for the first few months of life because the gradual build-up of ganglioside in neuronal lysosomes does not initially cause cellular dysfunction. However, by age 6 months the accumulation of glycolipids in the brain results in neuronal destruction. Subsequent neurologic degeneration typically manifests as developmental regression, as seen in this patient who is no longer able to sit or roll over.
Progressive destruction of neurons in the brain and spinal cord leads to macrocephaly, seizures, and spasticity; an exaggerated startle reflex with acoustic stimuli is the result of brainstem injury. Ganglioside accumulation also occurs in the retina but spares the fovea, which lacks ganglion cells. This leads to the characteristic funduscopic finding of a cherry-red macular spot, or a bright red unaffected fovea (which reflects the underlying choroid) that is accentuated due to surrounding opacification of the affected macula. Progressive neurodegeneration typically leads to death by age 2-5.
(Choice A) Krabbe disease (galactocerebroside accumulation) is a lysosomal storage disease that causes progressive neurodegeneration. However, affected infants have optic atrophy, which is visualized as optic nerve pallor rather than a bright red fovea.
(Choice B) Gaucher disease is a lysosomal storage disorder in which glucocerebroside accumulation results in bone pain, hepatosplenomegaly, and bone marrow suppression (eg, anemia, thrombocytopenia). This patient's normal abdominal examination and bright red fovea makes Gaucher disease unlikely.
(Choice D) Mucopolysaccharidoses (eg, Hurler syndrome, Hunter syndrome) are lysosomal storage disorders characterized by the build-up of glycosaminoglycans such as heparan and dermatan sulfate. Patients have neurocognitive decline, but coarse facial features and hepatosplenomegaly are also expected. Although Hurler syndrome is associated with corneal clouding, neither mucopolysaccharidosis causes a cherry-red macula.
(Choice E) Neurodegeneration and a cherry-red macular spot occur in Niemann-Pick disease, which is characterized by sphingomyelin accumulation. However, hepatosplenomegaly would be present and is not seen here.
Educational objective:
Tay-Sachs disease is an autosomal recessive disorder caused by β-hexosaminidase A deficiency, which results in GM2 ganglioside accumulation in neuronal lysosomes. Key clinical features include progressive neurodegeneration (eg, developmental regression), an exaggerated startle reflex, and a cherry-red macular spot.