Educational corner of the issuePart I: Educational caseA 3.5-year-old boy, the second in order of birth of first cousin parents presented to the genetics clinic for counseling. The patient had normal development till the age of 2 years then he started to have abnormal ataxic gait with frequent falls. At the age of 2.5 years, he started to lose previously acquired cognitive skills and speech and to develop convulsions. Neurological examination showed hypotonia and increased deep tendon reflexes. The patient had a sister and a paternal cousin with the same clinical picture who both died at the age of 5 and 6 years. MRI brain showed brain atrophy. Fundus examination showed cherry-red spot (Fig. 1). The mother is 10 weeks pregnant and asks about prenatal diagnosis.Download full-size imageFigure 1. Cherry-red spot in Tay-Sachs disease. The right frame shows normal retina. The circle surrounds the macula, lateral to the optic nerve. The left frame shows the macula of a child with Tay-Sachs disease. The cherry-red center is the normal retina of the fovea at the center of the macula [1].Q1: What is the most probable diagnosis?The most probable diagnosis is Tay Sachs disease which is a neurodegenerative disorder caused by intralysosomal storage of the specific glycosphingolipid GM2 ganglioside. Common clinical findings include progressive weakness and loss of motor and cognitive skills, decreased attentiveness and an increased startle response. The typical findings on physical examination are generalized muscular hypotonia, ankle clonus, hyperreflexia and normal-sized liver and spleen. This is followed by signs of progressive neurodegeneration, seizures, blindness, and spasticity. A cherry-red spot of the fovea centralis of the macula of the retina is usually found on fundus examination [1].Our patient has the juvenile (subacute) form. The disease often begins between the age of 2 and 10 years by loss of previously acquired skills and speech followed by spasticity and seizures. Loss of vision occurs much later than in the acute infantile form of the disease, and a cherry-red spot – in contrary to our case – is not consistently observed. Instead, optic atrophy and retinitis pigmentosa may be seen late in the course. A vegetative state with decerebrate rigidity develops by age 10–15 years, followed within few years by death, usually from infection. In some cases, the disease pursues a particularly aggressive course, culminating in death in 2–4 years [2].Q2: Are there other phenotypes of the disease?Other phenotypes include [1]:?Acute infantile (Tay-Sachs disease) with rapid progression and death before age 4 years.?Chronic and adult-onset Tay Sachs disease with long-term survival. Affected individuals have several different phenotypes, including progressive dystonia, spinocerebellar degeneration, motor neuron disease with muscle weakness and fasciculations, and/or psychosis.?Activator deficient Tay sachs disease: it is a rare infantile form (phenotype identical to classic disease) where the enzymatic activity of both hexosaminidase A (HEX A) and hexosaminidase B (HEX B) are normal, but GM2 ganglioside accumulation occurs because of a deficit of the intralysosomal glycoprotein (GM2 activator) that is required for the degradation of GM2 ganglioside, Fig. 2.Download full-size imageFigure 2. The three-gene system required for hexosaminidase A activity and the diseases that result from defects in each of the genes. The function of the activator protein is to bind the ganglioside substrate and present it to the enzyme. NANA, N-acetyl neuraminic acid [2].Q3: Are there other diseases characterized by the presence of cherry-red spot?Cherry-red spot can be found in other neurodegenerative diseases like GM1 gangliosidosis, Galactosialidosis, Metachromatic leukodystrophy, Niemann-Pick disease type A and Sandhoff disease.Q4: What is the differential diagnosis of this case?Differential diagnosis will include other diseases with neurologic regression like Krabbe’s disease, metachromatic leukodystrophy, Canavan disease, infantile Gaucher disease, and the neuronal ceroid-lipofuscinosis.Q5: How can you confirm your diagnosis?Diagnosis of Tay Sachs disease can be confirmed by assay of HEX A enzymatic activity. It relies upon the demonstration of absent to near-absent HEX A enzymatic activity in the serum, white blood cells, or other tissues from a symptomatic individual in presence of normal or elevated activity of the HEX B [3].Q6: How can you perform population screening for Tay Sachs disease?HEX A enzymatic activity is the primary method of population screening for carrier detection given its greater sensitivity compared to targeted mutation analysis. However, in the Ashkenazi Jewish population, some have gone directly to targeted mutation analysis (even though the sensitivity of this approach is lower) because there are three mutations accounting for 99% of mutations detected in this population. The commonest is 4-bp insertion (exo
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