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USMLE® Step 1 Question of the Day: Hypotonia

Osmosis Team
Published on Apr 15, 2024. Updated on Apr 15, 2024.

Learn about Tay-Sachs disease, an autosomal recessive neurodegenerative disorder characterized by regression of motor milestones, seizures, and a distinctive cherry-red macula.

An 8-month-old girl is brought to the emergency department with a seizure-like episode. The parents state the patient started contracting her upper and lower extremities for 30 seconds. Her mother has noticed she has been having difficulty feeding over the past several weeks due to an inability to suckle. Her parents state she was able to sit up on her own without support until a month ago, when they noticed that she could no longer sit up or roll over. Her birth was unremarkable. Temperature is 36.4°C (97.5°F), pulse is 135/min and blood pressure is 94/84.  Motor examination reveals hypotonia in all 4 limbs, as well as increased intensity of deep tendon reflexes in all extremities. Abdominal examination is unremarkable. Bilateral fundoscopic examination reveals a bright reddish area at the center of macula surrounded by retinal opacification. Which of the following is the most likely diagnosis in this patient? 

A. Tay-Sachs disease

B. Fabry disease

C. Hunter syndrome 

D. Niemann-Pick disease 

E. Metachromatic leukodystrophy

Scroll down for the correct answer!

The correct answer to today's USMLE® Step 1 Question is...

A. Tay-Sachs disease

Before we get to the Main Explanation, let's look at the incorrect answer explanations. Skip to the bottom if you want to see the correct answer right away!

Incorrect answer explanations

B. Fabry disease

Incorrect: Fabry disease results from the accumulation of ceramide trihexoside due to deficiency of the enzyme alpha-galactosidase. It is characterized by peripheral neuropathy and dermatological manifestations like angiokeratomas and hypohidrosis. Developmental delay and seizures are not likely. 

C. Hunter syndrome  

Incorrect: Hunter syndrome does present with developmental delay. However, abdominal examination will reveal hepatosplenomegaly and abdominal defects. It results from the accumulation of heparan sulfate due to a deficiency in the enzyme iduronate-2-sulfatase.

D. Niemann-Pick disease  

Incorrect: The presentation of Niemann-Pick disease and Tay-Sachs disease is very similar (e.g., hypotonia, cherry-red macula), although there are a few key differentiating factors. Niemann-Pick is characterized by hepatosplenomegaly (which is not seen in Tay-Sachs), as well as hyporeflexia (in contrast to hyperreflexia that is seen in Tay-Sachs). Niemann-Pick disease results from the deficient functioning of the enzyme sphingomyelinase.  

E. Metachromatic leukodystrophy

Incorrect: Metachromatic dystrophy is a central and peripheral demyelinating disease resulting in ataxia and dementia. It is caused by a deficiency of the enzyme arylsulfatase, resulting in accumulation of the enzyme cerebroside sulfate.  

Main Explanation

The patient described in the clinical vignette with regression of motor milestones, hypotonia, hyperreflexia, and a cherry-red macula on eye examination has features that are suggestive of Tay-Sachs disease.  

Tay-Sachs disease (TSD) is a lysosomal storage disorder that is inherited in an autosomal recessive pattern. Genetic testing (DNA sequencing) should be offered if either partner has a family history of Tay-Sachs disease or are members of susceptible populations, such as Ashkanazi Jews, Cajun and Amish populations.  

tay-sachs disease, lysosomal storage disorder

TSD is a neurodegenerative disease that results from the deficient functioning of the enzyme hexosaminidase that leads to the accumulation of the metabolic product GM2 ganglioside within cell lysosomes. Neuronal cells are particularly susceptible to GM2 ganglioside, and most clinical findings stem from the accumulation of this storage material. On histologic examination, neurons are ballooned with cytoplasmic vacuoles, which constitute distended lysosomes with ganglioside. On electron microscopy, the most prominent feature seen is a whorled configuration within lysosomes resembling “onion-skin layers.” 

TSD exists in two clinical phenotypes; the classic, infantile form and the late onset form. In the infantile form, most children born with TSD have normal motor development in the first couple of months of life. Then, in the first 3-5 months, they begin to demonstrate regression of milestones that they previously attained.  Physical examination findings include macrocephaly, hypotonia, hyperreflexia, blindness and spasticity. One of the characteristic fundoscopy findings include a cherry-red spot at the macula. Mental deterioration and motor dysfunction is progressive and offers a poor prognosis. Complications include seizures, pneumonia and issues with feeding. Most patients suffering from the infantile form of Tay Sachs have a life expectancy of 2-5 years of age.  

In the late onset form, symptoms are less progressive and may become evident anytime between adolescence and mid-to-late 30’s.  

tay-sachs disease symptoms

Diagnosis is made with estimation of hexosaminidase activity in leukocytes, serum and other body fluids. Management is predominantly directed towards supportive care. There is no known treatment currently.  

lysosomal storage disorders

Major Takeaway

Tay-Sachs disease is an autosomal recessive neurodegenerative disease that occurs due to deficiency of the enzyme hexosaminidase and the accumulation of substrates including GM2 gangliosides in lysosomes. Clinical manifestations include neurodegeneration (regression of attained milestones), seizures, and a cherry-red spot in the macula. 


Kaback M, Lim-Steele J, Dabholkar D, Brown D, Levy N, Zeiger K. Tay-Sachs disease--carrier screening, prenatal diagnosis, and the molecular era. An international perspective, 1970 to 1993. The International TSD Data Collection Network. JAMA. 1993;270(19):2307-2315. 

Bach G, Tomczak J, Risch N, Ekstein J. Tay-Sachs screening in the Jewish Ashkenazi population: DNA testing is the preferred procedure. Am J Med Genet. 2001;99(1):70-75. doi:10.1002/1096-8628(20010215)99:1<70::aid-ajmg1120>;2-0 


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