Spinocerebellar Ataxia (SCA1/2/3) — AD with Anticipation MCQ — NEET PG Practice Question | NEETPGAI
Spinocerebellar Ataxia (SCA1/2/3) — AD with Anticipation
medium
stethoscope Medicine
A 35-year-old man presents with progressive cerebellar ataxia, dysarthria, and pyramidal signs. His father was diagnosed with spinocerebellar ataxia at age 50, and his paternal grandfather at age 65. Genetic testing confirms SCA1 caused by CAG repeat expansion in the ATXN1 gene. The pedigree pattern shown in the diagram at **A** demonstrates which cardinal feature that explains the progressively earlier age of onset across three generations?
A. Genetic heterogeneity with different SCA subtypes segregating independently in the family
B. Incomplete penetrance leading to skipped generations and variable disease expression
C. Anticipation due to CAG repeat instability during paternal meiosis, causing further expansion of trinucleotide repeats in successive generations
D. X-linked dominant inheritance with male-to-male transmission and carrier females
Explanation
Why Anticipation due to CAG repeat instability during paternal meiosis, causing further expansion of trinucleotide repeats in successive generations is right
The pattern shown at A — autosomal dominant with progressively earlier onset (grandfather age 65 → father age 50 → son age 35) — is the hallmark of anticipation, the cardinal feature of spinocerebellar ataxias 1, 2, and 3. These are polyglutamine neurodegenerative disorders caused by expanded CAG trinucleotide repeats in ATXN1 (SCA1), ATXN2 (SCA2), or ATXN3 (SCA3). Anticipation occurs because CAG tracts undergo repeat instability during gametogenesis, with paternal transmission causing more dramatic expansions than maternal transmission. Larger repeat numbers correlate with earlier onset and greater severity. This mechanism directly explains the three-generation pattern in the clinical scenario (Bird TD, GeneReviews; Klockgether T, Lancet Neurol 2018).
Why each distractor is wrong
Genetic heterogeneity with different SCA subtypes segregating independently in the family: While SCA is genetically heterogeneous (multiple subtypes exist), the question specifies SCA1 confirmed by genetic testing. Heterogeneity does not explain the consistent pattern of earlier onset within a single family lineage; anticipation does.
Incomplete penetrance leading to skipped generations and variable disease expression: Incomplete penetrance causes skipped generations (unaffected carriers), not progressively earlier onset in consecutive affected individuals. The pedigree shows continuous vertical transmission with worsening severity, not skipped generations.
X-linked dominant inheritance with male-to-male transmission and carrier females: The anchor explicitly states autosomal dominant with documented male-to-male transmission (father to son). X-linked inheritance cannot show male-to-male transmission. This is a classic distractor testing whether students confuse the inheritance pattern.
High-YieldNEET PG
Anticipation in SCA1/2/3 = CAG repeat expansion during paternal meiosis → earlier onset and increased severity in offspring; paternal transmission causes larger expansions than maternal.
