Which of the following is the correct statement regarding Huntington’s chorea?

Correct Answer: A. It is a trinucleotide repeat disorder

Huntington's disease (Huntington's chorea) is a trinucleotide repeat disorder caused by expansion of CAG repeats (not CUG) in the huntingtin gene located on chromosome 4 (not chromosome 6). The disease demonstrates anticipation, particularly paternal anticipation, where repeat length increases across generations. Normal individuals have 10–35 CAG repeats; affected individuals have >40 repeats. The expanded repeats encode an abnormal huntingtin protein with a polyglutamine tract that accumulates in neurons, particularly in the striatum, causing selective neuronal death. This is a gain-of-function mutation (not loss-of-function), as the mutant protein acquires toxic properties through abnormal folding, aggregation, and impaired protein degradation. The pathology involves preferential loss of GABAergic medium spiny neurons in the caudate and putamen, leading to the characteristic movement disorder (chorea), cognitive decline, and psychiatric manifestations typically appearing in the 4th–5th decade. The trinucleotide repeat mechanism is the defining molecular feature that distinguishes Huntington's from other neurodegenerative diseases and is the basis for genetic testing and counseling in Indian clinical practice.

Why the other options are wrong

B. Abnormality is seen due to mutation in chromosome 6 — This is wrong because the huntingtin gene is located on chromosome 4, not chromosome 6. Chromosome 6 is associated with other genetic disorders (e.g., HLA-linked conditions, some forms of spinocerebellar ataxia). This is a classic NBE trap that tests knowledge of chromosomal localization of disease genes. Students who confuse chromosomal locations often fall for this distractor. C. There are abnormal repeats of CUG — This is wrong because Huntington's disease involves CAG repeats, not CUG repeats. CUG repeats are characteristic of myotonic dystrophy (DM1), another trinucleotide repeat disorder. This is a deliberate NBE trap that tests whether students can distinguish between different trinucleotide repeat disorders. Confusing CAG with CUG is a common error among students who memorize disorders without understanding the specific molecular basis. D. There is a loss of function type of mutation — This is wrong because Huntington's disease results from a gain-of-function mutation, not loss-of-function. The mutant huntingtin protein with expanded polyglutamine repeats acquires toxic properties—it misfolds, aggregates, and impairs cellular protein degradation and transcription. Loss-of-function mutations typically cause haploinsufficiency or absence of protein function, which is not the mechanism in Huntington's. This trap tests understanding of mutation mechanisms in neurodegeneration.

High-Yield Facts

Mnemonics

Trinucleotide Repeat Disorders – 'CAG-CTG-GAA' CAG = Chorea (Huntington's on chromosome 4); CTG = myoTonic dystrophy; GAA = Friedreich's Ataxia. Use this to anchor the specific repeats to each disorder. Huntington's Pathology – 'CHAMP' Chorea, Hyperkinesia, Anticipation, Middle-age onset, Polyglutamine toxicity. Covers clinical + molecular features.

NBE Trap

NBE pairs "trinucleotide repeat" with incorrect chromosomal location (chromosome 6) and wrong repeat type (CUG instead of CAG) to test whether students truly understand the molecular basis of Huntington's or merely recognize it as a "repeat disorder" superficially. The gain-of-function vs. loss-of-function distractor tests mechanistic understanding beyond simple classification.

Clinical Pearl

In Indian clinical practice, Huntington's disease is rare but increasingly recognized with improved neuroimaging and genetic testing availability. Family screening and genetic counseling are critical—affected families often present with multiple members showing chorea and cognitive decline across generations. Presymptomatic genetic testing in at-risk relatives is now standard of care in tertiary centers, allowing early intervention and family planning decisions.

_Reference: Robbins & Cotran Pathologic Basis of Disease, Ch. 28 (Central Nervous System); Harrison's Principles of Internal Medicine, Ch. 452 (Huntington's Disease and Other Trinucleotide Repeat Disorders)_