Huntington's Disease with Small CAG Repeat Expansions

Area of Science:

• Genetics
• Neuroscience
• Neurology

Background:

• Small cytosine-adenine-guanine (CAG) repeat expansions (36-38) in the HTT gene are traditionally linked to milder Huntington's disease (HD).
• The clinical presentation and detailed phenotype of these individuals remain understudied.
• Understanding their profile is crucial for accurate diagnosis and genetic counseling.

Purpose of the Study:

• To investigate the clinical and neuropsychological phenotype of individuals carrying CAG36-38 repeat expansions in the HTT gene.
• To compare the characteristics of CAG36-38 carriers with those of CAG40-42 carriers.
• To elucidate factors contributing to diagnostic delays in this subgroup.

Main Methods:

• Inclusion of 35 patients and premanifest carriers with CAG36-38 repeats.
• Comparative analysis of clinical and neuropsychological data between 11 CAG36-38 patients and 11 matched CAG40-42 patients.
• Utilizing data from 243 CAG36-38 individuals from the ENROLL study for comprehensive phenotype description.

Main Results:

• Similar global cognitive efficiency and subdomain performance were observed between CAG36-38 and CAG40-42 carriers.
• Chorea was a significantly less frequent initial symptom in CAG36-38 patients, despite comparable motor scores at initial assessment.
• CAG36-38 carriers exhibited significantly lower total motor scores at the last visit.
• Clinicians showed reduced confidence in diagnosing HD in CAG36-38 carriers, leading to significantly later diagnoses despite similar ages at symptom onset.
• Confirmation of similar cognitive and distinct motor profiles in larger cohorts (CAG36-38: n=243; CAG40-42: n=4675) from the ENROLL database.

Conclusions:

• Small CAG36-38 expansions in the HTT gene are associated with a cognitive profile similar to, but a distinct motor profile from, more common CAG40-42 expansions.
• Absence of chorea, rather than low symptom penetrance, may contribute to delayed molecular diagnosis in CAG36-38 carriers.
• Neurologists should consider HD in elderly patients with cognitive impairment but without typical chorea, with implications for genetic counseling of offspring.