The neurology and natural history of patients with indeterminate CAG repeat length mutations of the Huntington disease gene.

OBJECTIVE

This study aims to understand the neurological manifestations of patients with an indeterminate CAG repeat length (36-39) of the Huntingtin gene, HTT.

METHODS

A longitudinal evaluation of 10 patients was performed. Duration of follow-up was mean=4.23 years (standard deviation 1.068; 95% CI 3.466-4.994; range 3-6.4 years). Three patients had a CAG repeat length of 37, three 38 and four 39. Mean CAG repeat length=38 (standard deviation 0.88; 95% CI 37.47-38.73; range 37-39). Data from clinical histories, neurological examinations, the United Huntington's Disease Rating Scale (UHDRS) and MRI imaging were collected.

RESULTS

Four patients developed facial chorea, ataxia, impaired tongue protrusion, abnormal saccades and intermittent eye pursuits, dysarthria and impaired Luria 3 hand test. Early in its natural history the neurological syndrome is dominated by perioral chorea, subtle cognitive deficits and mild ataxia. Three patients developed a formal diagnosis of HD within 5 years. The illness progression was variable and associated with different co-morbidities. MRI scans showed ventricular dilatation as a common finding. Scores from UHDRS, Total Functional Capacity (TFC) and mini-mental state examination (MMSE) suggested significant behavioural and functional impairment with compromised cognitive abilities. Two patients had subtle manifestations and four remained asymptomatic (3 patients CAG=37; 1 patient CAG=39).

CONCLUSIONS

This study documents the disease manifestations and natural history of people with CAG repeat lengths within the indeterminate range. The findings reveal heterogeneity in disease progression and have implications on the advice that should be given to patients and families on risk assessment and prognosis. Long-term follow up of such patients is essential as the neurological presentation of indeterminate CAG repeat length mutation might be accelerated by associated medical disorders and treatments, environmental and modifying genetic factors.