Clinical phenotype in carriers of intermediate alleles in the huntingtin gene

Abstract

ObjectiveTo describe the phenotype of individuals with intermediate allele (IA) CAG repeat length in the huntingtin (HTT) gene evaluated at the Parkinson's Disease Center and Movement Disorders Clinic (PDCMDC) at Baylor College of Medicine (BCM). BackgroundHuntington disease (HD) is caused by a mutation in the HTT gene of 36 or more CAG trinucleotide repeats. Since our original case report of pathologically proven HD with 29 CAG repeats, a growing body of evidence has accumulated supporting the observation that individuals with IA (27 to 35 CAG repeats) may exhibit clinical, imaging, and pathologic manifestations of HD. About 6% of the general population has CAG repeats in the IA range in at least one allele of the HTT gene. The presence of IA is a challenge for genetic counseling. MethodsMedical records of patients with IAs seen at the PDCMDC at BCM from January 2008 to the present were reviewed to assess age at symptom onset, dominant clinical features and presence of psychiatric and cognitive symptoms. ResultsFour men and five women were found to have IAs (range: 27–35) in the course of their evaluation at the PDCMDC. The age at onset of clinically evident symptoms ranged from 27 to 78 years. Six individuals had chorea, three had gait disturbance, two had stereotypies, and one patient had multiple motor tics. All nine had psychiatric symptoms, with depression being the most common. ConclusionOur series of 9 individuals with IA in the HTT gene exhibit a variety of motor and non-motor features that overlap with the HD phenotype. These individuals and their offspring should be considered at risk for development of progressive HD.