Analysis of the Behavioral Features Conferred by the Intermediate Allele for Huntington Disease in the Prospective Huntington at Risk Observational Study (PHAROS) (PL01.003)

Objective: To explore the behavioral phenotype of individuals with an intermediate CAGn expansion in a cohort of subjects at-risk for Huntington disease (HD). Background Recent reports suggest that some individuals with intermediate CAGn repeat expansions in the huntingtin gene develop manifest HD (Mov Disord 2007;22:127). We previously demonstrated that PHAROS participants with the intermediate alleles had behavioral scores on the Unified Huntington Disease Rating Scale 999 (UHDRS 999) similar to gene expanded participants. We now further explore the behavioral features associated with the intermediate CAGn expansion. Design/Methods: Subjects at-risk for HD in the Prospective Huntington At Risk Observational Study (PHAROS) were assessed in all domains of the UHDRS by investigators unaware of participant gene status. Data were analyzed according to CAG repeat length: expanded > 36, intermediate = 27- 35, and non-expanded 39). Pair-wise analyses compared individual behavioral items of the UHDRS. Results: Of the 983 participants analyzed, 50 (5.2%) had an intermediate repeat expansion, 346 (35.1%) were expanded, and 587 (59.7%) were non-expanded. Like those with an expanded allele, participants with an intermediate expansion scored high on the UHDRS measure of apathy.Low self esteem/guilt and irritability were also increased in the intermediate repeat group, and approached the gene expanded group in this regard. Conclusions: In a cohort of individuals at-risk for HD, those with an intermediate CAGn expansion were motorically, cognitively and functionally similar to those without the gene expansion. However, they exhibited apathy and a tendency towards other behavioral abnormalities comparable to the gene expanded group. Though traditionally considered non-pathologic, the intermediate repeat length may manifest as a distinctly behavioral phenotype. Future studies in larger populations of individuals with intermediate CAGn expansions are needed to confirm these findings. Supported by: Huntington Study Group. Disclosure: Dr. Killoran has nothing to disclose. Dr. Biglan has received personal compensation for activities with Lundbeck and Theravance Inc as a consultant. Dr. Biglan received research support from Presbyterian Home of Central New York, Susquehana Nursing and Rehabilitation Center, Marvell Inc, and Google. Dr. Jankovic has received personal compensation for activities with Allergan, Inc., Chelsea Therapeutics, Serono Inc., Merz Pharma, Lundbeck Research USA, Inc, Teva Neuroscience as a consultant. Dr. Jankovic has received personal compensation in an editorial capacity for Medlink: Neurology in Clinical Practice. Dr. Jankovic has received research support from Allergan, Inc, Allon Therapeutics, Ceregene, Inc., Chelsea Therapeutics; Diana Helis Henry Medical Research Foundation, Serono Inc., Huntington9s Disease Society of America, Huntington Study Group, Impax Pharmaceuticals, Ipsen Limited, Lundbeck Research USA, Inc. Dr. Eberly has nothing to disclose. Dr. Kayson has nothing to disclose. Dr. Oakes has received personal compensation in an editorial capacity for the journal "Lifetime Data Analysis". Dr. Young has received royalty payments from Novartis. Dr. Young has received research support from Novartis. Dr. Shoulson has received personal compensation for activities with AstraZeneca, Keryx Pharmaceuticals, Jazz Pharmaceuticals, Neurogen Corp, Alexa Molecular Delivery Corp, Nouvel Pharma, Novartis, and Westat. Dr. Shoulson has received personal compensation in an editorial capacity for Archives of Neurology. Dr. Shoulson has received research support from NIH, NHGRI, NINDS, Cephalon, Inc., Pharmacia and Upjohn, Inc. (Pfizer), Parallel Group, and Prestwick Pharmaceuticals, Inc.