Multiple Genetic Variations of Huntington's Disease Identified

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Multiple Genetic Variations of Huntington's Disease Identified
Multiple Genetic Variations of Huntington's Disease Identified

An array of various phenocopies with multiple etiologies that are not associated with the main chromosomal mutation responsible for Huntington's disease (HD) can also produce HD symptoms, according to a study reported in JAMA Neurology.1

The primary cause of HD is a trinucleotide repeat expansion of the HTT gene in excess of 35 units, although a large number of other genes have also been suspected to contribute.2 To investigate these possible variants, the investigators performed a genetic evaluation of 226 patients referred to the French National Huntington Disease Reference Centre For Rare Diseases who had been identified as having HD phenotypes. The CAG repeat HTT expansion considered pathologic of HD was confirmed in 198 patients, and was absent in the remaining 28 patients who were classified as having HD-like (HDL) disease.

Louise-Laure Mariani, MD, of the Assistance Publique–Hôpitaux de Paris, Pitié-Salpêtrière University Hospital in Paris, France, and colleagues used a combination of clinical and genetic approaches to identify responsible genes from a panel of 63 potential candidate phenocopies, which were then matched to 10 of the 28 patients (35.7%) with HDL. Eight of those had family histories consistent with HD, including a combination of movement disorders and psychological symptoms. Cognitive patterns were similar across all variants, with more pronounced subcortical dementia in the HD-HTT group compared to the others.

HDL Variants

Patients were screened for known causes of HD phenocopies. Three patients had abnormal CTG/CAG expansions in the JPH3 gene. Other mutations were identified in the VPS13A, CACNA1A, and UBQLN2 genes, which are commonly associated with neurodegenerative diseases other than HD, as well as one patient who had a mutation to the VCP gene.

Two patients had chorea symptoms that disappeared with treatment: One case, identified as antiphospholipid syndrome, responded to corticosteroids and a second case identified as Biermer disease recovered after vitamin B12 administration.

Overlaps with Other Neurologic Disorders

Fourteen of the remaining 23 HDL patients had at least 1 first degree relative with psychiatric or movement disorders, 17 had family histories of behavioral disorders, and 20 had cognitive impairment. Findings on imaging studies — magnetic resonance imaging (MRI) and computed tomography (CT) — were abnormal in 21 of the 28 HDL patients, demonstrating atrophy to the global, caudate, or cerebellar regions. Six patients had abnormal signs in the basal ganglia on T1- or T2-weighted images or CT, some of whom also had atrophy. Ten patients had white matter lesions.

Symptoms evolved in many patients to overlap with other neurological disorders such as ALS (n=2), dementia (n=5), cerebellar ataxia (n=2), monoclonal (n=2), or a parkinsonian syndrome not caused by neuroleptic treatment (n=2).

The rate of phenocopy HDL in this study was 12.4% (28 of 226 patients), which was consistent with the 7-16% identified in 2 large cohort studies of 618 and 200 patients, respectively.3,4 This study helped to confirm the heterogeneous etiologies of HD phenotypes and supports the need for clinicians to initiate genetic counseling in patients who show clinical signs of HD to further evaluate nonpathologic etiologies due to phenocopies. The authors also suggested that the same combined clinical/genetic approach can be used to investigate variations in other late onset neurologic diseases.


  1. Mariani L, Tesson C, Charles P, et al. Expanding the Spectrum of Genes Involved in Huntington Disease Using a Combined Clinical and Genetic Approach. JAMA Neurol. 2016; doi:10.1001/jamaneurol.2016.2215.
  2. Huntington's Disease Collaborative Research Group. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. Cell. 1993;72:971-983.
  3. Schneider SA, Walker RH, Bhatia KP. The Huntington's disease–like syndromes: what to consider in patients with a negative Huntington's disease gene test. Nat Clin Pract Neurol. 2007;3:517-525.
  4. Vuillaume I, Meynieu P, Schraen-Maschke S, et al. Absence of unidentified CAG repeat expansion in patients with Huntington's disease–like phenotype. J Neurol Neurosurg Psychiatry. 2000;68:672-675.
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