C9orf72 expansions are the most common genetic cause of Huntington disease phenocopies

Abstract

Objective: In many cases where Huntington disease (HD) is suspected, the genetic test for HD is negative: these are known as HD phenocopies. A repeat expansion in the C9orf72 gene has recently been identified as a major cause of familial and sporadic frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Our objective was to determine whether this mutation causes HD phenocopies.

Methods: A cohort of 514 HD phenocopy patients were analyzed for the C9orf72 expansion using repeat primed PCR. In cases where the expansion was found, Southern hybridization was performed to determine expansion size. Clinical case notes were reviewed to determine the phenotype of expansion-positive cases.

Results: Ten subjects (1.95%) had the expansion, making it the most common identified genetic cause of HD phenocopy presentations. The size of expansion was not significantly different from that associated with other clinical presentations of C9orf72 expanded cases. The C9orf72 expansion-positive subjects were characterized by the presence of movement disorders, including dystonia, chorea, myoclonus, tremor, and rigidity. Furthermore, the age at onset in this cohort was lower than previously reported for subjects with the C9orf72 expansion and included one case with pediatric onset.

Discussion: This study extends the known phenotype of the C9orf72 expansion in both age at onset and movement disorder symptoms. We propose a revised clinico-genetic algorithm for the investigation of HD phenocopy patients based on these data.

Figure 1. Southern blot of 8 Huntington disease phenocopy patient DNAs

Southern blot of 8 Huntington disease phenocopy patient DNAs shows that C9orf72 repeat expansions can be seen in all cases. The asterisk indicates a GGGGCC containing a short tandem repeat genome motif unrelated to C9orf72. The samples are ordered from 1–8 from left to right; there was insufficient DNA to blot samples 9 and 10. The blot for cases 1–6 has been previously published. (Reprinted with permission from Elsevier.)

Figure 2. Algorithm for the investigation of Huntington disease phenocopy cases

Proposed clinico-genetic algorithm for the workup of Huntington disease (HD) phenocopy patients, highlighting key diagnoses to be considered. DRPLA = dentatorubral-pallidoluysian atrophy; HDL2 = Huntington disease–like 2; NBIA = neurodegeneration with brain iron accumulation; SCA = spinocerebellar ataxia.