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.
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.
Authors: Mariely DeJesus-Hernandez; Ian R Mackenzie; Bradley F Boeve; Adam L Boxer; Matt Baker; Nicola J Rutherford; Alexandra M Nicholson; NiCole A Finch; Heather Flynn; Jennifer Adamson; Naomi Kouri; Aleksandra Wojtas; Pheth Sengdy; Ging-Yuek R Hsiung; Anna Karydas; William W Seeley; Keith A Josephs; Giovanni Coppola; Daniel H Geschwind; Zbigniew K Wszolek; Howard Feldman; David S Knopman; Ronald C Petersen; Bruce L Miller; Dennis W Dickson; Kevin B Boylan; Neill R Graff-Radford; Rosa Rademakers Journal: Neuron Date: 2011-09-21 Impact factor: 17.173
Authors: J S Goldman; J M Farmer; E M Wood; J K Johnson; A Boxer; J Neuhaus; C Lomen-Hoerth; K C Wilhelmsen; V M-Y Lee; M Grossman; B L Miller Journal: Neurology Date: 2005-12-13 Impact factor: 9.910
Authors: F Persichetti; J Srinidhi; L Kanaley; P Ge; R H Myers; K D'Arrigo; G T Barnes; M E MacDonald; J P Vonsattel; J F Gusella Journal: Neurobiol Dis Date: 1994-12 Impact factor: 5.996
Authors: S E Andrew; Y P Goldberg; B Kremer; F Squitieri; J Theilmann; J Zeisler; H Telenius; S Adam; E Almquist; M Anvret Journal: Am J Hum Genet Date: 1994-05 Impact factor: 11.025
Authors: Jonathan Beck; Jonathan D Rohrer; Tracy Campbell; Adrian Isaacs; Karen E Morrison; Emily F Goodall; Elizabeth K Warrington; John Stevens; Tamas Revesz; Janice Holton; Safa Al-Sarraj; Andrew King; Rachael Scahill; Jason D Warren; Nick C Fox; Martin N Rossor; John Collinge; Simon Mead Journal: Brain Date: 2008-01-29 Impact factor: 13.501
Authors: Robert P Friedland; Jignesh J Shah; Lindsay A Farrer; Badri Vardarajan; Jovan D Rebolledo-Mendez; Kin Mok; John Hardy Journal: Front Neurol Date: 2012-10-04 Impact factor: 4.003