C9ORF72 hexanucleotide repeat expansions are a frequent cause of Huntington disease phenocopies in the Greek population

Karadima, Georgia; Kartanou, Chrisoula; Kladi, Athina; Πάνας, Μάριος

doi:10.1016/j.neurobiolaging.2014.08.020

Cited by 31 publications

(27 citation statements)

References 15 publications

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“…C9orf72 repeat expansion was identified in a small subset of patients with negative HD genetic testing and accounted for 0.8% (3/373) of all cases genetically tested for HD and 1.2% (3/258) with negative HD genetic testing. This finding is consistent with previous European studies that identified C9orf72 repeat expansions in patients with an HD-like phenotype and negative HD genetic testing (HD phenocopies) [41][42][43]. The slightly lower frequency of C9orf72 repeat expansion in the HD-negative patients in our series (1.2 vs. 2-5%) likely results from the higher frequency rates of C9orf72 repeat expansion in European populations versus a North American population [3], and the less strict inclusion criteria of our study, given the lack of clinical information precluding definitive classification of our HD-negative cases as HD phenocopies.…”

Section: Discussionsupporting

confidence: 93%

“…In addition, we identified 2 cases (1 HD-positive and 1 HD-negative) with an allele in the intermediate range (20-29 repeats). This finding, however, cannot be compared with the previous series that screened cases with negative HD genetic testing because the allele sizes of C9orf72 repeat expansion-negative cases were not stated [41][42][43]. In keeping with the previous series [29,69,[85][86][87][88][89][90][91], allele sizes of 2, 5, and 8 repeats were the most common wild-type allele sizes in our study.…”

Section: Discussionsupporting

confidence: 49%

“…Recent European studies of patients with the Huntington disease (HD) phenotype but negative genetic testing (termed HD phenocopies) have identified C9orf72 repeat expansion as the most common alternative genetic alteration, affecting approximately 2-5% of cases [41][42][43]. This finding markedly increased the proportion of alternative genetic diagnoses for HD phenocopies, which was previously estimated to be achieved for only about 2-3% of cases [44,45].…”

Section: Introductionmentioning

confidence: 99%

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C9orf72 Repeat Expansion Frequency among Patients with Huntington Disease Genetic Testing

et al. 2018

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Background: European studies identified the C9orf72 repeat expansion as the most frequent genetic alteration in patients with Huntington disease (HD)-like phenotypes but negative HD genetic testing. Objective: To investigate C9orf72 repeat expansion frequency in individuals tested for HD in a North American tertiary referral laboratory. Methods: Three hundred and seventy-three cases (115 positive and 258 negative for HD) were evaluated by genotyping PCR, with follow-up Southern blot and 5′ repeat methylation status assessment by combined repeat-primed and methylation-specific PCR in a subset. Results: Three cases (all HD-negative) tested positive: 2 had > 2,000 repeats and were methylated, 1 had 80–100 repeats and was unmethylated. Two cases (1 HD-positive and 1 HD-negative) had intermediate alleles (20–29 repeats) and were unmethylated. The remaining 368 cases were negative (< 20 repeats). C9orf72 repeat expansion was absent in patients with HD and was identified in a small subset (1.2%) of patients with negative HD genetic testing. Conclusion: These findings suggest that C9orf72 repeat expansion does not coexist with HTT repeat expansion and that C9orf72 repeat expansion testing is unnecessary for patients with HD. In addition, C9orf72 evaluation may be considered for individuals negative for HD genetic testing. Similar to in previous studies, methylation of C9orf72 repeat expansion was limited to large expansions.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 49%

Section: Introductionmentioning

confidence: 99%

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C9orf72 Repeat Expansion Frequency among Patients with Huntington Disease Genetic Testing

et al. 2018

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“…These studies were conducted on patients who presented with an HD-like phenotype and tested negative for pathogenic expansions in the huntingtin gene. Reported frequencies range from 1.75% to 5%, and all studies included populations of European origin: British, 11,73 Serbian, 74 Greek, 75 and Portuguese. 76 A study of the French population did not identify any C9orf72 positives.…”

Section: Prevalence Of C9orf72 In Other Movement Disordersmentioning

confidence: 99%

C9orf72 and its Relevance in Parkinsonism and Movement Disorders: A Comprehensive Review of the Literature

Bourinaris

Houlden

2018

Movement Disord Clin Pract

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Background The C9orf72 hexanucleotide expansion is one of the latest discovered repeat expansion disorders related to neurodegeneration. Its association with the FTD/ALS spectrum disorders is well established, and it is considered to be one of the leading related genes. It has also been reported as a possible cause of several other phenotypes, including parkinsonism and other movement disorders. Its significance, though outside the FTD/ALS spectrum, is not well defined. Methods A comprehensive search of the literature was performed. All relevant papers, including reviews and case series/reports on movement disorder phenotypes reported with the C9orf72 repeat expansion, were reviewed. Data on frequency, natural history, phenotype, genetics, and possible underlying mechanisms were assessed. Results and Discussion In a number of studies, C9orf72 accounts for a small fraction of typical PD. Atypical parkinsonian syndromes, including CBS, PSP, and MSA have also been reported. Features that increase the probability of positive testing include early cognitive and/or behavioral symptoms, positive family history of ALS or FTD, and the presence of UMN and LMN signs. Furthermore, several studies conclude that C9orf72 is the most common cause of HD‐phenocopies. Interestingly, many cases with the parkinsonian phenotype that bear an intermediate range of repeats are also reported, questioning the direct causal role of C9orf72 and suggesting the possibility of being a susceptibility factor, while the presence of the expansion in normal controls questions its clinical significance. Finally, studies on pathology reveal a distinctive broad range of C9orf72‐related neurodegeneration that could explain the wide phenotypic variation.

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“…Chorea may be marked in the lower face 8 or more severe in the limbs, as is typical of HD. 7 Temporal lobe atrophy on neuroimaging may be a useful diagnostic clue. 8 Upper motor neuron signs are helpful findings, although not invariable.…”

Section: C9orf72 Mutations As a Cause Of An Hd-like Phenotypementioning

confidence: 99%

The non–Huntington disease choreas

Walker

2016

Neur Clin Pract

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C9ORF72 hexanucleotide repeat expansions are a frequent cause of Huntington disease phenocopies in the Greek population

Cited by 31 publications

References 15 publications

C9orf72 Repeat Expansion Frequency among Patients with Huntington Disease Genetic Testing

C9orf72 Repeat Expansion Frequency among Patients with Huntington Disease Genetic Testing

C9orf72 and its Relevance in Parkinsonism and Movement Disorders: A Comprehensive Review of the Literature

The non–Huntington disease choreas

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