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.
Huntington disease (HD) is an autosomal dominantly inherited neurodegenerative condition typically characterized by a triad of psychiatric, movement, and cognitive impairment. In many cases in which HD is suspected clinically, patients lack the CAG repeat expansion that causes HD.1–4 Such individuals are said to have HD phenocopy syndromes or HD-like disorders.5 Wild and Tabrizi3 reviewed genes identified in different HD phenocopy cohorts to determine that spinocerebellar ataxia 17 (TBP) accounts for 1.1%, Huntington disease-like 2 (HDL2) for 0.7%, Friedreich ataxia (JPH3) for 0.35%, and inherited prion disease (PRNP) for 0.24% of HD phenocopies. Testing for these mutations is now routinely performed; however, the majority of HD phenocopy patients still do not attain a formal genetic diagnosis.
In 2011, an expanded hexanucleotide repeat in the C9orf72 gene was identified in large kindreds with frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS).6,7 This expansion is recognized as the most common genetic cause of ALS and FTLD in many, but not all, populations.6–9 The mutation is intronic, in a highly conserved gene,6,10 which has homology with the DENN-like superfamily, suggesting a role as regulator of membrane traffic,10–12 and which may be involved in other neurologic conditions.13 Several hundred thousands of repeats have been documented in pathogenic expansions.14 Elucidating the pathogenic mechanism of this expansion has generated much interest; several non–mutually exclusive possibilities exist.6,15–19
In this study, we undertook to examine whether the C9orf72 expansion causes HD phenocopy clinical presentations and hence whether testing for it should be considered in the routine genetic workup of this patient group.
METHODS
Case ascertainment.
As previously described,20 subjects were classified as having HD phenocopy syndromes on the basis of a clinical presentation consistent with HD when assessed by an experienced neurologist or neurogeneticist, and a negative test for the expanded CAG repeat in the HTT gene that causes HD (<36 repeats). At the Neurogenetics Unit of the National Hospital for Neurology and Neurosurgery (NHNN), London, UK, 63.5% of diagnostic HD tests (those done on symptomatic patients) are negative for HD. A cohort of 514 HD phenocopy patients who underwent negative diagnostic genetic testing for HD at NHNN were identified. The average age at onset in this cohort was 48.8 years in those with precise onset data (SD 19.3, n = 176). Three hundred subjects were seen at NHNN, 214 at other hospitals. Of those seen at NHNN, 45.3% were seen by a movement disorders consultant, 15.3% by a cognitive disorders consultant, 14.3% by a neurogenetics consultant, and 25% by other consultant neurologists.
Clinical summaries were reviewed for all cases, and all available clinical case notes reviewed for cases positive for the C9orf72 expansion mutation. Demographic data, family history, examination findings, first symptoms, and age at onset were recorded. Where available, neuropsychometry reports were reviewed, and additional investigations were documented including electrophysiologic assessments, MRI, CSF, and tissue biopsies. HTT CAG repeat length was recorded. Fisher exact test (Stata software) was used to examine the relationship between the presence of particular clinical signs and gene test outcome.
All C9orf72-positive cases were given a modified Goldman score,21,22 which was used to quantify the strength of the autosomal dominant family history.
Standard protocol approvals, registrations, and patient consents.
Ethical approval to undertake these analyses was given by the local NHNN/ION ethics committee. Informed consent for genetic studies was obtained from all participants.
Repeat primed PCR.
To test for the presence of an expansion at C9orf72, repeat primed PCR was carried out as previously described.7 Fragment length analysis was undertaken on an ABI (Carlsbad, CA) 3730xl automated sequencer. Analysis of repeat primed PCR electropherograms was performed using Peak Scanner v1.0 (ABI). Expansions with a characteristic sawtooth pattern were identified and put forward for Southern blotting.
Rs3849942 genotyping.
The surrogate marker rs3849942, reported to be associated with an increased risk of mutation,6,14 was genotyped by allelic discrimination using the 5′ nuclease assay in conjunction with minor groove binding probes. The assay was performed on the SDS7500 Fast Real-Time PCR system (ABI) and genotyping calls were made using software v2.0.6.
Southern hybridization.
A recently described Southern hybridization protocol was used.14 This combined the use of an oligonucleotide (GGGGCC)5 probe that targets multiple sites within the expansion and genomic DNA (gDNA) digested with 2 frequently cutting restriction endonucleases whose sites closely flanked the repeat region. Hexanucleotide repeat number was estimated by interpolation of autoradiographs using a plot of log10 base pair number against migration distance, which was created in Microsoft (Redmond, WA) Excel.
RESULTS
Genetic analyses.
Of the 514 HD phenocopy cases screened, 10 probands (1.95%, 95% confidence interval [CI] 1–4) were positive for the C9orf72 expansion, making this mutation the most common identified cause of HD phenocopy syndromes in a UK cohort.20
Genotyping of the C9orf72-positive cases was consistent with all previous reports in that these individuals were either heterozygous or homozygous for the rs3849942 A allele6 (table 1). No C9orf72-positive cases had intermediate-sized HD CAG repeats in the huntingtin gene, and there was no correlation between the larger HD normal allele and age at onset.
Table 1.
Age at onset and genetic results of C9orf72 expansion-positive cases
Southern hybridization (table 1 and figure 1) of 8/10 subjects for whom there was sufficient DNA demonstrated that the size of expansion in this HD phenocopy case series was not significantly different from that found in series with other clinical presentations of the C9orf72 expansion.14 There was no significant difference in expansion size between those with and without chorea/dystonia.
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.14 (Reprinted with permission from Elsevier.)
Of the entire cohort, 19.5% had a family history of similar neurodegenerative disease, whereas 70% of C9orf72-positive cases had a positive family history (see Goldman scores, table 1). These results suggest that there is a predominance of those with family history, but sporadic C9orf72-positive cases may be possible.
Clinical features of C9orf72 expansion gene carriers.
The mean age at onset was 42.7 years (range 8–60). Early psychiatric and behavioral problems were common; they were the first recorded symptoms in 6 of the cohort. Depression occurred in 4, obsessions in 2, apathy in 2, and psychosis in 2 cases (table 2).
Table 2.
Summary of the clinical features of 10 C9orf72 expansion–positive cases
Movement disorders were a prominent feature in this cohort: 3 exhibited chorea, 4 dystonia, 4 myoclonus, and 3 tremor. Six of the 10 subjects had rigidity and 5 bradykinesia. Chorea was observed periorally in 1, was generalized with predominant head and arm involvement in 1, and in the left arm and leg in another. Of the 4 subjects with dystonia, 3 were observed to have torticollis. In 4 of the 10 subjects, upper motor neuron signs were noted; lower motor neuron signs were not observed in any.
Cognitively, executive dysfunction was noted in 6 subjects, and memory impairment was present in 6; in subject 6, for whom limited history was available, “cognitive impairment” was noted.
Of 8 cases with available MRI reports, 4 had generalized atrophy.
Case 4 was found to be homozygous for the C9orf72 expansion mutation and has been described in detail in Fratta et al.23
Comparisons between C9orf72-positive cases and the rest of the HD phenocopy cohort.
To examine whether there are particular HD phenocopy cases in whom C9orf72 testing should be prioritized, we compared the frequencies of symptoms and signs between the whole cohort and those with the expansion (table 3). Fisher exact test was performed to investigate association between each clinical feature and the outcome of the C9orf72 genetic test. The presence of cognitive and psychiatric features, and some movement disorder features (dystonia, bradykinesia/rigidity, tremor, myoclonus, and upper motor neuron features), were significantly associated with a positive C9orf72 test (table 3). Though there may be some degree of ascertainment bias as more clinical detail was recorded for positive cases, it remains clear that many symptoms characteristic of HD phenocopies are associated with a C9orf72 gene expansion.
Table 3.
Phenotypic features of C9orf72-negative and -positive cases within HD phenocopy cohort, and outcome of Fisher exact test to test for association between clinical feature and genetic test outcome
An illustrative case.
Case 5, a right-handed Caucasian woman, had a normal birth and development and was university educated. She worked in a professional job and was well until a sudden bereavement when she was 50, after which she became depressed.
At around 55 years, increasing fatigue was noted, and she had her first falls, initially backwards. She stopped working and developed a change in personality with decreased interest in her environment and child-like behavior. She developed hypophonia and slurred speech.
By 58 years, she was having difficulty mobilizing, and within 12 months went from independent living to being mute, profoundly bradykinetic, and requiring a hoist to transfer. She developed dystonic posturing of her feet and hands, and involuntary movements and a tremor in her lower limbs.
In her family history, her father died of dementia without motor problems aged 69 years.
She was admitted to the hospital for investigation at age 60 years. On examination, there was akinetic mutism with marked axial rigidity. There was left laterocollis, minor right torticollis, perioral movements, and occasional right cheek movements. There was broken pursuit and slow broken saccades. There was moderate rigidity with spasticity in the upper limbs and severe rigidity in the lower limbs. Plantars were extensor. Palmomental and pout reflexes were present. There was perseveration and frontal features. Mini-Mental State Examination (MMSE) score was 16/25. See supplementary data, case 1, on the Neurology® Web site at www.neurology.org for more details of clinical investigations undertaken.
An unusual case.
Case 7, a right-handed Caucasian man, had a normal birth and early development. At age 3, in nursery school, it was noted that he did not mix well with the other children. At primary school, age 5, he was found to have slight difficulties with writing; at age 6, he was unable to follow basic lessons. Soon thereafter he was seen by an educational psychologist and was diagnosed with moderate learning difficulties and was transferred to special needs school.
By age 8 years, he had abnormal movements under stress, particularly affecting his hands and head. These became more prominent by 21 years of age, when they affected his walking. Occasionally his right leg was noted to jerk uncontrollably from under him, and he had some falls. The “fidgeting” and jerking movements of hands and neck deteriorated. From 21 years on, he had increased frustration and aggression.
His parents are nonconsanguineous. His maternal grandmother died of motor neuron disease; both parents were well.
At age 23 years, he was admitted to the hospital for investigation. Gait was slightly broad-based, with both arms tending to hold slightly dystonic postures, particularly on the right. There was decreased arm swing, nuchal more than axial rigidity, unsteadiness on heel-toe walking, and Romberg test was negative. Eye movements were abnormal, with poor gaze initiation, impaired pursuit, saccadic hypometria with head thrusts, and reduced vertical upgaze. There was generalized chorea with mainly head and arm involvement, oro-buccal chorea, myoclonic movements of the head and neck, and some additional dystonic elements with mild bradykinesia. In the limbs, there were prominent irregular myoclonic jerks, exacerbated by movement and stimuli. Reflexes and sensation were normal.
MMSE score was 20/28. On neuropsychological examination, the Wechsler Adult Intelligence Scale–Revised score was within the defective range, consistent with learning difficulties. There was evidence of memory impairment for visual and verbal memory.
MRI scan showed one small lacune. Nerve conduction studies and EMG were normal. EEG revealed a diffuse and nonspecific excess of theta activity with a trace of alpha-like activity. Although the bursts of high-voltage slow activity had a bursting paroxysmal quality, no definite epileptiform activity was seen. See supplementary data, case 2, for more details of clinical investigations undertaken.
DISCUSSION
HD is the most common genetically determined neurodegenerative disease, with a prevalence of at least 12.4 per 100,000 people,24 but in those in whom HD is suspected but a CAG repeat expansion in HTT is absent, attaining genetic diagnosis has been rare (2.8%20). We present data demonstrating that the C9orf72 expansion is the most common identified genetic cause of HD phenocopy presentations in a UK cohort, with a prevalence of 1.95% (95% CI 1–4).
HD is an autosomal dominant condition, classically presenting with a triad of movement, cognitive, and psychiatric symptoms. However, there is clinical heterogeneity, particularly early in disease, and not all characteristic features may be apparent: 90% of adults with HD develop chorea, but the clinical spectrum is broad, including parkinsonian akinetic-rigid syndromes and relatively pure dystonic, ataxic, and psychiatric presentations.25 Around 8% of patients with HD present without an apparent family history of HD.26 Because of this clinical diversity, it is accepted3,20 that any definition of HD phenocopy syndromes needs to encompass not only the classical triad of HD but also syndromes having a major degree of overlap with HD, and those without a known autosomal dominant family history. Those patients with a clear family history of HD and with classical manifest HD are more likely to have HD; however, many patients seen by neurologists do not present in such a clear-cut manner. Our cohort is composed of patients seen by experienced neurologists in whom the diagnosis of HD was considered, thus it reflects clinical reality. It is United Kingdom–based, and given that United Kingdom–based cohorts have similar ethnic descent to other European, Australian, and North American cohorts, our findings are likely to be representative of cohorts from these areas. In patients of African origin (particularly southern Africans), JPH3 expansion remains the most common cause of HD-like presentations.27 Identifying the causes of HD phenocopy syndromes is of importance to the diagnosis and management of patients with these presentations, as well as the counseling of such individuals and their relatives in matters of genetic testing, life choices, and reproduction.3
Diagnostic tests for this novel mutation have recently become available. Many symptoms characteristic of HD were associated with the subject being C9orf72-positive; given this, and the high frequency of C9orf72 expansion among HD phenocopies, it should be tested for in all HD phenocopy cases. In the future it is likely that multigene “disease panels” will supersede the need for sequential genetic testing; however, since C9orf72, like many other causes of HD phenocopies, is an expansion mutation, it will remain important for the clinician to be aware of which tests are most appropriate for different patients and request them accordingly. We propose a revised clinico-genetic algorithm for the investigation of HD phenocopy cases in figure 2.
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.
The effects of the C9orf72 expansion are known to be both clinically and pathologically varied28 and it is the major cause of both familial and sporadic ALS and FTLD, which are themselves phenotypically heterogeneous conditions. Parkinsonism, particularly rigidity and bradykinesia, has been previously noted in C9orf72-positive individuals29–31; the C9orf72 mutation has been found in some cohorts of patients with Parkinson disease32 and not others.30,33,34 In this study we have demonstrated that the clinical phenotypes caused by C9orf72 expansion mutations are broader than previously noted. It can present with a movement disorder including chorea, dystonia, myoclonus, and tremor. The combination of movement disorder, cognitive decline, and psychiatric and behavioral problems, often with a family history of similar problems, explains why C9orf72-positive cases can have a presentation very similar to HD. It is notable that ALS-type symptoms were relatively infrequent in the HD phenocopy C9orf72 cases: none had lower motor neuron signs, while 40% had upper motor neuron signs. By contrast, symptoms more characteristic of FTLD such as cognitive impairment were much more prevalent, suggesting that there is more overlap between the HD-like and FTLD-like cases.
The average age at onset for C9orf72 in published reports is around 57 years7,9,31,35; in this study, it is lower at 42.7 years (range 8–60), suggesting that the condition should be considered in the differential diagnosis not only in a wider range of clinical presentations, but in a wider demographic group than previously identified.
We examined whether the difference in phenotype could be accounted for by a different size of expansion by Southern hybridization: the size of expansion in our HD phenocopy cohort was not significantly different from that of other cohorts.14 Furthermore, among the 8 C9orf72-positive subjects examined here, there is no statistically significant association between expansion size and age at onset. Case 7, who had motor onset at 8 years, underwent whole-exome sequencing; no large-scale structural abnormalities were detected. An important caveat is that there is evidence of reduced penetrance of the C9orf72 expansion given that the population frequency of C9orf72 expansion is 1 in 69114 in the UK population, so there is a small possibility of false-positives accounting for one or more of these unusual presentations of C9orf72 mutations.
Among the 10 HD phenocopy C9orf72 cases, there was a tendency for those with chorea and dystonia to have younger ages at onset than those without them: the average age at onset of subjects with chorea/dystonia in this cohort is 28.3, whereas the average age at onset of those without them is 54.8 (p = 0.019, independent samples Mann-Whitney U test). This may reflect our ascertainment criteria, since HD phenocopy patients are more likely to be young and have movement disorders than patients with FTLD or ALS. However, it is possible that the C9orf72 expansion with these motor symptoms manifests with earlier onset.
Incomplete penetrance has been previously suggested in C9orf72 expanded individuals,13,31,36 which has important implications for genetic testing. In this case series there was no reported family history in 3 cases, and case 7's family history is compatible with incomplete penetrance—the subject's maternal grandmother had motor neuron disease, but the mother was well.
We present a large case series that not only demonstrates that the C9orf72 expansion is the most frequent cause of HD phenocopy presentations in this UK-based population, but also that the phenotype of the C9orf72 encompasses a diversity of movement disorders, and a younger age at onset than previously recorded.
Supplementary Material
ACKNOWLEDGMENT
The authors thank the patients who participated in this study, Ailbhe Burke for work on the NHNN HD phenocopy cohort database, Mark Gaskin for help with the curation and plating of samples, and James Uphill for technical advice.
GLOSSARY
- ALS
amyotrophic lateral sclerosis
- CI
confidence interval
- FTLD
frontotemporal lobar degeneration
- HD
Huntington disease
- MMSE
Mini-Mental State Examination
- NHNN
National Hospital for Neurology and Neurosurgery
Footnotes
Editorial, page 286
Supplemental data at www.neurology.org
AUTHOR CONTRIBUTIONS
Davina Hensman Moss: drafting/revising the manuscript for content, study design, analysis and interpretation of data, acquisition of data, statistical analysis. Mark Poulter: execution, drafting/revising the manuscript, acquisition of data, analysis and interpretation of data. Jon Beck: revising the manuscript, study design, analysis and interpretation of data. James M. Polke: revising the manuscript, analysis and interpretation of data. Tracy Campbell: revising the manuscript, acquisition of data, analysis or interpretation of data. Garry Adamson: revising the manuscript, acquisition of data, analysis or interpretation of data. Jason Hehir: revising the manuscript, acquisition of data, analysis or interpretation of data. Ese Mudanohwo: revising the manuscript, analysis or interpretation of data. Peter McColgan: revising the manuscript, acquisition of data. Andrea Haworth: study concept or design, revising the manuscript. Edward J. Wild: revising the manuscript, analysis or interpretation of data. Mary G. Sweeney: study concept or design, revising the manuscript. Henry Houlden: study concept or design, analysis or interpretation of data. Simon Mead: study concept or design, revising the manuscript, analysis and interpretation of data, study supervision. Sarah J. Tabrizi: study concept or design, revising the manuscript, analysis and interpretation of data, study supervision.
STUDY FUNDING
This work was undertaken at University College London Hospitals (UCLH)/University College London (UCL), which received a proportion of funding from the Department of Health's National Institute for Health Research Biomedical Research Centres funding scheme. S.M., J.B., M.P., and G.A. are funded by the Medical Research Council–MRC Prion Unit. T.C. is funded by UCL. E.J.W. is supported by the National Institute for Health Research. The work in S.J.T.'s laboratory is supported financially by BBSRC, UCL/UCLH Biomedical Research Centre, Medical Research Council, CHDI Foundation, EU FP7 grant (Paddington and Neuromics consortia), and the UK Dementia and Neurodegenerative Diseases Network (DeNDRoN).
DISCLOSURE
The authors report no disclosures relevant to the manuscript. Go to Neurology.org for full disclosures.
REFERENCES
- 1.Andrew SE, Goldberg YP, Kremer B, et al. Huntington disease without CAG expansion: phenocopies or errors in assignment? Am J Hum Genet 1994;54:852–863 [PMC free article] [PubMed] [Google Scholar]
- 2.Persichetti F, Srinidhi J, Kanaley L, et al. Huntington's disease CAG trinucleotide repeats in pathologically confirmed post-mortem brains. Neurobiol Dis 1994;1:159–166 [DOI] [PubMed] [Google Scholar]
- 3.Wild EJ, Tabrizi SJ. Huntington's disease phenocopy syndromes. Curr Opin Neurol 2007;20:681–687 [DOI] [PubMed] [Google Scholar]
- 4.The 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 [DOI] [PubMed] [Google Scholar]
- 5.Moore RC, Xiang F, Monaghan J, et al. Huntington's disease phenocopy is a familial prion disease. Am J Hum Genet 2001;69:1385–1388 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.DeJesus-Hernandez M, Mackenzie IR, Boeve BF, et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 2011;72:245–256 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Renton AE, Majounie E, Waite A, et al. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 2011;72:257–268 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Smith BN, Newhouse S, Shatunov A, et al. The C9ORF72 expansion mutation is a common cause of ALS+/-FTD in Europe and has a single founder. Eur J Hum Genet 2013;21:102–108 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Mahoney CJ, Beck J, Rohrer JD, et al. Frontotemporal dementia with the C9ORF72 hexanucleotide repeat expansion: clinical, neuroanatomical and neuropathological features. Brain 2012;135:736–750 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Morris HR, Waite AJ, Williams NM, Neal JW, Blake DJ. Recent advances in the genetics of the ALS-FTLD complex. Curr Neurol Neurosci Rep 2012;12:243–250 [DOI] [PubMed] [Google Scholar]
- 11.Levine TP, Daniels RD, Gatta AT, Wong LH, Hayes MJ. The product of C9orf72, a gene strongly implicated in neurodegeneration, is structurally related to DENN Rab-GEFs. Bioinformatics 2013;29:499–503 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Zhang D, Iyer LM, He F, Aravind L. Discovery of novel DENN proteins: implications for the evolution of eukaryotic intracellular membrane structures and human disease. Front Genet 2012;3:283. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Friedland RP, Shah JJ, Farrer LA, et al. Behavioral variant frontotemporal lobar degeneration with amyotrophic lateral sclerosis with a chromosome 9p21 hexanucleotide repeat. Front Neurol 2012;3:136. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Beck J, Poulter M, Hensman D, et al. Large C9orf72 hexanucleotide repeat expansions are seen in multiple neurodegenerative syndromes and are more frequent than expected in the UK population. Am J Hum Genet 2013;92:345–353 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Mori K, Weng SM, Arzberger T, et al. The C9orf72 GGGCC repeat is translated into aggregating dipeptide-repeat proteins in FTLD/ALS. Science 2013;339:1335–1338 [DOI] [PubMed] [Google Scholar]
- 16.Reddy K, Zamiri B, Stanley SY, Macgregor RB, Pearson CE. The disease-associated r(GGGGCC)n repeat from the C9ORF72 gene forms tract length-dependent uni- and multi-molecular RNA G-quadruplex structures. J Bio Chem 2013;288:9860–9866 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Fratta P, Mizielinska S, Nicoll AJ, et al. C9orf72 hexanucleotide repeat associated with amyotrophic lateral sclerosis and frontotemporal dementia forms RNA G-quadruplexes. Sci Rep 2012;2:1016. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Lashley T, Hardy J, Isaacs AM. RANTing about C9orf72. Neuron 2013;77:597–598 [DOI] [PubMed] [Google Scholar]
- 19.Ash PE, Bieniek KF, Gendron TF, et al. Unconventional translation of C9ORF72 GGGGCC expansion generates insoluble polypeptides specific to c9FTD/ALS. Neuron 2013;77:639–646 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Wild EJ, Mudanohwo EE, Sweeney MG, et al. Huntington's disease phenocopies are clinically and genetically heterogeneous. Mov Disord 2008;23:716–720 [DOI] [PubMed] [Google Scholar]
- 21.Goldman JS, Farmer JM, Wood EM, et al. Comparison of family histories in FTLD subtypes and related tauopathies. Neurology 2005;65:1817–1819 [DOI] [PubMed] [Google Scholar]
- 22.Beck J, Rohrer JD, Campbell T, et al. A distinct clinical, neuropsychological and radiological phenotype is associated with progranulin gene mutations in a large UK series. Brain 2008;131:706–720 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Fratta P, Poulter M, Lashley T, et al. Homozygosity for the C9orf72 GGGGCC repeat expansion in frontotemporal dementia. Acta Neuropathol 2013;126:401–409 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Rawlins M. Huntington's disease out of the closet? Lancet 2010;376:1372–1373 [DOI] [PubMed] [Google Scholar]
- 25.Bates GP, Harper PS, Jones L, eds. Huntington's Disease. Oxford: Oxford University Press; 2002 [Google Scholar]
- 26.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 [DOI] [PubMed] [Google Scholar]
- 27.Magazi DS, Krause A, Bonev V, et al. Huntington's disease: genetic heterogeneity in black African patients. S Afr Med 2008;98:200–203 [PubMed] [Google Scholar]
- 28.Murray ME, DeJesus-Hernandez M, Rutherford NJ, et al. Clinical and neuropathologic heterogeneity of c9FTD/ALS associated with hexanucleotide repeat expansion in C9ORF72. Acta Neuropathol 2011;122:673–690 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.O'Dowd S, Curtin D, Waite AJ, et al. C9ORF72 expansion in amyotrophic lateral sclerosis/frontotemporal dementia also causes parkinsonism. Mov Disord 2012;27:1072–1074 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Dejesus-Hernandez M, Rayaprolu S, Soto-Ortolaza AI, et al. Analysis of the C9orf72 repeat in Parkinson's disease, essential tremor and restless legs syndrome. Parkinsonism Relat Disord 2012;19:198–201 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Boeve BF, Boylan KB, Graff-Radford NR, et al. Characterization of frontotemporal dementia and/or amyotrophic lateral sclerosis associated with the GGGGCC repeat expansion in C9ORF72. Brain 2012;135:765–783 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Lesage S, Le Ber I, Condroyer C, et al. C9orf72 repeat expansions are a rare genetic cause of parkinsonism. Brain 2013;136:385–391 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Yeh TH, Lai SC, Weng YH, et al. Screening for C9orf72 repeat expansions in parkinsonian syndromes. Neurobiol Aging 2012;34:1311.e3–1311.e4 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34.Akimoto C, Forsgren L, Linder J, et al. No GGGGCC-hexanucleotide repeat expansion in C9ORF72 in parkinsonism patients in Sweden. Amyotroph Lateral Scler Frontotemporal Degener 2012;14:26–29 [DOI] [PubMed] [Google Scholar]
- 35.Majounie E, Abramzon Y, Renton AE, Keller MF, Traynor BJ, Singleton AB. Large C9orf72 repeat expansions are not a common cause of Parkinson's disease. Neurobiol Aging 2012;33:2527.e2521–2527e.2522 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36.Pamphlett R, Cheong PL, Trent RJ, Yu B. Transmission of C9orf72 hexanucleotide repeat expansions in sporadic amyotrophic lateral sclerosis: an Australian trio study. Neuroreport 2012;23:556–559 [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.