Expanding the Spectrum of Genes Involved in Huntington Disease Using a Combined Clinical and Genetic Approach

Research

JAMA Neurology | Original Investigation Expanding the Spectrum of Genes Involved in Huntington Disease Using a Combined Clinical and Genetic Approach

Louise-Laure Mariani, MD; Christelle Tesson, PhD; Perrine Charles, MD, PhD; Cécile Cazeneuve, MD; Valérie Hahn, MS; Katia Youssov, MD; Leorah Freeman, MD, PhD; David Grabli, MD, PhD; Emmanuel Roze, MD, PhD; Sandrine Noël, BSc; Jean-Noel Peuvion, BSc; Anne-Catherine Bachoud-Levi, MD, PhD; Alexis Brice, MD; Giovanni Stevanin, PhD; Alexandra Durr, MD, PhD

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IMPORTANCE Huntington disease (HD), a prototypic monogenic disease, is caused by an ex- Video at jamaneurology.com panded CAG repeat in the HTT gene exceeding 35 units. However, not all patients with an HD phenotype carry the pathological expansion in HTT, and the positive diagnosis rate is poor. Supplemental content at jamaneurology.com

OBJECTIVES To examine patients with HD phenotypes to determine the frequency of HD phenocopies with typical features of HD but without pathological CAG repeat expansions in HTT in an attempt to improve the positive diagnosis rate.

DESIGN, SETTING, AND PARTICIPANTS Between January 1, 2004, and April 18, 2011, a total of 226 consecutive index patients with an HD phenotype were referred to specialized clinics of the French National Huntington Disease Reference Centre for Rare Diseases. They underwent detailed clinical examination and follow-up, as well as neuropsychological, biological, imaging, and genetic examinations. Nucleotide expansions in JPH3, ATN1, TBP, and C9ORF72 and mutations in PRNP, as well as acquired conditions commonly causing HD phenocopies, were first screened.

MAIN OUTCOMES AND MEASURES The diagnostic rate of HD phenocopies and frequency of other etiologies using deep clinical phenotyping and next generation sequencing. Our goal was to improve the genetic diagnosis of HD phenocopies and to identify new HD related genes.

RESULTS One hundred ninety-eight patients carried a pathological CAG repeat expansion in HTT, whereas 28 patients (12 women and 16 men) did not. Huntington disease phenocopies accounted for 12.4%, and their mean (SD) age at onset was similar to those of the HD-HTT group (47.3 [12.7] years vs 50.3 [16.4] years, P = .29). We first identified 3 patients with abnormal CTG expansions in JPH3, a fourth patient with an antiphospholipid syndrome, and a

fifth patient with B12 avitaminosis. A custom-made 63-gene panel was generated based on clinical evolution and exome sequencing. It contained genes responsible for HD phenocopies and other neurodegenerative conditions, as well as candidate genes from exome sequencing in 3 index cases with imaging features of brain iron accumulation. We identified mutations in genes associated with neurodegeneration, including CACNA1A (n = 2), VPS13A (n = 1), UBQLN2 (n = 1), and VCP (n = 1).

CONCLUSIONS AND RELEVANCE Huntington disease phenocopies without CAG repeat expansions in HTT are not rare, occurring in 12.4% (28 of 226) herein, and should be considered in genetic counseling. We used next-generation sequencing combined with clinical data and disease evolution to explore multiple etiologies simultaneously. Our combined clinical and genetic exploration of 28 HD phenocopies identified the underlying cause in 35.7% (10 of 28). In conclusion, the etiologies of HD phenocopies are heterogeneous, and clinical evolution should be taken into account when searching for a genetic cause. The panel of candidate genes to be examined is larger than expected but can be guided by specific imaging and clinical features. Other neurodegenerative diseases with

late onset in which variant segregation cannot be verified could be productively explored Author Affiliations: Author with the combined approach illustrated herein. affiliations are listed at the end of this article. Corresponding Author: Alexandra Durr, MD, PhD, Institut du Cerveau et de la Moelle Epinière, 47 Blvd de JAMA Neurol. 2016;73(9):1105-1114. doi:10.1001/jamaneurol.2016.2215 l’Hôpital, 75651 Paris CEDEX 13, Published online July 11, 2016. France ([email protected]).

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untington disease (HD) is caused by a CAG repeat expansion in the HTT gene (OMIM 613004) exceeding 35 Key Points units.1 Clinical symptoms of HD in the absence of a H Question What are the frequency and etiologies of Huntington pathological HTT allele are referred to as HD phenocopies or HD- disease (HD) phenocopies, and how can we improve the positive like (HDL) disease.2 Huntington disease is an autosomal dominant diagnosis rate? disorder characterized by personality changes, cognitive decline, Findings In this study, 226 patients had an HD phenotype, 198 and movement disorders (most often chorea but also combined linked to expansions in HTT, and 28 were HD phenocopies. We 3,4 with dystonia and bradykinesia). Other genes implicated in HD identified 3 patients with abnormal expansions in JPH3, 1 patient

phenotypes include the following (by decreasing of frequency): with an antiphospholipid syndrome, and 1 patient with B12 (1) CTG/CAG repeat expansions in the gene encoding junctophilin avitaminosis, as well as identified mutations in genes associated 3(JPH3) (OMIM 605268) responsible for HDL2 (OMIM 606438),5 with neurodegeneration. (2) CAG triplet expansions in the gene encoding the TATA box- Meaning This study demonstrates the power of combining clinical binding protein (TBP/SCA17) (OMIM 600075) in HDL4 (OMIM assessment and next-generation sequencing to explore multiple 607136) in patients with cerebellar atrophy,6 (3) CAG expansions etiologies simultaneously and reveal novel HD genetic causes. in the gene encoding atrophin 1 (ATN1) (OMIM 607462) responsible for dentatorubral-pallidolluysian atrophy (OMIM 125370),7 (4) hexanucleotide expansions in a noncoding region of C9ORF72 (eMethods in the Supplement). Repeat expansions in C9ORF72 (OMIM 614260),8,9 and (5) a 192–base pair (bp) insertion in the were detected by repeat-primed PCR (in 1X Q-Solution; PRNP gene (OMIM 176640) causing an octapeptide expansion in QIAGEN) and 5% dimethyl sulfoxide, with substitution of de- the prion protein responsible for HDL1 (OMIM 603218).10,11 oxyguanosine triphosphate by 7-deaza-2-deoxyguanosine In this study, movement disorder specialists (L.-L.M, P.C., triphosphate14 as described previously.15 The PCR products K.Y., L.F.,D.G., E.R., A.-C.B.-L., A.B., and A.D.) examined 226 pa- were resolved on a sequencer (ABI3730; Applied Biosystems) tients with HD phenotypes to determine the frequency of HD and analyzed with a software program (GeneMapper; Ap- phenocopies with typical features of HD but without pathologi- plied Biosystems). cal CAG repeat expansions in HTT. Thorough investigations An exon capture kit (Agilent SureSelect Kit V4 50Mb; allowed us to discover novel etiologies for HD phenocopies. Nimblegen) was designed to target all exons of 63 genes identified because of clinical features and disease evolution in our cohort, such as those involved in HD, amyotrophic lateral scle- Methods rosis (ALS), and frontotemporal degeneration (FTD), as well as genes selected from exome sequencing (eTable 1 in the Supple- Study Design ment). Exon capture was followed by massive parallel sequenc- Between January 1, 2004, and April 18, 2011, a total of 226 con- ing (HiSeq 2000; Illumina) (eMethods in the Supplement). secutive index patients with an HD phenotype were referred to Treatment of sequence data was done using a web interface the diagnostic laboratory of the Department of Genetics of the (Eris; Integragen) as described previously.16 Pitié-Salpêtrière University Hospital (Paris, France) by the French The gene variants identified by exome and gene panel National Huntington Disease Reference Centre for Rare Diseases. screening were validated by PCR using specific primers, fol- Blood samples and video recordings were obtained with writ- lowed by Sanger sequencing with chemistry resolution (BigDye; ten informed consent according to French legislation. The study Applied Biosystems) on the sequencer (ABI3730; Applied Bio- was approved by CPP Ile de France II, the local ethical board systems) and analysis with a software program (SeqScape 2.6; (RBM03-48). Genomic DNA was extracted from peripheral blood Applied Biosystems). Exomes were sequenced in 3 patients at samples using standard methods. Inclusion criteria were an HD an outside facility (Integragen, Evry, France) (eMethods in the phenotype, defined as the presence of a movement disorder con- Supplement). sistent with HD and 1 or more of the following: a family history of psychiatric or neurological disorders compatible with dominant inheritance, cognitive impairment, and behavioral or psy- Results chiatric symptoms. An autosomal dominant family history was not compulsory because HD appears as a sporadic disease in 8% Among the 226 index patients with HD phenotypes, 198 to 15% of patients.12,13 (87.6%) carried expanded CAG repeats exceeding 35 units in Acquired causes, such as dysimmune and metabolic disor- HTT (HD-HTT group). The other 28 (12.4%) are referred to as ders, were assessed, and DNA samples were screened for expan- HD phenocopies (Figure). Using combined clinical and sions in JPH3, ATN1, TBP, and C9ORF72 and point mutations in genetic approaches, including a custom-made panel of 63 PRNP. Blood acanthocytes were looked for at least twice. Neu- selected candidate genes, we identified several unexpected ropsychological evaluations were performed (eMethods in the responsible genes and acquired conditions in 10 of 28 Supplement). (35.7%) patients with HD phenocopies (Figure and Table 1). The clinical characteristics of these 10 patients are summa- Genetic Analyses rized in Table 1, and the genetic characteristics of the vari- Repeat expansions in HTT, JPH3, TBP, and ATN1 were ana- ants identified in these patients are listed in eTable2 in the lyzed by polymerase chain reaction (PCR)–based genotyping Supplement.

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Figure. Flowchart of Patients With Huntington Disease (HD) Phenotype

226 Patients with HD phenotype

198 Patients with pathological polyQ expansion in HTT

28 HD phenocopies

Results 1 (after first row screening) 3 JPH3 Clinical evolution 1 Antiphospholipid syndrome 8 Typical HD 1 B avitaminosis 12 6 Deceased 23 Remaining HD 9 Atypical: Prominent sign at phenocopies outcome 5 Dementia 2 Cerebellar syndrome 2 Custom-made ALS-like 2 63-gene panel Parkinsonism 2 Myoclonus Brain MRI or CT 4 Normal Results 2 (after second 13 Global atrophy row panel screening) 10 White matter lesions 1 VPS13A, 2 CACNA1A, 6 Abnormal signal in 1 VCP, and 1 UBQLN2 basal ganglia 4 Cerebellar atrophy ALS indicates amyotrophic lateral 3 Caudate atrophy sclerosis; CT, computed tomography; and MRI, magnetic resonance imaging.

Clinical Comparison of HD-HTT vs HD Phenocopies pendent blood samples, but no variant was found in VPS13A The mean age at onset was similar in HD phenocopies (n = 28) despite a compatible clinical evolution. and the HD-HTT group (n = 114). Their mean (SD) ages were One patient (SAL-2772-001) had an antiphospholipid syn-

50.3 (16.4) years and 47.3 (12.7) years, respectively (P = .29). drome, and another patient (SAL-2846-001) had B12 avita- Eight of 28 (28.6%) HD phenocopies had typical family his- minosis related to Biermer disease (Table 1). In both patients, tories of HD with both psychiatric symptoms and movement chorea disappeared after treatment with corticosteroids and

disorders. Surprisingly, patient SAL-2806-002 had normal (17 vitamin B12, respectively. and 18) CAG repeats in HTT, verified in an independent sample, although he had the same choreic movements as his uncle, Further Investigations of HD Phenocopies aunt, and maternal first-degree cousin, with HTT expansions Based on MRI and Follow-up (41 ± 1 CAG [normal allele, 21 CAG]) confirmed in the latter. Pa- Among the remaining 23 HD phenocopies (Figure), 14 had fam- tient SAL-2575-006 had a heterozygous 12-bp inframe dele- ily histories of psychiatric or movement disorders in at least 1 tion in exon 1 of HTT, which removed 4 prolines from a stretch first-degree relative. Two had censored family histories, with usually containing 10, but its significance is unknown. one due to paternal death at age 44 years and another who was Neuropsychological evaluations, performed in 22 HD phe- an orphan. Seventeen had behavioral disorders, and cogni- nocopies and 22 HD-HTT patients matched for age and edu- tive impairment was present in 20. cational level, revealed similar cognitive patterns, but subcor- Follow-up revealed atypical evolutions with additional tical dementia was particularly marked in the HD-HTT group clinical features in 9 patients compatible with ALS (n = 2), de- (eTable 3 in the Supplement). The 2 groups had similar Mont- mentia (n = 5), cerebellar ataxia (n = 2), myoclonus (n = 2), or gomery-Åsberg Depression Rating Scale scores, and no major a parkinsonian syndrome (n = 2) not due to neuroleptic treat- depression was present in either group. ment. Six patients died during follow-up at a median age of 77.5 years (age range, 48-92 years) after a median of 9 years (range, Exploration of Known Causes of HD Phenocopies 6-20 years) of evolution. With a first row screening, we identified known causes of HD Cerebral magnetic resonance imaging (MRI) findings or phenocopies in 5 patients (Results 1 in the Figure and Table 1). computed tomography scans were abnormal in 21 patients with We identified abnormal CTG/CAG expansions in JPH3 in 3 pa- global (n = 13), caudate (n = 3), or cerebellar (n = 4) atrophy; tients (MON-1, SAL-2, and SAL-3 in Table 1). Two were of Afri- abnormal T1-weighted or T2-weighted MRI or computed to- can descent, with one from the Democratic Republic of the mography signals in basal ganglia (n = 6); and nonvascular and Congo (SAL-2) and the other from Haiti (MON-1). The third pa- vascular white matter lesions (n = 10). Some patients showed tient (SAL-3) was French Caucasian by her mother and French both atrophy and abnormal signals in the basal ganglia. West Indian by her father. No patients had pathological repeat expansions in TBP (>40 Generation of a Custom-made, 63-Gene Panel Kit repeats), C9ORF72,orATN1 (>35 repeats). Only 1 of 19 pa- Based on our clinical approach associating initial examina- tients tested (SAL-2848-001) had rare acanthocytes in 2 inde- tion and further follow-up of patients, we designed a custom-

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Table 1. Clinical Characteristics of Huntington Disease (HD) Phenocopies With Identified Causes

Typical HD Features Other Than Chorea Atypical Features UHDRS Behav- Gene or Score Positive ioral or Cognitive At First Brain Diag- (at Family Mood Impair- Parkin- Exami- During MRI Case ID nosis Sex Origin Age) History Disorder ment Dystonia sonism nation Evolution or CT Evolution Comment HD-Related Genes MON-1 JPH3 M Haiti ND Yes Yes Yes Yes No No No Global HD NA atrophy SAL-2 JPH3 F Congo 32 Yes Yes Yes No No No No Global HD NA (47 y) atrophy SAL-3 JPH3 F France 55 Yes Yes Yes Yes Yes No Hyper- Caudate HD NA and (64.5 y) reflexia atrophy French West Indies SAL-2697-3 VPS13A M North 31 Seizures Yes ND No No Seizures ND ND ND Parental Africa (36 y) consan- (Algeria) guinity Candidate Genes From Exome Sequencing SAL-2752 CACNA1A M France 38 Yes Yes Yes No No No Hypo- Basal NA NBIA case -1 (68 y) phonia ganglia and hypointensity dysarthria SAL-2755 CACNA1A M Ashkenazi 26 Yes Yes Yes No Yes No Cerebellar Global HD with NA -1 (64 y) (SARA atrophy cerebellar score, 11) syndrome Candidate Genes Suspected Because of Specific Clinical Features and Evolution of Our Cohort ALS/FTD SAL-2848 VCP M Portugal 38 Yes Yes Yes No No Chorea Chorea Mild HD Presence -1 (70 y) prominent prominent vascular of on face on face, white acantho- dementia, matter cytes, Kell and lesions negative aggressive- ness SAL-2850 UBQLN2 M North ND Unknown Yes Yes Yes No No Dementia Global HD Died of -1 Africa with atrophy choking (Algeria) episodic due to memory swallowing impairment difficulties Acquired causes SAL-2772 APL M Great 25 Yes No No No No No No Normal Remission Cortico- -001 syndrome Britain (26 y) steroid and responsive France

SAL-2846 B12 F France ND Yes Yes Yes No No No No Multiple Remission Responsive -001 avitamin- lacunar to B12 osis infarcts vitamins and for at least biputaminal 3y lesions (after suicide attempt) Abbreviations: ALS, amyotrophic lateral sclerosis; APL, antiphospholipid; NBIA, neurodegeneration with brain iron accumulation; ND, not done; CT, computed tomography; F, female; FTD, frontotemporal dementia; SARA, Scale for the Assessment and Rating of Ataxia; UHDRS, Unified M, male; MRI, magnetic resonance imaging; NA, not applicable; Huntington’s Disease Rating Scale.

made 63-gene panel. We included 7 genes involved in HD to NBIA-related genes. Variants affecting polyglutamine disease– check for point mutations and 14 genes involved in ALS or FTD, related or NBIA-related genes or interacting partners of genes 9 neurodegeneration with brain iron accumulation (NBIA) involved in HD, NBIA, or ALS were considered (eg, variants in genes, and 33 candidate genes from exome sequencing (Figure dynein proteins and their genes given the functions of hun- and eTable 1 in the Supplement). tingtin in axonal trafficking). We also included nuclear recep- Three patients with abnormal basal ganglia signals char- tor corepressor 2 (N-CoR2) because N-CoR1 is known to be a acteristic of NBIA (SAL-2687-009, SAL-315-001, and SAL-2752- partner of HTT in a transcription repressor complex.17,18 001) underwent exome sequencing (Figure and eResults and With this procedure, we identified variants in 33 differ- eFigure in the Supplement and Video). After filtration, no com- ent candidate genes that were absent in public databases mon variants were found in the 3 sequenced patients or in the and with high prediction of pathogenicity while affecting

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conserved amino acids or leading to truncation of the protein 2752-001, a second case (SAL-2755-001) (both listed in Table 1) (eTable 1 in the Supplement). No additional samples were avail- had a pathogenic variant in CACNA1A (c.2879G>T; able to test cosegregation in the families, but Sanger sequenc- p.Arg960Leu) predicted to be deleterious by all algorithms and ing confirmed that they were not false-positive variants. not previously reported in controls (eTable 2 in the Supple- ment). At first examination, the 2 cases looked like HD clini- Pathogenic Mutations and Their Associated Phenotypes cally because they showed no atypical features as specified in in HD Phenocopies Table 1. During evolution, cerebellar signs appeared in pa- With the 63-gene panel, we tested all 23 HD phenocopies and tient SAL-2755-1 (Scale for the Assessment and Rating of Ataxia 2 relatives, as well as SAL-2846-001 (Table 1), because Biermer [SARA] score of 11 [the SARA score ranges from 0 to 40, with disease was not known to cause HD phenocopies. All variants 40 being the most severe]), and dysarthria manifested in pa- (n = 4687) found are listed in eTable 4 in the Supplement. tient SAL-2752-1 (Table 1) (detailed clinical characteristics are With this second row panel screening, we identified pu- given in the eResults in the Supplement). We considered the tative pathogenic mutations in 5 additional patients (Results pathogenic variant identified in CACNA1A likely responsible 2 in the Figure, Table 1, and eTable 2 in the Supplement). As for the phenotype in these 2 patients (discussed below). detailed in eTable 2 in the Supplement, all of these variants were systematically searched through Exac (Exome Aggrega- tion Consortium; http://exac.broadinstitute.org) as well as the Discussion frequency of the variant in the Exome Variant Server (EVS; Na- tional Heart, Lung, and Blood Institute Exome Sequencing Proj- Our clinical and genetic approach, including a custom-made ect). Prediction scores of 3 software programs provided by Ala- panel of 63 selected candidate genes, allowed us to identify mut (Interactive Biosoftware) are specified as PolyPhen2, SIFT, the cause of HD phenocopy in 10 of 28 patients. We identified and MutationTaster in eTable 2 in the Supplement. mutations in the JPH3 and VPS13A genes as well as in unex- Patient SAL-2697-003 (Table 1) had a homozygous trun- pected genes, such as CACNA1A (n=2),UBQLN2 (n = 1), and cating mutation in VPS13A (c.9109C>T; p.Arg3037*). This VCP (n=1). These results are supported by algorithms premutation was previously reported in patients with dicting that the mutations are deleterious and by their ab- neuroacanthocytosis,19,20 a disorder already described as an sence in controls or online polymorphism public databases. Ad-

HD phenocopy. ditional investigations identified antiphospholipid and B12 Patient SAL-2848-001 (Table 1) carried a heterozygous avitaminosis in 2 patients. c.221A>T (p.Asp74Val) mutation in VCP encoding valosin- In our series, 12.4% (28 of 226) did not carry pathological containing protein, already known to cause an FTD pheno- expansions in HTT. Although our rate of phenocopy is higher type, in addition to Paget disease and myopathy21 and ALS.22 than the 1% reported by others (summarized in Table 2),27,37,40 This variant is predicted to be probably damaging by 2 of 3 it is consistent with the 7% and 16% found in large cohorts of prediction algorithms. The severe cognitive profile of the 618 and 200 cases, respectively (Table 2).13,28 In a study39 of patient during evolution, reminiscent of FTD, further sup- 101 more strictly selected patients tested for HD in Brazil, 29% ported our finding (Table 1). It is noteworthy that this patient were HD phenocopies. A recent search for genes responsible had acanthocytes on blood smear, but no mutations were for HD phenocopies found expansions in C9ORF72, a gene re- found in VPS13A and other genes, such as XK in McLeod sponsible for ALS and FTD in 2% of the patients of a cohort in Syndrome or NBIA genes, also known to be possibly associ- which 63.5% were considered to be HD phenocopies.8,9 ated with acanthocytes in blood film. We considered the Identifying HD phenocopies is especially important for ge- FTD mutation likely responsible for the phenotype in this netic counseling, which should not rely on clinical evidence patient. of HD but should be confirmed by genetic testing of the af- Male patient SAL-2850-001 (Table 1) carried 2 variants fected relatives. Even so, we report an HD phenocopy in a con- (c.1238G>T; p.Ser413Ile and c.425C>G; p.Pro142Arg) in UBQLN2 firmed HD-HTT family, even after resampling and reevalua- located on the X chromosome. Ubiquilin-2 encoded by UBQLN2 tion of the patient. In this patient with clinical HD phenocopy associates with ubiquitin ligases and proteasome to mediate and an affected relative with HD-HTT, no specific cause was protein degradation.23 Notably, ubiquilin-2 is associated with identified despite thorough investigations. huntingtin/polyQ aggregates.24 In addition, mutations in this Neuropsychological examination of HD phenocopies and gene have been reported to cause an FTD/ALS phenotype.25 the HD-HTT group showed dysexecutive syndromes in both Patient SAL-2850-001 (Table 1) had dementia with episodic groups. Hence, even detailed neuropsychological profiles will memory impairment and died from the consequences of a not distinguish HD phenocopies from HD-HTT patients. swallowing accident, a clinical evolution supporting our find- A strength of our study is the clinical reassessment of the ing together with the predictive effects of the mutations. It was HD phenocopies, which should be performed systematically impossible to determine which mutation in UBQLN2 was re- even if there is a family history of psychiatric disorders,27,39

sponsible for the phenotype in our patient. as in SAL-2846-001 (Table 1), who had B12 avitaminosis. In par- Patient SAL-2752-001 (Table 1) had a previously reported ticular, a dysimmune etiology, such as antiphospholipid syn- deleterious variant in CACNA1A in episodic ataxia (c.6418C>T; drome, should be ruled out. Only approximately 3% of pa- p.Arg2140Cys),26 rarely reported in controls (0 with AA alleles, tients with antiphospholipid syndrome develop chorea; 4withAG alleles, and 6022 with GG alleles). In addition to SAL- however, when it occurs, it is inaugural in about 88% of cases,

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Downloaded From: https://jamanetwork.com/ on 09/27/2021 Research Original Investigation Expanding the Spectrum of Genes Involved in Huntington Disease 2 28 30 6 32 27 5 33 29 31 2005 (continued) 34 Andrew et al, Rosenblatt et al, Holmes et al, Margolis et al, 1994 1998 2000 2001 2002 Stevanin et al, 2002 2003 2004 2004 2004 et al, from patient from JPH3 HD family Patients 8 to 11 from HD families NA Vuillaume et al, NANA Stevanin et al, Bauer et al, Only 3 index cases, 330 cases with heterogeneous semiology of movement disorder 1 North Africa North Africa TBP ,2 (43 repeats) NA Cellini et al, JPH3 JPH3 JPH3 JPH3 JPH3 TBP TBP Etiologies Identified or Reported Comment Source 2 1 1 hysteria, 1 tardive dyskinesia, 1 patient with an unknown CAG expansion 11 Likely sporadic cause (drug induced, stroke), 1 patient with an unknown CAG expansion 4 9 6 Diagnosis Rate Among HD Phenocopies 4/60 (6.7%) Typical cases, 4/252 (1.6%) atypical cases 1/98 (1.0%) 4/330 (1.2%) 02% NA 1 NA9/1712 (0.53%) 6/538 (1.1%) in North America (cases Bauer of et African al, origin), 0% in Japan 0 0 NA Keckarević NA11/32 (34.4%) 0-2 Benign familial chorea, TBP , and DRPLA TBP , DRPLA, and , FTL, SCA1, JPH3 JPH3 TBP in 582 (100%), DRPLA , DRPLA NA NA 1 Patient from an Etiologies Investigated JPH3 JPH3 JPH3 TBP JPH3 in 41 (7.0%) JPH3 SCA2, SCA3, and DRPLA SCA7, DRPLA, RED test, MRI, acanthocytosis, and copper studies (0.9%) Positive Family History Among HD Phenocopies Choreic, and 45% sporadic movement disorder with HDL, 36.5% if suspected HD, 28% of typical HD phenotype NA 9 HD Phenocopy Male-Female Sex Ratio NANA NA NA 147/1600 (9.2%) Among patients NANA NANA NA NA NA HDL1, NA NANA NA NA SCA1, SCA2, SCA3, SCA6, SCA1, SCA2, SCA3, SCA6, NA NA HDL1, ) ) ) ) ) ) HTT HTT HTT HTT HTT HTT (1.2%) Frequency of HD Phenocopies Among HD Phenotype NA (100% non- NA (100% non- 12% If suspected phenotype, 7% if typical phenotype (100% non- (100% non- NA (100% non- (100% non- 15/695 (2.2%) (16.0%) (36.4%) African American ancestry Germany, Austria (100% Caucasian) French cohort with 74 HDL, described as France (n = 60), continental Europe (n = 6), North Africa (n = 5), Colombia (n = 1), French West Indies (n = 1), and Guinea (n = 1) FranceGermany, Austria NA NA Canada, United States, Mexico, and Japan Italy NA United Kingdom HD HD HD HD HD HTT HTT HTT HTT HTT HTT 695200 United States, Lille, France 32/200 132 Yugoslavia 48/132 1004 Canada 12/1004 No. Origin 330 With non- movement disorder 1600 Non- 618 (583 With typical HD) 252 Non- 1712 Non- 582 Non- 98 Non- Table 2. Review of Previously Published Huntington Disease (HD) Phenocopy Series

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Downloaded From: https://jamanetwork.com/ on 09/27/2021 Expanding the Spectrum of Genes Involved in Huntington Disease Original Investigation Research 39 36 9 35 37 2008 2014 38 8 et al, Rodriquez- Revenga et al, et al, Present study Rodrigues et al, 2006 2008 2008 2011 2015 HTT NA Costa et al, NA Koutsis et al, NA Sulek-Piatkowska phenocopy, psychiatric disorder (mood disorder noted by the family), cognitive decline, and intention tremor NA Wild et al, NA Hensman Moss 1 HD phenocopy with no identified cause but from an HD- family 44% Of Brazilian population is of African descent , , UBQLN2 , ,2 ,1 JPH3 JPH3 , 1 (0.4%) VCP VPS13A ,1 TBP ,1 avitaminosis C9ORF72 12 C9ORF72 TBP JPH3 1 CNS vasculitis, 1 primary hypoparathyroidism, and 2 recessive mitochondrial encephalopathy Etiologies Identified or Reported Comment Source 1 antiphospholipid syndrome, 1B 2 5 (1.8%) 1 3 CACNA1A 1 FXTASHDL1, 1 (0.4%) Not1 a (0.4%) typical FRDA HD 10 3/29 (10.3%) 2/29 (6.9%) chorein elevated 4/107 (3.7%) Diagnosis Rate Among HD Phenocopies 2/40 (5.0%) 8/285 (2.8%) (0.4%) 10/28 (35.7%) (1.1%) 10/514 (1.9%) 5/29 (17.2%) , , , and JPH3 TBP TBP / POU3F2 , DRPLA, , DRPLA, like; MRI, magnetic resonance imaging; NA, notunstable applicable; expansion); RED, SCA, repeat spinocerebellar expansion ataxia. detection (detection >40 CAG TBP , SCA1, SCA2, TBP TBP , and C9ORF72 , , , and DRPLA 1/224 JPH3 JPH3 JPH3 TBP , C9ORF72, CREBBP , FTL, (and additional tests in 20% of patients) HDL1, Etiologies Investigated SCA1, SCA2, SCA3, DRPLA, and SCA1, SCA2, SCA3, exons 3 and 4 of FTL, and FRDA TBP acanthocytosis, dysimmune/acquired chorea, MRI, 3-exome sequencing, and custom-made 63-gene panel HDL1, JPH3 C9ORF72 Systematic DRPLA, chorein expression on Western blot SCA3, DRPLA, (44.9%) Positive Family History Among HD Phenocopies (35.0%) (21.1%) (19.5%) (67.9%) NA 48/107 HD Phenocopy Male-Female Sex Ratio 0.9:1 14/40 1.9:1 0NANA FXTAS 60/285 NA NA1.3:1 1/95 105/514 19/28 NA NA DRPLA, ), ) ) ) ) ) HTT HTT HTT HTT HTT HTT (100% non- but 27/107 (25.2%) of typical cases Frequency of HD Phenocopies Among HD Phenotype (100% non- (100% non- (100% non- (100% non- (100% non- 28/226 (12.4%) (43.9%) Portugal NA Greece NA Spain NA United Kingdom NA Poland NA United Kingdom NA Colombia (n = 1), Africa (n = 1), North Africa (n = 2), Haiti (n = 1), and Portugal (n = 2) HD HD HD HD HD HTT HTT HTT HTT HTT HTT 66 Brazil 29/66 107 Non- No. Origin 40 Non- 95 Non- late-onset movement disorder 285 Non- 224 Non- 514 Non- 226 France, including Table 2. Review of Previously Published Huntington Disease (HD) Phenocopy Series (continued) Abbreviations: CNS, central nervous system; DRPLA, dentatorubral-pallidolluysianataxia; atrophy; FRDA, FTL, Friedreich ferritin light chain; FXTAS, fragile X–associated tremor/ataxia syndrome; HDL, Huntington disease

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possibly mimicking HD.41,42 Cases with acquired causes of cho- Finally, our custom-made 63-gene panel allowed us to iden- rea are treatable, as in our patients, but relapses can occur. Dys- tify additional abnormalities in genes potentially responsible for immune chorea associated with Biermer disease has not been the phenotype in 5 other patients. One patient carried a previ- 19 previously reported, and the role of B12 avitaminosis in the ap- ously reported homozygous VPS13A truncating mutation. pearance of the choreic movements is debatable. However, cho- Acanthocytes had not been looked for initially.Two patients had

rea disappeared in SAL-2846-001 after vitamin B12 supple- mutations in CACNA1A, including one previously known mentation and did not recur. Other dysimmune diseases have mutation.26 Although unexpected, the mutation in CACNA1A been reported with chorea, including lupus, antiphospho- might cause an HD phenotype because of its interaction with lipid syndrome, Hashimoto thyroiditis, and celiac disease.43 junctophilin 3 in the nanoenvironment of the Cav2 channel.53 Furthermore, screening via the 63-gene panel did not detect The other variant (c.2879G>T; p.Arg960Leu) is predicted to be any pathological variants in SAL-2846-001. deleterious by all algorithms; it was unreported in controls and Patients without HTT expansions should first be screened affects a conserved amino acid in mammals. Although HD phe- for JPH3 because it is the only gene known to be responsible notype predominated in our 2 patients, with a typical neuro- for a neuropathological HD phenocopy.44 We found abnor- psychological profile, brain MRI showed global and cerebellar mal CTG expansions in JPH3 in 3 of 28 (10.7%) HD phenocop- atrophy. Notably, symptoms did not fluctuate, and CACNA1A ies herein, consistent with the 0% to 15% in previous studies mutations have also been reported to lead to more progressive (Table 2)5,29,30,32,35,37,39 and up to 30% in African populations.45 cerebellar ataxia, mental retardation, diplopia, tinnitus, ver- All previously published cases linked to abnormal JPH3 ex- tigo, and other movement disorders, such as dystonia and pansions were of African or Middle Eastern ancestry (Table 2) diploplia,54-56 with a high phenotypic variability even among (References 5, 6, 11, 29, 30, 32, 35, 37, 39). This was the case members of the same family.57 Therefore, our finding of a pro- for 2 patients herein (MON-1 and SAL-2 in Table 1), while a third gressive disorder with chorea further expands the clinical spec- patient (SAL-3 in Table 1) may have inherited the abnormal ex- trum of CACNA1A mutations. We must remain vigilant be- pansion from her French West Indian father or her French Cau- cause larger-scale sequencing reveals more putatively casian mother. The presence of a bidirectional transcription pathogenic variations, and some of them will turn out to be rare locus leading to CAG or CTG repeats according to the direc- variants and not necessarily cause HD. tion would explain the similar clinical presentations.46 How- Two of the 5 patients carried mutations in VCP or UBQNL2 ever, there is still no definite evidence that the expanded an- involved in ALS and FTD. This finding was less unexpected be- tisense transcript is translated as a polyQ repeat.47 cause dementia and behavioral abnormalities are predomi- We found no abnormal expansions in TBP/SCA17,previ- nant clinical signs in both HD and FTD. Predicted to be del- ously reported to be the most frequent genetic cause of HD phe- eterious by algorithms and never reported in controls or nocopy after HTT itself and before JPH3.37,40 Patients with ab- affecting a conserved amino acid, these variants are likely to normal TBP initially have cerebellar manifestations, in be implicated in the phenotype observed. particular ataxia and dysarthria, and they usually develop basal ganglia–related symptoms later, such as dystonia or chorea. The clinical heterogeneity is accompanied by MRI abnormalities Conclusions and atrophy of the cerebellum, cerebral cortex, and brain- stem in addition to the caudate nuclei.48 Therefore, patients In conclusion, the etiologies of HD phenocopies are heteroge- with abnormal TBP showing chorea were probably originally neous, and clinical evolution should be taken into account tested directly for mutations in this gene. when searching for a genetic cause. Only the JPH3-related HD We identified a subgroup of 4 patients with abnormal T2- phenocopy remains HDL as the disease progresses. The panel weighted signals in the basal ganglia caused by accumulation of candidate genes to be examined is larger than expected but of metal in the brain (eFigure in the Supplement). This finding can be guided by specific imaging and clinical features. We also led us to perform exome sequencing, but no variants were found identified mutations in VPS13A and unexpected genes, such in known NBIA-related genes (eTable 4 in the Supplement). The as CACNA1A (n=2),UBQLN2 (n = 1), and VCP (n = 1). These re- clinical and genetic spectrum of NBIA has broadened over the sults are supported by clinical evolution, predictions of del- last few years.49-51 During initial assessment, we did not sys- eterious effects of the mutations, and an absence of the vari- tematically look for PANK2 mutations because no patients had ants in healthy controls or public databases. Next-generation the eye-of-the-tiger sign, a hyperintensity in the center of the sequencing approaches need clinical feedback to guide inter- globi pallidi surrounded by hypointensity on T2-weighted pretation of the effects of the many genetic variants it identi- images.52 The PLA2G6 gene was not investigated initially be- fies. Other neurodegenerative diseases with late onset, such cause it is usually associated with adult-onset basal ganglia dis- as Parkinson disease, in which the segregation of variants can- ease, most often dystonia-parkinsonism, in which hypointen- not be verified, could be productively explored with a similar sity on T2-weighted sequences is a common finding. combined clinical and genetic approach.

ARTICLE INFORMATION Published Online: July 11, 2016. Department of Genetics, Paris, France (Mariani, Accepted for Publication: May9,2016. doi:10.1001/jamaneurol.2016.2215. Charles, Cazeneuve, Noël, Peuvion, Brice, Stevanin, Author Affiliations: Assistance Publique–Hôpitaux Durr); Assistance Publique–Hôpitaux de Paris, de Paris, Pitié-Salpêtrière University Hospital, Pitié-Salpêtrière University Hospital, Department of

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Neurology, Paris, France (Mariani, Charles, Hahn, received compensation. We are grateful to the and mosaic carriers in both sexes: implications for Freeman, Grabli, Roze); Institut du Cerveau et de la family members who contributed to the study. fragile X syndrome carrier and newborn screening. Moelle Epinière, Paris, France (Tesson, Grabli, Roze, Genet Med. 2010;12(3):162-173. Brice, Stevanin, Durr); Institut National de la Santé REFERENCES 16. Boukhris A, Schule R, Loureiro JL, et al. et de la Récherche Médicale Unité 1127, Centre 1. Huntington’s Disease Collaborative Research Alteration of ganglioside biosynthesis responsible National de la Recherche Scientifique Unité Mixte Group. A novel gene containing a trinucleotide for complex hereditary spastic paraplegia. Am J de Recherche 7225, Sorbonne Universités, repeat that is expanded and unstable on Hum Genet. 2013;93(1):118-123. Université Pierre et Marie Curie University Paris 06 Huntington’s disease chromosomes. Cell. 1993;72 17. Boutell JM, Thomas P, Neal JW, et al. Aberrant Unité Mixte de Recherche S1127, Paris, France (6):971-983. (Tesson, Roze, Brice, Stevanin, Durr); Ecole Pratique interactions of transcriptional repressor proteins des Hautes Etudes, Paris, France (Tesson, 2. Rosenblatt A, Ranen NG, Rubinsztein DC, et al. with the Huntington’s disease gene product, Stevanin); Assistance Publique–Hôpitaux de Paris, Patients with features similar to Huntington’s huntingtin. Hum Mol Genet. 1999;8(9):1647-1655. Unité de Neurologie de la Mémoire et du Langage, disease, without CAG expansion in huntingtin. 18. Kaltenbach LS, Romero E, Becklin RR, et al. Centre Hospitalier Saint-Anne, Paris, France (Hahn); Neurology. 1998;51(1):215-220. Huntingtin interacting proteins are genetic Assistance Publique–Hôpitaux de Paris, Reference 3. Bates GP, Tabrizi SJ, Jones L. Huntington’s Disease. modifiers of neurodegeneration. PLoS Genet.2007; Centre for Huntington’s Disease, Unité New York, NY: Oxford University Press; 2014. 3(5):e82. doi:10.1371/journal.pgen.0030082. Fonctionnelle de Neurologie Cognitive, Henri 4. Roze E, Bonnet C, Betuing S, Caboche J. 19. Rampoldi L, Dobson-Stone C, Rubio JP, et al. Mondor University Hospital, Créteil, France Huntington’s disease. Adv Exp Med Biol. 2010;685: A conserved sorting-associated protein is mutant in (Youssov, Bachoud-Levi); Institut National de la 45-63. chorea-acanthocytosis. Nat Genet. 2001;28(2): Santé et de la Récherche Médicale Unité 955 Team 119-120. 1, Institut Mondor de Recherche Biomédicale, 5. Holmes SE, O’Hearn E, Rosenblatt A, et al. Faculté de Médecine de Créteil, Créteil, France A repeat expansion in the gene encoding 20. Dobson-Stone C, Danek A, Rampoldi L, et al. (Youssov, Bachoud-Levi); Institut d’Etude de la junctophilin-3 is associated with Huntington Mutational spectrum of the CHAC gene in patients Cognition, Ecole Normale Supérieure, Paris, France disease–like 2 [published correction appears in Nat with chorea-acanthocytosis. Eur J Hum Genet. (Youssov, Bachoud-Levi); Department of Genet. 2002;30(1):123]. Nat Genet. 2001;29(4): 2002;10(11):773-781. Neurology, McGovern Medical School, UTHealth, 377-378. 21. Watts GD, Wymer J, Kovach MJ, et al. Inclusion Houston, Texas (Freeman). 6. Stevanin G, Fujigasaki H, Lebre AS, et al. body myopathy associated with Paget disease of Author Contributions: Dr Durr had full access to all Huntington’s disease–like phenotype due to bone and frontotemporal dementia is caused by the data in the study and takes responsibility for the trinucleotide repeat expansions in the TBP and mutant valosin-containing protein. Nat Genet. integrity of the data and the accuracy of the data JPH3 genes. Brain. 2003;126(pt 7):1599-1603. 2004;36(4):377-381. analysis. Drs Mariani and Tesson are co–first 7. Connarty M, Dennis NR, Patch C, Macpherson 22. Johnson JO, Mandrioli J, Benatar M, et al; authors. JN, Harvey JF. Molecular re-investigation of ITALSGEN Consortium. Exome sequencing reveals Study concept and design: Mariani, Brice, Stevanin, patients with Huntington’s disease in Wessex VCP mutations as a cause of familial ALS. Neuron. Durr. reveals a family with dentatorubral and 2010;68(5):857-864. Acquisition, analysis, or interpretation of data: pallidoluysian atrophy. Hum Genet. 1996;97(1): 23. Zhang KY, Yang S, Warraich ST, Blair IP. Ubiquilin Mariani, Tesson, Charles, Cazeneuve, Hahn, 76-78. 2: a component of the ubiquitin-proteasome Youssov, Freeman, Grabli, Roze, Noël, Peuvion, 8. Hensman Moss DJ, Poulter M, Beck J, et al. system with an emerging role in neurodegen Bachoud-Levi, Stevanin, Durr. C9ORF72 expansions are the most common genetic eration. Int J Biochem Cell Biol. 2014;50:123-126. Drafting of the manuscript: Mariani, Tesson, cause of Huntington disease phenocopies. Neurology. 24. Rutherford NJ, Lewis J, Clippinger AK, et al. Cazeneuve, Stevanin, Durr. 2014;82(4):292-299. Critical revision of the manuscript for important Unbiased screen reveals ubiquilin-1 and -2 highly intellectual content: All authors. 9. Koutsis G, Karadima G, Kartanou C, Kladi A, associated with huntingtin inclusions. Brain Res. Obtained funding: Mariani, Tesson, Hahn. Panas M. C9ORF72 hexanucleotide repeat 2013;1524:62-73. Administrative, technical, or material support: expansions are a frequent cause of Huntington 25. Deng HX, Chen W, Hong ST, et al. Mutations in Tesson, Charles, Cazeneuve, Youssov, Freeman, disease phenocopies in the Greek population. UBQLN2 cause dominant X-linked juvenile and Grabli, Roze, Noël, Peuvion, Bachoud-Levi, Neurobiol Aging. 2015;36(1):547.e13-547.e16. adult-onset ALS and ALS/dementia. Nature. 2011; Stevanin, Durr. doi:10.1016/j.neurobiolaging.2014.08.020. 477(7363):211-215. Study supervision: Brice, Stevanin, Durr. 10. Laplanche JL, Hachimi KH, Durieux I, et al. 26. Mantuano E, Veneziano L, Spadaro M, et al. Conflict of Interest Disclosures: None reported. Prominent psychiatric features and early onset in an Clusters of non-truncating mutations of P/Q type inherited prion disease with a new insertional 2+ Funding/Support: This work was funded by grant Ca channel subunit Cav2.1 causing episodic ataxia mutation in the prion protein gene. Brain. 1999;122 2. J Med Genet. 2004;41(6):e82. doi:10.1136/jmg ANR-10-IAIHU-06 from the Investissements (pt 12):2375-2386. d’Avenir program (to the Institut du Cerveau et de la .2003.015396. Moelle Epinière), by the VERUM Foundation (Dr 11. Moore RC, Xiang F, Monaghan J, et al. 27. Andrew SE, Goldberg YP, Kremer B, et al. Brice), by grant R12123DD from the Fondation Huntington disease phenocopy is a familial prion Huntington disease without CAG expansion: Roger de Spoelberch (Dr Brice), and by the Ministry disease. Am J Hum Genet. 2001;69(6):1385-1388. phenocopies or errors in assignment? Am J Hum of Health (to the Reference Centre for Huntington’s 12. Dürr A, Dodé C, Hahn V, et al. Diagnosis of Genet. 1994;54(5):852-863. Disease, coordinated by Dr Bachoud-Levi). “sporadic” Huntington’s disease. J Neurol Sci. 1995; 28. Vuillaume I, Meynieu P, Schraen-Maschke S, Role of the Funder/Sponsor: The funding sources 129(1):51-55. Destée A, Sablonnière B. Absence of unidentified had no role in the design and conduct of the study; 13. Schneider SA, Walker RH, Bhatia KP. The CAG repeat expansion in patients with Huntington’s collection, management, analysis, or interpretation Huntington’s disease–like syndromes: what to disease–like phenotype. J Neurol Neurosurg of the data; preparation, review, or approval of the consider in patients with a negative Huntington’s Psychiatry. 2000;68(5):672-675. manuscript; and decision to submit the manuscript disease gene test. Nat Clin Pract Neurol. 2007;3(9): 29. Bauer I, Gencik M, Laccone F, et al. for publication. 517-525. Trinucleotide repeat expansions in the Additional Contributions: The DNA and cell bank 14. DeJesus-Hernandez M, Mackenzie IR, junctophilin-3 gene are not found in Caucasian and genotyping/sequencing (Emeline Mundwiller) Boeve BF, et al. Expanded GGGGCC hexanucleotide patients with a Huntington’s disease–like and biostatistics/bioinformatics (Justine Guegan) repeat in noncoding region of C9ORF72 causes phenotype. Ann Neurol. 2002;51(5):662. facilities of the Institut du Cerveau et de la Moelle chromosome 9p–linked FTD and ALS. Neuron. 2011; 30. Stevanin G, Camuzat A, Holmes SE, et al. Epinière provided technical assistance. Thomas 72(2):245-256. CAG/CTG repeat expansions at the Huntington’s Meitinger, MD, PhD (Institute of Human Genetics, 15. Hantash FM, Goos DG, Tsao D, et al. Qualitative disease–like 2 locus are rare in Huntington’s disease Helmholtz Zentrum München, Neuherberg, assessment of FMR1 (CGG)n triplet repeat status in patients. Neurology. 2002;58(6):965-967. Germany) assisted with genetic analysis. None normal, intermediate, premutation, full mutation,

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31. Bauer P, Laccone F, Rolfs A, et al. Trinucleotide 40. Wild EJ, Tabrizi SJ. Huntington’s disease 50. Kruer MC, Boddaert N, Schneider SA, et al. repeat expansion in SCA17/TBP in white patients phenocopy syndromes. Curr Opin Neurol.2007;20 Neuroimaging features of neurodegeneration with with Huntington’s disease–like phenotype. J Med (6):681-687. brain iron accumulation. AJNR Am J Neuroradiol. Genet. 2004;41(3):230-232. 41. Reiner P, Galanaud D, Leroux G, et al. Long-term 2012;33(3):407-414. 32. Margolis RL, Holmes SE, Rosenblatt A, et al. outcome of 32 patients with chorea and systemic 51. Schneider SA, Hardy J, Bhatia KP. Syndromes of Huntington’s disease–like 2 (HDL2) in North lupus erythematosus or antiphospholipid neurodegeneration with brain iron accumulation America and Japan [published correction appears in antibodies. Mov Disord. 2011;26(13):2422-2427. (NBIA): an update on clinical presentations, Ann Neurol. 2004;56(6):911]. Ann Neurol. 2004;56 42. Reiner P, Piette JC, Leroux G, Vidailhet M, histological and genetic underpinnings, and (5):670-674. Costedoat-Chalumeau N. [Chorea, lupus and treatment considerations. Mov Disord. 2012;27(1): 33. Cellini E, Forleo P, Nacmias B, et al. antiphospholipid antibodies] [in French]. Rev Med 42-53. Spinocerebellar ataxia type 17 repeat in patients Interne. 2012;33(4):206-208. 52. Hayflick SJ, Hartman M, Coryell J, Gitschier J, with Huntington’s disease–like and ataxia. Ann Neurol. 43. Pereira AC, Edwards MJ, Buttery PC, et al. Rowley H. Brain MRI in neurodegeneration with 2004;56(1):163. doi:10.1002/ana.20146. Choreic syndrome and coeliac disease: a hitherto brain iron accumulation with and without PANK2 34. Keckarević M, Savić D, Svetel M, Kostić V, unrecognised association. Mov Disord. 2004;19(4): mutations. AJNR Am J Neuroradiol. 2006;27(6): Vukosavić S, Romac S. Yugoslav HD phenocopies 478-482. 1230-1233. analyzed on the presence of mutations in PrP, 44. Rudnicki DD, Pletnikova O, Vonsattel JP, Ross 53. Müller CS, Haupt A, Bildl W, et al. Quantitative ferritin, and JP-3 genes. Int J Neurosci. 2005;115(2): CA, Margolis RL. A comparison of Huntington proteomics of the Cav2 channel 299-301. disease and Huntington disease–like 2 nano-environments in the mammalian brain. Proc 35. Costa Mdo C, Teixeira-Castro A, Constante M, neuropathology. J Neuropathol Exp Neurol. 2008; Natl Acad SciUSA. 2010;107(34):14950-14957. et al. Exclusion of mutations in the PRNP, JPH3, 67(4):366-374. 54. Jung J, Testard H, Tournier-Lasserve E, et al. TBP, ATN1, CREBBP, POU3F2 and FTL genes as a 45. Krause A, Hetem C, Holmes SE, Margolis RL. Phenotypic variability of episodic ataxia type 2 cause of disease in Portuguese patients with a HDL2 mutations are an important cause of mutations: a family study. Eur Neurol. 2010;64(2): Huntington-like phenotype. J Hum Genet. 2006;51 Huntington’s disease in patients with African 114-116. (8):645-651. ancestry. J Neurol Neurosurg Psychiatry. 2005;76 55. Kinder S, Ossig C, Wienecke M, et al. Novel 36. Rodriguez-Revenga L, Santos MM, Sánchez A, (suppl 4):A16-A26. frameshift mutation in the CACNA1A gene causing a et al. Screening for FXTAS in 95 Spanish patients 46. Wilburn B, Rudnicki DD, Zhao J, et al. An mixed phenotype of episodic ataxia and familiar negative for Huntington disease. Genet Test. 2008; antisense CAG repeat transcript at JPH3 locus hemiplegic migraine. Eur J Paediatr Neurol. 2015;19 12(1):135-138. mediates expanded polyglutamine protein toxicity (1):72-74. 37. Wild EJ, Mudanohwo EE, Sweeney MG, et al. in Huntington’s disease–like 2 mice. Neuron. 2011; 56. Nachbauer W, Nocker M, Karner E, et al. Huntington’s disease phenocopies are clinically and 70(3):427-440. Episodic ataxia type 2: phenotype characteristics of genetically heterogeneous. Mov Disord. 2008;23 47. Seixas AI, Holmes SE, Takeshima H, et al. Loss a novel CACNA1A mutation and review of the (5):716-720. of junctophilin-3 contributes to Huntington literature. J Neurol. 2014;261(5):983-991. 38. Sułek-Piatkowska A, Krysa W, Zdzienicka E, disease–like 2 pathogenesis. Ann Neurol. 2012;71 57. García-Baró-Huarte M, Iglesias-Mohedano AM, et al. Searching for mutation in the JPH3, ATN1 and (2):245-257. Slöcker-Barrio M, et al. Phenotypic variability in a TBP genes in Polish patients suspected of 48. Zühlke C, Bürk K. Spinocerebellar ataxia type 17 four generation family with a p.Thr666Met Huntington’s disease and without mutation in the is caused by mutations in the TATA-box binding CACNA1A gene mutation. Pediatr Neurol. 2014;51 IT15 gene. Neurol Neurochir Pol. 2008;42(3): protein. Cerebellum. 2007;6(4):300-307. (4):557-559. 203-209. 49. Hartig MB, Iuso A, Haack T, et al. Absence of an 39. Rodrigues GR, Walker RH, Bader B, et al. orphan mitochondrial protein, C19orf12, causes a Clinical and genetic analysis of 29 Brazilian patients distinct clinical subtype of neurodegeneration with with Huntington’s disease–like phenotype. Arq brain iron accumulation. Am J Hum Genet. 2011;89 Neuropsiquiatr. 2011;69(3):419-423. (4):543-550.

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