Machado-Joseph Disease Research Articles

Ubiquitin-specific proteases are differentially expressed throughout the Schistosoma mansoni life cycle.

BackgroundThe ubiquitination process can be reversed by deubiquitinating enzymes (DUBs). These proteases are involved in ubiquitin processing, in the recovery of modified ubiquitin trapped in inactive forms, and in the recycling of ubiquitin monomers from polyubiquitinated chains. The diversity of DUB functions is illustrated by their number and variety of their catalytic domains with specific 3D architectures. DUBs can be divided into five subclasses: ubiquitin C-terminal hydrolases (UCHs), ubiquitin-specific proteases (USPs or UBPs), ovarian tumour proteases (OTUs), Machado-Joseph disease proteases (MJDs) and JAB1/MPN/Mov34 metalloenzymes (JAMMs).MethodsConsidering the role that the ubiquitin-proteasome system has been shown to play during the development of Schistosoma mansoni, our main goal was to identify and characterize SmUSPs. Here, we showed the identification of putative ubiquitin-specific proteases using bioinformatic approaches. We also evaluated the gene expression profile of representative USP family members using qRT-PCR.ResultsWe reported 17 USP family members in S. mansoni that present a conservation of UCH domains. Furthermore, the putative SmUSP transcripts analysed were detected in all investigated stages, showing distinct expression during S. mansoni development. The SmUSPs exhibiting high expression profiles were SmUSP7, SmUSP8, SmUSP9x and SmUSP24.ConclusionS. mansoni USPs showed changes in expression levels for different life cycle stages indicating their involvement in cellular processes required for S. mansoni development. These data will serve as a basis for future functional studies of USPs in this parasite.Electronic supplementary materialThe online version of this article (doi:10.1186/s13071-015-0957-4) contains supplementary material, which is available to authorized users.

Health and the Value of Inheritance: The meanings surrounding a rare genetic disease

In this article I explore the meanings acquired by the notion of 'genetic inheritance' for families in Rio de Janeiro affected by a rare hereditary disorder, Machado-Joseph disease. My analysis examines three points: 1) how experience of the disease was thematized in the family prior to knowledge of its genetic and hereditary origin; 2) how knowledge of genetics affected the family's perception of their health and reproduction through the notion of risk contained in medical explanations; 3) finally, I problematize the meanings of 'hope,' a sentiment frequently cited by people with the disease and their descendants. Notably, despite the high value attributed to science and 'medical progress,' the use of certain biotechnologies is not always seen as positive or capable of enabling choices and actions in response to a rare disease. Notions of risk, responsibility and hope thus acquire singular contours for managing life and the continuity of the family.

Heterozygous Deletion of KLHL1/ATX8OS at the SCA8 Locus Is Unlikely Associated With Cerebellar Impairment in Humans

Spinocerebellar ataxia type 8 (SCA8) (MIM 608768) is a dominantly inherited ataxia typically occurring in adulthood, with onset of the disease that may range from age 1 to 65 years [1–6]. Common initial symptoms are scanning dysarthria with a characteristic drawn-out slowness of speech and gait instability. Some individuals present with nystagmus, dysmetric saccades and, occasionally ophthalmoplegia. Hyperreflexia and extensor plantar responses are present in some severely affected individuals. Life span is typically not shortened. SCA8 is caused by repeat expansions initially thought to involve a non-coding CTG tract in the ATXN8OS gene— formerly known as SCA8 (MIM 603680)—an untranslated antisense transcript partially overlapping the Kelch-like 1 gene (KLHL1) (MIM 605332) [7]. The CTG repeat was later found to be transcribed also in the opposite direction as (CAG)n repeat in the ATXN8 gene, encoding a nearly pure polyglutamine protein [8]. An RNA toxic effect of the CUG expanded repeats has been suggested, together with the possibility of non-ATG translation (RAN translation) which occurs across long, hairpin-forming repeats and results in the accumulation of potentially toxic SCA8 polyalanine [9, 10]. The (CTG.CAG)n repeat length most often associated with ataxia ranges from 80 to 250. However, repeats from 71 to more than 1300 have been occasionally found in individuals with ataxia. The disease is characterized by a reduced penetrance most often with alleles of fewer than 100 repeats. We report two unrelated families with genomic deletions completely overlapping ATXN8OS gene and great part of KLHL1 gene. These deletions were present in a healthy parent in both families. A total of four subjects with ATXN8OS/ KLHL1 genes deletion could be studied and did not show any cerebellar symptoms or MRI changes in cerebellum.

Subjects At-Risk for Genetic Diseases in Portugal: Illness Representations.

This study investigates illness representations of subjects at-risk for 3 autosomal dominant late-onset disorders: Familial Amyloid Polyneuropathy (FAP) TTR V30M, Huntington's disease (HD) and Machado-Joseph disease (MJD), comparing them with the illness representations of subjects at-risk for Hemochromatosis (HH). The present study included a clinical group that consisted of 213 subjects at genetic risk (FAP, HD and MJD), comprising 174 subjects at-risk for FAP, 34 subjects at-risk for HD and only 5 subjects at-risk for MJD; and the control group consisting of 31 subjects at genetic risk for HH. All subjects at-risk were undergoing the process of genetic counseling to learn their genetic status (carrier or non-carrier). Subjects were assessed through a semi-structured single interview, in order to obtain sociodemographic data and the answer to an open-ended question relating to the illness representation issue: "What does this illness mean to you?/ What is this disease to you?" It was in the subjects' metaphors that subjects best expressed what they felt regarding the disease and the situation of being at-risk for this disease. Family is their mirror and their source of learning and, therefore, it is inevitable that family is related to the meaning of the disease itself.

582. Role of MicroRNA Deregulation in Machado-Joseph Disease

Machado-Joseph disease (MJD) or spinocerebellar ataxia type 3 (SCA3) is an autosomal dominant neurodegenerative disorder caused by an abnormal CAG expansion in the coding region of ATXN3/MJD1 gene. This confers a toxic gain-of-function to the ataxin-3 protein leading to neurodegeneration and severe motor impairments. There is no therapy to delay disease progression.MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate gene expression at post-transcriptional level. miRNAs have been reported to play a significant role in a variety of diseases, including neurodegenerative disorders. However, the profiles and regulation of miRNAs in MJD are not well understood. Therefore, the aims of this study were 1) to screen the microRNA levels in a MJD mouse model and 2) to investigate functional effects of reestablishing normal levels of the de-regulated miRNAs using the same MJD mouse model.For this purpose, we used a MJD striatal lentiviral mouse model that we previously described (Simoes et al., 2012), by injecting mutant ataxin-3 in one hemisphere and wild type ataxin-3 (as an internal control) in the other hemisphere. Two weeks post-injection, miRNA expression was profiled by miRNA microarray analysis.Six miRNAs were found differentially expressed in MJD striatal samples, a result that was validated by qRT-PCR. We then used bioinformatic tools to predict the targets for the validated miRNAs and analyzed the respective levels. One candidate miR was up-regulated and the predicted target was down-regulated. To investigate whether reinstating the normal levels of the candidate miR would alleviate neuropathology, we then co-injected lentiviral vectors encoding an inhibitor of the candidate miR and mutant ataxin-3 in one hemisphere, and mutant ataxin-3 with miR negative inhibitor (as an internal control) in the other hemisphere. Five weeks post-injection we evaluated the neuropathological features and observed that in the hemisphere injected with the miR inhibitor there was a significant reduction of the loss of DARPP-32 neuronal marker and also a reduction of the mutant ataxin-3 aggregates as verified by western blot.Altogether our results provide new insights in the pathogenesis of MJD and identify a candidate miR that may be a promising target for MJD.

PP12.16 – 2973: Congenital cerebellar ataxias – Clinical, radiological and genetic considerations

Objective Congenital ataxias, according to Harding's classification, represent a subgroup of early onset ataxias. The aim of this study was to evaluate initial clinical presentations, course of the disease and MRI characteristics in order to prioritize future investigations, including appropriate genetic testing. Methods The patients were selected from clinical ataxia registry at the tertiary center (n=51) after excluding patients with cerebellar malformations, later ataxia onset and known underlying disease. We focused on the following points: 1) congenital onset&clinical course 2) associated features 3) occurrence of peripheral neuropathy 4) neuroimaging results. The statistical analysis has done using T test,: version SPSS 15.0. Results There were 14 subjects (27.5%) from 10 kindred presented with congenital onset – 3 families with 2 or more affected members. Clinical characteristics: 86% subjects initially presented with mild to severe generalized hypotonia and global development delay – the mean age of independent walking was 3.9±2.8 and speech 2.5±0.7. Early generalized ataxia is noticed in all subjects, accompanied with nystagmus in 57% and other ocular abnormalities in 64%. Tendon reflexes were present in 79%. The accompanying findings (n=5) were orthopedic – 3, dystonia – 1 and optic atrophy – 1 and axonal motor neuropathy in one. Laboratory and metabolic workup were negative in all subjects. 86% are functioning within normal or low intellectual level. Global cerebellar hypoplasia was the most common MRI finding – in 93% and correlated significantly with clinical findings. Genetic confirmation was obtained for one family – missense mutation in ITPR1 gene. Conclusion The selected group of patient, presented as non-progressive cerebellar ataxia, showed rather uniform clinical characteristics – mostly isolated ataxia “improving” with aging (SARA, t test 0.015). The presence of cerebellar hypoplasia on MRI mostly correlated with phenotypes, suggesting genetic basis of the disease. We assume that new DNA sequencing technologies would help delineate genetic and pathophysiological mechanism of congenital ataxias. Congenital ataxias, according to Harding's classification, represent a subgroup of early onset ataxias. The aim of this study was to evaluate initial clinical presentations, course of the disease and MRI characteristics in order to prioritize future investigations, including appropriate genetic testing. The patients were selected from clinical ataxia registry at the tertiary center (n=51) after excluding patients with cerebellar malformations, later ataxia onset and known underlying disease. We focused on the following points: 1) congenital onset&clinical course 2) associated features 3) occurrence of peripheral neuropathy 4) neuroimaging results. The statistical analysis has done using T test,: version SPSS 15.0. There were 14 subjects (27.5%) from 10 kindred presented with congenital onset – 3 families with 2 or more affected members. Clinical characteristics: 86% subjects initially presented with mild to severe generalized hypotonia and global development delay – the mean age of independent walking was 3.9±2.8 and speech 2.5±0.7. Early generalized ataxia is noticed in all subjects, accompanied with nystagmus in 57% and other ocular abnormalities in 64%. Tendon reflexes were present in 79%. The accompanying findings (n=5) were orthopedic – 3, dystonia – 1 and optic atrophy – 1 and axonal motor neuropathy in one. Laboratory and metabolic workup were negative in all subjects. 86% are functioning within normal or low intellectual level. Global cerebellar hypoplasia was the most common MRI finding – in 93% and correlated significantly with clinical findings. Genetic confirmation was obtained for one family – missense mutation in ITPR1 gene. The selected group of patient, presented as non-progressive cerebellar ataxia, showed rather uniform clinical characteristics – mostly isolated ataxia “improving” with aging (SARA, t test 0.015). The presence of cerebellar hypoplasia on MRI mostly correlated with phenotypes, suggesting genetic basis of the disease. We assume that new DNA sequencing technologies would help delineate genetic and pathophysiological mechanism of congenital ataxias.

487. Non-Viral Silencing of Machado-Joseph Disease Through the Systemic Route

Tese de doutoramento em Ciencias Farmaceuticas, na area de especializacao de Biotecnologia Farmaceutica, apresentada a Faculdade de Farmacia da Universidade de Coimbra

MJD and OTU deubiquitinating enzymes in Schistosoma mansoni.

The ubiquitination and deubiquitination of proteins can alter diverse cellular processes, such as proteolysis, trafficking, subcellular localisation, DNA repair, apoptosis and signal transduction. Deubiquitinating enzymes (DUBs) are responsible for removing ubiquitin from their target proteins. Previous reports have shown the presence of two subfamilies of DUBs in Schistosoma mansoni: Ub carboxyl-terminal hydrolase (UCH) and Ub-specific protease (USP). In this study, we analysed the ovarian tumour (OTU) and Machado-Joseph disease protein domain (MJD) proteases found in the Schistosoma mansoni genome database. An in silico analysis identified two different MJD subfamily members, SmAtaxin-3 and SmJosephin, and five distinct OTU proteases, SmOTU1, SmOTU3, SmOTU5a, SmOTU6b and SmOtubain. The phylogenetic analysis showed the evolutionary conservation of these proteins. Furthermore, the 3D structures confirmed the similarity of these proteins with human proteins. In addition, we performed quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and observed distinct expression profiles for all of the investigated transcripts between the cercariae, schistosomula and adult worm stages. Taken together, our data suggest that MJD and OTU subfamily members contribute to regulating the activity of the Ub-proteasome system during the life cycle of this parasite.

Novel candidate blood‐based transcriptional biomarkers of machado‐joseph disease

Machado-Joseph disease (or spinocerebellar ataxia type 3) is a late-onset polyglutamine neurodegenerative disorder caused by a mutation in the ATXN3 gene, which encodes for the ubiquitously expressed protein ataxin-3. Previous studies on cell and animal models have suggested that mutated ataxin-3 is involved in transcriptional dysregulation. Starting with a whole-transcriptome profiling of peripheral blood samples from patients and controls, we aimed to confirm abnormal expression profiles in Machado-Joseph disease and to identify promising up-regulated genes as potential candidate biomarkers of disease status. The Illumina Human V4-HT12 array was used to measure transcriptome-wide gene expression in peripheral blood samples from 12 patients and 12 controls. Technical validation and validation in an independent set of samples were performed by quantitative real-time polymerase chain reaction (PCR). Based on the results from the microarray, twenty six genes, found to be up-regulated in patients, were selected for technical validation by quantitative real-time PCR (validation rate of 81% for the up-regulation trend). Fourteen of these were further tested in an independent set of 42 patients and 35 controls; 10 genes maintained the up-regulation trend (FCGR3B, CSR2RA, CLC, TNFSF14, SLA, P2RY13, FPR2, SELPLG, YIPF6, and GPR96); FCGR3B, P2RY13, and SELPLG were significantly up-regulated in patients when compared with controls. Our findings support the hypothesis that mutated ataxin-3 is associated with transcription dysregulation, detectable in peripheral blood cells. Furthermore, this is the first report suggesting a pool of up-regulated genes in Machado-Joseph disease that may have the potential to be used for fine phenotyping of this disease. © 2015 International Parkinson and Movement Disorder Society.

High Serum GFAP Levels in SCA3/MJD May Not Correlate with Disease Progression.

Spinocerebellar ataxia type 3(SCA3), also known as Machado-Joseph disease (MJD), is the most frequent subtype of autosomal dominant inherited spinocerebellar ataxias, which caused by the expansion of CAG repeats in the ATXN3 gene. The number of CAG repeats of the abnormal allele determines the rate of disease progression in patients with SCA3/MJD. Markers to assess the clinical severity, to predict the course of illness and to monitor the efficacy of therapeutic measures, can be clinical, biological, and radiological. Here, we aimed to explore whether the serum glial fibrillary acidic protein (GFAP) may act as a biomarker in SCA3/MJD patients and to evaluate the correlation between some markers with the number of CAG repeats in SCA3/MJD patients. We showed that the serum levels of GFAP were significantly higher in SCA3/MJD patients than in controls. There was a strong positive correlation between the age-adjusted GFAP levels with the number of CAG repeats. Age-adjusted International Cooperative Ataxia Rating Scale (ICARS) scores and Scale for the Assessment and Rating of Ataxia (SARA) scores correlated with the number of CAG repeats. Raw scores and disease duration-adjusted GFAP levels, ICARS scores, and SARA scores were not correlated with the number of CAG repeats. Our results reveal novel evidence for the role of the triplet expansion in SCA3/MJD-associated neuronal damage.

Heterozygous variant in the ITPR1 gene - Responsible of Cerebellar ataxia phenotype (P2.101)

Heterozygous variant in the ITPR1 gene - Responsible of Cerebellar ataxia phenotype (P2.101)

Spinocerebellar Ataxia Type 3 (Machado-Joseph Disease) in Israel: Clinical Phenotype and Genotype of a Jew Yemenite Subpopulation (P2.129)

Spinocerebellar Ataxia Type 3 (Machado-Joseph Disease) in Israel: Clinical Phenotype and Genotype of a Jew Yemenite Subpopulation (P2.129)

Two novel SNPs in ATXN3 3' UTR may decrease age at onset of SCA3/MJD in Chinese patients.

Spinocerebellar ataxia type 3 (SCA3), or Machado—Joseph disease (MJD), is an autosomal dominantly-inherited disease that produces progressive problems with movement. It is caused by the expansion of an area of CAG repeats in a coding region of ATXN3. The number of repeats is inversely associated with age at disease onset (AO) and is significantly associated with disease severity; however, the degree of CAG expansion only explains 50 to 70% of variance in AO. We tested two SNPs, rs709930 and rs910369, in the 3’ UTR of ATXN3 gene for association with SCA3/MJD risk and with SCA3/MJD AO in an independent cohort of 170 patients with SCA3/MJD and 200 healthy controls from mainland China. rs709930 genotype frequencies were statistically significantly different between patients and controls (p = 0.001, α = 0.05). SCA3/MJD patients carrying the rs709930 A allele and rs910369 T allele experienced an earlier onset, with a decrease in AO of approximately 2 to 4 years. The two novel SNPs found in this study might be genetic modifiers for AO in SCA3/MJD.

The role of the mammalian DNA end-processing enzyme polynucleotide kinase 3'-phosphatase in spinocerebellar ataxia type 3 pathogenesis.

DNA strand-breaks (SBs) with non-ligatable ends are generated by ionizing radiation, oxidative stress, various chemotherapeutic agents, and also as base excision repair (BER) intermediates. Several neurological diseases have already been identified as being due to a deficiency in DNA end-processing activities. Two common dirty ends, 3’-P and 5’-OH, are processed by mammalian polynucleotide kinase 3’-phosphatase (PNKP), a bifunctional enzyme with 3’-phosphatase and 5’-kinase activities. We have made the unexpected observation that PNKP stably associates with Ataxin-3 (ATXN3), a polyglutamine repeat-containing protein mutated in spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph Disease (MJD). This disease is one of the most common dominantly inherited ataxias worldwide; the defect in SCA3 is due to CAG repeat expansion (from the normal 14–41 to 55–82 repeats) in the ATXN3 coding region. However, how the expanded form gains its toxic function is still not clearly understood. Here we report that purified wild-type (WT) ATXN3 stimulates, and by contrast the mutant form specifically inhibits, PNKP’s 3’ phosphatase activity in vitro. ATXN3-deficient cells also show decreased PNKP activity. Furthermore, transgenic mice conditionally expressing the pathological form of human ATXN3 also showed decreased 3’-phosphatase activity of PNKP, mostly in the deep cerebellar nuclei, one of the most affected regions in MJD patients’ brain. Finally, long amplicon quantitative PCR analysis of human MJD patients’ brain samples showed a significant accumulation of DNA strand breaks. Our results thus indicate that the accumulation of DNA strand breaks due to functional deficiency of PNKP is etiologically linked to the pathogenesis of SCA3/MJD.

Ataxin-3, DNA damage repair, and SCA3 cerebellar degeneration: on the path to parsimony?

Ataxin-3, DNA damage repair, and SCA3 cerebellar degeneration: on the path to parsimony?

Inactivation of PNKP by mutant ATXN3 triggers apoptosis by activating the DNA damage-response pathway in SCA3.

Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease (MJD), is an untreatable autosomal dominant neurodegenerative disease, and the most common such inherited ataxia worldwide. The mutation in SCA3 is the expansion of a polymorphic CAG tri-nucleotide repeat sequence in the C-terminal coding region of the ATXN3 gene at chromosomal locus 14q32.1. The mutant ATXN3 protein encoding expanded glutamine (polyQ) sequences interacts with multiple proteins in vivo, and is deposited as aggregates in the SCA3 brain. A large body of literature suggests that the loss of function of the native ATNX3-interacting proteins that are deposited in the polyQ aggregates contributes to cellular toxicity, systemic neurodegeneration and the pathogenic mechanism in SCA3. Nonetheless, a significant understanding of the disease etiology of SCA3, the molecular mechanism by which the polyQ expansions in the mutant ATXN3 induce neurodegeneration in SCA3 has remained elusive. In the present study, we show that the essential DNA strand break repair enzyme PNKP (polynucleotide kinase 3’-phosphatase) interacts with, and is inactivated by, the mutant ATXN3, resulting in inefficient DNA repair, persistent accumulation of DNA damage/strand breaks, and subsequent chronic activation of the DNA damage-response ataxia telangiectasia-mutated (ATM) signaling pathway in SCA3. We report that persistent accumulation of DNA damage/strand breaks and chronic activation of the serine/threonine kinase ATM and the downstream p53 and protein kinase C-δ pro-apoptotic pathways trigger neuronal dysfunction and eventually neuronal death in SCA3. Either PNKP overexpression or pharmacological inhibition of ATM dramatically blocked mutant ATXN3-mediated cell death. Discovery of the mechanism by which mutant ATXN3 induces DNA damage and amplifies the pro-death signaling pathways provides a molecular basis for neurodegeneration due to PNKP inactivation in SCA3, and for the first time offers a possible approach to treatment.

Increases in PKC gamma expression in trigeminal spinal nucleus is associated with orofacial thermal hyperalgesia in streptozotocin-induced diabetic mice

Painful diabetic polyneuropathy (PDN) at the early phrase of diabetes frequently exhibits increased responsiveness to nociception. In diabetic patients and animal models, alterations in the transmission of orofacial sensory information have been demonstrated in trigeminal system. Herein, we examined the changes of protein kinase Cγ subunit (PKCγ) in trigeminal spinal nucleus (Sp5C) and observed the development of orofacial thermal sensitivity in streptozotocin (STZ)-induced type 1 diabetic mice. With hyperglycemia and body weight loss, STZ mice exhibited orofacial thermal hyperalgesia, along with increased PKCγ expression in Sp5C. Insulin treatment at the early stage of diabetes could alleviate the orofacial thermal hyperalgesia and impaired increased PKCγ in Sp5C in diabetic mice. In summary, our results demonstrate that PKCγ might be involved in orofacial thermal hyperalgesia of diabetes, and early insulin treatment might be effective way to treat orofacial PDN.

Transplantation of cerebellar neural stem cells improves motor coordination and neuropathology in Machado-Joseph disease mice.

Machado-Joseph disease is a neurodegenerative disease without effective treatment. Patients with Machado-Joseph disease exhibit significant motor impairments such as gait ataxia, associated with multiple neuropathological changes including mutant ATXN3 inclusions, marked neuronal loss and atrophy of the cerebellum. Thus, an effective treatment of symptomatic patients with Machado-Joseph disease may require cell replacement, which we investigated in this study. For this purpose, we injected cerebellar neural stem cells into the cerebellum of adult Machado-Joseph disease transgenic mice and assessed the effect on the neuropathology, neuroinflammation mediators and neurotrophic factor levels and motor coordination. We found that upon transplantation into the cerebellum of adult Machado-Joseph disease mice, cerebellar neural stem cells differentiate into neurons, astrocytes and oligodendrocytes. Importantly, cerebellar neural stem cell transplantation mediated a significant and robust alleviation of the motor behaviour impairments, which correlated with preservation from Machado-Joseph disease-associated neuropathology, namely reduction of Purkinje cell loss, reduction of cellular layer shrinkage and mutant ATXN3 aggregates. Additionally, a significant reduction of neuroinflammation and an increase of neurotrophic factors levels was observed, indicating that transplantation of cerebellar neural stem cells also triggers important neuroprotective effects. Thus, cerebellar neural stem cells have the potential to be used as a cell replacement and neuroprotective approach for Machado-Joseph disease therapy.

Spinocerebellar ataxia type 3/Machado-Joseph disease manifested as spastic paraplegia: A clinical and genetic study.

The aim of the present study was to conduct a familial investigation and provide a genetic diagnosis to a family presenting with spastic paraplegia and clinically diagnosed with hereditary spastic paraplegia (HSP). Blood samples were obtained from the family, and mutations in the gene causing spinocerebellar ataxia type 3 (SCA3)/Machado-Joseph disease (MJD), known as MJD1, were analyzed using the polymerase chain reaction, 8% denaturing polyacrylamide gel electrophoresis, and T-vector ligation and sequencing. The trinucleotide repeat number of the mutant allele was 80, leading to a genetic diagnosis of SCA3/MJD. This suggests that patients with SCA3/MJD characteristically present with typical spastic paraplegia without evident manifestations of ataxia. For those families with HSP involving the nervous system and showing genetic anticipation, an MJD1 genetic diagnosis should be considered to assist in clinical diagnosis of HSP.

Genetic movement disorders in patients of Jewish ancestry.

Genetic diseases often cluster in different ethnic groups and may present with recognizable unique clinical manifestations. To summarize current knowledge about movement disorders overrepresented among patients of Jewish ancestry. We searched PubMed and the OMIM and Israeli National Genetic Databases for articles published from 1969 through March 31, 2014, using the search terms Parkinson's disease,movement disorders, ataxia, dystonia, chorea, and Creutzfeldt-Jakob with and Jewish. The final reference list was generated by giving priority to articles directly related to the topic, articles with the latest information, and comprehensive but relevant reviews. About one-third of patients with sporadic Parkinson disease (PD) and more than 40% of patients with familial PD of Ashkenazi Jewish descent likely carry the G2019S mutation in the LRRK2 gene, a mutation in the glucocerebrosidase (GBA) gene, or both. This finding contrasts with only a 10% frequency of these mutations in patients with PD who are of non-Jewish ancestry. A dystonia due to a TOR1A gene mutation is responsible for most early-onset autosomal dominant dystonia, and 90% of Ashkenazi Jews who develop early-onset disease have TOR1A-related dystonia. Familial Creutzfeldt-Jakob disease and cerebrotendinous xanthomatosis tend to cluster among Jews of North African descent, and Machado-Joseph disease is particularly frequent in Yemenite Jews. Genetic forms of PD are much more common in patients of Ashkenazi Jewish ancestry with sporadic and familial PD than in the non-Jewish population. The recognition of the particular movement disorder phenotype, coupled with information about the ethnic origin of the patients, may point to specific genetic testing and lead to early and correct diagnosis.