Clinical Review & Education
Review
Genetic Movement Disorders in Patients of Jewish Ancestry Rivka Inzelberg, MD; Sharon Hassin-Baer, MD; Joseph Jankovic, MD
IMPORTANCE Genetic diseases often cluster in different ethnic groups and may present with
recognizable unique clinical manifestations. OBJECTIVE To summarize current knowledge about movement disorders overrepresented among patients of Jewish ancestry. EVIDENCE REVIEW 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. FINDINGS About one-third of patients with sporadic Parkinson disease (PD) and more than 40% ofpatientswithfamilialPDofAshkenaziJewishdescentlikelycarrytheG2019SmutationintheLRRK2 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. CONCLUSIONS AND RELEVANCE Genetic forms of PD are much more common in patients of Ashke-
nazi 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. JAMA Neurol. 2014;71(12):1567-1572. doi:10.1001/jamaneurol.2014.1364 Published online October 27, 2014.
G
enetic diseases often cluster in different ethnic groups with unique clinical manifestations and pathogenic mechanisms. Recognition of the particular clinical phenotype, coupled with information about the ethnic origin of the patients, often leads to early and correct diagnosis. The primary aim of this review is to summarize current knowledge about genetic hypokinetic and hyperkinetic movement disorders overrepresented among adult patients of Jewish ancestry. Jewish origins trace to the indigenous Israelite tribes of Canaan living in the Middle East more than 3 millennia ago who later generated the ethnic Ashkenazi, Sephardi, and Yemenite Jewish groups. In this review we focus on diseases apparently clustered in individuals of Jewish ancestry, although whether they are more prevalent in this ethnic subgroup compared with other populations is not always clear.
Methods We searched PubMed and the OMIM and Israeli National Genetic Databases1 from 1969 through March 31, 2014, and used references from relevant articles. Search terms included Parkinson’s disjamaneurology.com
Author Affiliations: Parkinson’s Disease and Movement Disorders Clinic, Sagol Neuroscience Center, Department of Neurology, Sheba Medical Center, Tel Hashomer, Israel (Inzelberg, Hassin-Baer); Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Israel (Inzelberg, Hassin-Baer); Parkinson’s Disease Center and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, Houston, Texas (Jankovic). Corresponding Author: Rivka Inzelberg, MD, Parkinson’s Disease and Movement Disorders Clinic, Sagol Neuroscience Center, Department of Neurology, Sheba Medical Center, 52621 Tel Hashomer, Israel ([email protected] or [email protected]). Section Editor: David E. Pleasure, MD.
ease, movement disorders, ataxia, dystonia, chorea, and CreutzfeldtJakob with and Jewish without language restrictions. The final reference list was generated by giving priority to the articles directly related to the topic, articles with the latest information, and comprehensive but relevant reviews.
Genetic Forms of Parkinson Disease in Patients of Jewish Ancestry An autosomal dominant form of Parkinson disease (PD), PARK8, has been observed with higher-than-expected frequency in Ashkenazi Jewish patients with PD (Figure 1 and Figure 2).2-4,9 The causative gene encodes for leucine-rich repeat kinase 2 (LRRK2 [OMIM *609007]; chromosome 12q12). The G2019S mutation (G2019S*LRRK2) is the most prevalent single genetic determinant of PD identified to date, present in about 4% of patients with familial PD and in 1% with sporadic PD worldwide (Table 1). Remarkably, the highest rates worldwide are observed among patients with familial PD who are of Ashkenazi Jewish (30%) and North African Arab (40%) origins.2,3,12,13 In Ashkenazi Jews, the frequency of this muJAMA Neurology December 2014 Volume 71, Number 12
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archneur.jamanetwork.com/ by a University of North Dakota User on 05/15/2015
1567
Clinical Review & Education Review
Genetic Movement Disorders in Jewish Patients
Figure 1. Mutations in Ashkenazi Jewish Patients With Apparent Sporadic Parkinson Disease (PD)
Ashkenazi Jewish Patients With Sporadic PD, %
40
30
20
10
0
LRRK2
GBA
LRRK2 and GBA
SMPD1
About one-third of Ashkenazi Jewish patients with sporadic PD carry a mutation. Data are derived for the gene encoding leucine-rich repeat kinase 2 (LRRK2) (reported range, 6%-3%)2-6; the glucocerebrosidase gene (GBA) (calculated as 18%)7; LRRK2 and GBA (calculated as
Review
Genetic Movement Disorders in Patients of Jewish Ancestry Rivka Inzelberg, MD; Sharon Hassin-Baer, MD; Joseph Jankovic, MD
IMPORTANCE Genetic diseases often cluster in different ethnic groups and may present with
recognizable unique clinical manifestations. OBJECTIVE To summarize current knowledge about movement disorders overrepresented among patients of Jewish ancestry. EVIDENCE REVIEW 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. FINDINGS About one-third of patients with sporadic Parkinson disease (PD) and more than 40% ofpatientswithfamilialPDofAshkenaziJewishdescentlikelycarrytheG2019SmutationintheLRRK2 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. CONCLUSIONS AND RELEVANCE Genetic forms of PD are much more common in patients of Ashke-
nazi 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. JAMA Neurol. 2014;71(12):1567-1572. doi:10.1001/jamaneurol.2014.1364 Published online October 27, 2014.
G
enetic diseases often cluster in different ethnic groups with unique clinical manifestations and pathogenic mechanisms. Recognition of the particular clinical phenotype, coupled with information about the ethnic origin of the patients, often leads to early and correct diagnosis. The primary aim of this review is to summarize current knowledge about genetic hypokinetic and hyperkinetic movement disorders overrepresented among adult patients of Jewish ancestry. Jewish origins trace to the indigenous Israelite tribes of Canaan living in the Middle East more than 3 millennia ago who later generated the ethnic Ashkenazi, Sephardi, and Yemenite Jewish groups. In this review we focus on diseases apparently clustered in individuals of Jewish ancestry, although whether they are more prevalent in this ethnic subgroup compared with other populations is not always clear.
Methods We searched PubMed and the OMIM and Israeli National Genetic Databases1 from 1969 through March 31, 2014, and used references from relevant articles. Search terms included Parkinson’s disjamaneurology.com
Author Affiliations: Parkinson’s Disease and Movement Disorders Clinic, Sagol Neuroscience Center, Department of Neurology, Sheba Medical Center, Tel Hashomer, Israel (Inzelberg, Hassin-Baer); Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Israel (Inzelberg, Hassin-Baer); Parkinson’s Disease Center and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, Houston, Texas (Jankovic). Corresponding Author: Rivka Inzelberg, MD, Parkinson’s Disease and Movement Disorders Clinic, Sagol Neuroscience Center, Department of Neurology, Sheba Medical Center, 52621 Tel Hashomer, Israel ([email protected] or [email protected]). Section Editor: David E. Pleasure, MD.
ease, movement disorders, ataxia, dystonia, chorea, and CreutzfeldtJakob with and Jewish without language restrictions. The final reference list was generated by giving priority to the articles directly related to the topic, articles with the latest information, and comprehensive but relevant reviews.
Genetic Forms of Parkinson Disease in Patients of Jewish Ancestry An autosomal dominant form of Parkinson disease (PD), PARK8, has been observed with higher-than-expected frequency in Ashkenazi Jewish patients with PD (Figure 1 and Figure 2).2-4,9 The causative gene encodes for leucine-rich repeat kinase 2 (LRRK2 [OMIM *609007]; chromosome 12q12). The G2019S mutation (G2019S*LRRK2) is the most prevalent single genetic determinant of PD identified to date, present in about 4% of patients with familial PD and in 1% with sporadic PD worldwide (Table 1). Remarkably, the highest rates worldwide are observed among patients with familial PD who are of Ashkenazi Jewish (30%) and North African Arab (40%) origins.2,3,12,13 In Ashkenazi Jews, the frequency of this muJAMA Neurology December 2014 Volume 71, Number 12
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archneur.jamanetwork.com/ by a University of North Dakota User on 05/15/2015
1567
Clinical Review & Education Review
Genetic Movement Disorders in Jewish Patients
Figure 1. Mutations in Ashkenazi Jewish Patients With Apparent Sporadic Parkinson Disease (PD)
Ashkenazi Jewish Patients With Sporadic PD, %
40
30
20
10
0
LRRK2
GBA
LRRK2 and GBA
SMPD1
About one-third of Ashkenazi Jewish patients with sporadic PD carry a mutation. Data are derived for the gene encoding leucine-rich repeat kinase 2 (LRRK2) (reported range, 6%-3%)2-6; the glucocerebrosidase gene (GBA) (calculated as 18%)7; LRRK2 and GBA (calculated as
