As I was sitting (and standing) in a synagogue over the holidays I let my mind wander, as I often do under similar circumstances, and tried to answer the eternal question: If God designated the Jews as the “Chosen People” why did he/she also referred to them as the “stiff-necked people”? (Exodus 32:9: “I have seen this people, and behold, it is a stiff-necked people”). Was God making an analogy between hard-to-control oxens and the stubborn and obstinate Isrealites who used them to plow the fields? While this is one explanation offered by Jewish scholars for the term “stiff-necked people”, as an academic neurologist, specializing in movement disorders, and someone who likes to challenge an established dogma, I raise the possibility that the stiff-necked Jews had a neurologic condition that caused neck spasms and/or neck stiffness. After all, it is well-accepted that Moses had a neurological condition that apparently caused a speech impediment (stuttering). Indeed, it is also well known that over the centuries and possibly millennia, Jews have had an increased risk for a variety of neurologic conditions, called movement disorders. This important association of neurologic movement disorders in people of Jewish ancestry has been recently described in a scientific article in JAMA Neurol (1), but I thought it would be important bring this to the attention of readers of this journal.
Recent analysis of DNA sequences shared by Ashkenazi Jewish (AJ) individuals has provided insight into early Ashkenazi history. This research suggests that the world AJ population shrunk to only 350 as recently as 700 years ago (“bottleneck”) and that subsequent AJ generations, now totaling in millions, were a mixture of European and Middle Eastern ancestry (2). Because of intermarriages various genetic metabolic and neurologic diseases, such as Tay-Sachs, Niemann-Pick disease, mucolipidosis type IV, and Gaucher disease, became more common in the AJ population. In this review we wish to focus on neurologic diseases,categorized as movement disorders, that are being increasingly recognized to be relatively more frequent in people of Jewish ancestry compared to general population.
What are movement disorders? Movement disorders is a group of neurologic conditions that can be divided into slow movements (hypokinetic disorders) or abnormal involuntary movements (hyperkinesias). The best example of a hypokinetic movement disorder is Parkinson’s disease. Hyperkinetic movement disorders are subdivided into tremors, dystonia, tics, chorea, athetosis, ballism, stereotypy, and akathisia. The latter term, akathisia, refers to motor restlessness, known in Yiddish as “the shpilke”. Restless legs syndrome, another movement disorder that could be described as “the shpilke”, refers to restlessness that occurs chiefly at night and predominantly involves the legs. Furthermore, incoordination, gait and balance disorders, and abnormalities in muscle tone (such as spasticity and rigidity) are also included among movement disorders (3,4). While the basal ganglia, the deep part of the brain that is involved in the fine controls of body movements, have been implicated in most of the movement disorders, there are many other parts of the central and peripheral nervous system that may be involved. Since the diagnosis of a movement disorder is based on accurate recognition of specific phenomenological features, clinicians who encounter patients with movement disorders must use their powers of observation to carefully characterize the disorder. Therefore, the phenomenological categorization of the movement disorder is absolutely critical in formulating the differential diagnosis, finding the cause, and selecting the most appropriate treatment (5).
The following is a brief summary of the most common movement disorders highlighting those that are particularly common in people of AJ ancestry.
Parkinson’s disease is a neurodegenerative disease starting typically in the 6th progressive slowness of movement, tremor, stiffness (rigidity), and gait and balance problems, and a variety of motor and non-motor symptoms. Although dopamine deficiency is the main neurotransmitter abnormality in the brains of patients with Parkinson’s disease, there are many other biochemical and pathological changes that result in the rich variety of symptoms associated with the disease (6).
While only about 5% of patients in general population have a specific genetic mutation causing their Parkinson’s disease, more than a third of all Israeli AJ Parkinson’s patients carry at least one of two mutations: GBA or LRRK2 (1). GBA gene, localized on chromosome 1, encodes the enzyme glucocerebrosidase, which is deficient in Gaucher disease, a rare metabolic disease, causing anemia, enlarged liver, and a variety of neurologic abnormalities. Mutations in LRRK2 gene (chromosome 12) have been identified in less than 4% of patients with Parkinson’s disease in general population but abnormalities in the LRRK2 gene account for about 30% of Parkinson’s cases in AJ patients. The original mutation in this gene has been estimated to have occurred in the North African Arab-Berbers between the 13th and 2nd century BC. Others have suggested that the founder lived 4,000 or 2,250 years ago in the Near East, when the ancestral Jewish and Arab populations lived in close proximity.
Dystonia is neurologic movement disorder characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive, movements, postures, or both (7). The condition was first described in 1911 by a German-Jewish neurologist Herrman Oppenheim (8). Oppenheim described four Jewish children who were referred to him from Galicia and Russia. He noted that these children had several features in common: 1) muscle spasms affecting limbs and trunk that resulted in twisted postures; 2) these abnormal movements worsened with walking and were associated with bent spine resembling the walk of a camel (dromedary gait); 3) the movements were rapid, but also sustained and rhythmic; 4) the postures progresses to fixed deformities; 5) muscle tone was either decreased or increased (spasmodic), but 6) there were no mental problems, weakness, or any other neurological abnormality. In addition to limbs and trunk, dystonia can affect the face and cause involuntary closure of the eyes due to contractions of the eyelids (“blepharospasm”), spasms of the jaw, tongue and other parts of the mouth and lower face (“oro-mandibular dystonia”), muscle contractions and turning of the neck (“torticollis” or “cervical dystonia”), spasms of the vocal cords (“spasmodic dysphonia”) and other involuntary muscle spasms. Dystonia may present only during specific activities (“task-specific dystonia”), such as a tight grip and painful spasm of the hand when writing (“dystonic writer’s cramp”), or during other occupational and sports activities and while performing a specific task, such as playing a musical instrument (9). One of the most recognized musicians whose career was severely impacted by focal, task-specific dystonia of his right hand was the world-renown concert pianist Leon Fleisher (http://vimeo.com/6684412
). Even a common problem, such as golfer’s yips, have been attributed to task-specific dystonia (10). In some cases dystonia may progress very rapidly and evolve into a “dystonic storm” which can be life-threatening.
Although dystonia has been attributed to a dysfunction of the basal ganglia and its connections, the major advance in the understanding of genetic causes of dystonia has come with the discovery the most common genetic (Oppenheim’s) dystonia, now referred to as DYT1 (also known as TOR1A) dystonia. Mutation in the DYT1 gene on chromosome 9 resulted in an abnormal function of a protein called torsinA. This mutation, which occurs 5-10 times more frequently in the AJ population as compared to non-AJ populations, was apparently introduced in the AJ population about 350 years ago in Lithuania or Byelorussia. It is responsible for approximately 90% of childhood-onset cases of dystonia in people of AJ ancestry.
There are now many treatment options for patients with dystonia. In 1987, we were the first to publish a double-blind, placebo controlled study of botulinum toxin treatment of patients with face and neck dystonia (11). Subsequent studies confirmed the efficacy and safety of botulinum toxin in many other forms of dystonia and other neurologic and non-neurologic disorders. Indeed Botox, one form of botulinum toxin, has become one the most recognized medicinal brands, used by nearly all disciplines of medicine. Other treatments of dystonia involve the use of medications that modify brain neurotransmitters and deep brain stimulation (12).
In addition to certain forms of Parkinson’s disease and dystonia, there are many other neurological movement disorders occurring with higher-than-expected frequency in people of Jewish descent. These include Creutzfeldt-Jakob disease, which is particularly common in Sephardic Jews of Libyan and Tunisian ancestry. The disorder is manifested by a rapidly progressive neurological dysfunction, jerk-like movements (myoclonus), and cognitive impairment. Cerebrotendinous xanthomatosis, particularly common in Moroccan Jews, is characterized by juvenile cataracts, lipid accumulations in tendons, and a variety of neurological abnormalities, including parkinsonism, dystonia, and myoclonus. Machado-Joseph disease (also known as SCA3), characterized by progressive incoordination (ataxia), parkinsonism, spastic paraplegia, and restless legs syndrome, originated in a Portuguese Azorean family, but was also noted to have a high prevalence among some Yemen Jews.
It is my hope that this brief review will increase awareness about movement disorders and highlight the importance of genetic counseling, particularly among Jewish people who have a family history of neurologic movement disorders, such as Parkinson’s disease, dystonia and other diseases manifested by incoordination or abnormal involuntary movements.
Joseph Jankovic, MD is Professor of Neurology, Distinguished Chair in Movement Disorders, Director, Parkinson's Disease Center and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, Houston, Texas
1. Inzelberg R, Hassin-Baer S, Jankovic J. Genetic movement disorders in patients of Jewish ancestry. JAMA Neurol 2014, in press).
2. Carmi S, Hui KY, Kochav E, et al. Sequencing an Ashkenazi reference panel supports population-targeted personal genomics and illuminates Jewish and European origins. Nat Commun. 2014 Sep 9;5:4835).
3. Fahn S, Jankovic J, Hallett M. Principles and Practice of Movement Disorders, Churchill Livingstone, Elsevier, Philadelphia, PA, 2011:1-548.
4. Albanese A, Jankovic J, Eds. Hyperkinetic Movement Disorders. Wiley-Blackwell,Oxford, UK, 2012:1-390).
5. Jankovic J. Treatment of hyperkinetic movement disorders. Lancet Neurol 2009;8:844-56.
6. Jankovic J, Sherer T. The future research in Parkinson’s disease. JAMA Neurol 2014 (in press).
7. Albanese A, Bhatia K, Bressman SB, Delong MR, Fahn S, Fung VS, Hallett M, Jankovic J, Jinnah HA, Klein C, Lang AE, Mink JW, Teller JK. Phenomenology and classification of dystonia: a consensus update. Mov Disord. 2013 Jun15;28(7):863-73).
8. (Klein C, Fahn S. Translation of Oppenheim's 1911 paper on dystonia. Mov Disord. 2013 Jun 15;28(7):851-62.
9. Jankovic J, Ashoori A. Movement disorders in musicians. Mov Disord 2008;14:1957-65.
10. Dhungana S, Jankovic J. Yips and other movement disorders in golfers. Mov Disord. 2013 May;28(5):576-81.
11. Jankovic J, Orman J. Botulinum A toxin for cranial-cervical dystonia: A double-blind, placebo-controlled study. Neurology 1987;37:616-623.
12. Thenganatt MA, Jankovic J. Treatment of dystonia. Neurotherapeutics. 2014 Jan;11(1):139-52.