Jewish movement disorders and genetics


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
 
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
 
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

References:

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.

Rare Ailment Occurs More in Ashkenazis


After David Rudolph sprained his ankle during a basketball game, his father noticed that the second-grader couldn’t seem to keep his left heel flat on the ground. The problem persisted, sidelining David from his position as catcher on his Little League team, and preventing him from progressing beyond his blue belt in karate.

An orthopedist suspected a contracted Achilles tendon, and sent David for physical therapy. When that failed, David underwent a series of neurological tests, none of which indicated a problem. One physician even suggested a psychological phenomenon called “conversion hysteria,” implying that David had created the problem to get attention.

“We knew that wasn’t the case, because it was keeping him from the activities he loved,” said Mark Rudolph, David’s father.

The Rudolphs continued searching. Finally, a pediatric neurologist diagnosed the problem as dystonia, a condition she had seen only four times in her career. A second specialist confirmed the finding. It had taken almost six months for David to receive a proper diagnosis.

A neurological movement disorder characterized by involuntary muscle contractions and spasms, dystonia forces the body into abnormal positions and twisting movements. It can affect a specific body part, such as the neck, hands or torso, or many parts simultaneously, and can vary in severity from mild to extreme.

Although few people have heard of the disease, dystonia affects approximately 300,000 people in North America — more than better-known conditions such as muscular dystrophy, Huntington’s disease and cystic fibrosis.

There are 16 types of dystonia, and it affects all races and ethnic groups, as well as both genders. However, Ashkenazi Jews have a higher than normal incidence of one type, called early onset (generalized) dystonia. This type of dystonia is associated with a mutation in a gene called DYT1.

Ashkenazi Jews carry the mutation at a rate about 10 times higher than that of the general population. DYT1, identified in 1997, somehow disrupts communication between the brain and muscles. Only one parent needs to have the mutation to pass it on to the next generation, yet most people are unaware that they are carriers.

“Two-thirds of individuals with the mutation are asymtomatic [have no symptoms] or have minor problems,” said Dr. John Menkes, the pediatric neurologist who confirmed David’s diagnosis and a co-founder of the Dystonia Medical Research Foundation. “Many people who have dystonia don’t realize it.”

Early onset dystonia tends to show up between the ages of 5 and 16, usually with symptoms in the foot or hand. The involuntary movements may progress quickly to involve all limbs and the torso, although the rate of progression usually slows noticeably after adolescence.

The disease is not fatal, but there is no cure. Physicians use a variety of therapies to reduce muscle spasms, pain and impaired function and posture.

For David, dytstonia means taking 12 pills daily and wearing a brace to stabilize his right foot and ankle. It also involves physical therapy twice weekly, chiropractor visits and Botox injections for the muscle spasms.

Dystonia does not affect mental functioning. A precocious, bright fourth-grader at Wilshire Boulevard Temple’s Brawerman Elementary School, David speaks in rapid-fire sentences, using such words as “curious” and “concerned” to describe classmates’ reactions to his condition. This summer, he will attend his third local session of the Johns Hopkins University’s Center for Talented Youth.

For David’s parents, dystonia is “the uninvited guest that hasn’t left,” said his mother, Diane. Each day, she and her husband wonder whether the cocktail of medications they administer to their son is really making a difference, and whether it may, in fact, be causing harm.

They try to find a balance between letting David pursue the activities he loves and shielding him from injury. Since being diagnosed two years ago, he has fractured his wrist, elbow and knee because of falls due to balance problems. Should he break a leg, David’s muscle contractions could prevent proper casting of the bone.

The Rudolphs have watched the condition progress from David’s left foot to his right foot and leg. Having read the literature and seen videos of patients who are bent at the waist or in wheelchairs, they wonder how bad it will get and which of David’s body parts will be affected. Most of all, they grapple with how much to tell their son about his condition.

“We’ve tried to shield him from what the worst could be,” said his father. “But he’s 10 years old. At some point, we won’t be able to protect him.”

Karen Ross understands the emotions experienced by the Rudolphs.

“Dystonia is damaging to individuals and to families,” said Ross, a clinical psychologist. “You never go back to the kind of family you once were.”

Ross became interested in psychology after her son, Michael, was diagnosed with dystonia in 1975. The family had spent three years trying to find out what was wrong. At that time, there were no organizations dedicated to the disease, no support system for families and no awareness of dystonia within the Jewish community.

Ross now serves on the board of the Dystonia Medical Research Foundation — as do the Rudolphs — to try to change that.

“We want to make this the last generation of Jews who have this disease,” Ross said. The Dystonia Medical Research Foundation has provided more than $19 million in grants to scientists since its inception in 1976.

Research is encouraging, although it remains to be seen whether the psychologist’s goal will be met. On the positive side, pediatric neurologist Menkes noted that in dystonia, unlike many other diseases, nothing is missing or defective. Since the gene implicated in dystonia “seems to prevent normal movement of certain cellular components, the idea would be to prevent the action of this bad gene,” he explained.

One disadvantage, however, is that dystonia “doesn’t get any attention in the research community,” said Dr. Marie-Francoise Chesselet, UCLA Medical School’s neurobiology department chair. Chesselet, who has served on the scientific advisory committee of the Dystonia Medical Research Foundation, said that researchers are more interested in working on conditions with greater visibility or prevalence.

Until the DYT1 gene mutation was identified, “dystonia was like a black box,” she said. “People had no idea even how to even approach it…. Now there are some extremely good researchers who, while not primarily interested in dystonia, are interested in those particular biological mechanisms, and are now applying their knowledge and experimental skills to dystonia.”

In fact, researchers have discovered how to silence the mutated DYT1 gene in cultured cells. They are currently trying to do so with worms, flies and mice.

The 1997 discovery of the DYT1 gene also allowed for the development of a genetic test for patients and family members who are possible carriers, as well as prenatal testing to determine if a fetus has the mutated gene.

Two years ago, a man with dystonia and his wife used a technology called premiplantation genetic diagnosis (PGD) to insure that their child would not be born with the disease. PGD involves fertilizing eggs outside the body and screening for genetic disease before returning them to the womb for gestation. The child, born in September 2003, was the first to be born using this technology to check for dystonia.

The condition has also received recent public recognition because of concert pianist Leon Fleisher. Focal dystonia in his right hand forced Fleisher to limit his playing to one-handed pieces. After he received Botox injections, the tension in his hands relaxed sufficiently for him to make his first two-handed recording in 40 years.

Fleischer has donated a portion of the profits from the CD, appropriately titled, “Two Hands,” to the Dystonia Medical Research Foundation and has worked with the foundation’s Musicians With Dystonia group to address the needs of musicians with the condition.

All of these developments are giving hope where there once was none. “Ten years ago, I never thought I’d see effective treatment or a cure. I can now say that’s possible,” said Ross’ son, Michael, now 45 years old and a rabbinical student at the Reconstructionist Rabbinical College in Pennsylvania.

The Rosses and Rudolphs want members of the Jewish community to know about dystonia so that should they encounter it in their own families, they won’t have to wait months or years for a proper diagnosis. They believe that lack of awareness is the only thing preventing the community from taking action.

In terms of awareness and education, “the community has successfully dealt with other Jewish disorders, such as Tay Sachs and Familial Dysautonomia,” said Karen Ross. “The Jewish community cares when it knows what to care about.”

For more information, contact the Dystonia Medical Research Foundation, www.dystonia-foundation.org, (800) 377-3978; Bachmann-Strauss Dystonia & Parkinson Foundation, www.dystonia-parkinsons.org, (212) 241-5614; WE MOVE www.wemove.org, (212) 875-8312; National Institute of Neurological Disorders and Stroke, www.ninds.nih.gov.

Surgery Offers Hope to Dystonia Victims


Twelve-year-old Josh Gaskin walks to the front door and shakes a visitor’s hand. While this gesture would seem routine for most adolescents, two years ago it would have been impossible for Josh.

By the time he had reached the fourth grade, Josh’s dystonia caused his right hand to involuntarily clench into a fist so tight that he could only open it by force. His feet turned inward, requiring him to wear braces. The symptoms had forced Josh to quit his baseball and basketball teams after six years of playing, leaving him depressed and angry.

Josh’s mother, Andrea, had read about an unusual procedure that might hold hope for her son. Deep brain stimulation (DBS) involves placing tiny electrodes deep in the brain. The electrodes are connected by wires running internally down each side of the neck to small pulse generators implanted under the skin of the chest.

The electrical pulses disrupt the brain signals that cause involuntary movement. The procedure had been used extensively to relieve Parkinson’s disease symptoms, and had recently been found to help some dystonia patients.

Andrea was intrigued. Still, DBS involves multiple surgical procedures. At the time, few procedures had been done for dystonia patients, and only a handful of them had involved children.

“Deep inside, I knew that this was going to be for us,” she said. “My husband was more hesitant…. You’re dealing with the brain and things can happen.”

But Andrea felt strongly. “The way I looked at it, why let it get worse before I make him better. The more your body starts twisting, the harder you have to work to put it back to what it was,” she said. “I didn’t want him go through any more suffering.”

In April 2004, Josh underwent DBS surgery at Mount Sinai Medical Center in New York. During the procedure, a metal halo was screwed into his skull to assure no movement. The doctor drilled a small hole in Josh’s skull and inserted the electrodes.

Josh was a awake for much of the six-hour surgery, because his doctors needed to ask him questions in order to place the electrodes most effectively. Two days after his surgery, Josh’s doctors inserted batteries into the device.

By the following day, Josh was able to play video games with his father at Times Square’s ESPN Zone. Within a month, he could walk without the foot braces. He began shooting hoops and hitting baseballs.

“I had forgotten how it felt to open my arms,” Josh said. “It felt good to go back to normal.”

Josh suffered a setback last June, when one of the leads caused a leakage of brain fluid, and the apparatus on one side of his body had to be removed. Within six months, his walking was worse than it had been before the surgery.

Last March, he returned to New York to have the device re-implanted, and has been slowly improving ever since. He can write again. He plays basketball and runs track at school. He hopes to re-join a sports league, and is practicing his skills. His speech remains slurred as it was prior to the surgery, but he hopes that it, too, will slowly improve.

Each month, Josh must visit the doctor to have his electrical settings fine tuned. He will need surgery to have his batteries replaced every three to four years.

Nevertheless, neither Josh nor his mother have any regrets. “It’s not for everybody, but for us, this surgery has been a blessing,” Andrea said. “We’ve seen a big improvement.”

Before the procedure, “I was angry, mad and sad. I didn’t know why I had [dystonia],” Josh said. “Now, I have a better outlook.”

As he recounted his story, Josh was asked about scabs on both his knees. They weren’t from surgery. He had been fooling around on his parent’s treadmill, put it on maximum and fell. Just like any other normal 12-year-old kid. — NSS