Paroxysmal exercise-induced dystonia
Encyclopedia
Paroxysmal exercise-induced dystonia or PED is a rare neurological disorder characterized by sudden, transient, involuntary movements, often including repetitive twisting motions and painful posturing triggered by exercise or other physical exertion. PED is in the class of paroxysmal dyskinesia
which are a group of rare movement disorders characterized by attacks of hyperkinesis
with intact consciousness. The term paroxysmal indicates that the episodes are sudden and short lived and usually unpredicted, and return to normal is rapid. The number of reported cases of people with PED is very small leading to difficulty in studying and classifying this disease and most studies are limited to a very small number of test subjects.
. Age of onset is usually sometime in childhood, but can range from 1–30 years old. In one study it was found that the mean age of onset was around 8 years. Similarly in the study, the legs were the most common affected part of the body and the attacks were reported as stiffening and cramps by those affected.During an episode of PED patients find walking nearly impossible.Cerebral spinal fluid (CSF) analysis showed a two-fold increase of homovanillic acid
and 5-hydroxyindoleacetic acid immediately following exercise compared to normal levels. This indicated that increased dopaminergic transmission could contribute to PED and other paroxysmal dyskinesias. Neurological examinations, EEG, and brain imaging are all normal in PED patients.
, epilepsy
and migraines, although the exact relationship between these is unknown.
A suspected contributor to familial PED is a mutation in the GLUT1
gene, SLC2A1, which codes for the transporter GLUT1, a protein responsible for glucose entry across the blood-brain barrier
. It is not thought that the mutation causes a complete loss of function of the protein but rather only slightly reduces the transporter's activity. In a study of PED patients, a median CSF/blood glucose ratio of .52 compared to a normal .60 was found. In addition, reduced glucose uptake by mutated transporters compared with wild-type in Xenopus oocytes confirmed a pathogenic role of these mutations.
Another recent study was performed to continue to look at the possible connection between PED and mutations on the SLC2A1 gene which codes for the GLUT1 transporter. While PED can occur in isolation it was also noted that it occurs in association with epilepsy as well. In this study the genetics of a five-generation family with history of PED and epilepsy were evaluated. From the results it was noted that most of the mutations were due to frameshift and missense mutations. When looking at homologous GLUT1 transporters in other species it was noted that serine (position 95), valine (position 140), and asparagine (position 317) were highly conserved and therefore mutations in these residues would most likely be pathogenic. Therefore these are areas of interest when looking at what could lead to PED.All mutations that were observed appeared to only affect the ability of GLUT1 to transport glucose and not the ability for it to be inserted in the membrane. The observed maximum transport velocity of glucose was reduced anywhere from 3 to 10 fold.
A study was performed to determine if the mutation known for the PNKD
locus on chromosome 2q33-35 was the cause of PED. In addition, other loci were observed such as the familial hemiplegic migraine
(FHM) locus on chromosome 19p, or the familial infantile convulsions and paroxysmal choreoathetosis
(ICCA). All three of these suspected regions were found to not contain any mutations, and were therefore ruled out as possible candidates for a cause of PED.
s, after removal of which the symptoms of PED were resolved.
and cerebellum
. While all these correlations are not fully understand as to what exactly is happening in the brain it provides areas of interest to study further to hopefully understand PED more fully.
(PNKD), based on what brings on the symptoms, namely prolonged exercise, such as brisk walking or running for at least 10 minutes. This is in contrast to PKD where the symptoms are brought about by sudden movements, and PNKD where the symptoms are spontaneous in nature and prolonged. PED is usually affects muscles on both sides of the body (bilateral), it has also been observed to have unilateral effects.
PED has also been shown to be a precursor to Parkinson's Disease
. In two observed cases, PED preceded any symptoms of Parkinson's Disease by 1.5 and 5 years. Although a rare indicator, PED can be an early sign of the disorder, suggesting they are related. In one case a patient with PED showed evidence of dopamine depletion revealed by a dopamine transporter SPECT scan. This is typical of Parkinson's Disease, further showing the linkage between the diseases.
A correlation between Epilepsy
and PED has been observed in several families across multiple generations, demonstrating an autosomal dominant inheritability of symptoms. The occurrence of coexistent seizures and PED symptoms are observed mainly during infancy and childhood, with symptoms of PED continuing throughout a lifetime. Epileptic seizures vary in type and have been observed as absence and generalized seizures
. Simultaneous seizure and PED attacks are often premeditated by bouts of dizziness. Attacks have been shown to be reduced or prevented with food ingestion, although the reasons for this are unclear. Various evidence shows that the disorders are likely caused by dysfunction in voltage-gated ion channels, which may lead to abnormal excitability in different brain regions, specifically the cerebral cortex
and basal ganglia
.
. The diet is a strict 3:1 ratio of fat (3) to protein and carbohydrates (1). This diet is thought to help restore the unbalance created by the decreased amount of glucose in the brain caused by the faulty GLUT1 transporter. This diet was administered to three patients who had been screened and found to have mutation in their SLC2A genes coding for GLUT1 and were experiencing PED symptoms. All three showed benefit from this treatment and a reduction in their PED episodes. They were able to exercise and run long distances for the first time in their lives. No other studies have been performed using this diet as many patients feel the advantages of the diet do not outweigh its disadvantages.
As some cases have noted that patients were able to alleviate or lessen there PED attacks with a sugary snack, another diet that was tried on patients was one rich in carbohydrates with additional frequent carbohydrate-containing snacks. Four patients with reported PED symptoms were put on this diet but no observable improvements were noted and in fact one patient even complained of worsening symptoms.
Additionally it has been observed that levodopa
may reduce some symptoms associated with PED. This may demonstrate that PED is a precursor to Parkinson's disease. Acetazolamide
was beneficial to some patients, but also worsened symptoms in others. Additionally, a modified version of the Atkin's Diet helped to regulate glucose levels in the CSF. Patients with PED associated with insulinomas appeared to have symptoms resolved after consuming sugary drinks. Currently, there are no drugs that are particularly useful in completely curing all symptoms.
Paroxysmal dyskinesia
The paroxysmal dyskinesias are a group of rare movement disorders characterized by attacks of hyperkinesis with intact consciousness.-Types:* Paroxysmal kinesogenic choreoathetosis* Paroxysmal nonkinesogenic dyskinesia* Paroxysmal exercise-induced dystonia...
which are a group of rare movement disorders characterized by attacks of hyperkinesis
Hyperkinesis
Hyperkinesia, also known as hyperkinesis, refers to an increase in muscular activity that can result in excessive abnormal movements, excessive normal movements, or a combination of both...
with intact consciousness. The term paroxysmal indicates that the episodes are sudden and short lived and usually unpredicted, and return to normal is rapid. The number of reported cases of people with PED is very small leading to difficulty in studying and classifying this disease and most studies are limited to a very small number of test subjects.
Symptoms
Episodes are relatively short-lived, lasting anywhere from 5–30 minutes, and in most cases disappear completely after cessation of the physical exercise. Most patients will experience 1 to 5 episodes per month, but some can have attacks daily. The muscles most often affected are usually in the legs and feet (75% of reported cases), but the upper body muscles such as the arms, face, neck, and trunk have also been observed to be affected during the episodes of dystoniaDystonia
Dystonia is a neurological movement disorder, in which sustained muscle contractions cause twisting and repetitive movements or abnormal postures. The disorder may be hereditary or caused by other factors such as birth-related or other physical trauma, infection, poisoning or reaction to...
. Age of onset is usually sometime in childhood, but can range from 1–30 years old. In one study it was found that the mean age of onset was around 8 years. Similarly in the study, the legs were the most common affected part of the body and the attacks were reported as stiffening and cramps by those affected.During an episode of PED patients find walking nearly impossible.Cerebral spinal fluid (CSF) analysis showed a two-fold increase of homovanillic acid
Homovanillic acid
Homovanillic acid is a major catecholamine metabolite...
and 5-hydroxyindoleacetic acid immediately following exercise compared to normal levels. This indicated that increased dopaminergic transmission could contribute to PED and other paroxysmal dyskinesias. Neurological examinations, EEG, and brain imaging are all normal in PED patients.
Familial
In most cases, PED is familial, but can also be sporadic. In familial cases, pedigrees examined have shown PED to be an autosomal-dominant inheritance trait. PED also has been associated with Parkinson's diseaseParkinson's disease
Parkinson's disease is a degenerative disorder of the central nervous system...
, epilepsy
Epilepsy
Epilepsy is a common chronic neurological disorder characterized by seizures. These seizures are transient signs and/or symptoms of abnormal, excessive or hypersynchronous neuronal activity in the brain.About 50 million people worldwide have epilepsy, and nearly two out of every three new cases...
and migraines, although the exact relationship between these is unknown.
A suspected contributor to familial PED is a mutation in the GLUT1
GLUT1
Glucose transporter 1 , also known as solute carrier family 2, facilitated glucose transporter member 1 is a protein that in humans is encoded by the SLC2A1 gene...
gene, SLC2A1, which codes for the transporter GLUT1, a protein responsible for glucose entry across the blood-brain barrier
Blood-brain barrier
The blood–brain barrier is a separation of circulating blood and the brain extracellular fluid in the central nervous system . It occurs along all capillaries and consists of tight junctions around the capillaries that do not exist in normal circulation. Endothelial cells restrict the diffusion...
. It is not thought that the mutation causes a complete loss of function of the protein but rather only slightly reduces the transporter's activity. In a study of PED patients, a median CSF/blood glucose ratio of .52 compared to a normal .60 was found. In addition, reduced glucose uptake by mutated transporters compared with wild-type in Xenopus oocytes confirmed a pathogenic role of these mutations.
Another recent study was performed to continue to look at the possible connection between PED and mutations on the SLC2A1 gene which codes for the GLUT1 transporter. While PED can occur in isolation it was also noted that it occurs in association with epilepsy as well. In this study the genetics of a five-generation family with history of PED and epilepsy were evaluated. From the results it was noted that most of the mutations were due to frameshift and missense mutations. When looking at homologous GLUT1 transporters in other species it was noted that serine (position 95), valine (position 140), and asparagine (position 317) were highly conserved and therefore mutations in these residues would most likely be pathogenic. Therefore these are areas of interest when looking at what could lead to PED.All mutations that were observed appeared to only affect the ability of GLUT1 to transport glucose and not the ability for it to be inserted in the membrane. The observed maximum transport velocity of glucose was reduced anywhere from 3 to 10 fold.
A study was performed to determine if the mutation known for the PNKD
Paroxysmal Nonkinesigenic Dyskinesia
Paroxysmal Nonkinesigenic Dyskinesia is an episodic movement disorder first described by Mount and Reback in 1940 under the name "Familial paroxysmal choreoathetosis"...
locus on chromosome 2q33-35 was the cause of PED. In addition, other loci were observed such as the familial hemiplegic migraine
Familial hemiplegic migraine
Familial hemiplegic migraine is an autosomal dominant classical migraine subtype that typically includes hemiparesis during the aura phase. It can be accompanied by other symptoms, such as ataxia, coma and epileptic seizures...
(FHM) locus on chromosome 19p, or the familial infantile convulsions and paroxysmal choreoathetosis
Paroxysmal kinesogenic choreoathetosis
Wikipedia ArticleParoxysmal kinesigenic choreathetosis, ' also called Paroxysmal Kinesigenic Dyskinesia ' is a hyperkinetic movement disorder characterized by attacks of involuntary movements, which are triggered by sudden voluntary movements...
(ICCA). All three of these suspected regions were found to not contain any mutations, and were therefore ruled out as possible candidates for a cause of PED.
Sporadic
Sporadic cases may be brought on by minor head injuries and concussions. This was observed in one patient who started experiencing painless dystonia after mild exercise following a concussion. More research still needs to be done to determine how injuries can induce PED, as little is known in this area. Two cases of PED have been associated with insulinomaInsulinoma
An insulinoma is a tumour of the pancreas that is derived from beta cells and secretes insulin.Beta cells secrete insulin in response to increases in blood glucose. The resulting increase in insulin acts to lower blood glucose back to normal levels at which point further secretion of insulin is...
s, after removal of which the symptoms of PED were resolved.
Diagnosis
Since the age of onset is relatively young of PED it is important to correctly diagnose this disease. The limited cases and limited knowledge of the disease makes this difficult but a few characteristics seem to be consistent. It appears that patients with PED would have normal neurological examinations and MRI but the noticeable characteristic would be in low levels of glucose in the cerebral spinal fluid due to the GLUT1 mutations.Reported Cases
There are very few reported cases of PED, there are approximately 20 reported sporadic cases of PED and 9 PED families but there is some dispute on the exact number of cases. In addition it appears that PED becomes less severe with aging. Prior to onset of a PED episode some patients reported onset of symptoms including sweating, pallor, and hyperventilation. In brain scans it was observed that patients suffering form frequent PEDs there was increased metabolism in the putamen of the brain and decreased metabolism in the frontal lobe. Another study using subtraction single photon emission computed tomographic (SPECT) imaging technique which was coregistered with an MRI on a patient presented with PED symptoms showed increased cerebral perfusion in the primary somatosensory cortex area, and a mild increase in the region of the primary motor cortexPrimary motor cortex
The primary motor cortex is a brain region that in humans is located in the posterior portion of the frontal lobe. Itworks in association with pre-motor areas to plan and execute movements. M1 contains large neurons known as Betz cells, which send long axons down the spinal cord to synapse onto...
and cerebellum
Cerebellum
The cerebellum is a region of the brain that plays an important role in motor control. It may also be involved in some cognitive functions such as attention and language, and in regulating fear and pleasure responses, but its movement-related functions are the most solidly established...
. While all these correlations are not fully understand as to what exactly is happening in the brain it provides areas of interest to study further to hopefully understand PED more fully.
Related Disorders
PED differs from two closely related disorders, for example paroxysmal kinesogenic dyskinesia (PKD) and paroxysmal nonkinesigenic dyskinesiaParoxysmal Nonkinesigenic Dyskinesia
Paroxysmal Nonkinesigenic Dyskinesia is an episodic movement disorder first described by Mount and Reback in 1940 under the name "Familial paroxysmal choreoathetosis"...
(PNKD), based on what brings on the symptoms, namely prolonged exercise, such as brisk walking or running for at least 10 minutes. This is in contrast to PKD where the symptoms are brought about by sudden movements, and PNKD where the symptoms are spontaneous in nature and prolonged. PED is usually affects muscles on both sides of the body (bilateral), it has also been observed to have unilateral effects.
PED has also been shown to be a precursor to Parkinson's Disease
Parkinson's disease
Parkinson's disease is a degenerative disorder of the central nervous system...
. In two observed cases, PED preceded any symptoms of Parkinson's Disease by 1.5 and 5 years. Although a rare indicator, PED can be an early sign of the disorder, suggesting they are related. In one case a patient with PED showed evidence of dopamine depletion revealed by a dopamine transporter SPECT scan. This is typical of Parkinson's Disease, further showing the linkage between the diseases.
A correlation between Epilepsy
Epilepsy
Epilepsy is a common chronic neurological disorder characterized by seizures. These seizures are transient signs and/or symptoms of abnormal, excessive or hypersynchronous neuronal activity in the brain.About 50 million people worldwide have epilepsy, and nearly two out of every three new cases...
and PED has been observed in several families across multiple generations, demonstrating an autosomal dominant inheritability of symptoms. The occurrence of coexistent seizures and PED symptoms are observed mainly during infancy and childhood, with symptoms of PED continuing throughout a lifetime. Epileptic seizures vary in type and have been observed as absence and generalized seizures
Seizure types
The numerous epileptic seizure types are most commonly defined and grouped according to the scheme proposed by the International League Against Epilepsy in 1981...
. Simultaneous seizure and PED attacks are often premeditated by bouts of dizziness. Attacks have been shown to be reduced or prevented with food ingestion, although the reasons for this are unclear. Various evidence shows that the disorders are likely caused by dysfunction in voltage-gated ion channels, which may lead to abnormal excitability in different brain regions, specifically the cerebral cortex
Cerebral cortex
The cerebral cortex is a sheet of neural tissue that is outermost to the cerebrum of the mammalian brain. It plays a key role in memory, attention, perceptual awareness, thought, language, and consciousness. It is constituted of up to six horizontal layers, each of which has a different...
and basal ganglia
Basal ganglia
The basal ganglia are a group of nuclei of varied origin in the brains of vertebrates that act as a cohesive functional unit. They are situated at the base of the forebrain and are strongly connected with the cerebral cortex, thalamus and other brain areas...
.
Treatments
As there appeared to be a connection with PED and mutated GLUT1 transporters a possible treatment was looking at changing patients diets. A common treatment for another disorder with a mutated GLUT1 transporter is the ketogenic dietKetogenic diet
The ketogenic diet is a high-fat, adequate-protein, low-carbohydrate diet that in medicine is used primarily to treat difficult-to-control epilepsy in children. The diet mimics aspects of starvation by forcing the body to burn fats rather than carbohydrates...
. The diet is a strict 3:1 ratio of fat (3) to protein and carbohydrates (1). This diet is thought to help restore the unbalance created by the decreased amount of glucose in the brain caused by the faulty GLUT1 transporter. This diet was administered to three patients who had been screened and found to have mutation in their SLC2A genes coding for GLUT1 and were experiencing PED symptoms. All three showed benefit from this treatment and a reduction in their PED episodes. They were able to exercise and run long distances for the first time in their lives. No other studies have been performed using this diet as many patients feel the advantages of the diet do not outweigh its disadvantages.
As some cases have noted that patients were able to alleviate or lessen there PED attacks with a sugary snack, another diet that was tried on patients was one rich in carbohydrates with additional frequent carbohydrate-containing snacks. Four patients with reported PED symptoms were put on this diet but no observable improvements were noted and in fact one patient even complained of worsening symptoms.
Additionally it has been observed that levodopa
Levodopa
L-DOPA is a chemical that is made and used as part of the normal biology of some animals and plants. Some animals including humans make it via biosynthesis from the amino acid L-tyrosine. L-DOPA is the precursor to the neurotransmitters dopamine, norepinephrine , and epinephrine collectively...
may reduce some symptoms associated with PED. This may demonstrate that PED is a precursor to Parkinson's disease. Acetazolamide
Acetazolamide
Acetazolamide, sold under the trade name Diamox, is a carbonic anhydrase inhibitor that is used to treat glaucoma, epileptic seizures, Idiopathic intracranial hypertension , altitude sickness, cystinuria, and dural ectasia...
was beneficial to some patients, but also worsened symptoms in others. Additionally, a modified version of the Atkin's Diet helped to regulate glucose levels in the CSF. Patients with PED associated with insulinomas appeared to have symptoms resolved after consuming sugary drinks. Currently, there are no drugs that are particularly useful in completely curing all symptoms.
Current Situation
Since paroxysmal exercise-induced dystonia is such a rare disorder it makes it difficult to study the disease and find consistencies. Many of the current studies seem to have contradicting conclusion but this is due to the fact that studies are usually limited to a very small number of test subjects. With such small numbers it is hard to determine what is a trend and what is random when in comes to characterizing the disease. Further study is needed to find better diagnostic techniques and treatments for PED. Patients with PED are living a limited lifestyle since simple tasks like walking and exercise are often impossible.See also
- Paroxysmal dyskinesiaParoxysmal dyskinesiaThe paroxysmal dyskinesias are a group of rare movement disorders characterized by attacks of hyperkinesis with intact consciousness.-Types:* Paroxysmal kinesogenic choreoathetosis* Paroxysmal nonkinesogenic dyskinesia* Paroxysmal exercise-induced dystonia...
- Paroxysmal nonkinesogenic dyskinesia
- Paroxysmal kinesogenic choreoathetosisParoxysmal kinesogenic choreoathetosisWikipedia ArticleParoxysmal kinesigenic choreathetosis, ' also called Paroxysmal Kinesigenic Dyskinesia ' is a hyperkinetic movement disorder characterized by attacks of involuntary movements, which are triggered by sudden voluntary movements...