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Episodic Disorders

Episodic phenomena are common in humans. These include (but are not limited to) seizures, headaches, cardiac arrhythmias, episodic movement disorders, and periodic paralyses. These disorders have strong genetic determinants and often affect people who are completely normal between attacks. Although episodic disorders of the brain, heart, and muscle seem quite different on the surface, they share many similarities. They often come on in childhood or adolescence and frequently improve with aging. In addition to being episodic, attacks in all of these disorders can often be precipitated by stress, fatigue, and some dietary factors. The medications used to treat these disorders overlap significantly. Thus, insights gained by study of any of these disorders can impact on our understanding of the others.

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Paroxysmal Dyskinesia

Paroxysmal dyskinesias are neurologic conditions characterized by sudden episodes of abnormal involuntary movements (hyperkinesias). These may include any combination of involuntary, rapid, randomly irregular jerky movements (chorea); relatively slow, writhing motions that appear to flow into one another (athetosis); increased muscle tone with repetitive, twisting, patterned movements and distorted posturing (dystonia); and uncontrollable flinging movements of an arm, a leg, or both (ballismus). The term paroxysmal indicates that the abnormal movements are sudden and unpredictable, with a relatively rapid return to normal motor function and behavior.

Paroxysmal dyskinesias are often classified into paroxysmal kinesigenic dyskinesia (PKD) and paroxysmal non-kinesigenic dyskinesia (PNKD), based upon precipitating factors that precede or trigger the episodes of abnormal, involuntary movement. In patients with PKD the episodes of hyperkinetic movements are provoked by sudden voluntary movement or unexpected stimuli (startle). In contrast, in those with non-kinesigenic dyskinesia, the attacks may occur spontaneously while at rest or out of a background of normal motor activity, but may be exacerbated by alcohol or caffeine consumption, stress, fatigue, or other factors. Other types of paroxysmal dyskinesias include episodes precipitated by prolonged exertion (paroxysmal exertion-induced dyskinesia) or sleep (paroxysmal hypnogenic dyskinesia).

Our Research

We have localized genes causing familial PNKD and PKD to chromosome 2q and chromosome 16cen respectively. The focus of our research is on the identification of the disease-causing genes for PNKD and PKD. Detection of these genes and study of the encoded proteins will result in a greater insight into paroxysmal dyskinesias and other episodic disorders of the nervous system.

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Periodic Paralysis

The periodic paralyses are a collection of rare disorders characterized by episodic often disabling weakness.

► Hypokalemic Periodic Paralysis

► Hyperkalemic Periodic Paralysis

 

Our Research

 

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Periodic Paralysis

The periodic paralyses are a collection of rare disorders characterized by episodic often disabling weakness.

Thyrotoxic Periodic Paralysis

Thyrotoxic Periodic Paralysis (THPP) usually appears as an acquired, sporadic disorder that resolves with treatments of the underlying thyrotoxicosis. Thyrotoxic periodic paralysis occurs most frequently in Asian adults; as many as 10% of Thyrotoxic Asian males may develop THPP. 

Our Research

Until recently the genetic basis for Thyrotoxic Periodic Paralysis (THPP) was unknown, but a group in Brazil identified the first genetic association with THPP, a mutation in the KCNE3 gene. Our group is working hard to further understand the genetic basis of this disease. We are working to detect new genetic variants predisposing individuals to Thyrotoxic periodic paralysis.

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Periodic Paralysis

The periodic paralyses are a collection of rare disorders characterized by episodic often disabling weakness.

Andersen-Tawil Syndrome

Andersen-Tawil Syndrome (ATS) is a rare inherited disorder characterized by cardiac arrhythmias, periodic paralysis, and characteristic physical features including low-set ears, clinodactyly (an inward curvature of the fifth finger), widely spaced eyes, a broad forehead, and a poorly developed jaw. The symptoms of this disorder vary from individual to individual and can be subtle. As a result, individuals with mutations in genes causing ATS can have all, some, or (rarely) no features of this disease.

Our Research

Recently, we discovered that mutations in an ion channel (KCNJ2) are responsible for a majority of ATS cases. However, a large number of families do not contain mutations in KCNJ2 and ATS seems to be caused by mutations in other, unidentified genes. What are the other genes causing ATS? What do these genes do and how can we correct the muscle weakness and arrhythmias? These questions are the current focus of our research. By studying Andersen-Tawil Syndrome we hope to help those suffering from this disease and other forms of periodic paralysis and cardiac arrhythmia. Medical treatment can help severe ATS some patients and recognition of disease is very important in order to monitor serious (potentially fatal) cardiac arrhythmias.

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Paramyotonia Congenita

 

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Episodic Ataxia

Episodic ataxia, a disorder affecting the cerebellum, is a rare inherited syndrome of intermittent ataxia. Affected individuals are normal between attacks but become ataxic under stressful conditions and with fatigue.  There are two distinct forms, both with an early onset of symptoms and episodic attacks of ataxia responsive to acetazolamide (AZM).

Episodic Ataxia type 1 (EA1), an autosomal dominant disorder involving both the central and the peripheral nervous system, is characterized by attacks of ataxia and persistent myokymia, a form of involuntary muscular movement. Episodes of ataxia, with gait imbalance and slurring of speech, occur spontaneously or can be precipitated by sudden movement, excitement, or exercise. The attacks generally last from seconds to several minutes at a time and may recur many times a day.

Episodic Ataxia type 2 (EA2), is an autosomal dominant disorder with episodes of markedly impaired upper-body ataxia lasting hours to days, with interictal eye movement abnormalities. Exertion and stress commonly precipitate the episodes. Often the episodes of ataxia resolve with AZM treatment. In some individuals, there may be a gradual baseline ataxia with evidence of cerebellar atrophy. Affected patients also may have migraine; some even complain of basilar migraine.

Our Research

Linkage analysis of several large pedigrees with EA1 mapped the disease locus to 12p13, near a cluster of three potassium channel genes: KCNA1, KCNA5 and KCNA6. Based on the clinical phenotype and its analogy to episodic disorders of muscle, ion channel genes were considered good candidate genes for EA1.

The disease locus in EA2 in several pedigrees was localized to chromosome 19p.

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Migraine

Migraine headache affects approximately 10-20% of the population and places a huge cost on society in terms of pain suffering and work loss. People with migraine usually have a strong family history and may vary in frequency, intensity, duration, pattern of associated symptoms, and degree of disability. They are usually moderate to severe in intensity, and may be incapacitating. They are episodic in nature, with some patients experiencing one attack annually and others experiencing attacks several times a week

Our Research

It is clear that there are strong genetic factors involved in migraine, but the mode of inheritance still remains unclear. One rare form of migraine called familial hemiplegic migraine is transmitted as an autosomal dominant trait, but it is likely that multiple genes contribute to headache susceptibility in common migraine types. By studying families suffering from migraine headache, we hope to elucidate the complicated genetics of this disorder to gain insight into the biology of headache and to apply such understanding toward developing better therapies for patients.

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Epilepsy

Epilepsy is a family of more than 40 neurological conditions with a common symptom, seizures or convulsions. It is documented to affect 2.5% of the population. A large percentage of epileptic conditions are recognized to be idiopathic and familial. Of particular interest are the forms of epilepsy that arenít caused by structural or developmental lesions like trauma or brain tumors because they suggest some inherent hyperexcitablilty. Reflex epilepsies include seizures that can be induced by various sensory stimuli in humans. Audiogenic seizures are common in inbred mouse strains and share similar precipitants. The most common reflex recognized in epilepsy is that strobe lights flashing at a particular frequency induce spikes on EEG and blatant seizures in some patients.

Our Research

While it is clear that there is a strong genetic component associated with Epilepsy, the mode of transmission is not well understood. The complexity of the inheritance pattern probably reflects genetic and clinical heterogeneity. We speculate that the understanding gained from the study of rare monogenic traits such as Familial Adult Myoclonic Epilepsy (FAME), a rare form of myoclonic epilepsy, will provide clues into the more complicated genetics and biology of epilepsy. In addition, statistical approaches and association studies in large patient populations will facilitate the molecular characterization of polygenic episodic disorders like migraine and epilepsy.

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Photic Sneeze Reflex

Photic Sneeze Reflex is a trait characterized by involuntary sneezing after an individual is exposed to bright light after adapting to the dark. This trait is believed to be inherited, but identification of the specific genes involved has not been made yet. Photic sneeze reflex occurs in about 10 percent of people. This trait is of interest when considering the reflex component of the disorders already mentioned.

Our Research

By studying families with Photic Sneeze Reflex, researchers are trying to find the cause of this trait by identifying the gene. This work will aid in understanding the cause of this condition and other episodic disorders.

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Participate in a Research Study

For our episodic disorder studies, we are currently enrolling participants affected by:

 

Paroxysmal Kinesigenic Dyskinesia

Thyrotoxic Periodic Paralysis

Andersen-Tawil Syndrome

 

As an initial screening process, you will be asked to fill out questionnaires or be asked about your medical history. These questions are used to determine if you would be a good candidate for our studies. Dr. Ptacek will review your information and determine your eligibility for participation. Participants will then sign consent forms detailing the study objectives, UCSF health privacy policy, and procedures and donate either a blood or saliva sample for DNA extraction.  We may also request clinical files or other medical records.

We would truly appreciate hearing from you if you feel you have any of these movement disorders and are interested in participating in our studies.

Please refer to our Contact Page for more instructions.

We are currently not enrolling participants for the other episodic disorders. However, we may open enrollment in the future. If you would like to be contacted in the future for our circadian studies, please contact our clinical coordinators with your information. Please refer to the Contact Page for more information.

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Recent Publications

1. A protein   mutated in paroxysmal dyskinesia suppresses synaptic vesicle exocytosis through the active zone protein RIM Proc Natl Acad Sci USA. 2015 Mar 10;112(10):2935-41

2. Casein kinase Iδ mutations in familial migraine and advanced sleep phase. Science Translational Medicine. 2013 May 1;5(183):183ra53

3. Familial Cortical Myoclonus Caused by Mutation in NOL3. Annals of Neurology. 2012 Aug;72(2):175-83

4. Mutations in the novel protein PRRT2 cause paroxysmal kinesigenic dyskinesia with infantile convulsions Cell Reports. 2012 Jan 26: 1(1):2-12

5. Dopamine dysregulation in a mouse model of paroxysmal non-kinesigenic dyskinesia. Journal of Clinical Investigation. 2012 Feb 1; 122(2):507-18

6. Mutations in PNKD causing paroxysmal dyskinesia alter protein cleavage and stability. Hum Mol Genet 2011 Jun 15; 20(12):2322-32

7. Paroxysmal Non-Kinesigenic Dyskinesia caused by the mutation of MR-1 in a large polish kindred. Eur Neurology. 2008 Oct 24; 61(1): 39-41.

8. Flecainide suppresses bidirectional ventricular tachycardia and reverses tachycardia-induced cardiomyopathy in Andersen-Tawil Syndrome. J Cardiovasc Electrophysiol. 2008 Jan; 19(1):95-7.

9. Genetic association studies of the chromosome 15 GABA-A receptor cluster in migraine with aura. Am J Med Genet B Neuropsychiatr Genet. 2008 Jan 5; 147B (1):37-41.

10. Enrichment of HapMap recombination hotspot predictions around human nervous system genes: evidence for positive selection ? Eur J Hum Genet.  2007 Oct;15(10):1071-8

11. Genotype-phenotype correlation of proxysmal nonkinesigenic dyskinesia. Neurology. 2007 May 22;68(21):1782-9.

12. Human Recombination Rates Are Increased Around Accelerated Conserved Regions - Evidence for Continued Selection? Bioinformatics. 2007 Jun 15;23(12):1441-3

13. FAME 3: a novel form of progressive myoclonus and epilepsy. Neurology. 2007 Apr 24;68(17):1382-9.

14. Bioinformatic analysis of human CNS-expressed ion channels as candidates for episodic nervous system disorders. Neurogenetics. 2007 Aug;8(3):159-68.

15. Andersen-Tawil syndrome: definition of a neurocognitive phenotype. Neurology. 2006 Jun13;66(11):1703-10.

16. Andersen-Tawil syndrome: prospective cohort analysis and expansion of the phenotype. Am J Med Genet A. 2006 Feb;140(4):312-21

 

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Other Episodic Disorder Resources

For more information, please visit the following sites:

Dystonia Medical Research Foundation

National Organization for Rare Disorders

The Movement Disorder Society

Worldwide Education and Awareness for Movement Disorders

International Dystonia On-line Support Group

National Institute of Neurological Disorders & Stroke

Periodic Paralysis Resource Center

UCSF Headache Center

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