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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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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 aren’t 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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Publications
1.
Clinical evaluation of
idiopathic paroxysmal dyskinesia: new diagnostic criteria.
Neurology 63; 2280-2287;
Dec 2004.
2. 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.
3. 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.
4. Flecainide
suppresses bidirectional ventricular tachycardia and reverses
tachycardia-induced cardiomyopathy in Andersen-Tawil Syndrome. J Cardiovasc
Electrophysiol. 2008 Jan; 19(1):95-7.
5.
Genotype-phenotype correlation of proxysmal nonkinesigenic dyskinesia.
Neurology. 2007 May 22;68(21):1782-9.
6. FAME 3: a
novel form of progressive myoclonus and epilepsy. Neurology. 2007 Apr
24;68(17):1382-9.
7.
Bioinformatic analysis of human CNS-expressed ion channels as candidates for
episodic nervous system disorders. Neurogenetics. 2007 Aug;8(3):159-68.
8.
Andersen-Tawil syndrome: definition of a neurocognitive phenotype.
Neurology. 2006 Jun13;66(11):1703-10.
9.Andersen-Tawil syndrome: prospective cohort analysis and expansion of the
phenotype. Am J Med Genet A. 2006 Feb;140(4):312-21.
10.
Clinic-based study of family history of vascular rish factors and migraine.
J Headache Pain. 2005 Oct;6(5):412-6.
11. The primary
periodic paralyses: diagnosis, pathogenesis and treatment. Brain. 2006 Jan;
129 (Pt 1):8-17.
12. Defective
potassium channel Kir2.1 trafficking underlies Andersen-Tawil syndrom. J
Biol Chem. 2003 Dec 19;278(51):51779-85.
13.
Electrocardiographic features in Andersen-Tawil syndrome patients with KCNJ2
mutations: characteristc T-U-wave patters predict the KCNJ2 genotype.
Circulation. 2005 May 31;111(21):2720-6.
14. Correlating
phenotype and genotype in the periodic paralyses. Neurology. 2004 Nov
9;63(9):1647-55.
15. Familial
adult myoclonic epilepsy (FAME). Adv Neurol. 2005;95:281-8.
16. The gene
for paroxysmal non-kinesigenic dyskinesia encodes an enzyme in a stress
response pathway. Hum Mol Genet. 2004 Dec 15;13(24):3161-70.
17.
Andersen-Tawil syndrome: a model of clinical variability, pleiotropy, and
genetic heterogeneity. Ann Med. 2004;36 Suppl 1:92-7.
18. Alternating
hemiplegia of childhood or familial hemiplegic migraine? A novel ATP1A2
mutation. Ann Neurol. 2004 Jun;55(6):88-7
19. Molecular
biology of episodic movement disorders. Adv Neurol. 2002;89:453-8.
20.
Dihydropyridine receptor mutations cause hypokalemic periodic paralysis.
Cell. 1994 Jun 17;77(6):863-8.
21.
Paramyotonia congenita: abnormal short exercise test, and improvement after
mexiletine therapy. Muscle Nerve. 1994 jul;17(7):763-8.
22. Mutations
in the human skeletal muscle chloride channel gene (CLCN1) associated with
dominant and recessive myotonia congenita. Neurology. 1996 Oct;47(4):993-8.
23.
Characterization of a new sodium channel mutation at argenine 1448
associated with moderate Paramyotonia congenita in humans. J Physiol. 1999
Jul 15;518 (Pt 2):337-44.
24. Functional
consequences of chloride channel gene (CLCN1) mutations causing myotonia
congenita. Neurology. 2000 Feb22;54(4):937-42.
25. Mechanism
of inverted activation of ClC-1 channels caused by a novel myotonia
congenita mutation. J Biol Chem. 2000 Jan 28;275(4):2999-3005.
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