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Episodic Ataxia

Familial Episodic Ataxia


Presentation

  • In rare instances, GLUT1 DS can present as a paroxysmal movement disorder without the other classic symptoms.[ncbi.nlm.nih.gov]
  • Episodic ataxia type-3 (EA3) is similar to EA1 but often also presents with tinnitus and vertigo. Patients typically present with bouts of ataxia lasting less than 30 minutes and occurring once or twice daily.[en.wikipedia.org]
  • Abstract This report describes the clinical features of a 29 year female presenting with a 3 years history of episodes of cerebellar ataxia, dysarthria and nystagmus lasting 3-5 days, recurring almost every month.[ncbi.nlm.nih.gov]
  • Moreover, patients sharing a given CACNA1A mutation may present very different phenotypes even within the same family. Copyright 2010 S. Karger AG, Basel.[ncbi.nlm.nih.gov]
  • OBJECTIVE: To describe aspects in clinical and genetic presentation in five patients with episodic ataxia type 2 (EA2). METHODS: CACNA1A gene screening identified a mutation in three probands and in two of their children.[ncbi.nlm.nih.gov]
Weakness
  • All but one young patient had additional neurologic symptoms that included paresthesia, weakness, headache, tinnitus, vertigo, and myotonia. All symptoms were prevented by acetazolamide.[ncbi.nlm.nih.gov]
  • We describe a 10-year-old girl with EA1 who has distal weakness with paresis of the extensors of the feet and prolonged spells of limb stiffness (neuromyotonia) lasting up to 12 hours.[ncbi.nlm.nih.gov]
  • Affected individuals experienced recurrent attacks with or without nystagmus, dysarthria, seizure, myokymia, dystonia, weakness, blurred vision, visual field defects, diplopia, migraine, dizziness, nausea and vomiting, sweating and abdominal pain.[ncbi.nlm.nih.gov]
  • Vertigo, dysarthria, weakness No EA8 616055 AD UBR4 (1p36.13) Ubiquitin-protein ligase Early infancy Min to 24 h Vertigo, weakness Nystagmus, ataxia myokymia Table 2.[e-jmd.org]
  • Vertigo and weakness accompanied the ataxia in more than half of the genetically defined patients. One family had multiple members with epilepsy. A wide range of mutations in CACNA1A were associated with episodic ataxia.[neurology.org]
Hypothermia
  • Additionally, they suffered from ictal hyperhidrosis with acute hypothermia of the extremities. Lastly, the father presented with interictal chronic diarrhea not associated to a known primary gastrointestinal disorder.[ncbi.nlm.nih.gov]
  • Less common symptoms during attacks Choreoathetosis Carpal spasm Clenching of the fists Mild lower limb sensory impairment Isolated neuromyotonia Hypothermia, which led to the death of an individual with EA1 due to exposure to anesthesia [ Mestre et al[ncbi.nlm.nih.gov]
Impaired Balance
  • Symptoms - Hereditary paroxysmal cerebral ataxia The list of signs and symptoms mentioned in various sources for Episodic ataxia, type 2 includes the 10 symptoms listed below: * Dizziness * Unsteadiness * Incoordination * Impaired balance * Slurred speech[checkorphan.org]
Nausea
  • She experienced recurrent attacks of loss of equilibrium and loss of coordination of the extremities accompanied by dysarthria and nausea beginning at about 10 years old. These episodes usually lasted for several hours two or three times a week.[ncbi.nlm.nih.gov]
  • Affected individuals experienced recurrent attacks with or without nystagmus, dysarthria, seizure, myokymia, dystonia, weakness, blurred vision, visual field defects, diplopia, migraine, dizziness, nausea and vomiting, sweating and abdominal pain.[ncbi.nlm.nih.gov]
  • Associated symptoms include vertigo, nausea, vomiting, and mild photophobia. Sometimes, the day after an attack, she experiences bilateral headache not associated with nausea, vomiting, phonophobia, or photophobia.[doi.org]
  • Attacks may last for minutes, but occasional longer episodes lasting for hours, can lead to nausea, vomiting, and headaches. Rare individuals have seizures.[wohproject.org]
  • […] abruptly and reached a peak within 10 minutes: (1) Palpitations, pounding heart, or accelerated heart rate (2) Sweating (3) Trembling or shaking (4) Sensations of shortness of breath or smothering (5) Feeling of choking (6) Chest pain or discomfort (7) Nausea[books.google.ro]
Vomiting
  • Affected individuals experienced recurrent attacks with or without nystagmus, dysarthria, seizure, myokymia, dystonia, weakness, blurred vision, visual field defects, diplopia, migraine, dizziness, nausea and vomiting, sweating and abdominal pain.[ncbi.nlm.nih.gov]
  • Since then, he has had periodic attacks of ataxic gait, repeated vomiting, and abnormal eye movement. He was diagnosed as having episodic ataxia type 2 because the administration of acetazolamide seemed effective.[ncbi.nlm.nih.gov]
  • Associated symptoms include vertigo, nausea, vomiting, and mild photophobia. Sometimes, the day after an attack, she experiences bilateral headache not associated with nausea, vomiting, phonophobia, or photophobia.[doi.org]
  • Attacks may last for minutes, but occasional longer episodes lasting for hours, can lead to nausea, vomiting, and headaches. Rare individuals have seizures.[wohproject.org]
  • Case Report The proband presented to us at the age of 42years with history of ataxia, vertigo and vomiting since the age of 14years. He had experienced several attacks of vertigo and ataxia lasting for 3 to 6 hours.[japi.org]
Chronic Diarrhea
  • Lastly, the father presented with interictal chronic diarrhea not associated to a known primary gastrointestinal disorder. Both ictal hyperhidrosis and interictal diarrhea ameliorated upon acetazolamide intake, the typical treatment for EA2.[ncbi.nlm.nih.gov]
Back Pain
  • The patient presented with neonatal-onset seizures and variable episodes of ataxia, myoclonia, headache, and back pain after 18 months of age.[ncbi.nlm.nih.gov]
  • In early childhood, they started to experience repeated episodes of ataxia, accompanied in part by headache or back pain lasting minutes to several hours. In two of the new cases, we detected the novel mutation p.Arg1882Gly.[ncbi.nlm.nih.gov]
Foot Deformity
  • He walked at 14 months and his foot deformity had resolved, but he had a continued tendency to adduct his thumbs across his palms. Episodes of ataxia began at the age of 4 years.[doi.org]
Diplopia
  • Affected individuals experienced recurrent attacks with or without nystagmus, dysarthria, seizure, myokymia, dystonia, weakness, blurred vision, visual field defects, diplopia, migraine, dizziness, nausea and vomiting, sweating and abdominal pain.[ncbi.nlm.nih.gov]
  • In addition, the authors identified the first pathogenic duplication in CACNA1A in an index case with isolated episodic diplopia without ataxia and in a first degree relative with episodic ataxia.[ncbi.nlm.nih.gov]
  • During attacks, they also have vertigo, nausea, vomiting, tinnitus and diplopia. These attacks are sometimes accompanied by headaches and precipitated by stress, fatigue, movement and arousal after sleep.[en.wikipedia.org]
  • […] analysis of the mutation carriers showed the highly variable penetrance and expression of this disorder: Several of the carriers did not show any clinical symptom; others displayed atypical or permanent neurologic symptoms (such as recurrent, transient diplopia[n.neurology.org]
  • Additional features include diplopia, tinnitus, seizure, dystonia, and cognitive impairment.[e-jmd.org]
Blurred Vision
  • Affected individuals experienced recurrent attacks with or without nystagmus, dysarthria, seizure, myokymia, dystonia, weakness, blurred vision, visual field defects, diplopia, migraine, dizziness, nausea and vomiting, sweating and abdominal pain.[ncbi.nlm.nih.gov]
  • Attacks are often associated with nausea, vomiting, photophobia, phonophobia, vertigo, diplopia, slurred speech, and blurred vision. No headache was reported.[doi.org]
  • Attacks always included severe truncal and limb ataxia with dysarthria, vertigo, and oscillopsia and diplopia sometimes associated with nausea, vomiting, and blurred vision.[doi.org]
  • When the nerves in your vestibular system wear away, you can have the following problems: Blurred vision and other eye issues Nausea and vomiting Problems standing and sitting Staggering when you walk Trouble walking in a straight line Vertigo , or dizziness[webmd.com]
Strabismus
  • Two probands had a history of strabismus. All responded well to acetazolamide. Two children were found to have both clinical and genetic abnormalities.[ncbi.nlm.nih.gov]
  • His medical history was unremarkable except for a strabismus, which needed surgical repair at age 22 years. Ataxic spells were strongly stereotyped.[doi.org]
Tinnitus
  • Vestibular ataxia, vertigo, tinnitus, and interictal myokymia are prominent; attacks are diminished by acetazolamide.[ncbi.nlm.nih.gov]
  • All but one young patient had additional neurologic symptoms that included paresthesia, weakness, headache, tinnitus, vertigo, and myotonia. All symptoms were prevented by acetazolamide.[ncbi.nlm.nih.gov]
  • Homepage Rare diseases Search Search for a rare disease Episodic ataxia type 3 Disease definition Episodic ataxia type 3 (EA3) is a very rare form of Hereditary episodic ataxia (see this term) characterized by vestibular ataxia, vertigo, tinnitus, and[orpha.net]
  • During attacks, they also have vertigo, nausea, vomiting, tinnitus and diplopia. These attacks are sometimes accompanied by headaches and precipitated by stress, fatigue, movement and arousal after sleep.[en.wikipedia.org]
Severe Mental Retardation
  • One of his daughters had severe mental retardation and epilepsy, and the other had paroxysmal ataxic attacks and mild mental retardation. Analysis of the subject's CACNA1A gene and that in his daughter revealed neither mutations nor CAG expansion.[ncbi.nlm.nih.gov]
  • mental retardation and hypogonadism recognized in later years Laboratory findings Decreased serum glycoproteins MRI showing striking pontocerebellar atrophy Reduced thyroxine-binding globulin levels Sialic acid, galactose, and N -acetylglucosamine deficiency[emedicine.com]
Neonate-Onset
  • We evaluated the clinical characteristics in a patient with a neonatal-onset complex episodic neurologic phenotype.[ncbi.nlm.nih.gov]
  • In total, four probands presented with neonatal-onset seizures remitting after five to 13 months.[ncbi.nlm.nih.gov]
Myokymia
  • One type of EA is characterized by brief episodes of ataxia with myokymia (rippling of muscles) evident between attacks.[ncbi.nlm.nih.gov]
  • An Italian family has been identified where related members displayed continuous myokymia, episodes of ataxia, attacks characterized by myokymia only, and neuromyotonia.[ncbi.nlm.nih.gov]
  • Studies of a large EA family with a different clinical phenotype (MIM 108500), which lacks myokymia but is associated with nystagmus, have excluded the gene causing that disease from the chromosome 12p locus.[ncbi.nlm.nih.gov]
  • Episodic ataxia and myokymia syndrome is an autosomal dominant disorder characterized by persistent myokymia and attacks of unsteadiness, slurred speech, and tremulousness.[ncbi.nlm.nih.gov]
  • All of the affected family members had episodes typically lasting for several hours, and none of them had muscle abnormalities including myokymia.[ncbi.nlm.nih.gov]
Vertigo
  • Given the familial aggregation of migraine and migrainous vertigo, our objective was to identify predisposing genetic factors. Preliminary findings demonstrate that migrainous vertigo is genetically heterogeneous and complex.[ncbi.nlm.nih.gov]
  • At 23 months, one child started to have short attacks of imbalance mimicking benign paroxysmal vertigo of childhood. Then, the frequency and duration of his attacks increased and some were associated with headache.[ncbi.nlm.nih.gov]
  • At least two groups of disorders have been separated clinically: (1) episodic ataxia type 1 (EA-1), which manifests without vertigo and is associated with 'interictal' myokymia, and (2) episodic ataxia type 2 (EA-2), which often manifests with vertigo[ncbi.nlm.nih.gov]
  • Patients with pure EA5 present with recurrent episodes of ataxia with vertigo. Between attacks they have nystagmus and dysarthria. These patients are responsive to acetazolamide.[en.wikipedia.org]
  • Vestibular ataxia, vertigo, tinnitus, and interictal myokymia are prominent; attacks are diminished by acetazolamide.[ncbi.nlm.nih.gov]
Seizure
  • Mutations in SCN2A, encoding the brain sodium channel Na(V)1.2, have previously been reported to be associated with benign familial neonatal infantile seizures, febrile seizures plus, and intractable epilepsy of infancy.[ncbi.nlm.nih.gov]
  • Isolated acetazolamide-responsive EA secondary to GLUT1 DS without deficits on neurological examination and without seizures has not been described.[ncbi.nlm.nih.gov]
  • RESULTS: The 7 family members had episodic ataxia (5), self-limited infantile seizures (5), evolving to genetic generalized epilepsy (4), focal seizures (2), and EE (1).[ncbi.nlm.nih.gov]
  • Mutations in CACNA1A encoding a neuronal calcium channel and ATP1A2 encoding an ion pump cause episodic ataxia, hemiplegic migraine, and seizures.[ncbi.nlm.nih.gov]
  • In total, four probands presented with neonatal-onset seizures remitting after five to 13 months.[ncbi.nlm.nih.gov]
Headache
  • Headache. 2009 Jul;49(7):1042-6. doi: 10.1111/j.1526-4610.2009.01464.x. Epub 2009 May 27. Author information 1 The Montefiore Headache Center, Saul R.[ncbi.nlm.nih.gov]
  • CASE REPORT: A 24-year-old woman consulted the headache clinic because of frequent paroxysmal attacks of strong sensoriphobia, digestive signs, moderate ataxia and a need to lie in the dark, without any headache.[ncbi.nlm.nih.gov]
  • RESULTS: The three probands had attacks of imbalance, associated with dizziness/vertigo and/or headache. Two of them had independent migraine attacks. Interictal oculomotor examination revealed a gaze evoked nystagmus and central oculomotor signs.[ncbi.nlm.nih.gov]
  • The author reports the first Thai patient with a rare inherited ataxic disorder characterized by intermittent episodes of ataxia, headache and vertigo. The patient was well between attacks despite persistent nystagmus on examination.[ncbi.nlm.nih.gov]
  • All but one young patient had additional neurologic symptoms that included paresthesia, weakness, headache, tinnitus, vertigo, and myotonia. All symptoms were prevented by acetazolamide.[ncbi.nlm.nih.gov]
Slurred Speech
  • Episodic ataxia and myokymia syndrome is an autosomal dominant disorder characterized by persistent myokymia and attacks of unsteadiness, slurred speech, and tremulousness.[ncbi.nlm.nih.gov]
  • The proband exhibited typical EA2-like symptoms such as recurrent ataxia, slurred speech with a duration of several hours, interictal nystagmus and response to acetazolamide, but had late-onset age of sixth decade.[ncbi.nlm.nih.gov]
  • speech, headache, confusion and hemiplegia.[orpha.net]
  • It begins in childhood and consists of attacks of dizziness, unsteadiness, clumsiness and slurred speech which can last for hours.[action.org.uk]
  • Episodic ataxias are characterized by intermittent symptoms or episodes that can vary in duration, lasting from minutes to days, consisting of slurred speech, a feeling of dizziness, ringing in the ears, abnormal posturing, unsteadiness and sometimes[ataxiacenter.umn.edu]

Workup

  • In adults, Vitamin E and occasionally Vitamin B-12 deficiency are rarely a cause of chronic progressive ataxia and should not be overlooked in a diagnostic workup.[movementdisorders.org]
Normal Interictal EEG
  • Neurological examination was normal. Interictal EEG was normal. A 24-h video EEG study was performed during which several episodes were captured. These were shown to be complex partial seizures.[doi.org]

Treatment

  • Prospective 2-year follow-up of the natural history of the main presenting symptoms in a homozygous DARS2 mutation carrier, followed by a 60 day treatment with acetazolamide in two different doses and with two random treatment interruptions.[ncbi.nlm.nih.gov]
  • Approximately 70% of all patients respond to treatment with ACTZ, but the effect is often only transient.[ncbi.nlm.nih.gov]
  • When treatment with 4-AP was paused the patient was suffering from marked gait and stance ataxia. After re-initiation of treatment with 5 mg 4-AP t.i.d., there was pronounced improvement in gait and stance ataxia.[ncbi.nlm.nih.gov]
  • Attacks recurred after treatment was stopped; subsequent treatment alleviated the symptoms (mean follow-up time 6 months). These effects might be due to an improvement of the impaired functioning of Purkinje cells.[ncbi.nlm.nih.gov]
  • This review examines our current understanding of episodic ataxia type 1, focusing on its clinical and genetic features, pathophysiology, and treatment.[ncbi.nlm.nih.gov]

Prognosis

  • Prognosis: Excellent prognosis if treated. No permanent brain damage has been found. Ancillary treatments and support: Protection apparel for severe cases to protect from traumatic falls. Specialists and specialty centers: Neurologist.[wohproject.org]
  • Prognosis - Hereditary paroxysmal cerebral ataxia Not supplied. Treatment - Hereditary paroxysmal cerebral ataxia Not supplied. Resources - Hereditary paroxysmal cerebral ataxia Not supplied.[checkorphan.org]
  • Prognosis The prognosis for a person with ataxia depends upon the type and nature of the disease. Ataxia as a result of trauma or infection may be a temporary condition, or leave some degree of permanent disability.[encyclopedia.com]

Etiology

  • Episodic neurologic disorders, such as epilepsy, migraine, and paroxysmal movement disorders, often coexist and are thought to have a shared channel-related etiology.[ncbi.nlm.nih.gov]
  • These cases involve patients with rare diseases that likely have a genetic etiology but have failed to be diagnosed by clinical evaluation and targeted gene testing.[ncbi.nlm.nih.gov]
  • The term covers a number of multisensory and sensorimotor syndromes of various etiologies and pathogeneses, which can be elucidated only with an interdisciplinary approach.[books.google.ro]
  • Impaired P/Q-type calcium channel function is the etiology, and the mutation is again on CACNL1A(Ophoff et al, 1996). One of the numerous to count spinocerebellar ataxias , SCA6, is due to a tri-nucleotide repeat on this gene.[dizziness-and-balance.com]
  • Impaired P/Q-type calcium channel function is the etiology, and the mutation is again on CACNL1A(Ophoff et al, 1996). One of the numerous to count spinocerebellar ataxias, SCA6, is due to a tri-nucleotide repeat on this gene.[dizziness-and-balance.com]

Epidemiology

  • Esther De Theije‐Kors and Joost Haan, Hemiplegic and Basilar‐type Migraine: Epidemiology, Genetics, and Mechanisms, Headache Currents, 3, 4, (73-81), (2006).[doi.org]
  • Epidemiology: The episodic ataxias are very rare. In our clinic database of mainly adult dizzy patients, containing roughly 12,000 distinct patients with dizziness, we have only 23 patients diagnosed as "episodic ataxia".[dizziness-and-balance.com]
  • "Fragile X-Associated Tremor Ataxia Syndrome: The Expanding Clinical Picture, Pathophysiology, Epidemiology, and Update on Treatment". Tremor and Other Hyperkinetic Movements. 2. doi : 10.7916/D8HD7TDS. ISSN 2160-8288. PMC 3570061. PMID 23439567.[en.wikipedia.org]
  • The Global Epidemiology of Hereditary Ataxiaand Spastic Paraplegia: A systematic review of prevalence studies. Neuroepidemiology 2014; 24:174-183. Ashizawa T, Figueroa KP, Perlman SL, et al.[rarediseases.org]
Sex distribution
Age distribution

Pathophysiology

  • So far, reduced glutamate uptake by mutant excitatory amino acid transporter-1 has been thought to be the main pathophysiological process in episodic ataxia type 6.[ncbi.nlm.nih.gov]
  • This review examines our current understanding of episodic ataxia type 1, focusing on its clinical and genetic features, pathophysiology, and treatment.[ncbi.nlm.nih.gov]
  • Many aspects of the pathophysiology (e.g., induction of the attacks) and treatment of EA 2 (e.g., mode of action of ACTZ and 4-AP) still remain unclear and need to be addressed in further animal and clinical studies.[ncbi.nlm.nih.gov]
  • These results suggest that as in many neurodegenerative disorders, intracellular aggregation of misfolded Kv1.1-containing channels may contribute to the pathophysiology of EA-1.[doi.org]
  • […] of schizophrenia. 1– 3 The analysis of associations between psychosis and neurodegenerative diseases may improve our understanding of the pathophysiology of schizophrenia and facilitate the search for susceptibility genes for this disorder. 4 To our[jnnp.bmj.com]

Prevention

  • As effective as acetazolamide is in preventing attacks, prospective studies still have to prove whether it can prevent progressive ataxia in EA-2 or even improve chronic cerebellar deficits.[ncbi.nlm.nih.gov]
  • All symptoms were prevented by acetazolamide. Between attacks, serum pyruvate and lactate levels and urinary amino acids were normal, but electroencephalograms showed paroxysmal, high-amplitude, slow and sharp activity.[ncbi.nlm.nih.gov]
  • Suppression is prevented by addition of an N-terminal tag (XFP) to the full-length and truncated constructs.[ncbi.nlm.nih.gov]
  • Acetazolamide prevented further episodes of ataxia, dystonia and encephalopathy.[ncbi.nlm.nih.gov]
  • The authors report three patients with EA2 (two with proven mutations in the CACNA1A gene) whose attacks were prevented with the potassium channel blocker 4-aminopyridine (4-AP; 5 mg tid).[ncbi.nlm.nih.gov]

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