Episodic ataxia

PEO [25] A myopathy with progressive muscle weakness and external ophthalmoplegia. Ataxia, episodic ke-toacidotic coma, and early death have been reported associated with single or multiple DNA deletions. Mutations in the gene encoding the muscle isoform of the adenylate carrier (ANTI) have been reported to cause PEO, presumably due to abnormal nucleotide availability for mtDNA synthesis. 

Psychomotor retardation/regression Extrapyramidal signs Ataxia (episodic)... 

Episodic ataxia (EA) is an autosomal dominant disorder that brief episodes of ataxia can be triggered by physical or emotional stress. The symptom can occur several times during the day, last for seconds to minutes, and be associated with dysarthria and motor neuron activity, which causes muscle rippling (myokymia) between and during attacks. It is caused by a mutation in a neuronal voltage dependent Ca2+ channel. 

Mutation in the neuronal Cav2.1 channel is associated with familial hemiplegic migraine and episodic ataxia in humans. Deletion of the Cav2.1, Cav2.2 and Cav2.3 gene is compatible with life accompanied by a variety of central and peripheral defects. 

EA, episodic ataxia LQT, long QT syndrome JLN, Jervell-Lange Nielsen syndrome BFNC, benign familial epilepsy DFNB2, deafness syndrome... 

Mutations in human Kv-channel genes have been detected that are associated with hereditary diseases ranging from heart arrythmia (long QT-syndrome) and deafness to epilepsy and ataxia (see Table 2). Typically, many Kv-channel related channelopathies are correlated with a mutant phenotype that is episodic in nature and appears as a dominant hereditary trait. 

Patients with partial enzymatic deficiencies may present later in life with intermittent ketoacidosis, prostration and recurrent ataxia. The plasma concentrations of BCAA are elevated during these episodes but they maybe normal or near-normal during the periods when patients are metabolically compensated. 

Ophoff, R.A., et al., "Familial Hemiplegic Migraine and Episodic Ataxia type-2 are Caused by Mutations in the Ca2+ Channel Gene CACNL1A4," Cell, 87, 543-552 (1996). 

Do not treat more than 5 episodes per month or more than 1 episode every 5 days. Elderly and debilitated Adjust dosage downward to reduce ataxia or oversedation. 

Drug intoxication. Cocaine and amphetamine intoxication may cause an agitated paranoid psychotic episode. Physical signs include dilated pupils, slurred speech, ataxia, hyperreflexia, and nystagmus, as well as evidence of drug use (e.g., needle tracks, nasal septum erosion). Vital signs, if obtainable, include elevated blood pressure, pulse rate, and temperature (see also the section The Alcoholic Patient in Chapter 14). 

In previously treated epileptic patients, the administration of a large loading dose of phenytoin may cause some dose-related toxicity such as ataxia. This is usually a relatively minor problem during the acute status episode and is easily alleviated by later adjustment of plasma levels. 

Table 1. CACNA1A (Ca 2.1, a 1A) Functional results for mutations associated with FHM = familial hemiplegic migraine, EA2 = episodic ataxia type 2, SCA6 = spinocerebellar ataxia type 6, PCA = progressive cerebellar ataxia (although addition mutations have been associated with these disorders, only those with reported functional data are listed)...

R1820X Generalized epilepsy and episodic and progressive ataxia nt.4778-4780 ctt deletion, deletion of A1593 and Y1594- EA2... 

EA2, similar to FHM1, is an autosomal dominant disorder associated with mutations in the CACNA1A gene, but is clinically quite distinct. EA2 patients experience spontaneous episodes of ataxia (poor muscle coordination) that last for hours to days. In between attacks, patients often experience gaze-evoked or down-beat nystagmus (rapid, involuntary eye oscillations). Approximately 50% of patients experience migraine-like symptoms, and cerebellar atrophy is common (Lorenzon and Beam, 2000). Attacks are often initiated by emotional stress, exercise, or alcohol. Most patients respond well to treatment with acetazolamide (reviewed in (Jen et al., 2004)). EA2 is genetically variable and has been associated with missense, truncation and alternative splice site mutations. 

Figure 2. Mutations in the human Cav2.1 (P/Q-type) voltage-gated calcium channel associated with Episodic Ataxia Type-2 (EA2) mutations in the Cav2.1 mouse homolog associated with tottering (tg), leaner (tgla), rolling nagoya (tgrol) and rocker phenotypes...

Table 8. CACNB4 ( i, ) Functional results for mutations associated with JME= juvenile myoclonic epilepsy, GE = generalized epilepsy and EA = episodic ataxia...

Imbrici P, Jaffe SL, Eunson LH, Davies NP, Herd C, Robertson R, Kullmann DM, Hanna MG (2004) Dysfunction of the brain calcium channel CaV2.1 in absence epilepsy and episodic ataxia. Brain... 

Jen J, Kim GW, Baloh RW (2004) Clinical spectrum of episodic ataxia type 2. Neurology 62 17-22. 

Jeng CJ, Chen YT, Chen YW, Tang CY (2006) Dominant-negative effects of human P/Q-type Ca2+ channel mutations associated with episodic ataxia type 2. Am J Physiol Cell Physiol 290 0209-1220. 

Ophoff RA, Terwindt GM, Vergouwe MN, van Eijk R, Oefner PJ, Hoffman SM, Lamerdin JE, Mohrenweiser HW, Bulman DE, Ferrari M, Haan J, Lindhout D, van Ommen GJ, Hofker MH, Ferrari MD, Frants RR (1996) Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNL1A4. Cell 87 543-552. 

Wan J, Khanna R, Sandusky M, Papazian DM, Jen JC, Baloh RW (2005) CACNA1A mutations causing episodic and progressive ataxia alter channel trafficking and kinetics. Neurology 64 2090-2097. 

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