Episodic Ataxia, Type 1

A number sign (#) is used with this entry because episodic ataxia-1 (EA1) is caused by heterozygous mutation in the potassium channel gene KCNA1 (176260) on chromosome 12p13.

Description

Episodic ataxia is a neurologic condition characterized by spells of incoordination and imbalance, often associated with progressive ataxia (Jen et al., 2007).

Genetic Heterogeneity of Episodic Ataxia

Episodic ataxia is a genetically heterogeneous disorder. See also EA2 (108500), caused by mutation in the CACNA1A gene (601011) on chromosome 19p13; EA3 (606554), which maps to chromosome 1q42; EA4 (606552); EA5, caused by mutation in the CACNB4 gene (601949) on chromosome 2q22-q23; EA6 (612656), caused by mutation in the SLC1A3 gene (600111) on chromosome 5p13; EA7 (611907), which maps to chromosome 19q13; and EA8 (616055), which maps to chromosome 1p36-p34.

Isolated myokymia-2 (see 121200) is associated with mutation in the KCNQ2 gene (602235).

Clinical Features

VanDyke et al. (1975) described a kindred in which 11 persons in 3 consecutive generations had continuous muscle movement (myokymia) and periodic ataxia. Only 2 of the 11 affected were male and no male-to-male transmission was noted. Indeed, neither affected male had children. The disorder presented in early childhood with attacks of ataxia of 1 to 2 minutes in duration, with associated jerking movements of the head, arms, and legs. Attacks were provoked by abrupt postural change, emotional stimulus, and caloric-vestibular stimulation. Myokymia of the face and limbs began at about age 12 years. Physical findings included large calves, normal muscle strength, and widespread myokymia of face, hands, arms, and legs, with a hand posture resembling carpopedal spasm. EMG at rest showed continuous spontaneous activity. Gastrocnemius biopsy showed changes consistent with denervation, as well as enlargement of muscle fibers. The same disorder was reported in 2 other families (Hanson et al., 1977; Gancher and Nutt, 1986).

Brunt and van Weerden (1990) described a large family with paroxysmal ataxia and continuous myokymic discharges. There was at least 1 instance of male-to-male transmission. Often a postural tremor of the head and hands and fine twitching in the face and hand muscles were present. The attacks, which usually lasted a few minutes, might occur several times a day. They first appeared in childhood and tended to abate after early adulthood. The attacks were frequently precipitated by kinesigenic stimuli similar to the phenomenon observed in paroxysmal kinesigenic choreoathetosis (128200). In about half the adults, fine rippling myokymia could be detected on close inspection; in a few, it was obvious. Brunt and van Weerden (1990) concluded that the myokymic activity resulted from multiple impulse generation in peripheral nerves.

Vaamonde et al. (1991) described the disorder in a 26-year-old woman who had had episodic unsteadiness lasting for a few minutes since the age of 6 years. The mother and 1 sister were identically affected. Electromyographic studies revealed myokymia (neuromyotonia). Phenytoin produced good control of the symptoms but acetazolamide was ineffective.

Lubbers et al. (1995) studied 6 affected individuals in a 4-generation pedigree in which paroxysmal ataxia and myokymia were linked to markers on chromosome 12p in affected individuals who demonstrated kinesigenic provocation, attacks being brought on by repeat knee bends or sudden rising from a chair. Myokymic discharges were invariably demonstrable electromyographically, although not all affected members showed clinical myokymia. One affected family member also had attacks of paroxysmal kinesigenic choreoathetosis (see 601042 for kinesigenic choreoathetosis that has been mapped to chromosome 1p). Members of Lubbers' kindred responded to low doses of acetazolamide, although there was some loss of efficacy after prolonged treatment.

Graves et al. (2010) reported 2 unrelated sets of monozygotic twins with genetically confirmed EA1 who showed remarkably different phenotypes. In the first family, twin sisters had onset of symptoms at ages 14 and 16 years, respectively. One sister had daily episodes lasting from 10 to 15 minutes and required maintenance on carbamazepine, whereas her twin had a less severe phenotype with weekly episodes lasting 5 to 10 minutes and did not require medication. Both had dizziness, slurred speech, and incoordination of the hands during attacks, but the more severely affected sister also had unsteady gait, weakness, and myokymia. In the second family, 1 twin brother had onset at age 1 year of weekly episodes lasting seconds to 10 minutes; medication was not required. His twin brother had onset at age 6 years of daily episodes lasting seconds to 3 minutes; carbamazepine was not effective. The attacks in both brothers were characterized by imbalance, weakness, blurred vision, slurred speech, myokymia, and incoordination of the hands. These symptoms were less severe in the first brother, although he had associated vertigo, headache, and nausea. Their affected mother had a progressive interictal cerebellar syndrome with ataxia and dysarthria. The report indicated that nongenetic factors play a role in the severity of EA1.

Isolated Myokymia

Isolated spontaneous muscle twitches occur in many persons and have no grave significance. Wieczorek and Greger (1962) described a dominant pedigree with myokymia. Sheaff (1952) observed myokymia in a man and his 4 sons. In a portion of muscle removed for biopsy, fasciculations persisted for 8 minutes. Affected persons probably have an increased frequency of muscle cramps ('night cramps').

A syndrome of continuous muscle fiber activity was described by Ashizawa et al. (1983). Cerebrospinal fluid levels of homovanillic acid and 5-hydroxyindoleacetic acid were increased in the proband. Referred to as continuous motor neuron discharge, the disorder was present in 7 members of 3 generations.

McGuire et al. (1984) described the syndrome of continuous muscle fiber activity in a 3-year-old boy and his 28-year-old mother. The boy had shown persistent fisting from the age of 4 months. Previously the family had observed diminished spontaneous motor activity with flexion contractures of the lower limbs. Cardiopulmonary studies, prompted by recurrent episodes of peripheral cyanosis, showed eventration of both diaphragms with poor motion. Increased muscle tone and stiffness persisted during sleep. EMG showed continuous motor unit activity which continued despite peripheral nerve blockade or general anesthesia. Phenytoin sodium effected 'considerable improvement.' The cyanotic episodes disappeared after plication of the diaphragms and phenytoin therapy. The mother had demonstrated persistent stiffness and fisting in early childhood. No form of medication was beneficial until phenytoin was given at age 8 for suspected seizures. She was still taking phenytoin at age 28 and showed toxic effects with a serum level of 36 mg/L. With decreased dosage, serpentine movements of the fingers and lower eyelids appeared. After discontinuation of phenytoin, myokymia continued in sleep and transient stiffness developed after initiation of movements.

Chen et al. (2007) reported a family in which a mother and 3 sons had isolated myokymia without epilepsy or episodic ataxia. The proband was a 13-year-old boy who was diagnosed with cerebral palsy due to leg stiffness and showed delayed walking at age 18 months. At age 4 years, he was hospitalized with increasing leg pain, stiffness, and inability to walk during a flu-like illness. Serum creatine kinase was elevated during the acute attack. Examination showed periorbital myokymia, spastic gait, hyperreflexia, and extensor plantar responses. EMG studies showed continuous motor unit discharges. His mother and 2 affected brothers showed a similar phenotype; 3 of the patients also had esotropia. The 3 brothers were asymptomatic with carbamazepine treatment. Genetic studies identified a heterozygous mutation in the KCNA1 gene (176260.0014) that segregated with the disorder. Chen et al. (2007) noted that patients in this family showed unusual features, such as extensor plantar responses suggestive of corticospinal tract involvement and worsening of symptoms with febrile illness or anesthesia.

Association With Hypomagnesemia

Glaudemans et al. (2009) studied a large 5-generation Brazilian family segregating autosomal dominant hypomagnesemia, in which 21 of 46 family members were affected. Beginning in infancy, the proband had recurrent muscle cramps, tetanic episodes, tremor, and muscle weakness, especially in the distal limbs. The proband reported several episodes during which she was 'not able to walk straight,' but no objective clinical signs of cerebellar dysfunction were apparent on examination; cerebral MRI showed slight atrophy of the cerebellar vermis. A younger brother had died in infancy from a severe attack of cramps and tetany, during which time his serum magnesium was as low as 0.28 mmol/l. Serum electrolyte levels measured during severe episodes of cramps and tetany in 2 affected family members revealed low serum magnesium with normal calcium and potassium concentrations; urinary magnesium excretion was normal, suggesting impaired tubular magnesium reabsorption, and urinary calcium excretion was normal. During the course of the study, the proband was hospitalized due to a sudden episode of facial myokymia, tremor, severe muscle spasms, muscular pain, cramps, muscular weakness, and intermittent tetanic contraction, all of which improved shortly after intravenous magnesium administration. Electromyographs of some affected family members showed myokymic discharge.

Mapping

Using a group of Genethon markers from a region of 12p carrying the potassium channel genes, Litt et al. (1993, 1994) demonstrated linkage in 4 AEMK kindreds. A maximum combined lod score of 13.6 was obtained with the marker D12S99 at theta = 0. They were prompted to study linkage to this region because potassium channel genes, e.g., KCNA1 and KCNA2 (176262), mapped there. The KCNA5 gene (176267) also maps to that region but was ruled out as the site of the defect by the observation of a single crossover between the disease gene and a (CA)n repeat marker in the KCNA5 cosmid. Studies of a large episodic ataxia family with a clinical phenotype that lacks myokymia but is associated with nystagmus (108500) excluded the gene causing that disease from the chromosome 12p region.

In a 5-generation Brazilian family segregating autosomal dominant hypomagnesemia and myokymia, Glaudemans et al. (2009) performed SNP-based linkage analysis that identified a 14.3-cM locus on chromosome 12q. Fine mapping with microsatellite markers narrowed the region of interest to an 11.6-cM interval between D12S1626 and D12S1623, with a maximum multipoint lod score of 3.0.

Molecular Genetics

Browne et al. (1994) demonstrated mutations in the KCNA1 gene in 4 families with AEMK (176260.0001-176260.0004). A different missense point mutation was present in heterozygous state in each. All affected individuals are heterozygous.

In 2 families with myokymia without ataxic episodes, Eunson et al. (2000) identified mutations in the KCNA1 gene (176260.0010-176260.0011). One of these families also segregated seizures.

In a 5-generation Brazilian family segregating autosomal dominant hypomagnesemia and myokymia mapping to chromosome 12q, Glaudemans et al. (2009) identified a heterozygous missense mutation in the KCNA1 gene (N255D; 176250.0015) that segregated with the disease and was not found in 100 control chromosomes.

Reviews

For a comprehensive review of episodic ataxia type 1 and its causative mutations, see Brandt and Strupp (1997).

Jen et al. (2007) provided a detailed review of the pathophysiology and molecular genetics of known episodic ataxia syndromes.

Animal Model

Using homologous recombination, Herson et al. (2003) introduced the Kcna1 val408-to-ala mutation (V408A; 176260.0001) into mice. In contrast to Kcna1 null mice, homozygous V408A mice died after embryonic day 3, consistent with V408A being a homozygous lethal allele. V408A heterozygous mice showed stress-induced loss of motor coordination that was ameliorated by acetazolamide, similar to patients with EA1. Cerebellar Purkinje cells from V408A heterozygous mice showed a greater frequency and amplitude of spontaneous GABAergic inhibitory postsynaptic currents than did wildtype. The authors noted that Kcna1 is localized to GABAergic interneurons in the cerebellum, suggesting that it may be important for regulating GABA release, and that mutations in the gene may alter excitability in the cerebellum, leading to clinical symptoms.