Clinical characteristics.

Episodic ataxia type 1 (EA1) is a potassium channelopathy characterized by constant myokymia and dramatic episodes of spastic contractions of the skeletal muscles of the head, arms, and legs with loss of both motor coordination and balance. During attacks individuals may experience a number of variable symptoms including vertigo, blurred vision, diplopia, nausea, headache, diaphoresis, clumsiness, stiffening of the body, dysarthric speech, and difficulty in breathing, among others. EA1 may be associated with epilepsy. Other possible associations include delayed motor development, cognitive disability, choreoathetosis, and carpal spasm. Usually, onset is in childhood or early adolescence.

Diagnosis/testing.

Diagnosis is based on clinical findings, an electrophysiologic test of axonal superexcitability and threshold electrotonus, and/or the identification of a heterozygous pathogenic variant in KCNA1 by molecular genetic testing.

Management.

Treatment of manifestations: Acetazolamide, a carbonic-anhydrase inhibitor, may reduce the frequency and severity of attacks in some but not all affected individuals. Antiepileptic drugs may significantly reduce the frequency of attacks in some individuals. Supportive therapies, such as physical therapy, may reduce the risk of later-onset orthopedic complications. Routine treatment of seizure disorders, scoliosis, and developmental disabilities.

Prevention of primary manifestations: In addition to pharmacologic treatments, behavioral measures including avoidance of stress, abrupt movements, loud noises, and caffeine may be used to reduce disease manifestations in both symptomatic and asymptomatic individuals.

Prevention of secondary complications: Joint contractures can be prevented by appropriate physiotherapy.

Surveillance: Annual neurologic examination.

Agents/circumstances to avoid: Triggers of attacks, including physical exertion, emotional stress, and changes in environmental temperature; marked generalized myokymia has been reported during induction of anesthesia.

Pregnancy management: Affected women should be made aware that pregnancy may trigger attacks; possible loss of balance and falls could endanger the fetus. Several stressors that trigger attacks may cause breathing difficulties; thus, delivery by C-section should be considered.

Genetic counseling.

EA1 is inherited in an autosomal dominant manner. Most individuals diagnosed with EA1 have an affected parent; however, de novo pathogenic variants have been reported. Each child of an individual with EA1 has a 50% chance of inheriting the KCNA1 pathogenic variant. Prenatal testing for a pregnancy at increased risk is possible if the pathogenic variant has been identified in an affected family member.

Suggestive Findings

Episodic ataxia type 1 (EA1) should be suspected in individuals with the following clinical, imaging, and laboratory findings.

Clinical manifestations

• Episodic attacks of:
  • Generalized ataxia, loss of balance, and jerking movements of the head, arms, and legs
  • Dysarthria
  • Incoordination of hands
  • Weakness
  • Tremors
  • Muscle twitching/stiffening
  • Dizziness
  • Stiffening of the body
  • Blurred vision, diplopia
  • Nausea, headache, and vomiting
• Neuromyotonia (muscle cramps and stiffness)
• Myokymia (muscle twitching with a rippling appearance) occurring in the limbs or especially in the muscles of the face or hands
• Childhood or early-adolescent disease onset (average age of onset: ~8 years)

Imaging and laboratory findings

• Normal brain MRI
• Routine laboratory blood tests including serum concentration of creatine kinase and electrolytes
• EMG that displays a pattern of either rhythmically or arrhythmically occurring singlets, duplets, or multiplets
  Note: In some individuals myokymic activity on the EMG becomes apparent after the application of regional ischemia.
  • To evaluate for interictal motor activity (neuromyotonia/myokymia): surface or needle EMG recordings are performed before, during, and after the application of regional ischemia (e.g., using an inflated sphygmomanometer cuff applied around the upper or lower arm for up to 15 minutes).
  • In specialized centers, electrophysiologic assessments of axonal superexcitability and threshold electrotonus performed according to the TRONDHM protocol (using Qtrac^© software; UCL Institute of Neurology [Kiernan et al 2000]) differentiate individuals with EA1 from normal controls with high sensitivity and specificity [Tomlinson et al 2010].

Family history. Consistent with autosomal dominant inheritance

Note: (1) Lack of a family history of EA1 does not preclude the diagnosis. (2) Muscle biopsy is usually not helpful in establishing the diagnosis, although bilateral calf hypertrophy, enlargement of type 1 and type 2 gastrocnemius muscle fibers, abnormal mitochondria, and variable glycogen depletion have been observed [VanDyke et al 1975, Kinali et al 2004, Demos et al 2009, Brownstein et al 2016]. Nevertheless, these changes have not been consistently reported among individuals with EA1.

Establishing the Diagnosis

The diagnosis of EA1 is established in a proband by means of electrophysiology assessments and/or by identification of a heterozygous pathogenic variant in KCNA1 by molecular genetic testing (see Table 1).

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of EA1 is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of EA1 has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

Episodic ataxia type 1 (EA1), first described by VanDyke et al [1975], is a potassium channelopathy characterized by constant myokymia and dramatic episodes of spastic contractions of the skeletal muscles of the head, arms, and legs with loss of both motor coordination and balance.

Typical attacks in individuals with EA1. In addition to the features noted in Suggestive Findings, Clinical manifestations, individuals may experience the following symptoms:

• Vertigo
• Diaphoresis
• Clumsiness
• Difficulty in breathing, which can occur during ataxic episodes or as isolated episodes [Shook et al 2008]

The duration of the attacks is brief, lasting seconds to minutes, although prolonged attacks lasting hours have been described [Lee et al 2004a, D'Adamo et al 2015a]. Episode occurrence is variable, with some individuals experiencing severe ataxia more than 15 times per day and others experiencing attacks less often than once a month.

The first symptoms typically manifest in the first or second decade of life.

Less common symptoms during attacks

• Choreoathetosis
• Carpal spasm
• Clenching of the fists
• Mild lower limb sensory impairment
• Isolated neuromyotonia
• Nystagmus [Hasan et al 2017]
• Hyperthermia [D'Adamo et al 2015a, Mestre et al 2016]
• Hypothermia, which led to the death of an individual with EA1 due to exposure to anesthesia [Mestre et al 2016]
  Note: Anesthetic agents have an inhibitory effect on kv1.1 channels.

Triggers. A specific traumatic event, physical or emotional, may determine the onset and worsening of the disease [Imbrici et al 2008]. Attacks may be brought on by the following stimuli:

• Stress or anxiety
• Intercurrent illness or fever
• Excitement or emotional upset
• Fatigue
• Menstruation or pregnancy
• Environmental temperature, including hot baths or use of a hairdryer [Eunson et al 2000]
• Startle response
• Abrupt movements or sudden postural changes (kinesigenic stimulation), including riding a merry-go-round
• Vestibular stimulation (turning head from side to side while standing still; sitting still on a rotating chair; instillation of cold water [i.e., ≤30° C] into either external auditory canal)
• Exercise, such as repeat knee bends
• Ingestion of the following:
  • Caffeine
  • Alcohol
  • Foods rich in salt
  • Bitter oranges
  • Chocolate

Interictal ataxia has not been reported to date in individuals with EA1.

Myokymia manifests clinically during and between attacks as fine twitching of groups of muscles and intermittent cramps and stiffness. The severity of some symptoms may either improve or worsen with age [Imbrici et al 2008].

• Myokymia is typically evident as a fine rippling in the perioral or periorbital muscles and by lateral finger movements when the hands are held in a relaxed, prone position.
• Exposure of the forearm to warm or cold temperatures may increase or decrease, respectively, the spontaneous activity recorded from a hand muscle.
• Rarely, episodes of intense myokymic activity during attacks without either ataxia or other neurologic deficits may be observed.
• Myokymic activity is continuous and present in almost all affected individuals [Lee et al 2004b, D'Adamo et al 2015a].

Cognitive dysfunction includes the following:

• Severe receptive and expressive language delay
• Inability to learn to ride a bicycle
• The need for life-skill programs or schools for children with mild to moderate learning difficulties [Zuberi et al 1999, Demos et al 2009]

Neuromuscular findings

• Moderate muscle hypertrophy with generalized increase in muscle tone and bilateral calf hypertrophy are observed.
• Increased muscle tone can cause the following:
  • Unusual hypercontracted posture
  • Abdominal wall muscle contraction
  • Elbow, hip, and knee contractures
  • Shortened Achilles tendons that may result in tiptoe walking

Seizures. Tonic-clonic and partial seizures, an isolated episode consisting of photo-sensitive epilepsy [Imbrici et al 2008], as well as head-turning and eyes deviating to the same side, flickering eyelids, lip-smacking, apnea, and cyanosis have been reported [Zuberi et al 1999]. Prolonged episodes (more than 30 minutes) have been reported in an individual with severe early-onset epilepsy, albeit without the typical ataxia [Rogers et al 2018].

Other anomalies [Kinali et al 2004, Klein et al 2004]

• Scoliosis
• Kyphoscoliosis
• High-arched palate
• Minor craniofacial dysmorphism

Electroencephalogram (EEG) abnormalities have been observed in persons with EA1 [VanDyke et al 1975, Zuberi et al 1999, Lee et al 2004a].

• EEG may be characterized by intermittent and generalized slow activity, frequently intermingled with spikes.
• Zuberi et al [1999] described a boy age three years who presented with an ictal EEG with rhythmic slow-wave activity over the right hemisphere, becoming spike-and-wave complexes that subsequently spread to the left hemisphere.

Compound muscle action potentials (CMAP) from electromyography (EMG) showed presence of repetitive components of CMAP in ulnar as well as in tibial nerves. They were evident both on routine motor studies and on F-wave studies, making F-waves unrecognizable [Hasan et al 2017].

• Sensory conduction test results were normal.
• Abnormal neuromuscular transmission was reported from Hasan et al [2017] after a train of stimuli at 20 Hz or 50 Hz that resulted in a decrement of the amplitude of the first CMAP elicited followed by an increment of the second CMAP amplitude elicited (decrement-increment phenomenon), similar to what is usually observed in organophosphate intoxication.

Brain MRI is usually normal; however, rare findings include the following:

• Cerebellar atrophy in one family [Demos et al 2009]
• Mild vermian hypoplasia [Tacik et al 2015]
• Small right subcortical frontal gliosis [Brownstein et al 2016]

Genotype-Phenotype Correlations

Due to significant inter- and intrafamilial phenotypic variability, reliable genotype-phenotype correlations have been extremely difficult to establish. It is now apparent that phenotypic differences exist not only across families, but also among affected individuals within a family. Indeed, differences in severity and frequency of EA1 attacks have been reported even in monozygotic twins [Graves et al 2010].

Penetrance

Most individuals harboring a KCNA1 pathogenic variant exhibit features of EA1; however, penetrance is incomplete.

Nomenclature

EA1 has also been known as:

• Acetazolamide-responsive periodic ataxia
• Continuous muscle fiber activity
• Episodic ataxia with myokymia
• Familial paroxysmal kinesigenic ataxia and continuous myokymia
• Isaacs-Mertens syndrome
• Hereditary paroxysmal ataxia with neuromyotonia

Prevalence

EA1 is a rare disease and the prevalence can be estimated only roughly. Several families from Australia, Brazil, Canada, Germany, Italy, Russia, Spain, the Netherlands, United Kingdom, and the United States have been described. Based on limited data, a disease prevalence of 1:500,000 has been proposed. Actual prevalence may well be considerably higher, as the disorder may remain either unrecognized in many families or be incorrectly diagnosed.

The populations that are more or less at risk are also unknown.

Evaluations Following Initial Diagnosis

To establish the extent of disease and therapeutic needs in an individual diagnosed with episodic ataxia type 1, the evaluations summarized in Table 3 (if not already completed) are recommended.