Causes of Episodic Ataxia
Episodic ataxia is primarily caused by genetic mutations affecting ion channels (EA1 and EA2 being most common), but can also result from metabolic disorders, migraines, benign positional vertigo, and various secondary causes including vascular, inflammatory, and toxic-metabolic etiologies. 1, 2
Primary Genetic Causes
Autosomal dominant channelopathies represent the most well-characterized primary causes:
- EA1 is caused by heterozygous mutations in KCNA1, which encodes the α1 subunit of the neuronal voltage-gated potassium channel Kv1.1 3
- EA2 (the most common type) is caused by heterozygous mutations in CACNA1A, encoding the α1A subunit of the P/Q-type voltage-gated calcium channel Cav2.1, primarily expressed in Purkinje cells 3, 4
- EA6 results from heterozygous mutations in SLC1A3, encoding a glial excitatory amino acid transporter subunit (EAAT1) 3
- Additional genetic causes include mutations in genes associated with other channelopathies: KCNA2, SCN2A, PRRT2, CLCN1, SCN1B, SCN9A, CACNA1E, and ATP1A3 2, 5, 6
The genetic landscape has expanded significantly, with EA now recognized as an unusual presentation of several other genetic disorders including SCA-14, SCA-27, SCA-42, AOA2, and CAPOS syndrome 2.
Metabolic Causes
Inborn errors of metabolism can present with intermittent ataxia during times of stress or illness 1:
- Intermittent maple syrup urine disease 1, 2
- Pyruvate dehydrogenase deficiency (PDHA1, PDHX mutations) 1, 2
- Hartnup disease 1, 2
- Type I citrullinemia 2
- Thiamine and biotin metabolism defects 2
- GLUT-1 deficiency 2
- Mitochondrial disorders (ACO2 mutations) 2
MR spectroscopy may be useful when an underlying metabolic disorder is suspected 1.
Migraine-Related and Benign Causes
- Basilar migraines are diagnosed based on clinical symptoms with normal neuroimaging 1
- Benign paroxysmal vertigo is diagnosed by history, physical examination, and normal vestibular testing and neuroimaging 1
- Childhood benign paroxysmal ataxia typically shows normal neuroimaging, which supports the diagnosis in the appropriate clinical setting 1
Secondary Causes
Secondary causes are more commonly encountered than primary EA 2:
- Vascular causes including rotational occlusion of the vertebral artery (bow hunter syndrome), though rare 1
- Inflammatory disorders 2
- Toxic-metabolic causes 2
Diagnostic Approach
Head MRI without contrast is the preferred initial imaging for episodic ataxia, as it can identify metabolic disorders and genetic abnormalities, while normal imaging supports benign diagnoses like basilar migraine or benign paroxysmal ataxia 1. Imaging findings in EA2 may include vermian atrophy 1.
Common Pitfalls
- Do not overlook EA due to phenotype-genotype variability and clinical overlap between primary and secondary causes 2
- EA can be misdiagnosed as migraine, peripheral vestibular disorders, anxiety, or functional symptoms 2
- For atypical phenotypes without clear EA1 or EA2 features, next-generation sequencing (whole exome sequencing) should be considered, as it identifies causative variants in approximately 50% of cases negative for CACNA1A mutations 6
- Contrast-enhanced MRI is not supported for initial evaluation of episodic ataxia 1
The recognition that EA is highly treatable (with acetazolamide, 4-aminopyridine, dalfampridine, or fampridine for EA2) makes identifying the cause critically important 2, 4.