Mutations in SETX (senataxin) account for two separate clinical syndromes. Oculomotor apraxia type 2 (AOA2), an autosomal recessive spinocerebellar ataxia, with adolescent or early adult onset progressive ataxia, oculomotor apraxia, neuropathy, cerebellar atrophy, and elevated alpha-fetoprotein levels. Autosomal dominant juvenile-onset motor neuron disease (ALS4) is also characterized. There is a single case report of a 4 year old boy presenting with isolated severe EA attacks lasting 20-30 minutes, and intermittent mild impaired tandem gait between attacks. Genetic testing excluded EAs 1,2,5,6. Whole exome sequencing (WES) identified a heterozygous deletion in SETX gene, possibly explaining the milder phenotype compared to homozygous mutations in AOA2.
Mutations in the ATP1A3 gene mutation cause a broad spectrum of neurologic disorders. These include the clinical syndrome of cerebellar ataxia, areflexia, pes cavus, optic atrophy and sensorineural hearing loss (CAPOS), rapid-onset dystonia parkinsonism (RODP), and alternating hemiplegia of childhood (AHM). It may also present with paroxysmal ataxia triggered by fever, with attacks responsive to acetazolamide. Dystonia, hypotonia, neuropsychiatric symptoms, cognitive impairment, and microcephaly may also be observed.
The SLC2A1 gene encodes glucose transporter protein type 1 (GLUT1) which facilitates glucose transport across the blood-brain barrier, and is critical for brain energy. The GLUT-1 deficiency syndrome is a result of inadequate brain glucose transport. The main phenotype is a severe chronic neurologic disorder (microcephaly, developmental delay, early infantile seizures, ataxia). About 10% do not have this phenotype, and instead have milder paroxysmal variants often provoked by fasting or exercise, such as EA or paroxysmal exercise-induced dyskinesia (PED). Amongst 25 SLC2A1 carriers, 1 had EA. The GLUT-1 spectrum disorder has grown to encompass other paroxysmal dyskinesias (PKD, PNKD), myotonia, migraine, hemiplegic migraine and episodic eye movements. EA may be pure or with additional neurological findings. A diagnostic test to assess for GLUT1 deficiency is spinal tap showing a low CSF to serum glucose ratio (hypoglycorrhachia). Treatment for GLUT1 deficiency is avoidance of triggers, or ketogenic diet to provide an alternative energy substrate for brain energy metabolism. However EA attacks may also respond to acetazolamide, which may lead to misdiagnosis as EA2.
A spectrum of neurological disorders may be caused by mutations in the KCNA2 gene, which encodes voltage-gated potassium channel Kv1.2. Early onset developmental and epileptic encephalopathy, intellectual disability, and ataxia are recognized. A milder phenotype of episodic ataxia, epilepsy, and complicated hereditary spastic paraplegia is reported.
Mutations in SCN2A are associated with a spectrum of neurological disorders from benign to severe epilepsies, autism spectrum disorder and intellectual disability. SCN2A encodes the alpha subunit of voltage gated neuronal Nav1.2 channel. Loss-of-function mutations result in severe epilepsy, intellectual disability and autism, whereas gain-of-function mutations cause benign familial neonate infantile seizures (BFNIS) with or without EA. Patients with BFNIS have seizures before age 3 months which resolve in early life, and may later develop EA between age 10 months to age 14 years. Cognitive outcome is mostly favorable in these cases. Amongst cases with a more severe intellectual disability phenotype, EA appears to be uncommon. Phenotypes may vary in family members, e.g. EA in infant and episodic hemiplegia in parent. EA may be triggered by vaccinations, minor head trauma, and sleep deprivation. Some but not all have a favorable response to acetazolamide. Seizures, but not EA attacks, respond to Na-channel blockers (phenytoin, carbamazepine) suggesting different pathophysiologic mechanisms. Some authors have designated this EA9.
PRRT2 (proline-rich transmembrane protein 2) mutations are responsible for a spectrum of paroxysmal neurological disorders. The 3 main phenotypes are paroxysmal kinesogenic dyskinesia (PKD), benign familial infantile convulsions (BFIC) and infantile convulsions and choreoathosis (ICCA). Other phenotypes include migraine, FHM and epilepsy. EA appears to be a rare manifestation of PPRT2 mutations. In 1 large study of 374 PRRT2-positive patients, episodic ataxia was only occasionally reported. In another study of 182 EA patients, only one case was attributed to a PRRT2 gene mutation. MRI brain imaging performed in a PRRT2 patient during an EA attack showed cerebellar diffusion restriction. Most PRRT2 mutations respond exquisitely to carbamazepine so EA attacks due to PRRT2 may cause diagnostic confusion with EA1. The PRRT2 protein interacts with SNAP-25 and may play a role in synaptic transmission. Most mutations are loss-of-function, which may result in disrupted synaptic transmission and neuronal hyperexcitability. This does not explain phenotype variation, and no specific phenotype-genotype correlation is identified. A handful of cases are reported with homozygous PRRT2 mutations and a severe phenotype with episodic ataxia, intellectual disability, and infantile seizures.
Mutations in the TBC1D24 presynaptic protein are associated with a neurological spectrum of epilepsy, chronic encephalopathy, DOORS (deafness, onychodystrophy, osteodystrophy, mental retardation and seizures), hearing loss, and myoclonus. Biallelic mutations of TBC1D24 were found in an infant with EA and myoclonus, with a later finding of cerebellar atrophy in adolescence.
EA cases are reported in mitochondrial disorders, such as pyruvate dehydrogenase complex deficiency, (PDHx, PDHA1), TPK1, DARS2, MTATP6, ACO2 genes. EA can be isolated or occur with other neurological abnormalities. Diagnostic clues are the presence of serum and CSF lactic acidosis. A mild presentation of fever-triggered EA attacks lasting 2 to 7 days, and a normal interictal exam, was observed in a young child with PDH deficiency. Tests showed elevated serum and CSF lactate, and MRI brain showed dentate nucleus hyperintensity. Attacks responded to thiamine, levocarnitine, and alpha-lipoic acid. In comparison, homozygous or compound heterozygous mutations in ACO2 (encodes mitochondrial aconitase 2 that catalyzes citrate to isocitrate) can cause a spectrum of disorders with often severe neurologic impairment. A recent report of 2 siblings with ACO2 mutations had EA plus mild developmental delay and neuropsychiatric symptoms.
A "late-onset EA" was reported in 2009 of 4 cases in a single 2-generation family but the gene is not known. Onset was in the fifth or sixth decade. Phenotype severity was variable, with more severe cases exhibiting daily attacks with slowly progressive ataxia and poor acetazolamide response. Screening excluded KCNA1 (EA1), CACNA1A, (EA2), and locus for EA2, EA5, EA6 and EA7.
There is a broad differential diagnosis for acute-onset recurring ataxia. (Table 2). Secondary or acquired EA may resemble primary EA with regards to onset-age, attack variability, and interictal cerebellar findings, but are more likely to have abnormal laboratory and MRI imaging. Many secondary causes are treatable, and collectively more common that primary EAs, so they are important to consider.
The most common secondary disorders are transient ischemic attacks or stroke, multiple sclerosis or other immune-mediated disorders. "Paroxysmal dysarthria and ataxia" (PDA) is a well-recognized phenomenon in multiple sclerosis, with stereotyped multiple daily episodes of sudden ataxia lasting seconds to minutes, attributed to ephaptic transmission. This PDA syndrome can mimic genetic EA, and is also reported in immune-mediated diseases such as antiphospholipid syndrome, Bickerstaff's/Bickerstaff-like encephalitis, certain autoimmune ataxias, and ischemic stroke. This has been attributed to a lesion in the midbrain, near or in the red nucleus. Other inflammatory disorders (postinfectious cerebellitis, Miller-Fisher syndrome) and vascular disorders (Behcet's disease with brainstem and red nuclei involvement, Kawasaki disease) can present with prolonged attacks of acute ataxia. Structural lesions in the posterior fossa or cerebellum such as a tumor or occult neuroblastoma can present with recurrent ataxia.
Epileptic pseudoataxia may transiently occur after a seizure. Hypothyroidism can present with recurrent ataxic episodes, and responds to thyroxine. Toxins (e.g. alcohol, antiseizure medications, lead) can present with reversible acute ataxia. Metabolic disorders (e.g. maple syrup urine disease, pyruvate dehydrogenase deficiency, ornithine transcarbamylase deficiency, biotinidase deficiency, Hartnup disease, argininosuccinic aciduria, citrullinemia, thiamine pyrophosphate deficiency) causing EA usually present in childhood with severe neurologic symptoms, but may present in adults with much milder features. Thiamine pyrophosphate deficiency has been reported in a small number of patients with EA, delayed development and dystonia, and may respond to thiamine supplementation. Maple syrup urine disease may also have significant clinical or biochemical improvement with thiamine supplementation. Citrullinemia is a rare recessive urea cycle disorder due to mutations in the ASS1 (type I citrullinemia) gene which cause deficiency of arginosuccinate synthetase enzyme, necessary for catalyzing the formation of arginosuccinic acid from citrulline and aspartic acid. A typical presentation is a neonate with toxic hyperammonemia and progressive encephalopathy. Mild late-onset childhood or adult-onset forms with intermittent symptoms (ataxia, headache, stroke, intellectual disability, or encephalopathy) are reported. A case of citrullinemia presented in late childhood with brief EA attacks with fever, a normal interictal neurological exam, cerebellar atrophy, and elevated citrulline and ammonia blood levels.
Autoimmune ataxias are usually chronic, but three types to date may manifest with EA. CASPR2 (VGKC complex) can present with episodic ataxia and dysarthria, seizures and cognitive dysfunction. MRI brain may be normal or show medial temporal hyperintensity, with elevated CSF protein and positive CASPR2-IgG in serum and CSF. It responds to immunotherapy. Anti-NMDA receptor autoimmunity can present with paroxysmal dysarthria-ataxia syndrome. Anti-Hu (ANNA-1)-associated paraneoplastic limbic encephalitis presented in a child as episodic ataxia and progressive behavioral changes evolving to intractable epilepsy. Iatrogenic intermittent ataxia may be provoked during deep brain stimulation programming. Finally, functional ataxia may be suggested by incongruent examination findings, distractibility, and the presence of other functional signs.
EA can be mimicked by other paroxysmal disorders with stereotyped attacks of central or peripheral origin (e.g. vestibular migraine, migraine with brainstem aura, seizures, paroxysmal dyskinesias or benign paroxysmal positional vertigo). Patients with EA have been misdiagnosed with migraine, seizures, functional or anxiety disorders, resulting in premature diagnostic closure. A personal or family history of epilepsy or migraine may have suggested these alternative more common diagnoses, rather than EA. It may also be difficult to distinguish chronic ataxia with stepwise exacerbations or stepwise decline (e.g. SCA 6), from EA with persistent cerebellar dysfunction. Suspicion for EA should be heightened with acetazolamide-responsive attacks.
EA can be readily misdiagnosed or overlooked. In order to recognize, it is important to routinely include it in the differential diagnosis of spells, whether these are movement or non-movement based. A detailed history should include: onset age, triggers, duration, frequency, aura, baseline between spells, and response to treatment trials. Patient descriptors may pose challenges (e.g. episodic stiffening due to EA1 versus PKD attack, or EA with episodic cognitive impairment due to EA2 versus seizure). Events during early childhood development (e.g. infantile paroxysmal torticollis, episodic oculomotor dysfunction, BFNIS) may provide diagnostic clues for EA2. The interictal examination can offer clues to primary EAs when findings are present (e.g. nystagmus EA2, myokymia EA1). Ictal examination or a video of the attack can help reconstruct the phenomenology. A 3-generation family history is important to look for other paroxysmal neurologic disorders because of considerable phenotypic variability in families. Family history may appear negative with de novo mutations, false paternity, early death, or estrangement from biological family, deceptively pointing away from a genetic cause. Secondary EAs or mimicking conditions can be suggested by history, examination, and imaging findings. While functional features may suggest a non-genetic EA, functional embellishment of primary EA may lead to diagnostic uncertainty regarding the predominant etiology. Diagnostic delay or misdiagnosis include patient factors (young children cannot give a history, atypical features) or clinician factors (bias towards alternative diagnosis, atypical or evolving phenotype). Diagnostic challenges may also arise where attack duration or triggers overlap between categories. For example, EA1 and EA2 attacks may both last hours and have permanent cerebellar signs, so one needs to look for interictal myokymia or nystagmus or ancillary tests to distinguish them.
Brain imaging looking carefully for cerebellar atrophy or other structural brain lesions can provide diagnostic clues for primary or secondary EA. Electroencephalography during a triggered attack can help differentiate EA from an epileptic event. However, baseline EEG abnormalities may be encountered in both EA2 and genetic epilepsies with EA. Laboratory testing (e.g. serum and CSF lactate or glucose can assist diagnosis of mitochondrial disorders or GLUT-1 syndromes respectively). For secondary cases, blood tests for metabolic disorders and toxins may be necessary.
If one suspects a primary EA that is fairly classical for either EA1 or EA2, proceeding to single gene testing for KCNA1 or CACANA1A may be an appropriate choice. In uncertain cases, a multigene EA panel could be used. For atypical or complex cases, where other investigations have failed, next generation sequencing or whole exome sequencing has diagnostic utility to detect a causal gene mutation. Reaching a specific genetic diagnosis can provide clinical value: guide treatment, reduce unnecessary investigative tests, aid genetic counselling, and further refine phenotype-genotype profiles.
For cases that resemble EA1 or EA2, one may proceed directly to first-line treatment (antiseizure medication or acetazolamide, respectively), without requiring genetic confirmation. If unsuccessful, consider second-line treatment trials. Ultimately, genetic testing is gold-standard for the diagnosis to guide appropriate treatment and long-term management. Many of the primary EAs, other genetic causes of EA, and secondary forms of EA are treatable. (See Table 4).