Pearls & Oy-sters: Episodic ataxia type 2

DISCUSSION

The first published clinical description of EA2 dates back to 1946 while the molecular basis of the disorder was identified in 1996 with the discovery of mutations in the P/Q type voltage-gated calcium channel CACNA1A. It is an autosomal dominant disorder and the most common inherited episodic ataxia, though the prevalence is estimated at less than 1 in 100,000 with high though incomplete penetrance.^1,2

Clinically, the disorder is characterized by ataxic spells lasting hours to days, often with interictal nystagmus; however, there is considerable variation in disease presentation.³ The spells may be characterized by isolated ataxia or, as seen in our patient, a broader range of symptoms, often localizing to the brainstem. Associated features include generalized and hemiplegic weakness, migraine, intellectual disability, dystonia, and seizures. Indeed, there is a broad range of neurocognitive deficits associated with CACNA1A mutations, although until recently this has been largely unexplored.³ While initially an episodic disorder, some patients will develop a secondarily progressive ataxia, as in our patient. Notable triggers include physical and emotional stress. Disease onset is typically between 5 and 20 years of age.³ It is clinically differentiated from other episodic ataxias through a variety of features including age at onset, spell duration, interictal nystagmus, and genetic locus (table 2).^2,4,5

Genetically, the disorder has been linked to CACNA1A, which encodes the pore-forming subunit of the P/Q-type voltage-gated calcium channel.¹ The P/Q channel is expressed throughout the CNS, but is most densely expressed in cerebellar Purkinje cells and granule layer neurons. It is found principally on presynaptic terminals and plays a key role in synaptic transmission.⁶ Over 80 different pathologic mutations have been identified to date, and they typically result in premature truncation of the protein via nonsense or frameshift mutations though a number of missense mutations have also been found to be pathologic. Based on these observations, EA2 is believed to be characterized by loss of P/Q channel function in the cerebellum. This hypothesis is supported by electrophysiologic studies that demonstrate that EA2-associated mutations result in loss of or diminished channel function when expressed in vitro.⁷ Research also suggests that the mutation may exert a dominant negative effect on the wild-type channel by interfering with proper channel folding and trafficking rather than simple haploinsufficiency.⁶ None of these explanations, however, clearly accounts for the unmistakably episodic nature of the disease.⁸

Interestingly, mutations in CACNA1A have also been identified in familial hemiplegic migraine type 1 and spinocerebellar ataxia type 6 (SCA6).^1,3 Thus, EA2 is allelic with these disorders and there is recognized clinical overlap. Familial hemiplegic migraine is reliably associated with a wide range of missense mutations.⁹ In SCA6, a CAG repeat expansion in the C-terminus of the gene is believed to cause cerebellar degeneration. These and other mechanisms of disease in P/Q-type channel dysfunction have been well reviewed previously.⁸

Our patient was found to have a novel single base pair deletion (3,535C) leading to a frameshift mutation in exon 20 of CACNA1A resulting in a premature stop codon and aberrant mRNA likely destined for nonsense mediated decay. He has no family history of the disease, though nonpaternity was not explored. He has 3 children, all of whom are under age 20 and are currently healthy with no neurologic symptoms, including migraine and intellectual disability.

Therapeutically, acetazolamide responsiveness is a hallmark of the disease. Though there are patients who do not have symptomatic benefit, an estimated 50%–75% of patients report improvement in episode severity and frequency with acetazolamide doses ranging from 250 to 1,000 mg daily.² Therapeutic benefit was seen in our patient. He developed nephrolithiasis while on acetazolamide 1,000 mg/d and discontinued the medication; however, after his genetic diagnosis, the medication was restarted at a lower dose with close clinical monitoring. For those who cannot tolerate acetazolamide, the potassium channel blocker 4-aminopyridine at doses of 5 mg 3 times daily has also been shown to decrease episode frequency and improve quality of life in a randomized controlled trial of 10 patients.¹⁰

Finally, there are no earlier reports of functional disorders among patients with EA2. Comorbid functional disorders create a diagnostic challenge. In patients with psychogenic nonepileptic seizures, time to correct diagnosis is estimated to be 7 years from spell onset.¹¹ Our patient's experience would suggest that equally lengthy diagnostic delays are possible in EA2 when comorbid functional disorder is present. Importantly, this case also highlights the fact that functional overlay can lead to premature diagnostic closure after the symptoms are labeled as such. Improved recognition and understanding of episodic ataxias is necessary. EA2 must be considered for any patient with episodes of ataxia lasting hours, although shorter and longer attacks do occur, and more rarely in patients who present with a progressive ataxia syndrome.