Sporadic late onset paroxysmal cerebellar ataxia in four unrelated patients: a new disease?

Abstract

We describe a peculiar form of late onset paroxysmal cerebellar ataxia including clinical features similar to episodic ataxia type 2 (EA2) but unresponsive to acetazolamide. Four unrelated patients were clinically investigated. Neuropathological examination was performed in one patient and molecular analysis in all four. All 47 exons of CACNA1A were screened by a combination of single-strand conformer polymorphism and sequencing analysis in three patients. In addition, the length of the CAG repeat was determined in all four patients. The four patients were in their 60s at the onset of the disease, which was characterized by cerebellar ataxia attacks lasting from a few minutes to 1-2 h and occurring mainly in the morning. In the interictal period a nystagmus was present together with a slowly progressive cerebellar ataxia over the years. The neuropathological examination disclosed a dramatic loss of Purkinje cells mainly in the vermis. Moreover, certain cerebellar granular neurons had a strong cytoplasmic staining at immunopathological examination with an anti-tau protein serum. Search for truncating mutations or CAG repeat expansion in CACNA1A was negative. This late-onset paroxysmal cerebellar ataxia with neuropathological lesions restricted to Purkinje cells and with negative results both for truncating mutations and CAG expansion in the CACNA1A gene represents a new entity. Further studies are needed to delineate the underlying process.

Episodic vertical oscillopsia with progressive gait ataxia: clinical description of a new episodic syndrome and evidence of linkage to chromosome 13q

“…A sporadic late onset episodic ataxia syndrome was described by Julien et al in four probands who presented in their 60s with episodic ataxia, slurred speech, diplopia, downbeat nystagmus and interictal progressive ataxia,10 and tested negative for EA2 and SCA6. Although there is stronger evidence of a genetic aetiology in our patients, these are clearly related disorders of episodic cerebellar dysfunction and may represent a spectrum.…”

Late-onset episodic ataxia type 2 associated with a novel loss-of-function mutation in the CACNA1A gene

“…Mutant cDNA produced a marked reduction in current amplitudes when injected into oocytes [2]. However, in a previous report [18], one out of four unrelated, sporadic, acetazolamide-unresponsive, late-onset EA patients that were screened for mutations in CACNA1A was found to bear a missense change in the Cterminus region of the protein. Since clinical findings were considered atypical for EA2 and the mutation was non-truncating, the authors proposed that their cases represented a new clinical entity.…”

Sporadic late onset paroxysmal cerebellar ataxia

“…There is no sign of dysautonomia. Brain MRI shows a marked cerebellar and brainstem atrophy, unlike the cases reported by Julien et al [3]. Needle EMG and nerve conduction velocities show a mild sensori-motor axonal peripheral neuropathy, which was not suspected clinically.…”

“…Worsening was unexplained, happening in the absence of a concomitant general disease such as an infection. The duration of these exacerbations is larger than in the cases reported by Julien et al [3]. I would like to point out that it may be very difficult to assess paroxysmal episodes of ataxia in patients who are no longer able to walk unaided, in particular when the intensity of the attack is mild or moderate.…”

“…Sirs: The recent article by Julien et al raises questions on the natural history, the pathogenesis and the classification of sporadic late onset cerebellar disorders [3]. The authors describe 4 patients presenting with attacks of ataxia lasting from a few minutes to 1-2 hours, occurring mainly in the morning.…”