No biallelic intronic AAGGG repeat expansion in RFC1 was found in patients with late-onset ataxia and MSA

CANVAS: a late onset ataxia due to biallelic intronic AAGGG expansions

“…The pathogenic AAGGG allele are fully penetrant, while so far, carriers of one AAGGG expanded allele are all unaffected [8]. Furthermore, biallelic (AAGGG) exp appears to be CANVAS specific: no mutant configurations were found in two separate cohorts of patients, in a cohort of 336 multiple system atrophy mainly Caucasian patients from various brain banks and 102 Chinese Han MSA patients [10,11].…”

“…Fan and colleagues screened a cohort of late-onset ataxia patients found in the Chinese Han population [11]. They established that the frequency of heterozygous AAGGG repeat expansion alleles in their ataxia cohort was similar to their multiple system atrophy cohort: 2.75% and 2.45%, respectively; however, no biallelic cases were found.…”

Dopa‐Responsive Parkinsonism in a Patient With Homozygous RFC1 Expansions

“…It also allows for the accurate sizing of the expansion, which would be interesting in this case because of the phenotypic differences seen in this patient. 3 Since the identification of RFC1 expansions in CANVAS we have seen this disorder as a clinical spectrum. 4 This ranges from mild ataxia with sensory neuropathy, to the CANVAS clinical syndrome, through to a more rapidly progressive ataxia with parkinsonism, autonomic dysfunction, and an abnormal dopamine transporter scan; a clinical overlap between CANVAS and multiple systems atrophy, with RFC1 expansions on repeatprimed PCR and Southern blotting (unpublished data).…”

“…Since the description of biallelic intronic RFC1 expansions as the underlying cause for cerebellar ataxia with neuropathy and vestibular areflexia syndrome in 2019, the full phenotypic spectrum related to this genetic abnormality remains to be determined. [1][2][3] Herein we report a patient with RFC1 expansions leading to cerebellar ataxia with neuropathy and vestibular areflexia syndrome and dopa-responsive parkinsonism as part of her clinical picture. Although different cohorts involving patients with parkinsonism in the context of multiple system atrophy failed to demonstrate intronic RFC1 expansions as a causative factor, 1,3 we hypothesize that parkinsonism could be related to RFC1 in our patient.…”

“…[1][2][3] Herein we report a patient with RFC1 expansions leading to cerebellar ataxia with neuropathy and vestibular areflexia syndrome and dopa-responsive parkinsonism as part of her clinical picture. Although different cohorts involving patients with parkinsonism in the context of multiple system atrophy failed to demonstrate intronic RFC1 expansions as a causative factor, 1,3 we hypothesize that parkinsonism could be related to RFC1 in our patient. Indeed, the absence of autonomic features (with normal quantitative sudomotor axonal reflex) and hypo/anosmia combined with the lack of rapid eye movement behavior disorder all argue against the diagnosis of classical Parkinson's disease.…”