Investigation of the RFC1 Repeat Expansion in a Canadian and a Brazilian Ataxia Cohort: Identification of Novel Conformations

Chen

et al. 2020

Annals of Neurology

Objective: A recessive biallelic repeat expansion, (AAGGG) exp , in the RFC1 gene has been reported to be a frequent cause of late-onset ataxia. For cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS), the recessive biallelic (AAGGG) exp genotype was present in $92% of cases. This study aimed to examine whether the pentanucleotide repeat (PNR) was related to multiple system atrophy (MSA), which shares a spectrum of symptoms with CANVAS. Methods: In this study, we screened the pathogenic (AAGGG) exp repeat and 5 other PNRs in 104 Chinese sporadic adult-onset ataxia of unknown aetiology (SAOA) patients, 282 MSA patients, and 203 unaffected individuals. Multiple molecular genetic tests were used, including long-range polymerase chain reaction (PCR), repeat-primed PCR (RP-PCR), Sanger sequencing, and Southern blot. Comprehensive clinical assessments were conducted, including neurological examination, neuroimaging, nerve electrophysiology, and examination of vestibular function. Results: We identified biallelic (AAGGG) exp in 1 SAOA patient and 3 MSA patients. Additionally, 1 MSA patient had the (AAGGG) exp /(AAAGG) exp genotype with uncertain pathogenicity. We also described the carrier frequency for different PNRs in our cohorts. Furthermore, we summarized the distinct phenotypes of affected patients, suggesting that biallelic (AAGGG) exp in RFC1 could be associated with MSA and should be screened routinely in the MSA diagnostic workflow. Interpretation: Our results expanded the clinical phenotypic spectrum of RFC1-related disorders and raised the possibility that MSA might share the same genetic background as CANVAS, which is crucial for re-evaluating the current CANVAS and MSA diagnostic criteria.

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See 3 more Smart Citations

Biallelic Intronic AAGGG Expansion of RFC1 is Related to Multiple System Atrophy

Chen

et al. 2020

Annals of Neurology

Movement Disord Clin Pract

Cranial Nerve Thinning Distinguishes RFC1‐Related Disorder from Other Late‐Onset Ataxias

Lobo,

Wertheimer,

Schmitt

et al. 2023

Self Cite

BackgroundRFC1‐related disorder (RFC1/CANVAS) shares clinical features with other late‐onset ataxias, such as spinocerebellar ataxias (SCA) and multiple system atrophy cerebellar type (MSA‐C). Thinning of cranial nerves V (CNV) and VIII (CNVIII) has been reported in magnetic resonance imaging (MRI) scans of RFC1/CANVAS, but its specificity remains unclear.ObjectivesTo assess the usefulness of CNV and CNVIII thinning to differentiate RFC1/CANVAS from SCA and MSA‐C.MethodsSeventeen individuals with RFC1/CANVAS, 57 with SCA (types 2, 3 and 6), 11 with MSA‐C and 15 healthy controls were enrolled. The Balanced Fast Field Echo sequence was used for assessment of cranial nerves. Images were reviewed by a neuroradiologist, who classified these nerves as atrophic or normal, and subsequently the CNV was segmented manually by an experienced neurologist. Both assessments were blinded to patient and clinical data. Non‐parametric tests were used to assess between‐group comparisons.ResultsAtrophy of CNV and CNVIII, both alone and in combination, was significantly more frequent in the RFC1/CANVAS group than in healthy controls and all other ataxia groups. Atrophy of CNV had the highest sensitivity (82%) and combined CNV and CNVIII atrophy had the best specificity (92%) for diagnosing RFC1/CANVAS. In the quantitative analyses, CNV was significantly thinner in the RFC1/CANVAS group relative to all other groups. The cutoff CNV diameter that best identified RFC1/CANVAS was ≤2.2 mm (AUC = 0.91; sensitivity 88.2%, specificity 95.6%).ConclusionMRI evaluation of CNV and CNVIII using a dedicated sequence is an easy‐to‐use tool that helps to distinguish RFC1/CANVAS from SCA and MSA‐C.

Brain Structural Signature of RFC1‐Related Disorder

et al. 2021

Self Cite

A BS TRACT: Background: The cerebellar ataxia, neuropathy, and vestibular areflexia syndrome was initially described in the early 1990s as a late-onset slowly progressive condition. Its underlying genetic cause was recently mapped to the RFC1 gene, and additional reports have expanded on the phenotypic manifestations related to RFC1, although little is known about the pattern and extent of structural brain abnormalities in this condition.Objective: The aim is to characterize the structural signature of brain damage in RFC1-related disorder, correlating the findings with clinical symptoms and normal brain RFC1 expression. Methods: We recruited 22 individuals with molecular confirmation of RFC1 expansions and submitted them to high-resolution 3T magnetic resonance imaging scans. We performed multimodal analyses to assess separately cerebral and cerebellar abnormalities within gray and white matter (WM). The results were compared with a group of 22 age-and sex-matched controls. Results:The mean age and disease duration of patients were 62.8 and 10.9 years, respectively. Ataxia, sensory neuronopathy, and vestibular areflexia were the most frequent manifestations, but parkinsonism and pyramidal signs were also noticed. We found that RFC1-related disorder is characterized by widespread and relatively symmetric cerebellar and basal ganglia atrophy. There is brainstem volumetric reduction along all its segments. Cerebral WM is also involved-mostly the corpus callosum and deep tracts, but cerebral cortical damage is rather restricted. Conclusion: This study adds new relevant insights into the pathophysiological mechanisms of RFC1-related disorder. It should no longer be considered a purely cerebellar and sensory pathway disorder. Basal ganglia and deep cerebral WM are additional targets of damage.