Biallelic RFC1-expansion in a French multicentric sporadic ataxia cohort

Montaut, Solveig; Diedhiou, Nadège; Fahrer, P.; Marelli, Cécilia; Lhermitte, Benoît; Robelin, Laura; Vincent, Marie; Corti, Lucas; Taïeb, Guillaume; Gebus, Odile; Rudolf, Gabrielle; Tarabeux, Julien; Dondaine, Nicolas; Canuet, Matthieu; Almeras, Marilyne; Benkirane, Mehdi; Larrieu, Lise; Chanson, Jean‐Baptiste; Nadaj‐Pakleza, Aleksandra; Echaniz‐Laguna, Andoni; Cauquil, Cécile; Lannes, Béatrice; Chelly, Jamel; Anheim, Mathieu; Puccio, Hélène; Tranchant, Christine

doi:10.1007/s00415-021-10499-5

Cited by 29 publications

(38 citation statements)

References 15 publications

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“…In the largest retrospective cohort of RFC1-mutated CANVAS patients described so far, features of sensory neuro(no)pathy were accordantly observed in most patients and often reported since onset, while the involvement of other systems manifested later in the history of the disease or emerged only from extensive instrumental investigations [8]. An archetypic pattern of progression could then explain the lower yield of genetic investigations for RFC1 mutation expansion observed in previous reports on patients with adult-onset ataxia of unknown etiology [20][21][22][23][24][25][26] or Multiple System Atrophy [20,23] compared to ours, even though the differences in study design prevent valid comparisons.…”

Section: Discussionmentioning

confidence: 66%

RFC1 AAGGG repeat expansion masquerading as Chronic Idiopathic Axonal Polyneuropathy

et al. 2021

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Background A biallelic intronic AAGGG repeat expansion in the Replication Factor C subunit 1 (RFC1) gene has been recently associated with Cerebellar Ataxia, Neuropathy, Vestibular Areflexia Syndrome, a disorder often presenting as a slowly evolving sensory neuropathy at the onset. “Chronic Idiopathic Axonal Polyneuropathy” (CIAP) is a common indolent axonal neuropathy of adulthood which remains without an identifiable cause despite thorough investigations. Methods We screened 234 probands diagnosed with CIAP for a pathogenic biallelic RFC1 AAGGG repeat expansion. Patients were selected from 594 consecutive patients with neuropathy referred to our tertiary-care center for a sural nerve biopsy over 10 years. Results The RFC1 AAGGG repeat expansion was common in patients with pure sensory neuropathy (21/40, 53%) and less frequent in cases with predominantly sensory (10/56, 18%, P < 0.001) or sensorimotor (3/138, 2%, P < 0.001) neuropathy. The mutation was associated with sensory ataxia (τb = 0.254, P < 0.001), autonomic disturbances (35% vs 8%, Prevalence Odds Ratio—POR 6.73 CI 95% 2.79–16.2, P < 0.001), retained deep tendon reflexes (score 18.0/24 vs 11.5/24, R = 0.275, P < 0.001). On pathology, we observed absent/scant regenerative changes (τb = − 0.362, P < 0.001), concomitant involvement of large (100% and 99%, n.s.), small myelinated (97% vs 81%, POR 7.74 CI 95% 1.03–58.4, P = 0.02) and unmyelinated nerve fibers (85% vs 41%, POR 8.52 CI 95% 3.17–22.9, P < 0.001). Cerebellar or vestibular involvement was similarly rare in the two groups. Conclusions This study highlights the frequent occurrence of the RFC1 AAGGG repeat expansion in patients diagnosed with CIAP and characterizes the clinical and pathological features of the related neuro(no)pathy.

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Section: Discussionmentioning

confidence: 66%

RFC1 AAGGG repeat expansion masquerading as Chronic Idiopathic Axonal Polyneuropathy

et al. 2021

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“…However, in a further patient it was accompanied by atrophy of the pons and midbrain [42]. CANVAS is recessive condition with marked clinical heterogeneity that has recently been recognized responsible of apparently sporadic progressive ataxia [14,45,46,66]. CANVAS showed the more pronounced heterogeneity concerning the distribution of the CNS atrophy in an inherited progressive ataxia.…”

Section: Discussionmentioning

confidence: 91%

“…Since last decade of the twentieth century, genetic and molecular genetic studies have revealed that an increasing number of mutations of different protein coding genes can underlie dominant, recessive and X-linked progressive ataxias and this allows to classify inherited ataxias according to presumed molecular pathogenesis [6][7][8]. Moreover, screening has revealed that genetic causes are also involved in up to 22% of patients presenting with sporadic progressive ataxia [2,[9][10][11][12][13][14]. This justifies systematic search of possible gene mutations also in such patients.…”

Section: Introductionmentioning

confidence: 99%

MRI CNS Atrophy Pattern and the Etiologies of Progressive Ataxias

Mascalchi¹

2021

Preprint

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MRI shows in-vivo the three archetypal patterns of CNS volume loss underlying progressive ataxias, namely spinal atrophy (SA), cortical cerebellar atrophy (CCA) and olivopontocerebellar atrophy (OPCA). The MRI-based CNS atrophy pattern was reviewed in 128 progressive ataxias. A CNS atrophy pattern was identified in 91 conditions: SA in Freidreich’s ataxia, CCA in 5 acquired and 72 (24 dominant, 47 recessive,1 X-linked) inherited ataxias, OPCA in Multi-System Atrophy and 12 (9 dominant, 2 recessive,1 X-linked) inherited ataxias. The MRI-based CNS atrophy pattern may be useful for genetic assessment, identification of shared cellular targets, and repurposing therapies or enlargement of drugs indications in progressive ataxias.

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“…[5] Of note, cough precedes neurological symptoms in most cases, with an interval that may be as long as three decades. [1][2][3][4][5][6] In a recent report, 35 out of 70 CANVAS patients had chronic cough. [6] Median age of cough onset was 35 years, and cough preceded gait ataxia in 80% of cases with a median interval of 16 years between cough onset and ataxia onset.…”

Section: Dear Editormentioning

confidence: 99%

“…The disease has a slowly progressive course, and gait impairment related to cerebellar ataxia or sensory neuronopathy is usually the main symptom. [3] Half of the patients need walking aid ten years after disease onset, and 25% are wheelchair-dependent five years later. [1] CANVAS phenotypic spectrum is not yet completely defined, and parkinsonism and motor neuron involvement have been described in some cases.…”

Section: Dear Editormentioning

confidence: 99%