Publications by authors named "Mehdi Benkirane"

3 Publications

  • Page 1 of 1

Biallelic RFC1-expansion in a French multicentric sporadic ataxia cohort.

J Neurol 2021 Mar 5. Epub 2021 Mar 5.

Department of Neurology, Strasbourg University Hospital, 1 avenue Molière, 67098, Strasbourg, France.

Objective: Cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS) is a recessively inherited multisystem ataxia compromising cerebellar, vestibular, and sensory nerves, which has been associated to a pathogenic AAGGG(n) biallelic expansion repeat in the RFC1 gene. Our objective was to assess its prevalence in a French cohort of patients with idiopathic sporadic late-onset ataxia (ILOA), idiopathic early-onset ataxia (IEOA), or Multiple System Atrophy of Cerebellar type (MSA-C).

Methods: 163 patients were recruited in 3 French tertiary centers: 100 ILOA, 21 IEOA, and 42 patients with possible or probable MSA-C.

Results: A pathogenic biallelic RFC1 AAGGG(n) repeat expansion was found in 15 patients: 15/100 in the ILOA group, but none in the IEOA and MSA-C subgroups. 14/15 patients had a CANVAS phenotype. Only 1/15 had isolated cerebellar ataxia, but also shorter biallelic expansions. Two RFC1 AAGGG(n) alleles were found in 78% of patients with a CANVAS phenotype. In one post-mortem case, the pathophysiological involvement of cerebellum and medullar posterior columns was found.

Conclusion: Our study confirms the genetic heterogeneity of the CANVAS and that RFC1 repeat expansions should be searched for preferentially in case of unexplained ILOA associated with a sensory neuronopathy, but not particularly in patients classified as MSA-C.
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March 2021

Expanding the clinical spectrum of STIP1 homology and U-box containing protein 1-associated ataxia.

J Neurol 2021 Jan 8. Epub 2021 Jan 8.

Service de Génétique Médicale, Hôpitaux de Brabois, CHRU de Nancy, Rue du Morvan, 54500, Vandoeuvre-lès-Nancy, France.

Background: STUB1 has been first associated with autosomal recessive (SCAR16, MIM# 615768) and later with dominant forms of ataxia (SCA48, MIM# 618093). Pathogenic variations in STUB1 are now considered a frequent cause of cerebellar ataxia.

Objective: We aimed to improve the clinical, radiological, and molecular delineation of SCAR16 and SCA48.

Methods: Retrospective collection of patients with SCAR16 or SCA48 diagnosed in three French genetic centers (Montpellier, Strasbourg and Nancy).

Results: Here, we report four SCAR16 and nine SCA48 patients from two SCAR16 and five SCA48 unrelated French families. All presented with slowly progressive cerebellar ataxia. Additional findings included cognitive decline, dystonia, parkinsonism and swallowing difficulties. The age at onset was highly variable, ranging from 14 to 76 years. Brain MRI showed marked cerebellar atrophy in all patients. Phenotypic findings associated with STUB1 pathogenic variations cover a broad spectrum, ranging from isolated slowly progressive ataxia to severe encephalopathy, and include extrapyramidal features. We described five new pathogenic variations, two previously reported pathogenic variations, and two rare variants of unknown significance in association with STUB1-related disorders. We also report the first pathogenic variation associated with both dominant and recessive forms of inheritance (SCAR16 and SCA48).

Conclusion: Even though differences are observed between the recessive and dominant forms, it appears that a continuum exists between these two entities. While adding new symptoms associated with STUB1 pathogenic variations, we insist on the difficulty of genetic counselling in STUB1-related pathologies. Finally, we underscore the usefulness of DAT-scan as an additional clue for diagnosis.
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January 2021

ATP8A2-related disorders as recessive cerebellar ataxia.

J Neurol 2020 Jan 14;267(1):203-213. Epub 2019 Oct 14.

Laboratoire de Génétique de Maladies Rares EA7402, Institut Universitaire de Recherche Clinique, Université de Montpellier, CHU Montpellier, 640 av. Doyen G. Giraud CEDEX 5, 34295, Montpellier, France.

ATP8A2-related disorders are autosomal recessive conditions that associate encephalopathy with or without hypotonia, psychomotor delay, abnormal movements, chorea, tremor, optic atrophy and cerebellar atrophy (CARMQ4). Through a multi-centric collaboration, we identified six point mutations (one splice site and five missense mutations) involving ATP8A2 in six individuals from five families. Two patients from one family with the homozygous p.Gly585Val mutation had a milder presentation without encephalopathy. Expression and functional studies of the missense mutations demonstrated that protein levels of four of the five missense variants were very low and lacked phosphatidylserine-activated ATPase activity. One variant p.Ile215Leu, however, expressed at normal levels and displayed phospholipid-activated ATPase activity similar to the non-mutated protein. We therefore expand for the first time the phenotype related to ATP8A2 mutations to less severe forms characterized by cerebellar ataxia without encephalopathy and suggest that ATP8A2 should be analyzed for all cases of syndromic or non-syndromic recessive or sporadic ataxia.
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January 2020