Molecular and clinical study of a cohort of 110 Algerian patients with autosomal recessive ataxia

Abstract

BackgroundAutosomal recessive cerebellar ataxias (ARCA) are a complex group of neurodegenerative disorders with great genetic and phenotypic heterogeneity, over 30 genes/loci have been associated with more than 20 different clinical forms of ARCA. Genetic heterogeneity combined with highly variable clinical expression of the cerebellar symptoms and overlapping features complicate furthermore the etiological diagnosis of ARCA. The determination of the most frequent mutations and corresponding ataxias, as well as particular features specific to a population, are mandatory to facilitate and speed up the diagnosis process, especially when an appropriate treatment is available.MethodsWe explored 166 patients (115 families) refered to the neurology units of Algiers central hospitals (Algeria) with a cerebellar ataxia phenotype segregating as an autosomal recessive pattern of inheritance. Genomic DNA was extracted from peripheral blood samples and mutational screening was performed by PCR and direct sequencing or by targeted genomic capture and massive parallel sequencing of 57 genes associated with inherited cerebellar ataxia phenotypes.ResultsIn this work we report the clinical and molecular results obtained on a large cohort of Algerian patients (110 patients/76 families) with genetically determined autosomal recessive ataxia, representing 9 different types of ARCA and 23 different mutations, including 6 novel ones. The five most common ARCA in this cohort were Friedreich ataxia, ataxia with isolated vitamin E deficiency, ataxia with oculomotor apraxia type 2, autosomal recessive spastic ataxia of Charlevoix-Saguenay and ataxia with oculomotor apraxia type 1.ConclusionWe report here a large cohort of patients with genetically determined autosomal recessive ataxia and the first study of the genetic context of ARCA in Algeria. This study showed that in Algerian patients, the two most common types of ataxia (Friedreich ataxia and ataxia with isolated vitamin E deficiency) coexist with forms that may be less common or underdiagnosed. To refine the genotype/phenotype correlation in rare and heteregeneous diseases as autosomal recessive ataxias, more extensive epidemiological investigations and reports are necessary as well as more accurate and detailed clinical characterizations. The use of standardized clinical and molecular protocols would thus enable a better knowledge of the different forms of ARCA.

Homozygous SYNE1 mutation causes congenital onset of muscular weakness with distal arthrogryposis: a genotype–phenotype correlation

“…13,14 SCAR8 patients can present with pure cerebellar atrophy, ataxia, and dysarthria, with variable age at onset of symptoms (6-50 years). 9,12,15,16 More frequently, signs of upper and lower motor neuron disease, of brainstem dysfunction, or musculoskeletal abnormalities are variably present in SCAR8 patients. 12 Out of more than 80 Figure 2 Nesprin-1 isoforms and human nesprin-1 variants.…”

“…Italic gray letters denote bi-allelic SYNE1 variants that were identified in patients with cerebellar ataxia with slow progression accompanied by dysarthria and cerebellar atrophy (spinocerebellar ataxia, recessive, type 8 (SCAR8, ARCA-1; OMIM #610743). 8,9,11,12,[15][16][17] Heterozygous SYNE1 missense variants shown in black letters were identified in patients with autosomal dominant Emery-Dreifuss muscular dystrophy, characterized by childhood-onset progressive muscle weakness and development of limb contractures (EDMD4; OMIM #612998), 19,20 and in patients with dilated cardiomyopathy. 18 Bi-allelic truncating variants shown in bold black letters were identified in three families with recessively inherited myogenic AMC, associated with severe hypotonia from birth, delayed motor milestones, evolution of severe scoliosis and progressive motor decline after the first decade in one family, 6,7 and in this study.…”

Degenerative Ataxias: challenges in clinical research

“…Among a large cohort of patients with AR ataxias referred to a genetic laboratory, fully 47% could not be precisely diagnosed; two‐thirds of those in whom a molecular diagnosis could be established had FA. Another study from Algeria found mutations in 110 out 166 patients with AR ataxia with FA and AVED being the most common . In contrast, in a population‐based study of chronic childhood ataxia in Manitoba, the most common diagnoses were Angelman syndrome, ataxia telangiectasia, and mitochondrial disease, followed by Friedreich's ataxia, vascular lesions, and other familial ataxias .…”

Eye-tracking-aided Characterization of Saccades and Antisaccades in SYNE1 Ataxia Patients – A Pilot Study

“…In the following years, the SYNE1 ataxia was observed almost exclusively in Quebec province, Canada [1,3]. From 2013, some sporadic cases were reported as well outside the French-Canadian population [4][5][6][7]. In 2016, Synofzik and Mademan et al described 33 non-Canadian patients with SYNE1 ataxia from a large multi-centre study, which delineated that mutations of SYNE1 gene are much more common causes of ARCA than previously thought [2,8].…”