Dysferlinopathy in Tunisia: clinical spectrum, genetic background and prognostic profile.

Dysferlinopathy is a rare group of hereditary muscular dystrophy with an autosomal recessive mode of inheritance caused by a mutation in the DYSF gene. It encodes for the dysferlin protein, which has a crucial role in multiple cellular processes, including muscle fiber membrane repair. This deficit has heterogeneous clinical presentations. In this study, we collected 20 Tunisian patients with a sex ratio of 1 and a median age of 50.5 years old (Interquartile range (IQR) = [36,5-54,75]). They were followed for periods ranging from 5 to 48 years. The median age at onset was 17 years old (IQR = [16,8-28,4]). Five major phenotypes were identified: Limb-girdle muscular dystrophy (LGMDR2) (35%), a proximodistal phenotype (35%), Miyoshi myopathy (10%),  Distal myopathy with anterior tibial onset (DMAT) (10%), and asymptomatic HyperCKemia (10%). At the last evaluation, more than half of patients (55%) were on wheelchair. Loss of ambulation occurred generally during the fourth decade. After 20 years of disease progression, two patients with a proximodistal phenotype (10%) developed dilated cardiomyopathy and mitral valve regurgitation. Restrictive respiratory syndrome was observed in three patients (DMAT: 1 patient, proximodistal phenotype: 1 patient, LGMDR2: 1 patient). Genetic study disclosed five mutations. We observed clinical heterogeneity between families and even within the same family. Disease progression was mainly slow to intermediate regardless of the phenotype.

Mild limb girdle muscular dystrophy R9 phenotype caused by novel compound heterozygous FKRP gene mutation.

Fukutin-related protein (FKRP) mutations cause a broad spectrum of muscular dystrophies, from a relatively mild limb-girdle muscular dystrophy type 9 (LGMDR9) to severe congenital muscular dystrophy (CMD). This study aims to report two siblings belonging to a non-consanguineous Tunisian family harboring a novel compound heterozygous FKRP variant and presenting a mild LGDMR9 phenotype. For mutation screening, massive parallel sequencing was performed, followed by Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA) to validate the existence of the discovered variants. The absence of alpha-dystroglycan was determined by immunohistochemistry. Brain and thigh magnetic resonance imaging (MRI) were performed to detect thigh and brain abnormalities. The two siblings had a late age at onset and clinical examination showed that the pelvic girdles had a predominantly proximal and symmetrical distribution of weakness without cardiac or respiratory involvement. They both had a modified Gardner-Medwin Walton Scale mGMWS grade of 4 and a modified Rankin Scale (mRS) score of 1. The DNA sequencing revealed a novel deletion of exons 2 and 3 in one allele and a missense mutation c.1364C > A, which has been reported to be responsible for congenital muscular dystrophy and mental retardation on the second allele. The simultaneous presence of the two variations in the two cases suggests that the variants segregate with the pathophysiology.