Clinical, Neurophysiological, Radiological, Pathological, and Genetic Features of Dysferlinopathy in Saudi Arabia

Abstract

BackgroundTo characterize the phenotypic, neurophysiological, radiological, pathological, and genetic profile of 33 Saudi Arabian families with dysferlinopathy.MethodsA descriptive observational study was done on a cohort of 112 Saudi Arabian families with LGMD. Screening for the Dysferlin (DYSF) gene was done in a tertiary care referral hospital in Saudi Arabia. Clinical, Neurophysiological, Radiological, Pathological, and Genetic findings in subjects with dysferlin mutation were the primary outcome variables. Statistical analysis was done by Epi-info.Results33 out of 112 families (29.46%) registered in the LGMD cohort had Dysferlinopathy. 53 subjects (28 males, 52.83%) from 33 families were followed up for various periods ranging from 1 to 28 years. The mean age of onset was 17.79 ± 3.48 years (Range 10 to 25 years). Miyoshi Myopathy phenotype was observed in 50.94% (27 out of 53), LGMDR2 phenotype in 30.19% (16 out of 53), and proximodistal phenotype in 15.09% (8 out of 53) of the subjects. Loss of ambulation was observed in 39.62% (21 out of 53 subjects). Electrophysiological, Radiological, and histopathological changes were compatible with the diagnosis. Mean serum Creatinine Kinase was 6,464.45 ± 4,149.24 with a range from 302 to 21,483 IU/L. In addition, 13 dysferlin mutations were identified two of them were compound heterozygous. One founder mutation was observed c.164_165insA in 19 unrelated families.ConclusionThe prevalence of Dysferlinopathy was 29.46% in the native Saudi LGMD cohort. It is the most prevalent subtype seconded by calpainopathy. The clinical course varied among the study subjects and was consistent with those reported from different ethnic groups. One founder mutation was identified. Initial screening of the founder mutations in new families is highly recommended.

Genetic screening of an endemic mutation in the DYSF gene in an isolated, mountainous population in the Republic of Dagestan

“…This may be due to isolation factors including cultural, geographical, and social. The isolation of large Avar families identifies this population as being part of a unique cluster of ethnic communities with an identified founder effect and the accumulation of a single pathogenic mutation that has also been observed in Jewish populations in Libya (Leshinsky‐Silver et al, 2007) and the mountainous regions of the Caucasus (Leshinsky‐Silver et al, 2007), as well as in Italians (Cagliani et al, 2003), Swiss (Petersen et al, 2015), Spaniards (Vilchez et al, 2005), Portuguese (Santos et al, 2010), and Saudi Arabians (Alharbi et al, 2022).…”

“…The presence of geographically, or culturally mediated, isolate populations with a high level of consanguineous marriages or the presence of the founder effect significantly increases the local prevalence of the condition. In particular, ethnic groups in which the proportion of individual mutations is high include Jewish populations in Tripoli, Libya (c.1624delG; frequency = 9.75%) (Argov et al, 2000), Spaniards (c.6086C>T (p.R1905X)) (Vilchez et al, 2005), Italians (c.2875C>T (p.R959W)) (Cagliani et al, 2003), Jewish populations in the Caucasus (c.2779delG; approximate frequency of 4%) (Leshinsky‐Silver et al, 2007), Mexicans (c.1418G>D) (Rosas‐Vargas et al, 2007), Saudi Arabians (c.164_165insA) (Alharbi et al, 2022), and the Avars of the Republic of Dagestan (c.200_201delinsAT (p.Val67Asp)) (Illarioshkin et al, 2000; Umakhanova et al, 2017). However, screening for endemic variants of the DYSF gene have only been carried out in a minority of the described ethnic groups.…”

Missense mutation of c.635 T > C in CAPN3 impairs muscle injury repair in a Limb‐Girdel Muscular Dystropy Model

“…5 The clinical manifestations of the LGMDR1 type are highly heterogeneous, with differences in the age of onset, disease progression, and severity of disease among different patients. [6][7][8] Even if some patients carry the same gene mutation, their clinical phenotypes can be significantly different, notably those caused by missense mutations, which are difficult to predict. 9 LGMDR1-type lines are located at the defect of the calpain-3 gene (CAPN3) of chromosome 15q15-q21, which contains 24 exons and encodes the calpain-3 (CAPN3) protein with a relative molecular weight of 94kD.…”

An in‐frame pseudoexon activation caused by a novel deep‐intronic variant in the dysferlin gene

“…Dysferlinopathy is one of the most common subtypes of autosomal recessive limb‐girdle muscular dystrophies 2 and covers a spectrum of muscle diseases with high clinical heterogeneity, including hyper creatine‐kinase emia, distal myopathy with anterior tibial onset, Miyoshi muscular dystrophy 1, and limb‐girdle muscular dystrophy type 2B (LGMD2B) which is recently renamed as limb‐girdle muscular dystrophy recessive type 2 3 . The broad spectrum of pathogenic DYSF variants consists of both coding and noncoding variants, ranging from single‐nucleotide variants (SNVs) to large‐scale copy number variants 4–6 . Pathogenic DYSF variants, occurring throughout the entire gene with no apparent hot spots, are predominantly located in exons and/or flanking intronic regions 4,5 .…”

“… 3 The broad spectrum of pathogenic DYSF variants consists of both coding and noncoding variants, ranging from single‐nucleotide variants (SNVs) to large‐scale copy number variants. 4 , 5 , 6 Pathogenic DYSF variants, occurring throughout the entire gene with no apparent hot spots, are predominantly located in exons and/or flanking intronic regions. 4 , 5 Therefore, most pathogenic DYSF variants can be detected by routine exonic detection approaches which comprise of multiplex ligation‐dependent probe amplification (MLPA) and next‐generation sequencing (NGS) of all exons and flanking intronic sequences of DYSF .…”