Disease Progression and Mutation Pattern in a Large Cohort of LGMD R1/LGMD 2A Patients from India

Abstract

Calpainopathy is caused by mutations in the CAPN3. There is only one clinical and genetic study of CAPN3 from India and none from South India. A total of 72 (male[M]:female [F] = 34:38) genetically confirmed probands from 72 independent families are included in this study. Consanguinity was present in 54.2%. The mean age of onset and duration of symptoms are 13.5 ± 6.4 and 6.3 ± 4.7 years, respectively. Positive family history occurred in 23.3%. The predominant initial symptoms were proximal lower limb weakness (52.1%) and toe walking (20.5%). At presentation, 97.2% had hip girdle weakness, 69.4% had scapular winging, and 58.3% had contractures. Follow-up was available in 76.4%, and 92.7% were ambulant at a mean age of 23.7 ± 7.6 years and duration of 4.5 years, remaining 7.3% became wheelchair-bound at 25.5 ± 5.7 years of age (mean duration = 13.5 ± 4.6), 4.1% were aged more than 40 years (duration range = 5–20). The majority remained ambulant 10 years after disease onset. Next-generation sequencing (NGS) detected 47 unique CAPN3 variants in 72 patients, out of which 19 are novel. Missense variants were most common occurring in 59.7% (homozygous = 29; Compound heterozygous = 14). In the remaining 29 patients (40.3%), at least one suspected loss of function variant was present. Common recurrent variants were c.2051–1G > T and c.2338G > C in 9.7%, c.1343G > A, c.802–9G > A, and c.1319G > A in 6.9% and c.1963delC in 5.5% of population. Large deletions were observed in 4.2%. Exon 10 mutations accounted for 12 patients (16.7%). Our study highlights the efficiency of NGS technology in screening and molecular diagnosis of limb-girdle muscular dystrophy with recessive form (LGMDR1) patients in India.

A Case of a Patient with Calpainopathy Carrying Compound Heterozygous Mutations of a <i>de novo</i> Pathogenic Variant of c.1333G>A and a Novel Variant of c.1331C>T in <i>CAPN3</i>

“…Calpainopathy is typically inherited in an AR manner; however, in recent years, families with a genetic pattern suggesting an AD inheritance have been reported (2)(3)(4)(5)(6). Variants associated with AD calpainopathy include c.643_663del21, c.598_621del15, and the one observed in our patient, c.1333 G>A.…”

“…Furthermore, a study conducted in the Netherlands involving patients diagnosed with autosomal recessive LGMD (ARLGMD) through genetic testing revealed that asymptomatic hyperCKemia was present in 6% of all ARLGMD patients and in 3% of calpainopathy patients (7). Case reports from India indicate that 52.1% of calpainopathy patients have limb muscle weakness as their initial symptom, and 20.5% present with toe walking (2). In addition, a high prevalence of ankle contractures and toe walking was observed in a subgroup of patients with an onset age of <12 years.…”

“…Calpainopathy typically presents with progressive proximal limb muscle weakness but sometimes with asymptomatic serum creatine kinase (CK) level elevation (hyperCKemia) or toe walking (1). The inheritance of calpainopathy is primarily autosomal recessive (AR), but there have been reports of families in which an autosomal dominant (AD) inheritance is suspected (2)(3)(4)(5)(6), particularly in association with specific variants, such as c.1333G>A.…”

Management of a 25-Year-Old Female Patient With Limb-Girdle Muscular Dystrophy With Physiotherapy: A Case Report

“…The global frequency of LGMD is estimated to be 1one in 14,500-45,000 [ 6 ]. Calpainopathy is prevalent in all autosomal dominant and recessive forms of LGMD, ranging from 40% to 50% in Turkey, Bulgaria, and Indian populations [ 7 ].…”

Cas9-induced single cut enables highly efficient and template-free repair of a muscular dystrophy causing founder mutation

“…One mutation, CAPN3 c.550delA, is a founder mutation originating from the Eastern Mediterranean and is, with a reported prevalence of 1 in 144,000, the most common mutation of LGMD2A. 1 , 2 , 3 , 4 , 5…”