Clinical and Molecular Characterization of Patients With Limb-Girdle Muscular Dystrophy Type 2I

Abstract

Background: Limb-girdle muscular dystrophy type 2I is caused by mutations in the fukutin-related protein gene (FKRP). FKRP encodes a putative glycosyltransferase protein that is involved in ␣-dystroglycan glycosylation.Objectives: To identify patients with limb-girdle muscular dystrophy type 2I and to derive genotypephenotype correlations.Design: Two hundred fourteen patients who showed muscle histopathologic features consistent with muscular dystrophy or myopathy of unknown etiology were studied. The entire 1.5-kilobase FKRP coding sequence from patient DNA was analyzed using denaturing highperformance liquid chromatography of overlapping polymerase chain reaction products, followed by direct sequencing of heteroduplexes.Results: Thirteen patients with limb-girdle muscular dystrophy type 2I (6% of all patients tested) were identified by FKRP mutation analysis, and 7 additional patients were identified by family screening. Six missense mutations (1 novel) were identified. The 826CϾA nucleotide change was a common mutation, present in 35% of the mutated chromosomes. Clinical presentations included asymptomatic hyperCKemia, severe early-onset muscular dystrophy, and mild late-onset muscular dystrophy. Dilated cardiomyopathy and ventilatory impairment were frequent features. Significant intrafamilial and interfamilial clinical variability was observed.Conclusions: FKRP mutations are a frequent cause of limb-girdle muscular dystrophies. The degree of respiratory and cardiac insufficiency in patients did not correlate with the severity of muscle involvement. The finding of 2 asymptomatic patients with FKRP mutations suggests that modulating factors may ameliorate the clinical phenotype.

Common recessive limb girdle muscular dystrophies differential diagnosis: why and how?

“…Symptoms usually start in a broad age range from 2 to 40 years, with a mean onset age around 19 years 45,46 (Table 2). Most patients present clinical symptoms and signs that mimic dystrophinopathy (both "Duchenne-like" and "Becker-like" cases), with predominant proximal muscle weakness and calf volume increase in about 76% of the patients 45,46 .…”

“…Most patients present clinical symptoms and signs that mimic dystrophinopathy (both "Duchenne-like" and "Becker-like" cases), with predominant proximal muscle weakness and calf volume increase in about 76% of the patients 45,46 . Other muscles may present increased volume such as the brachioradialis 45,46 . Unexpected to limb girdle muscular dystrophies, about 20% of the patients with fukutin related proteinopathy may present facial weakness 45 .…”

“…Unexpected to limb girdle muscular dystrophies, about 20% of the patients with fukutin related proteinopathy may present facial weakness 45 . About 30% (15% to 46%) of the patients present cardiac complications 45,46 . Respiratory abnormalities are common and occur in about 65% of the cases, even in ambulant patients, on the contrary to most muscular dystrophies 45,46 ( Table 2).…”

“…About 30% (15% to 46%) of the patients present cardiac complications 45,46 . Respiratory abnormalities are common and occur in about 65% of the cases, even in ambulant patients, on the contrary to most muscular dystrophies 45,46 ( Table 2). It is important to remind that Pompe disease (glycogen storage disease type 2) may present respiratory insufficiency and has already been excluded from the differential diagnosis ( Figure 5).…”

Congenital Muscular Dystrophy

“…However, when amalgamating these results, it remains clear that FKRP mutations are the most frequently found in this group of conditions. We and others have previously published extensively on the spectrum of these mutations (128,205,211,258,(262)(263)(264)(265)(266)(267)(268)(269)(270)(271). (Figure 12 and Table 10).…”