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Chiara A. Boito, MS; Paola Melacini, MD; Andrea Vianello, MD; Paola Prandini, PhD; Bruno F. Gavassini, MS; Alessia Bagattin, MS; Gabriele Siciliano, MD, PhD; Corrado Angelini, MD; Elena Pegoraro, MD, PhD

Arch Neurol. 2005;62:1894-1899.

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 genotype-phenotype 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 high-performance 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 826C>A 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.

Author Affiliations: Department of Neurosciences (Ms Boito, Drs Prandini, Angelini, and Pegoraro, and Mr Gavassini), Cardiology Section, Departments of Clinical and Experimental Medicine (Dr Melacini) and Biology (Ms Bagattin), University of Padova, and Department of Respiratory Pathophysiology, Padova Hospital (Dr Vianello), Padova; and Department of Neurosciences, University of Pisa, Pisa (Dr Siciliano); Italy.