Brain Advance Access originally published online on September 28, 2006
Brain 2007 130(2):368-380; doi:10.1093/brain/awl270
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
A novel autosomal recessive limb-girdle muscular dystrophy with quadriceps atrophy maps to 11p13–p12
1 Neurogenetics of Locomotion Laboratory, Centre de Recherche du Centre Hospitalier de l'Université de Montréal Montréal, Quebec, Canada 2 Département de radiologie, Centre Hospitalier de l'Université de Montréal Montréal, Quebec, Canada 3 Hôpital Ste-Justine, Montréal Montréal, Quebec, Canada 4 CHA-Hôpital Enfant-Jésus, Université Laval Quebec, Canada 5 CHUS, Université de Sherbrooke Sherbrooke, Quebec, Canada
Correspondence to: B. Brais, Centre for the Study of Brain Diseases, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada E-mail: Bernard.Brais{at}umontreal.ca
Limb-girdle muscular dystrophies (LGMD) are a heterogeneous group of pathologies. We have identified a cohort of 14 French–Canadian patients from eight different families displaying a novel form of LGMD with an autosomal recessive inheritance. These patients share some features with previously described cases of ‘quadriceps myopathy’ that evolved into an LGMD. All demonstrate quadriceps femoris asymmetrical atrophy. Creatine kinase values were variable from normal to 6000 U/l. Clinical evaluations and MRI studies demonstrate a variable intrafamilial and interfamilial phenotype. Asymmetrical muscle involvement was clinically observed and confirmed by imaging. MRI studies suggest that the hamstrings and the adductor magnus are the first limb muscles to demonstrate fatty infiltration. Muscle pathology shows no sign of active inflammation but increased endomysial connective tissue associated with basal lamina duplication and collagen disorganization. A genome-wide scan using the two largest families uncovered linkage to marker D11S1360 on chromosome 11p12 [multipoint logarithm of the odds (LOD) score of 2.78]. Further genotyping for the eight families confirmed linkage to this new LGMD locus (multipoint LOD score of 4.56). Fine mapping subsequently defined a less than 3.3 cM candidate interval on 11p13–p12. Haplotype analysis of carrier chromosomes suggests that the most frequent mutation may account for up to 81.3% of French–Canadian mutations. In this study, we describe the chromosomal locus of a new form of recessive LGMD with prominent quadriceps femoris atrophy.
Key Words: autosomal recessive limb-girdle muscular dystrophy; quadriceps atrophy; genome-wide scan; linkage analysis
Abbreviations: CK, creatine kinase; EMG, electromyogram; IBM, inclusion body myositis; LGMD, limb-girdle muscular dystrophy; LOD, logarithm of the odds; TRIM, tripartite motif
Received June 27, 2006. Revised August 11, 2006. Accepted August 23, 2006.