ABSTRACT: Background: We have recruited a group of four living and reviewed the records of six deceased distantly related French-Canadians of Acadian descent affected by a childhood-onset form of recessive limb-girdle muscular dystrophy (LGMD). All cases originate from the small archipelago of the Magdalen Islands (population: 13,000) isolated in the Gulf of St-Lawrence. Methods: Based on the likely sharing of the same founder mutation we completed a 319K SNPs genome-wide scan to identify the disease locus and then screen candidate genes in this region. Results: All patients had normal initial motor milestones. They presented with limb girdle weakness at the average age of seven years (5-11). Progressive weakness led to loss of ambulation at a wide range of ages (10-39). Patients also developed macroglossia, large calves and mild to moderate contractures, hyperlordosis and decreased pulmonary function. Creatine kinase levels were elevated (1,800-10,000 U/L) in the first decades, but decreased with progression of disease. Homozygosity mapping uncovered a shared chromosomal region of 6.33Mb. The alpha sarcoglycan (SGCA) gene, mutated in LGMD2D, lay in this candidate interval. Sequencing of all SGCA exons uncovered a shared homozygous missense mutation (c.229C>T, p.R77C), the most common SGCA mutation internationally reported. Using demographic data, we estimated a high carrier rate of 1/22. Conclusion: The p.R77C mutation has also been observed in many populations, including in France and Spain (Basques). This corresponds to the first reported recessive founder disease for the Magdalen Islands, an archipelago settled in the XlXth century, largely by Acadian immigrants.

An abstract is not available for this content so a preview has been provided. As you have access to this content, a full PDF is available via the ‘Save PDF’ action button.

Hereditary sensory and autonomic neuropathy type 2 (HSAN2) is a rare recessive genetic disorder characterized by severe sensory loss affecting the tactile, thermal and nociceptive modalities. Although heterozygous carriers of nonsense mutations in the HSN2 gene, called with-no-lysine(K)-1 (WNK1), do not develop the disease, historical and experimental evidence suggests that these individuals might perceive somatosensory stimuli differently from others. Using the method-of-limits, we assessed the thresholds for warmth detection, cool detection, heat pain and cold pain in 25 mutation carriers and 35 controls. In group analyses, carriers displayed significantly lower warmth (p < 0.001) and cool (p < 0.05) difference thresholds, and also tended to report cold pain at higher temperatures (p < 0.095), than controls. Similarly, matched-pair analyses showed that carriers are significantly more sensitive to warm stimuli (p < 0.01) and cold pain stimuli (p < 0.05), and tend to be more sensitive to cool stimuli (p < 0.11). Furthermore, the differences between the warmth detection thresholds of the carriers and those of gender- and sex-matched wild types significantly increased with age (r = 0.76, p = 0.02), and in carriers cool detection thresholds did not increase with age (r = 0.27, p = 0.24) as expected and observed in controls (r = 0.34, p = 0.05). This study demonstrates that the carriers of a recessive mutation for HSAN2 display greater sensitivity to innocuous thermal stimuli, as well as for cold pain, suggesting a possible environmental adaptive advantage of the heterozygous state.

Charcot–Marie–Tooth polyneuropathies (CMT) are clinically and genetically heterogeneous. We describe a French-Canadian cluster of 17 recessive CMT cases belonging to 10 families with variable early-onset CMT and scoliosis. The patients demonstrate great intra- and inter-familial variability. Linkage analysis confirmed that all families are linked to CMT4C locus on chromosome 5q32 (multipoint LOD score of 9.06). Haplotype analysis suggests that two SH3TC2 mutations are present in this cohort. The majority of carrier chromosomes, 26 of 34 (76%), carry the c.2860C→T mutation. Despite extensive sequencing, the other mutation is not yet uncovered. This study demonstrates that the clinical variability observed in CMT4C is due to other factors than the nature of the mutation and that further work is needed to better define the SH3TC2 gene to ensure the identification of all CMT4C mutations.

Congenital muscular dystrophies (CMDS) are a heterogeneous group of disorders. A growing number of CMDS have been found to be associated with joint hyperlaxity. We recruited 14 French-Canadian cases belonging to 11 families affected by a novel autosomal recessive congenital muscular dystrophy with hyperlaxity (CMDH). All cases come from the southwestern part of Quebec, suggesting a new French-Canadian founder effect. All patients present muscle weakness, proximal contractures coexisting with distal joint hyperlaxity. Pathological and genetic studies have excluded that mutations in the three genes coding for collagen VI subunits are responsible for this disease. A genome-wide scan established linkage of two CMDH families to a region on chromosome 3p23-21. Further linkage analysis confirmed that all families are linked to the same region (log of the odds score of 5.3). Haplotype analysis defines a 1.6-cM candidate interval and suggests that two common mutations may account for 78% of carrier chromosomes. This study describes and maps a new form of recessive CMD with joint hyperlaxity distinct from Ullrich and Bethlem myopathies with a founder effect in the French-Canadian population.

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.

Senataxin recently was identified as the mutated gene in ataxia‐oculomotor apraxia 2, which is characterized by ataxia, oculomotor apraxia, and increased α‐fetoprotein levels. In this study, we evaluated 24 ataxic patients from 10 French‐Canadian families. All cases have a homogeneous phenotype consisting of a progressive ataxia appearing between 2 and 20 (mean age, 14.8) years of age with associated dysarthria, saccadic ocular pursuit, distal amyotrophy, sensory and motor neuropathy, and increased α‐fetoprotein levels but absence of oculomotor apraxia. Linkage disequilibrium was observed with markers in the ataxia‐oculomotor apraxia 2 locus on chromosome 9q34. We have identified four mutations in senataxin in the French‐Canadian population including two novel missense mutations: the 5927T→G mutation changes the leucine encoded by codon 1976 to an arginine in the helicase domain (L1976R), and the 193G→A mutation changes a glutamic acid encoded by codon 65 into a lysine in the N‐terminal domain of the protein (E65K). The common L1976R mutation is shared by 17 of 20 (85%) carrier chromosomes. The study of this large French‐Canadian cohort better defines the phenotype of this ataxia and presents two novel mutations in senataxin including the more common founder mutation in the French‐Canadian population. Ann Neurol 2005;57:408–414