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Clinical, genetic and epidemiological study of major autosomal recessive limb girdle muscular dystrophy (lgmd2) in croatia
Compte-rendu de congrès • Neuroméditerranée VIII
© 2007. Elsevier Masson SAS. Tous droits réservés
USA). Also the first step in molecular analysis is the search for the p.R50X mutation by RFLP. 3– Many other nonsense mutations are private like p.Y52X in Greece, p.W361X in Japan, p.E540X in Finland and p.R650X in France. 4– Twenty nine missense mutations have been described. Among them two are private, p.G204S in Spain and p.V456M in 3 patients from North Africa at homozygous state due to consanguineous marriages (Algeria, Morocco and Tunisia). 5– Seven frame shift (fs) mutations which result in a premature stop codon have been described. They are dues to small base insertions or deletions, different from 3, like c.delAA (p.R795fs). 6– One conservative mutation p.K608K located at the 3’ end of exon 15 leads to an aberrant splicing (FernandezCadenas et al., 2004). 7– Mutations in the methionine initiation codon (ATG) (c.77A>G or C) leads to the destruction of start codon. 8– Pseudo-dominant transmission of McArdle’s disease has been described two fold (Tsujino et al., 1993; Isackson et al., 2005) and results from the union between an heterozygous asymptomatic father and a symptomatic compound heterozygote mother. 9– Molecular analysis of 34 patients from Southern France allows us to characterize mutations in all 68 chromosomes and to identify 10 novel mutations (submitted to Neuromuscular Disorders).
● Clinical, genetic and epidemiological study of major autosomal recessive limb girdle muscular dystrophy (lgmd2) in Croatia N. Canki-Klain
489
to be type 2I caused by mutation in fukutin related protein (FKRP). Since introduction of direct analysis of C826A, a year ago, we found five unrelated families with identical C826A mutation those results in the substitution of isoleucin for leucin. Three patients from two unrelated, informative families are affected by presumed MM/ LGMD2B. Haplotype analysis using microsatellites flanking the dysferlin gene and non-invasive western blot (WB) analysis of dysferlin (DYSF) gene from peripheral blood confirmed diagnosis, but mutation(s) is/are still unidentified. Discussion. Surprisingly, we have identified any sarcoglycanopathy probably because of sampling bias (small no of children) and limited methodology (lack of biopsy and WB of different proteins). Because of high frequency of healthy 550delA heterozygotes (1 in 133) and relative frequency of healthy heterozygotes for C826A mutation, which is responsible for LGMD2I (1 in 524) in our general population, we need to know both allele to confirm the diagnosis of LGMD2A and 2I. Conclusion. To study natural history of any LGMD2 both alleles must be known as well as genetically homogenous groups should be follow up according to as simple as possible protocol.
● Phenotypical features of 11 Moroccan families with autosomal recessive Charcot-Marie-tooth disease associated with mutations in the gdap1 gene N. Birouk1, A. Bouhouche2, H. Azzedine3, O. Dubourg4, A. Benomar2, H. Belaïdi1, M.P. Muriel3, T. Maisonobe4, M. Yahyaoui2, E. Le Guern3, R. Ouazzani1 1
Croatian Institute for Brain Research and Department of Neurology University Medical School, Zagreb Croatia.
Introduction. In september 1998 we started a genetic and epidemiological study of muscular dystrophies (mds) in Croatia. This report concerns results obtained for lgmd2, a group of muscle diseases presenting great clinical and genetic heterogeneity making an etiologic diagnosis very difficult and clinically in majority of patients impossible. Material and methods. Specific diagnostic strategy adapted to our country of 4,4million people was used. Results. A 7-year long study showed that calpainopathy was the prevalent LGMD2. Analysis of 30 apparently unrelated families (47 patients) with calpain 3 (CAPN3) gene mutations and LGMD has discovered six different CAPN3 mutations: 550delA, R541W, P82L, delFWSAL, R49H, Y537X, accounting for 93p.100 of CAPN3 chromosomes in the studied population. 550 delA was the most frequent mutation found on 43/60 (72p.100) analyzed CAPN3 chromosomes; other five mutations ranged from 8 to 2p.100. In 26 families two CAPN3 alleles were identified. In remaining 4 families with only one known CAPN3 allele, 550delA was present in 3 of 4 alleles, and P82L in one. The second, most common LGMD2 seems
Service de Neurophysiologie Clinique. Service de Neurologie B, Hôpital des Spécialités Rabat Maroc. 3 INSERM U289. 4 Laboratoire de Neuropathologie Raymond Escourolle, Hôpital de la Salpêtrière, Paris. 2
Mutations in GDAP1 gene located in 8q13 chromosome have been recently identified in families with either axonal or demyelinating form of autosomal recessive CharcotMarie-Tooth (CMT) disease. Twenty patients belonging to 11 Moroccan consanguineous families were examined clinically and electrophysiologically. In one patient, a peroneal nerve biopsy was performed. Linkage to 8q13 was then demonstrated and a mutation in the coding region of the GDAP1 gene was identified by direct sequencing. Neuropathy was evident very early in childhood, walking was delayed in 6 cases and onset of symptoms occurred before 6 years in the others. The phenotype was very severe: foot deformities and disability involving the hands and feet developed towards the end of the first decade and followed by involvement of proximal muscles in the lower limbs leading to loss of autonomy in 12 cases. Only two patients had hoarse voice. Thirteen patients belonging to
NEUROMÉDITERRANÉE VIII
© 2007. Elsevier Masson SAS. Tous droits réservés
USA). Also the first step in molecular analysis is the search for the p.R50X mutation by RFLP. 3– Many other nonsense mutations are private like p.Y52X in Greece, p.W361X in Japan, p.E540X in Finland and p.R650X in France. 4– Twenty nine missense mutations have been described. Among them two are private, p.G204S in Spain and p.V456M in 3 patients from North Africa at homozygous state due to consanguineous marriages (Algeria, Morocco and Tunisia). 5– Seven frame shift (fs) mutations which result in a premature stop codon have been described. They are dues to small base insertions or deletions, different from 3, like c.delAA (p.R795fs). 6– One conservative mutation p.K608K located at the 3’ end of exon 15 leads to an aberrant splicing (FernandezCadenas et al., 2004). 7– Mutations in the methionine initiation codon (ATG) (c.77A>G or C) leads to the destruction of start codon. 8– Pseudo-dominant transmission of McArdle’s disease has been described two fold (Tsujino et al., 1993; Isackson et al., 2005) and results from the union between an heterozygous asymptomatic father and a symptomatic compound heterozygote mother. 9– Molecular analysis of 34 patients from Southern France allows us to characterize mutations in all 68 chromosomes and to identify 10 novel mutations (submitted to Neuromuscular Disorders).
● Clinical, genetic and epidemiological study of major autosomal recessive limb girdle muscular dystrophy (lgmd2) in Croatia N. Canki-Klain
489
to be type 2I caused by mutation in fukutin related protein (FKRP). Since introduction of direct analysis of C826A, a year ago, we found five unrelated families with identical C826A mutation those results in the substitution of isoleucin for leucin. Three patients from two unrelated, informative families are affected by presumed MM/ LGMD2B. Haplotype analysis using microsatellites flanking the dysferlin gene and non-invasive western blot (WB) analysis of dysferlin (DYSF) gene from peripheral blood confirmed diagnosis, but mutation(s) is/are still unidentified. Discussion. Surprisingly, we have identified any sarcoglycanopathy probably because of sampling bias (small no of children) and limited methodology (lack of biopsy and WB of different proteins). Because of high frequency of healthy 550delA heterozygotes (1 in 133) and relative frequency of healthy heterozygotes for C826A mutation, which is responsible for LGMD2I (1 in 524) in our general population, we need to know both allele to confirm the diagnosis of LGMD2A and 2I. Conclusion. To study natural history of any LGMD2 both alleles must be known as well as genetically homogenous groups should be follow up according to as simple as possible protocol.
● Phenotypical features of 11 Moroccan families with autosomal recessive Charcot-Marie-tooth disease associated with mutations in the gdap1 gene N. Birouk1, A. Bouhouche2, H. Azzedine3, O. Dubourg4, A. Benomar2, H. Belaïdi1, M.P. Muriel3, T. Maisonobe4, M. Yahyaoui2, E. Le Guern3, R. Ouazzani1 1
Croatian Institute for Brain Research and Department of Neurology University Medical School, Zagreb Croatia.
Introduction. In september 1998 we started a genetic and epidemiological study of muscular dystrophies (mds) in Croatia. This report concerns results obtained for lgmd2, a group of muscle diseases presenting great clinical and genetic heterogeneity making an etiologic diagnosis very difficult and clinically in majority of patients impossible. Material and methods. Specific diagnostic strategy adapted to our country of 4,4million people was used. Results. A 7-year long study showed that calpainopathy was the prevalent LGMD2. Analysis of 30 apparently unrelated families (47 patients) with calpain 3 (CAPN3) gene mutations and LGMD has discovered six different CAPN3 mutations: 550delA, R541W, P82L, delFWSAL, R49H, Y537X, accounting for 93p.100 of CAPN3 chromosomes in the studied population. 550 delA was the most frequent mutation found on 43/60 (72p.100) analyzed CAPN3 chromosomes; other five mutations ranged from 8 to 2p.100. In 26 families two CAPN3 alleles were identified. In remaining 4 families with only one known CAPN3 allele, 550delA was present in 3 of 4 alleles, and P82L in one. The second, most common LGMD2 seems
Service de Neurophysiologie Clinique. Service de Neurologie B, Hôpital des Spécialités Rabat Maroc. 3 INSERM U289. 4 Laboratoire de Neuropathologie Raymond Escourolle, Hôpital de la Salpêtrière, Paris. 2
Mutations in GDAP1 gene located in 8q13 chromosome have been recently identified in families with either axonal or demyelinating form of autosomal recessive CharcotMarie-Tooth (CMT) disease. Twenty patients belonging to 11 Moroccan consanguineous families were examined clinically and electrophysiologically. In one patient, a peroneal nerve biopsy was performed. Linkage to 8q13 was then demonstrated and a mutation in the coding region of the GDAP1 gene was identified by direct sequencing. Neuropathy was evident very early in childhood, walking was delayed in 6 cases and onset of symptoms occurred before 6 years in the others. The phenotype was very severe: foot deformities and disability involving the hands and feet developed towards the end of the first decade and followed by involvement of proximal muscles in the lower limbs leading to loss of autonomy in 12 cases. Only two patients had hoarse voice. Thirteen patients belonging to
NEUROMÉDITERRANÉE VIII