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Clinical presentation in merosin-positive congenital muscular dystrophy
434
Abstracts
merosin deficiency. These results suggest that although optic radiations and occipital lobes show imaging changes on brain MR1, these are not associated with any impairment of visual function.
Two developed respiratory failure, requiring night time ventilation. The CK was elevated in all cases, ranging from 245 to 2410 IU/I. In our case material early presentation at birth was associated with a more favourable prognosis compared to the later onset group.
Keywords: Vision; Congenital muscular dystrophy; Merosin Keywords: Congenital muscular dystrophy; Merosin-positive; Phenotype GP1A.7 Mutations in the LAMA2 gene in patients with muscular dystrophy due to partial merosin deficiency I. Naom a, M. D'Alessandroa, C.A. Sewry a, A. Ferlini a, H. Topaloglub, V. Dubowitz ", F. Muntoni a
GP1A.9 Skewed X inactivation in manifesting carriers of Duchenne muscular dystrophy
aNeuromuscular Unit, Department of Paediatrics & Neonatal Medicine, Hammersmith Hospital' London, UK and bDepartment of Child Neurology, Ankara, Turkey
"Departments of Pediatrics, Kobe General Hospital, Kobe, bKyoto University Hospital, Kyoto and "~Utano National Hospital, Kyoto, Japan
A proportion of children with congenital muscular dystrophy (CMD) have a deficiency of laminin a2 chain of merosin. We have shown that milder disease variants can be due to a partial deficiency of this protein. These individuals were deficient for the 300 kDa laminin u2 chain fragment, while the 80 kDa fragment was only minimally affected. We now report mutation analysis in three families. In family 1 there was a single affected child, in family 2 two siblings and in family 3 four affected children. All the patients are ambulant. In the first two families onset was in the second year with delayed motor milestones, in the third family in the teens with proximal muscle weakness. In the 8-year-old girl from family 1, the first mutation was a de-novo single nucleotide deletion at position 5702 in the cDNA sequence, leading to a frameshift and a stop codon 45 nucleotides downstream. The mutation in the second allele was a G ---) C transition at position +5 of the acceptor splice site of intron 37. Transcription analysis indicated that this mutation did not induce exon skipping or alternative spicing, but probably reduced the efficiency of splicing. Southern blot analysis in the second family showed an abnormal fragment in domain IIIa. Characterisation of the mutation in this and in the third family is currently in progress. These mutations in milder cases should allow us to clarify the correlation between the mutations in the LAMA2 gene and the processing of this protein, and possibly also the severity of the clinical pheuotype.
Keywords: Laminin ~2 chain; Congenital muscular dystrophy; Mild variant
GP1A.8 Clinical presentation in merosin-positive congenital muscular dystrophy
Mieko Yoshiokaa, Tohrn Yorifuji b, Izuru Mituyoshi~
It has been assumed that female dystrophinopathy patients are heterozygous carriers who show preferential inactivation of the X chromosome harboring the normal dystrophin gene. We have studied X-inactivation patterns of familial and sporadic manifesting or unaffected carriers of Duchenne muscular dystrophy (DMD) by analysis of the methylation of HpalI sites in the first exon of the human androgen-receptor gene (HUMARA) from their peripheral blood samples. A PCR-based assay was developed to distinguish the paternal from the maternal X chromosome and their methylation status. The degree of X inactivation skewing in the HpaII-digested DNA is expressed as % skewing. Three of the four manifesting carriers, 4 of 5 asymptomatic carriers, and 31 of the 32 female controls are heterozygous at the CAG repeat of HUMARA. All manifesting carriers show skewed X inactivation, while all unaffected carriers reveal symmetrical inactivation, in one family we studied three generations; this is especially noteworthy because it includes mother/daughter pairs, both affected, along with phenotypically normal carrier mother/ daughter pair. In this family the affected mother/daughter pair shows skewing (70 and 93% skewing, respectively), while in the unaffected pair random X inactivation is apparent (54 and 56% skewing, respectively). The extent of X inactivation for each X chromosome in 31 female controls is widely distributed, though over 70% skewing is present only in 2 cases (6%). These data suggest that in carriers of DMD, both affected and unaffected, it is valuable to analyze the pattern of skewed X inactivation, because it provides important information for prognosis. However, it is not a reliable diagnostic marker, as skewing is also found in control females.
Keywords: Duchenne muscular dystrophy; Manifesting heterozygote; Skewed X-inactivation
J. Philpot, M. Brockinton, C.A. Sewry, V. Dubowitz, F. Muntoni
Department of Paediatric and Neonatal Medicine, Hammersmith Hospital, London, UK
GP1A.10 Genetic counseling and molecular analysis of muscular dystrophy families in Israel
In contrast to children with merosin-deficient CMD, merosin-positive cases have a very variable clinical phenotype. We reviewed the mode of presentation in 24 merosin-positive cases. Eleven presented with hypotonia at birth. All had mild contractures of at least two joints, usually wrists and ankles. Feeding and respiratory difficulties occurred in 3 but resolved within 2 weeks. Nine mothers recalled reduced fetal movements. Five of the deliveries were breech or unstable lie presentation. Prognosis was good (follow up 4 - 2 0 years), with 10 achieving independent walking, although two lost this ability in adolescence. The remaining case lost ambulation at 4 years. Creatine kinase (CK) was slightly elevated in 3 cases (maximum 340 IU/I) and normal in the rest. Four cases presented with arthrogryposis at birth. Three were breech presentation. Two had respiratory and feeding difficulties and one of them died at 8 weeks. The others had a static clinical course (follow up 3-12 years) and were limited more by joint contractures than muscle weakness. CK in all cases was normal. The remaining 9 children were normal at birth but presented by 6 months with hypotonia or delayed motor development. This group appeared clinically heterogeneous and prognosis was variable (follow up 18 months-17 years). All achieved independent walking but 3 lost ambulation before 8 years of age.
Cyril Legum a b Avi Orr-Urtreger ~, Adi Ben Yehuda a, Chedva Perek a, Sigal Tsabari a, Ruth Shomrat ~
aGenetic Institute, the Elias-Sourasky Medical Center, lchilov Hospital and bHuman Genetics Department, Sackler Facul~ of Medicine, University of Tel Aviv, Israel Since 1983 over 300 unrelated families with a muscular dystrophy or myopathy proband have been seen at our genetic institute. Over 140 families have undergone molecular analysis at the dystrophin locus and over 110 prenatal diagnoses for Duchenne and Becker muscular dystrophies have been carried out. Recently we have commenced a preliminary service for other muscular dystrophies, including the non-dystrophin muscular dystrophies, involving genes coding for proteins associated with dystrophin. We wish to present our methodology and approach to the management of these families and discuss examples of diagnostic and counseling dilemmas. The ethnic distribution of these families will be sununarized.
Keywords: Muscular dystrophy; Myopathy; Genetic counseling
Abstracts
merosin deficiency. These results suggest that although optic radiations and occipital lobes show imaging changes on brain MR1, these are not associated with any impairment of visual function.
Two developed respiratory failure, requiring night time ventilation. The CK was elevated in all cases, ranging from 245 to 2410 IU/I. In our case material early presentation at birth was associated with a more favourable prognosis compared to the later onset group.
Keywords: Vision; Congenital muscular dystrophy; Merosin Keywords: Congenital muscular dystrophy; Merosin-positive; Phenotype GP1A.7 Mutations in the LAMA2 gene in patients with muscular dystrophy due to partial merosin deficiency I. Naom a, M. D'Alessandroa, C.A. Sewry a, A. Ferlini a, H. Topaloglub, V. Dubowitz ", F. Muntoni a
GP1A.9 Skewed X inactivation in manifesting carriers of Duchenne muscular dystrophy
aNeuromuscular Unit, Department of Paediatrics & Neonatal Medicine, Hammersmith Hospital' London, UK and bDepartment of Child Neurology, Ankara, Turkey
"Departments of Pediatrics, Kobe General Hospital, Kobe, bKyoto University Hospital, Kyoto and "~Utano National Hospital, Kyoto, Japan
A proportion of children with congenital muscular dystrophy (CMD) have a deficiency of laminin a2 chain of merosin. We have shown that milder disease variants can be due to a partial deficiency of this protein. These individuals were deficient for the 300 kDa laminin u2 chain fragment, while the 80 kDa fragment was only minimally affected. We now report mutation analysis in three families. In family 1 there was a single affected child, in family 2 two siblings and in family 3 four affected children. All the patients are ambulant. In the first two families onset was in the second year with delayed motor milestones, in the third family in the teens with proximal muscle weakness. In the 8-year-old girl from family 1, the first mutation was a de-novo single nucleotide deletion at position 5702 in the cDNA sequence, leading to a frameshift and a stop codon 45 nucleotides downstream. The mutation in the second allele was a G ---) C transition at position +5 of the acceptor splice site of intron 37. Transcription analysis indicated that this mutation did not induce exon skipping or alternative spicing, but probably reduced the efficiency of splicing. Southern blot analysis in the second family showed an abnormal fragment in domain IIIa. Characterisation of the mutation in this and in the third family is currently in progress. These mutations in milder cases should allow us to clarify the correlation between the mutations in the LAMA2 gene and the processing of this protein, and possibly also the severity of the clinical pheuotype.
Keywords: Laminin ~2 chain; Congenital muscular dystrophy; Mild variant
GP1A.8 Clinical presentation in merosin-positive congenital muscular dystrophy
Mieko Yoshiokaa, Tohrn Yorifuji b, Izuru Mituyoshi~
It has been assumed that female dystrophinopathy patients are heterozygous carriers who show preferential inactivation of the X chromosome harboring the normal dystrophin gene. We have studied X-inactivation patterns of familial and sporadic manifesting or unaffected carriers of Duchenne muscular dystrophy (DMD) by analysis of the methylation of HpalI sites in the first exon of the human androgen-receptor gene (HUMARA) from their peripheral blood samples. A PCR-based assay was developed to distinguish the paternal from the maternal X chromosome and their methylation status. The degree of X inactivation skewing in the HpaII-digested DNA is expressed as % skewing. Three of the four manifesting carriers, 4 of 5 asymptomatic carriers, and 31 of the 32 female controls are heterozygous at the CAG repeat of HUMARA. All manifesting carriers show skewed X inactivation, while all unaffected carriers reveal symmetrical inactivation, in one family we studied three generations; this is especially noteworthy because it includes mother/daughter pairs, both affected, along with phenotypically normal carrier mother/ daughter pair. In this family the affected mother/daughter pair shows skewing (70 and 93% skewing, respectively), while in the unaffected pair random X inactivation is apparent (54 and 56% skewing, respectively). The extent of X inactivation for each X chromosome in 31 female controls is widely distributed, though over 70% skewing is present only in 2 cases (6%). These data suggest that in carriers of DMD, both affected and unaffected, it is valuable to analyze the pattern of skewed X inactivation, because it provides important information for prognosis. However, it is not a reliable diagnostic marker, as skewing is also found in control females.
Keywords: Duchenne muscular dystrophy; Manifesting heterozygote; Skewed X-inactivation
J. Philpot, M. Brockinton, C.A. Sewry, V. Dubowitz, F. Muntoni
Department of Paediatric and Neonatal Medicine, Hammersmith Hospital, London, UK
GP1A.10 Genetic counseling and molecular analysis of muscular dystrophy families in Israel
In contrast to children with merosin-deficient CMD, merosin-positive cases have a very variable clinical phenotype. We reviewed the mode of presentation in 24 merosin-positive cases. Eleven presented with hypotonia at birth. All had mild contractures of at least two joints, usually wrists and ankles. Feeding and respiratory difficulties occurred in 3 but resolved within 2 weeks. Nine mothers recalled reduced fetal movements. Five of the deliveries were breech or unstable lie presentation. Prognosis was good (follow up 4 - 2 0 years), with 10 achieving independent walking, although two lost this ability in adolescence. The remaining case lost ambulation at 4 years. Creatine kinase (CK) was slightly elevated in 3 cases (maximum 340 IU/I) and normal in the rest. Four cases presented with arthrogryposis at birth. Three were breech presentation. Two had respiratory and feeding difficulties and one of them died at 8 weeks. The others had a static clinical course (follow up 3-12 years) and were limited more by joint contractures than muscle weakness. CK in all cases was normal. The remaining 9 children were normal at birth but presented by 6 months with hypotonia or delayed motor development. This group appeared clinically heterogeneous and prognosis was variable (follow up 18 months-17 years). All achieved independent walking but 3 lost ambulation before 8 years of age.
Cyril Legum a b Avi Orr-Urtreger ~, Adi Ben Yehuda a, Chedva Perek a, Sigal Tsabari a, Ruth Shomrat ~
aGenetic Institute, the Elias-Sourasky Medical Center, lchilov Hospital and bHuman Genetics Department, Sackler Facul~ of Medicine, University of Tel Aviv, Israel Since 1983 over 300 unrelated families with a muscular dystrophy or myopathy proband have been seen at our genetic institute. Over 140 families have undergone molecular analysis at the dystrophin locus and over 110 prenatal diagnoses for Duchenne and Becker muscular dystrophies have been carried out. Recently we have commenced a preliminary service for other muscular dystrophies, including the non-dystrophin muscular dystrophies, involving genes coding for proteins associated with dystrophin. We wish to present our methodology and approach to the management of these families and discuss examples of diagnostic and counseling dilemmas. The ethnic distribution of these families will be sununarized.
Keywords: Muscular dystrophy; Myopathy; Genetic counseling