1/101. Fetal muscle biopsy as a diagnostic tool in Duchenne muscular dystrophy. Duchenne muscular dystrophy (DMD) is a relentless progressive disorder, leading to severe disability during childhood and death in adolescence or early adulthood. In most families, prenatal diagnosis is readily achieved by molecular detection of dna deletions using chorionic villi or amniocytes, or by linkage analysis. In some cases, however, molecular methods fail to provide a definitive diagnosis and in such cases in utero fetal muscle biopsy may serve as a diagnostic option. We describe three families in whom fetal muscle biopsy was performed, focusing on the prenatal diagnostic dilemmas, the indications and timing for in utero fetal muscle biopsy, and the difficulties encountered. ( info) |
2/101. Novel mutations in the muscle chloride channel CLCN1 gene causing myotonia congenita in Spanish families. Mutations in the muscular voltage-dependent chloride channel gene (CLCN1), located at 7q35, lead to recessive and dominant myotonia congenita. We report four novel mutations identified in this gene, after clinical, electromyographic, and genetic studies performed on 13 unrelated families. Two of the four mutations (2512insCTCA and A218T) were identified in families with Thomsen's disease, one (Q658X) in a family with Becker's disease, and the fourth (R669C) in a presumably sporadic patient with the Becker phenotype. Although identification of the mutations allows us to establish some genotype/phenotype correlations, this does not wholly account for the clinical heterogeneity and the inheritance patterns of the disease. ( info) |
3/101. Clinical characteristics of aged Becker muscular dystrophy patients with onset after 30 years. To elucidate the clinical characteristics of aged patients with Becker muscular dystrophy (BMD), 4 patients with this disease who were over 50 years were examined. The ages at onset in all patients were later than 30 years. All were proven to have a deletion around exons 45-55 of the Duchenne muscular dystrophy (DMD) gene. Two patients became wheelchair bound in their 40s or beyond, while the other 2 (aged 73 and 69, respectively) were still able to walk at the time of examination. Three of 4 patients had no obvious hypertrophy in their calves, which is known to be one of the characteristic clinical features in the juvenile BMD patients. serum creatine kinase levels were elevated in all patients, but not markedly (mean 444.8 /- 230.3 U/l; normal value < 180 U/l). Dilated cardiomyopathy was clinically apparent in 2 patients. We emphasize that some BMD patients are free of muscular symptoms until their 50s and are still self-supporting in their 60s or 70s. ( info) |
4/101. Duchenne muscular dystrophy and concomitant metastatic alveolar rhabdomyosarcoma. The authors report the concomitant occurrence of Duchenne muscular dystrophy (DMD) and alveolar rhabdomyosarcoma (RMS). A 4-year-old boy presented with symptoms involving his neuromuscular system that affected primarily his left hip and leg. Duchenne muscular dystrophy was diagnosed. Seven months later, metastatic alveolar RMS in the ipsilateral pelvis was documented. The diagnosis of one major disorder affecting striated muscle (DMD) may have prevented the early detection of another (RMS). ( info) |
5/101. Cardiac involvement in Becker's muscular dystrophy, necessitating heart transplantation, 6 years before apparent skeletal muscle involvement. In Becker's muscular dystrophy cardiac abnormalities usually occur after onset of neuromuscular symptoms. We describe a Becker muscular dystrophy patient in whom chronic heart failure, necessitating cardiac transplantation, was the initial manifestation. Neuromuscular symptoms occurred not earlier than 6 years after the initial cardiac symptoms and 5 years after heart transplantation. In conclusion, severe heart failure due to dilated cardiomyopathy may be the initial manifestation of Becker's muscular dystrophy and may predate neuromuscular symptoms for years. ( info) |
6/101. Noval mutation (Y184C) in exon 4 of the beta-sarcoglycan gene identified in a Portuguese patient. Mutations in brief no. 177. Online. We report a novel beta-sarcoglycan gene mutation identified in a 21-year-old Portuguese male with a progressive myopathy of intermediate severity, who had been misdiagnosed as Becker Muscular Dystrophy (BMD) based on clinical observations and muscle immunocytochemical anaylsis with dystrophin antibodies only. Since no detectable deletions or duplications were found in the dystrophin gene, we screened for mutations in the sarcoglycan genes by PCR-SSCP. The patient's sample showed a band of increased mobility in exon 4 of the beta-sarcoglycan gene which, upon sequencing, was found to represent a homozygous A-->G transversion at nucleotide 551, resulting in a tyrosine to cysteine substitution at position 184 (Y184C). Carrier status was ascertained in both parents and a sister. These aberrant conformers were not detected in 85 unrelated control individuals screened by PCR-SSCP analysis. All seven beta-sarcoglycan mutations reported to date are associated with a severe phenotype and occur in exons 3 and 4, which correspond to the immediate extracellular domain of the protein. This region contains five conserved cysteine residues. In our patient, the presence of an extra cysteine residue could interefere with intra- and/or inter-molecular disulphide bond formation. The intermediate phenotype could perhaps result from the assembly of both normal and abnormal complexes, depending on the formation of the disulphide bonds. ( info) |
7/101. A female carrier of Duchenne muscular dystrophy complicated with cardiomyopathy. A 45-year-old female carrier of Duchenne muscular dystrophy (DMD) complicated with cardiomyopathy is described. She had no symptoms of muscle weakness or heart failure. Her chest x-ray film revealed marked cardiomegaly. Echocardiogram showed marked enlargement and severe hypokinesis of the left ventricle. In myocardial scintigraphic images, perfusion defects of the myocardium were revealed. dystrophin immunostaining of myocardial biopsy specimens showed a mosaic pattern of dystrophin-negative and -positive fibers. Cardiomyopathy is sometimes the only clinical symptom in female carriers of DMD. They are thought to be in a high risk group for developing heart failure. ( info) |
8/101. Complete skipping of exon 66 due to novel mutations of the dystrophin gene was identified in two Japanese families of Duchenne muscular dystrophy with severe mental retardation. Severe mental retardation is a rare complication of Duchenne muscular dystrophy (DMD). Here we report that two DMD cases showing severe mental retardation exhibit the same exon skipping event induced by different intron mutations. In the two Japanese DMD patients studied, the complete sequence of exon 66 of the dystrophin gene was found to be absent from the dystrophin mRNA, creating a premature stop codon in exon 67. Novel point mutations at the consensus sequence of the splice donor site of intron 66 (T9857( 2) to C in one case and G9857( 5) to T in the other case) were found to be the cause of complete exon skipping. Remarkably, severe mental retardation cosegregated with an exon 66-skipping event in their families. Furthermore, pachygyria was disclosed by magnetic resonance imaging (MRI) examination of the brain of one case. Our results suggested that exon 66 skipping should be examined in DMD cases with a severe form of mental retardation. ( info) |
9/101. Elevation of serum creatine kinase as the only manifestation of an intragenic deletion of the dystrophin gene in three unrelated families. This study reports three children from three unrelated families, aged from 9 to 12 years, who were investigated because of the incidental finding of elevated serum creatine kinase (CK) levels and were found to have a dystrophinopathy. The molecular defect consisted of a deletion of variable extent within the central rod domain of the dystrophin gene, involving either exons 32-44 or 48-51 or 48-53. In each family we found the same deletion in at least one adult male relative aged from 40 to 77 years, who was either completely asymptomatic or had very mild muscle involvement (thin muscles and/or mild scoliosis), with normal or borderline CK levels. This study suggests once again that deletions of the central rod domain of dystrophin may be associated with elevation of serum CK as the only manifestation and that prediction of the clinical severity based solely on the molecular findings should be interpreted with caution. ( info) |
10/101. Detection of deletion in the dystrophin gene of a patient with quadriceps myopathy. A 43 year old male presented with slowly progressive weakness of limbs and hypertrophy of triceps, brachioradialis and calf muscles for four years. There was thinning of quadriceps muscles in both thighs. Histological study was compatible with Becker muscular dystrophy (BMD). Genomic dna analysis showed a deletion of the Hind III fragments, spanning exons 45-47. A junction fragment of 11.0 kb was observed along with a deletion of a 3.4 kb PstI fragment containing exon 51 in the patient, and in one of his two sisters. The clinical and laboratory characteristics in this patient are in keeping with what has been described 'quadriceps myopathy' and fall within the phenotypic variants of BMD as has been shown by others. ( info) |