Quimico Farmaceutico Biologo
Páginas: 7 (1623 palabras)
Publicado: 11 de febrero de 2013
Acta Myologica • 2011; XXX: p. 182-184
Case reports
Deletion of exon 26 of the dystrophin gene is associated with a mild Becker muscular dystrophy phenotype
Nanna Witting1, Morten Duno2, John Vissing1
Neuromuscular Research Unit, 1Department of Neurology and 2Department of Clinical Genetics, University of Copenhagen, Rigshospitalet, Denmark
With the possible introduction of exonskipping therapy in Duchenne muscular dystrophy, it has become increasingly important to know the role of each exon of the dystrophin gene to protein expression, and thus the phenotype. In this report, we present two related men with an unusually mild BMD associated with an exon 26 deletion. The proband, a 23-year-old man, had slightly delayed motor milestones, walking 1½ years old. He had no complaintsof muscle weakness, but had muscle pain. Clinical examination revealed no muscle wasting or loss of power, but his CK was 1500-7000 U/l. Muscle biopsy showed dystrophic changes. He had comorbidity with dystonia, slight mental retardation, low stature and neuropathy. The brother of the proband’s mother came to medical attention when he was 43 years old. He complained about muscle pain. Onexamination, a MRC grade 4+ hip extention palsy and a discrete calf hypertrophy was noted. Creatine kinase was normal or raised maximally to 500U/l. The muscle biopsy was myopathic with increased fiber size variation and many internal nuclei, but no dystrophy. No comorbidity was found. In both cases, western blot showed a reduced dystrophin band. Genetic evaluation revealed a deletion of exon 26 of thedystrophin gene in both. This is the first description of patients with a exon 26 deletion of the dystrophin gene. Assuming the proband’s comorbidity is unrelated, exon 26 deletion results in a very mild phenotype. This might be of interest in planning exon skipping therapy for Duchenne muscular dystrophy. This report also shows that BMD may present with a normal CK. Key words: BMD, dystrophin,deletion, exon 26
deterioration of muscle strength in Duchenne muscular dystrophy (1), and is now routinely offered to many, preferentially ambulatory, patients. Symptomatic treatment such as ventilatory support and physiotherapy has also led to improvements of life quality and survival. In spite of this progress, however, the dystrophinopathies progress relentlessly and typically result in severedisability. A promising new treatment is exon-skipping therapy which is based on converting an “out-of-frame” mutation into an “in-frame” mutation, and thus transforming a severe Duchenne phenotype to a mild Becker phenotype. Phase 1-2 trials are ongoing to investigate the feasibility of exon skipping for Duchenne (2, 3). With the possible introduction of exon skipping therapy, it has becomeincreasingly important to know the exact role of each exon of the dystrophin gene on protein expression, and thus the phenotype. In this report, we present two related men with an unusually mild Becker muscular dystrophy phenotype associated with a novel exon 26 deletion.
Methods
After informed consent, we studied the phenotype of the index person and his maternal uncle. The disease history wasobtained in a formal interview and clinical examination was carried out with estimation of muscle strength and evaluation of muscle bulk. Needle biopsies were performed in the lateral vastus muscle. Multiplex western blots were performed as described by Anderson (4). An electrocardiogram and echocardiography were performed in both patients.
Introduction
No curative treatment is available for thetwo dystrophinopathies, Becker and Duchenne muscular dystrophies. In 1995, low-dose steroid treatment was shown to diminish
Address for correspondence: Nanna Witting, Neuromuscular Research Unit, Department of Neurology University of Copenhagen, Rigshospitalet, Denmark. E-mail: nanna.witting@rh.regionh.dk
182
Mild BMD with exon 26 deletion
results
The proband, a 23-year-old man,...
Case reports
Deletion of exon 26 of the dystrophin gene is associated with a mild Becker muscular dystrophy phenotype
Nanna Witting1, Morten Duno2, John Vissing1
Neuromuscular Research Unit, 1Department of Neurology and 2Department of Clinical Genetics, University of Copenhagen, Rigshospitalet, Denmark
With the possible introduction of exonskipping therapy in Duchenne muscular dystrophy, it has become increasingly important to know the role of each exon of the dystrophin gene to protein expression, and thus the phenotype. In this report, we present two related men with an unusually mild BMD associated with an exon 26 deletion. The proband, a 23-year-old man, had slightly delayed motor milestones, walking 1½ years old. He had no complaintsof muscle weakness, but had muscle pain. Clinical examination revealed no muscle wasting or loss of power, but his CK was 1500-7000 U/l. Muscle biopsy showed dystrophic changes. He had comorbidity with dystonia, slight mental retardation, low stature and neuropathy. The brother of the proband’s mother came to medical attention when he was 43 years old. He complained about muscle pain. Onexamination, a MRC grade 4+ hip extention palsy and a discrete calf hypertrophy was noted. Creatine kinase was normal or raised maximally to 500U/l. The muscle biopsy was myopathic with increased fiber size variation and many internal nuclei, but no dystrophy. No comorbidity was found. In both cases, western blot showed a reduced dystrophin band. Genetic evaluation revealed a deletion of exon 26 of thedystrophin gene in both. This is the first description of patients with a exon 26 deletion of the dystrophin gene. Assuming the proband’s comorbidity is unrelated, exon 26 deletion results in a very mild phenotype. This might be of interest in planning exon skipping therapy for Duchenne muscular dystrophy. This report also shows that BMD may present with a normal CK. Key words: BMD, dystrophin,deletion, exon 26
deterioration of muscle strength in Duchenne muscular dystrophy (1), and is now routinely offered to many, preferentially ambulatory, patients. Symptomatic treatment such as ventilatory support and physiotherapy has also led to improvements of life quality and survival. In spite of this progress, however, the dystrophinopathies progress relentlessly and typically result in severedisability. A promising new treatment is exon-skipping therapy which is based on converting an “out-of-frame” mutation into an “in-frame” mutation, and thus transforming a severe Duchenne phenotype to a mild Becker phenotype. Phase 1-2 trials are ongoing to investigate the feasibility of exon skipping for Duchenne (2, 3). With the possible introduction of exon skipping therapy, it has becomeincreasingly important to know the exact role of each exon of the dystrophin gene on protein expression, and thus the phenotype. In this report, we present two related men with an unusually mild Becker muscular dystrophy phenotype associated with a novel exon 26 deletion.
Methods
After informed consent, we studied the phenotype of the index person and his maternal uncle. The disease history wasobtained in a formal interview and clinical examination was carried out with estimation of muscle strength and evaluation of muscle bulk. Needle biopsies were performed in the lateral vastus muscle. Multiplex western blots were performed as described by Anderson (4). An electrocardiogram and echocardiography were performed in both patients.
Introduction
No curative treatment is available for thetwo dystrophinopathies, Becker and Duchenne muscular dystrophies. In 1995, low-dose steroid treatment was shown to diminish
Address for correspondence: Nanna Witting, Neuromuscular Research Unit, Department of Neurology University of Copenhagen, Rigshospitalet, Denmark. E-mail: nanna.witting@rh.regionh.dk
182
Mild BMD with exon 26 deletion
results
The proband, a 23-year-old man,...
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