Clinical examination, at the age of 16 years, revealed no muscle wasting or loss of power, but his creatine kinase was increased to 1500-7000 U/l (< 400). His muscle biopsy showed dystrophic changes (Fig. 1A). He had co-morbidity with segmental dystonia including torticollis, slight mental retardation, low stature and axonal neuropathy verified by ENG. His dystonia was treated with Clonazepam, Orphenadrin and botulinum injections. At age 20, he still had preserved muscle strength and bulk. Figure 1. HE stained muscle section Inhibitors,research,lifescience,medical from the vastus lateralis muscle. 1A is from the proband, showing marked fibre size variability, central nuclei and fibrosis. 1B is from his maternal uncle, showing milder changes without
fibrosis. The brother of the proband’s 3-MA mother came to medical attention when he was 43 years old. He complained about muscle pain. On examination, a MRC grade 4+ hip extension palsy and a discrete calf hypertrophy (Fig. 2) was noted. Creatine kinase was normal or increased to maximally Inhibitors,research,lifescience,medical 500 U/l. The muscle biopsy was myopathic with increased fiber size variation and multiple internal
nuclei, but no dystrophic changes as seen in his nephew (Fig. 1B). No co-morbidity was found. Inhibitors,research,lifescience,medical In both cases, western blot revealed a marginally reduced size of dystrophin, with a severely decreased expression level to less than 5% of normal. α-Sarcoglycan, β-dystroglycan, Calpain and merosin were down-regulated in parallel (Fig. 3). Genetic evaluation, through MPLA and direct PCR, revealed a deletion of exon 26, (c.3433-?_3603+?del) of the dystrophin Inhibitors,research,lifescience,medical gene in both
patients. The mutation is predicted to induce an in-frame transcript. Figure 2. The maternal uncle of the proband showing slight hypertrophy of his calves. Figure 3. Western blots of the proband (3A) and his maternal uncle (3B). The blots show weak dystrophin bands with a slightly shorter dystrophin than the wild-type. α-Sarcoglycan and β-dystroglycan are down-regulated secondary to the dystrophin … Discussion Mutations involving exon 26 have been described Inhibitors,research,lifescience,medical several times (5), most often leading to a Duchenne phenotype. These mutations introduce premature stop codons (6-8) or disrupts correct reading, all leading to loss of functional dystrophin protein. Here Carnitine palmitoyltransferase II we present the first report of patients hemizygous for a deletion in exon 26. The deletion is predicted to result in an “in-frame” transcript of the dystrophin gene. Exon 26 is part of the central rod domain of dystrophin that connects the actin at the sarcomer to the glycoprotein complex at the membrane. The exact function of exon 26 or the central rod domain is not entirely understood, and the consequence of exon 26 deletion can therefore not be predicted theoretically. Assuming the proband’s co-morbidity is unrelated to the dystrophinopathy, our findings suggest that exon 26 deletion results in a very mild phenotype.