Elsheikh BH, Bollman E, Peruggia M, King W, Galloway G, Kissel JT.

Department of Neurology, The Ohio State University, Columbus, OH 43210, USA.

Sveen ML, Jeppesen TD, Hauerslev S, Krag TO, Vissing J.

Department of Neurology 2082, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. RH18329@rh.hosp.dk

We studied the effect of aerobic training on conditioning in patients with limb-girdle muscular dystrophy type 2I (LGMD2I). Nine patients with LGMD2I cycled fifty 30-minute sessions at 65% of their maximal oxygen uptake over 12 weeks. Training significantly improved work capacity, paralleled by self-reported improvements. Creatine kinase levels did not increase significantly, and muscle morphology was unaffected. Moderate-intensity endurance training is a safe method to increase exercise performance and daily function in patients with LGMD2I.

Comment in:

    Neurology. 2007 Jan 9;68(2):88-9.

Kishnani PS, Corzo D, Nicolino M, Byrne B, Mandel H, Hwu WL, Leslie N, Levine J, et al.

Division of Medical Genetics, Department of Pediatrics, Box 3528, Duke University Medical Center, Durham, NC 27710, USA. kishn001@mc.duke.edu

BACKGROUND: Pompe disease is a progressive metabolic neuromuscular disorder resulting from deficiency of lysosomal acid alpha-glucosidase (GAA). Infantile-onset Pompe disease is characterized by cardiomyopathy, respiratory and skeletal muscle weakness, and early death. The safety and efficacy of recombinant human (rh) GAA were evaluated in 18 patients with rapidly progressing infantile-onset Pompe disease. METHODS: Patients were diagnosed at 6 months of age and younger and exhibited severe GAA deficiency and cardiomyopathy. Patients received IV infusions of rhGAA at 20 mg/kg (n = 9) or 40 mg/kg (n = 9) every other week. Analyses were performed 52 weeks after the last patient was randomized to treatment. RESULTS: All patients (100%) survived to 18 months of age. A Cox proportional hazards analysis demonstrated that treatment reduced the  risk of death by 99%, reduced the risk of death or invasive ventilation by 92%, and reduced the risk of death or any type of ventilation by 88%, as compared to an untreated historical control group. There was no clear advantage of the 40-mg/kg dose with regard to efficacy. Eleven of the 18 patients experienced 164 infusion-associated reactions; all were mild or moderate in intensity. CONCLUSIONS: Recombinant human acid alpha-glucosidase is safe and effective for treatment of infantile-onset Pompe disease. Eleven patients experienced adverse  events related to treatment, but none discontinued. The young age at which these patients initiated therapy may have contributed to their improved response compared to previous trials with recombinant human acid alpha-glucosidase in which patients were older.

Multiexon skipping leading to an artificial DMD protein lacking amino acids from exons 45 through 55 could rescue up to 63% of patients with Duchenne muscular dystrophy.

Béroud C, Tuffery-Giraud S, Matsuo M, Hamroun D, Humbertclaude V, Monnier N et al.

Laboratoire de Génétique Moléculaire, Institut Universitaire de Recherche Clinique, Unité de Formation et de Recherche Médecine Site Nord Unité Pédagogique Médicale/IURC, Montpellier, France. christophe.beroud@igh.cnrs.fr

Approximately two-thirds of Duchenne muscular dystrophy (DMD) patients show intragenic deletions ranging from one to several exons of the DMD gene and leading to a premature stop codon. Other deletions that maintain the translational reading frame of the gene result in the milder Becker muscular dystrophy (BMD) form of the disease. Thus the opportunity to transform a DMD phenotype into a BMD phenotype appeared as a new treatment strategy with the development of antisense oligonucleotides technology, which is able to induce an exon skipping at the pre-mRNA level in order to restore an open reading frame.

Because the DMD gene contains 79 exons, thousands of potential transcripts could be produced by exon skipping and should be investigated. The conventional approach considers skipping of a single exon. Here we report the comparison of single- and multiple-exon skipping strategies based on bioinformatic analysis. By using the Universal Mutation Database (UMD)-DMD, we predict that an optimal

multiexon skipping leading to the del45-55 artificial dystrophin (c.6439_8217del)could transform the DMD phenotype into the asymptomatic or mild BMD phenotype. This multiple-exon skipping could theoretically rescue up to 63% of DMD patients with a deletion, while the optimal monoskipping of exon 51 would rescue only 16% of patients.

Cell therapy of primary myopathies.

Sampaolesi M, Biressi S, Tonlorenzi R, Innocenzi A, Draghici E, Cusella de Angelis MG, Cossu G.

Stem Cell Research Institute, H. S. Raffaele, Milan, Italy. sampaolesi.maurilio@hsr.it

Mesoangioblasts are multipotent progenitors of mesodermal tissues. In vitro mesoangioblasts differentiate into many mesoderm cell types, such as smooth, cardiac and striated muscle, bone and endothelium. After transplantation mesoangioblasts colonize mostly mesoderm tissues and differentiate into many cell types of the mesoderm. When delivered through the arterial circulation, mesoangioblasts significantly restore skeletal muscle structure and function in a mouse model of muscular dystrophy. Their ability to extensively self-renew in vitro, while retaining multipotency, qualifies mesoangioblasts as a novel class of stem cells. Phenotype, properties and possible origin of mesoangioblasts are addressed in the first part of this paper. In the second part we will focus on the cell therapy approach for the treatment of Muscular Dystrophy and we will describe why mesangioblasts appear to be promising candidates for this strategy.

Comment in: Neurology. 2007 Feb 13;68(7):535; author reply 535-6. Diagnostic evaluation of clinically normal subjects with chronic hyperCKemia. Fernandez C, de Paula AM, Figarella-Branger D, Krahn M, Giorgi R, Chabrol B, Monfort MF, Pouget J, Pellissier JF. Laboratoire d’Anatomie Pathologique et Neuropathologie, Hôpital de la Timone Adultes, Marseille, France. The authors analyzed muscle biopsy specimens of 104 patients with creatine kinase activity greater than 500 UI/L (normal 10 to 170 UI/L) without signs of muscle weakness. They achieved a definite or probable diagnosis in 55% of cases. The most frequently identified diseases were glycogen storage diseases, muscular dystrophies, and inflammatory myopathies. The probability of making a diagnosis was higher in children and when creatine kinase level was greater than 2,000 UI/L.