DMD is a genetic X-linked recessive disease that affects approximately one in 3500 male births. Boys with DMD have progressive and predictable muscle destruction because of the absence of Dys, a protein present under the muscle fiber membrane. Dys deficiency induces contraction-related membrane damages, activation of inflammatory-necrosis-fibrosis up to the cardiac-diaphragmatic failure and death. This review supports the therapeutic role of MT associated with immunosuppression in DMD patients, describing the history and the rationale of such approach. The authors underline the importance to evaluate a protocol of myoblast intradermal multi-injection to apply in young DMD patients

© 2010 John Wiley & Sons A/S.

Mutations in the FKRP (Fukutin Related Protein) gene produce a range of phenotypes including Limb Girdle Muscular Dystrophy Type 2I (LGMD2I). In order to investigate the prevalence, the mutation spectrum and possible genotype-phenotype correlation, we studied a cohort of Norwegian patients with LGMD2I, ascertained in a 4-year period. In this retrospective study of genetically tested patients, we identified 88 patients from 69 families, who were either homozygous or compound heterozygous for FKRP mutations. This gives a minimum prevalence of 1/54,000 and a corresponding carrier frequency of 1/116 in the Norwegian population. Seven different FKRP mutations, including three novel changes, were detected. Seventy-six patients were homozygous for the common c.826C>A mutation. These patients had later disease onset than patients who were compound heterozygous – 14.0 vs. 6.1years. We detected substantial variability in disease severity among homozygous patients.

Copyright © 2010 Elsevier B.V. All rights reserved.

Six genes including POMT1, POMT2, POMGNT1, FKRP, Fukutin (FKTN) and LARGE encode proteins involved in the glycosylation of ?-dystroglycan (?-DG). Abnormal glycosylation of ?-DG is a common finding in Walker-Warburg syndrome (WWS), muscle-eye-brain disease (MEB), Fukuyama congenital muscular dystrophy (FCMD), congenital muscular dystrophy types 1C and 1D and some forms of autosomal recessive limb-girdle muscular dystrophy (LGMD2I, LGMD2K, LGMD2M), and is associated with mutations in the above genes. FCMD, caused by mutations in Fukutin (FKTN), is most frequent in Japan, but an increasing number of FKTN mutations are being reported outside of Japan. We describe four new patients with FKTN mutations and phenotypes ranging from: severe WWS in a Greek-Croatian patient, to congenital muscular dystrophy and cobblestone lissencephaly resembling MEB-FCMD in two Turkish patients, and limb-girdle muscular dystrophy and no mental retardation in a German patient. Four of the five different FKTN mutations have not been previously described.

Copyright © 2010 Elsevier B.V. All rights reserved.

We report a 29-year-old man with limb-girdle muscular dystrophy type 2M (LGMD2M) caused by a compound heterozygous mutation of 3-kb insertion in the 3'-untranslated region and c.1073A > C (p.Q358P) mutation in exon 9 in FKTN. He had been diagnosed since childhood as having Becker muscular dystrophy based on limb-girdle muscle weakness and calf muscle hypertrophy. Loss of ambulation occurred at age 26 years and cardiomyopathy was noted one year later. Muscle biopsy at age 29 revealed dystrophic changes with loss of immunoreactivity to alpha-dystroglycan (alpha-DG), which prompted us to analyze FKTN and subsequent establishment of the diagnosis of LGMD2M. Brain MRI revealed hypoplasia of the right cerebellar hemisphere and tonsil. Dysplastic part was present in the lower medial part of the hypoplastic hemisphare, which was bordered by a deep cleft. Previously reported LGMD2M patients had mild or minimal muscle weakness in addition to dilated cardiomyopathy. In contrast, our patient had more severe skeletal muscle weakness and loss of ambulation. Treatment with 3-blockers or angiotensin II converting enzyme blockers has been reported to be efficacious for cardiomyopathy in patients with muscular dystrophy. The precise diagnosis should be established early in patients with muscular dystrophy complicated with cardiomyopathy.

Sleep hypoventilation is seen in patients with neuromuscular disease, as well as in those with obesity hypoventilation syndrome (OHS), which is defined as the combination of obesity, chronic hypercapnia, and hypoxemia during wakefulness that is aggravated during sleep. In 90% of cases, OHS is accompanied by obstructive sleep apnea. The diagnosis of OHS is based on hypoventilation and pulmonary hypertension that cannot be explained by alterations in pulmonary function. The mortality of patients with OHS is greater than is that of obese patients without hypoventilation. The principal neuromuscular diseases associated with OHS are the muscular dystrophies. The progression to chronic respiratory failure results from respiratory muscle weakness and impaired airway secretion clearance, causing atelectasis and pneumonia. With a decrease of greater than 50% in respiratory muscle strength, there is a reduction in VC. Cough peak flow < 160 L/min is associated with impaired airway secretion clearance, and values near 270 L/min indicate the need for assisted cough techniques. Obstructive sleep apnea usually worsens sleep hypoventilation. Noninvasive ventilation during sleep can improve survival, symptoms, and hypoventilation during wakefulness, as well as being able to improve pulmonary function in patients with neuromuscular disease. Patients with OHS can require oxygen therapy.

Phenotypic expression in the muscular dystrophies is variable, even with the identical mutation, providing strong evidence that genetic modifiers influence outcome. To identify genetic modifier loci, we now used quantitative trait locus mapping in two differentially affected mouse strains with muscular dystrophy. Using the Sgcg model of limb girdle muscular dystrophy that lacks the dystrophin associated protein ?-sarcoglycan, we evaluated chromosomal regions that segregated with two distinct quantifiable characteristics of muscular dystrophy, membrane permeability and fibrosis. We previously identified a single major locus on murine chromosome 7 that influences both traits of membrane permeability and fibrosis in the quadriceps muscle. Using a larger cohort, we now found that this same interval strongly associated with both traits in all limb skeletal muscle groups studied including the gastrocnemius/soleus, gluteus/hamstring, and triceps muscles. In contrast, the muscles of the trunk were modified by distinct genetic loci possibly reflecting the embryological origins and physiological stressors unique to these muscle groups. A locus on chromosome 18 was identified that modified membrane permeability of the abdominal muscles, and a locus on chromosome 3 was found that regulated diaphragm and abdominal muscle fibrosis. Fibrosis in the heart associated with a region on chromosome 9, and likely reflects differential function between cardiac and skeletal muscle. These data underscore the complexity of inheritance and penetrance of single gene disorders.

We investigated the spatial and temporal expression patterns of hypoxia-inducible factor-1? (HIF-1?) during muscle regeneration and myogenesis in a C2C12 cell culture system. The expression of HIF-1? synchronized with that of myogenic regulatory genes during muscle regeneration at both the mRNA and protein levels. The HIF-1? protein was localized in the nuclei of newly formed regenerating myofibers in three different muscle injury models, including freezing, bupivacaine injection, and muscular dystrophy. In myogenic cell culture, the HIF-1? protein was localized in the nucleus and cytoplasm of the majority of myoblasts and myotubes. HIF-1? protein expression decreased concomitant with the increased expression of MyoD and myogenin proteins after the induction of myogenic differentiation. We investigated the adaptive response of myoblasts to hypoxia-like conditions induced by treatment of cobalt chloride. This treatment allowed HIF-1? to accumulate and translocate to the nucleus to activate transcription of its target genes, suggesting that myoblasts adapted to acute hypoxia-like conditions through enhancing an HIF-1-dependent pathway. Our results provide insight into the possible involvement of HIF-1? in myogenesis in vivo and in vitro.

OBJECTIVE: To investigate the expression of Akt pathway and their correlation with pathological changes in the skeletal muscle of myotonic dystrophy 1 (DM1) patients.

METHODS: We chose 7 DM1 patients who were confirmed through clinical, electrophysiological and pathological data as DM1 patients group, and 7 patients without muscle pathological change as control group. The age range of DM1 patients group was from 6 to 35 years and disease duration was from 1 to 20 years. The clinical spectrum included distal myotonia, muscle weakness and atrophy. The serum creatine kinase ranged from 271 to 1 325 U/L; Electromyography showed myopathic changes together with diffusive myotonic discharges. We performed muscle biopsies in all the patients and tested total Akt, phosphorelated Akt, phosphorelated p70s6k in skeletal muscle specimens. We compared the Akt pathway activity of DM1 patients group with that of the control group and analyzed their correlation with the ratio of muscular hypertrophy, internal nuclei and basophilic sarcoplasmic masses.

RESULTS: Skeletal muscle biopsies revealed muscular dystrophic changes accompanied by peripherally placed sarcoplasmic masses and numerous internal nuclei. Increased optical density (D) of Akt, p-Akt,p-p70s6k had been noted in DM1 patients as compared with the controls(Akt: t=4.110 ,P=0.006; p-Akt: t=4.408 ,P=0.004; p-p70s6k: t=4.113,P=0.005; p-Akt/Akt: t=4.055, P=0.002). A positive linear correlation was observed between Akt pathway activity and muscle hypertrophy proportion(Akt group:r=0.825,P=0.015; p-Akt group:r=0.914,P=0.004;p-p70s6k group:r=0.916,P=0.004). But, no correlation was observed between Akt pathway and sarcoplasmic masses or internal nuclei.

CONCLUSION: Akt signaling pathway activity increased diffusively in skeletal muscle of the DM1 patient. Such elevation might be the cause of pathological muscle hypertrophy.

This study explored the perspectives of children with disabilities regarding the concept of inclusion in physical activity. Participants were children (two girls, nine boys, Mage = 10 years, five months, age range: 8-12 years) with disabilities, including cerebral palsy, fine and gross motor delays, developmental coordination disorder, muscular dystrophy, nemaline myopathy, brachial plexus injury, and severe asthma. Children’s perspectives on inclusion in physical activity (e.g., sports, games, and play) were explored through semistructured interviews. Interviews were digitally audio taped and transcribed verbatim. Data were analyzed through content analysis. Three themes emerged from the data: gaining entry to play, feeling like a legitimate participant, and having friends. These themes were associated with feeling included to varying degrees in sports, games, and play. In essence, it was the actions of others that were the prominent features identified by children that contributed to feeling more or less included in physical activity contexts. These results are discussed in relation to inclusion in physical education, recreation, and unstructured free play.