Loss-of-Function Mutations in LGI4, a Secreted Ligand Involved in Schwann Cell Myelination, Are Responsible for Arthrogryposis Multiplex Congenita.

Arthrogryposis multiplex congenita (AMC) is a developmental condition characterized by multiple joint contractures resulting from reduced or absent fetal movements. Through genetic mapping of disease loci and whole-exome sequencing in four unrelated multiplex families presenting with severe AMC, we identified biallelic loss-of-function mutations in LGI4 (leucine-rich glioma-inactivated 4). LGI4 is a ligand secreted by Schwann cells that regulates peripheral nerve myelination via its cognate receptor ADAM22 expressed by neurons. Immunolabeling experiments and transmission electron microscopy of the sciatic nerve from one of the affected individuals revealed a lack of myelin. Functional tests using affected individual-derived iPSCs showed that these germline mutations caused aberrant splicing of the endogenous LGI4 transcript and in a cell-based assay impaired the secretion of truncated LGI4 protein. This is consistent with previous studies reporting arthrogryposis in Lgi4-deficient mice due to peripheral hypomyelination. This study adds to the recent reports implicating defective axoglial function as a key cause of AMC.

The Clinical Outcome Study for dysferlinopathy: An international multicenter study.

OBJECTIVE: To describe the baseline clinical and functional characteristics of an international cohort of 193 patients with dysferlinopathy. METHODS: The Clinical Outcome Study for dysferlinopathy (COS) is an international multicenter study of this disease, evaluating patients with genetically confirmed dysferlinopathy over 3 years. We present a cross-sectional analysis of 193 patients derived from their baseline clinical and functional assessments. RESULTS: There is a high degree of variability in disease onset, pattern of weakness, and rate of progression. No factor, such as mutation class, protein expression, or age at onset, accounted for this variability. Among patients with clinical diagnoses of Miyoshi myopathy or limb-girdle muscular dystrophy, clinical presentation and examination was not strikingly different. Respiratory impairment and cardiac dysfunction were observed in a minority of patients. A substantial delay in diagnosis was previously common but has been steadily reducing, suggesting increasing awareness of dysferlinopathies. CONCLUSIONS: These findings highlight crucial issues to be addressed for both optimizing clinical care and planning therapeutic trials in dysferlinopathy. This ongoing longitudinal study will provide an opportunity to further understand patterns and variability in disease progression and form the basis for trial design.

CINRG pilot trial of coenzyme Q10 in steroid-treated Duchenne muscular dystrophy.

INTRODUCTION: Corticosteroid treatment slows disease progression and is the standard of care for Duchenne muscular dystrophy (DMD). Coenzyme Q10 (CoQ10) is a potent antioxidant that may improve function in dystrophin-deficient muscle. METHODS: We performed an open-label, "add-on" pilot study of CoQ10 in thirteen 5-10-year-old DMD patients on steroids. The primary outcome measure was the total quantitative muscle testing (QMT) score. RESULTS: Twelve of 16 children (mean age 8.03 ± 1.64 years) completed the trial. Target serum levels of CoQ10 (≥2.5 µg/ml) were shown to be subject- and administration-dependent. Nine of 12 subjects showed an increase in total QMT score. Overall, CoQ10 treatment resulted in an 8.5% increase in muscle strength (P = 0.03). CONCLUSIONS: Addition of CoQ10 to prednisone therapy in DMD patients resulted in an increase in muscle strength. These results warrant a larger, controlled trial of CoQ10 in DMD.

Limb-girdle and congenital muscular dystrophies: current diagnostics, management, and emerging technologies.

The muscular dystrophies show muscle degeneration and regeneration (necrotizing myopathy) on muscle biopsy, typically associated with elevated serum creatine kinase, and muscle weakness. In 1986, the first causative gene was identified for the most prevalent and best-characterized form of muscular dystrophy, Duchenne muscular dystrophy. Over the past 25 years, the number of other genes determined to cause different subtypes has grown rapidly. This review gives a synopsis of the 45 genetically defined types of muscular dystrophies and describes the clinical, pathologic, and molecular aspects of each disease. DNA diagnosis remains the most sensitive and specific method for differential diagnosis, but molecular diagnostics can be expensive and complex (because of multiple genes at multiple testing facilities) and reimbursement may be challenging to obtain. However, emerging DNA sequencing technologies (eg, single-molecule third-generation sequencing units) promise to dramatically reduce the complexity and costs of DNA diagnostics. Treatment for nearly all forms remains supportive and is aimed at preventing complications. However, several promising approaches have entered clinical trials, providing tangible hope that quality of life will improve for many patients in the near future.