Towards the molecular elucidation of congenital myasthenic syndromes: identification of mutations in MuSK.

Congenital myasthenic syndromes (CMS) are rare genetic diseases affecting the neuromuscular junction (NMJ) and characterized by a dysfunction of the neurotransmission. They are heterogeneous at the pathophysiological level and can be classified in three categories according to their origin: presynaptic, synaptic or postsynaptic. The strategy for the diagnosis and characterization of CMS relies on the clinic, EMG, muscle biopsy, identification of mutations in genes known to be responsible for CMS and the demonstration that the gene mutations are the cause of the disease by using experimental approaches. As an example of such strategy, we report briefly here the characterization of the first case of a human neuromuscular transmission dysfunction due to mutations in the gene encoding a postsynaptic molecule, the muscle-specific receptor tyrosine kinase (MuSK). Gene analysis identified two heteroallelic mutations, a frameshift mutation (c.220insC) and a missense mutation (V790M). The muscle biopsy showed marked pre- and postsynaptic structural abnormalities of the neuromuscular junction as well as a severe decrease in acetylcholine receptor epsilon-subunit and MuSK expression. In vitro and in vivo expression experiments were performed using mutant MuSK reproducing the human mutations. The results obtained strongly suggested that the missense mutation, in the presence of a null mutation on the other allele, was responsible for the severe synaptic changes observed in the patient and, hence, is causing the disease. However the molecular origin of a large number of CMS is still unknown. There are hundreds of molecules known to be present at the NMJ and mutations in the genes coding for these synaptic molecules are likely to be responsible for a neuromuscular block.

[Betamethasone in the prevention of respiratory distress syndrome. Results of 6 years' experience (author's transl)]. / Prévention de la maladie des membranes hyalines par bétaméthasone. Bilan de six années d'utilisation.

The purpose of this study was to find out whether the administration of corticosteroids to mothers with threatening premature labour reduced the risk of respiratory distress syndrome (RDS) in premature babies. Between XOU4 and 1979, the mothers of 62 children received 4 doses of a long-acting betamethasone preparation intramuscularly at 12-hour intervals followed, if required by 2 booster doses 15 days later. Salbutamol injections were sometimes given to delay labour. During the same period, the mothers of 81 other children (control group) with unavoidable premature delivery were left untreated. The incidence of RDS was similar in both groups. A study of the various factors likely to modify the incidence of RDS showed the same lack of effectiveness of the treatment. Neonatal mortality and morbidity did not appear to be altered.