Résumé :
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Distal arthrogryposis (DA) is a subgroup of arthrogryposis multiplex congenita (AMC) characterized by multiple congenital joint limitations. Using a pangenomic approach in 2 consanguineous families with DA, we identified a common morbid locus that mapped to chromosome 2q37 and harbored the Endothelin Converting Enzyme Like 1 (ECEL1) gene. We screened a panel of 20 DA families and identified 7 different mutations in six families. All mutations resulted either in the absence of the protein or into the synthesis of a non-functional protein, suggesting a loss of function mechanism. ECEL1 encodes a neuronal endopeptidase expressed in the peripheral (PNS) and central nervous system during fetal life and plays a major role in intramuscular branching of motoneurons in skeletal muscle. Patients presented with a homogeneous phenotype characterized by limited knee flexion, flexed third to fifth fingers and relatively spared index finger, severe muscle atrophy in lower limbs and tongue. Muscle imaging showed a recognizable pattern of the thigh muscles. No dysfunction of the neuromuscular transmission was evidenced. On the whole, clinical features point towards a disorder involving the PNS. A developmental dysfunction is suggested by the predominantly prenatal expression of ECEL1, the non-progressive course of the disease and K.O. mouse data.
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