Hydrops foetalis als mogelijk gevolg van erfelijke stofwisselingsziekten.

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Spondyloepiphyseal dysplasia, Omani type: Further definition of the phenotype

Spondyloepiphyseal dysplasia (SED), Omani type (OMIM 608637) is a recessively inherited skeletal dysplasia previously described in two distantly related families from the Republic of Oman. The phenotype consists of short stature, severe kyphoscoliosis, arthritic joints (elbows, wrists, knees), secondary large joint dislocations, rhizomelia, fusion of carpal bones and mild brachydactyly. Affected individuals were homozygous for a missense mutation, R304Q in CHST3 that encodes the enzyme chondroitin 6-O-sulfotransferase-1 (C6ST-1). This enzyme mediates the sulfation of proteoglycans, particularly chondroitin sulfate (CS), in the extracellular matrix of cartilage. Here we describe the identification of a mutation (857T > C predicting the substitution L286P) in CHST3 in a Turkish family and extend the clinical phenotype of SED-Omani type to include congenital joint dislocation, club feet, ventricular septal defect, deafness, metacarpal shortening and accessory carpal ossification centers. Fibroblasts and urine obtained from affected patients demonstrated negligible levels of 6-O-sulfated GalNAc residue in CS. Furthermore, the 6-O-sulfotransferase activity of cloned C6ST-1 into which the L286P mutation had been introduced was dramatically reduced, confirming the pathogenicity of this substitution. These results indicate that the clinical consequences of a deficiency of 6-O-sulfation in CS can be varied and that a clinical spectrum may exist similar to that seen in other skeletal dysplasias characterized by disorders of proteoglycan sulfatio

Identification of a Dutch founder mutation in MUSK causing fetal akinesia deformation sequence.

Fetal akinesia deformation sequence (FADS) refers to a clinically and genetically heterogeneous group of disorders with congenital malformations related to impaired fetal movement. FADS can result from mutations in CHRNG, CHRNA1, CHRND, DOK7 and RAPSN; however, these genes only account for a minority of cases. Here we identify MUSK as a novel cause of lethal FADS. Fourteen affected fetuses from a Dutch genetic isolate were traced back to common ancestors 11 generations ago. Homozygosity mapping in two fetuses revealed MUSK as a candidate gene. All tested cases carried an identical homozygous variant c.1724T>C; p.(Ile575Thr) in the intracellular domain of MUSK. The carrier frequency in the genetic isolate was 8%, exclusively found in heterozygous carriers. Consistent with the established role of MUSK as a tyrosine kinase that orchestrates neuromuscular synaptogenesis, the fetal myopathy was accompanied by impaired acetylcholine receptor clustering and reduced tyrosine kinase activity at motor nerve endings. A functional assay in myocytes derived from human fetuses confirmed that the variant blocks MUSK-dependent motor endplate formation. Taken together, the results strongly support a causal role of this founder mutation in MUSK, further expanding the gene set associated with FADS and offering new opportunities for prenatal genetic testing