Here we present evidence that the principle of disturbed ER processing represents a more general concept in ECM disorders. We report on six patients with a novel congenital myopathy Ehlers-Danlos overlap syndrome caused by autosomal-recessive mutations in an ER enzyme. Key clinical features include severe muscular hypotonia at birth, delayed motor development, muscular weakness, severe progressive scoliosis, joint hypermobility, sensorineural deafness, and normal intelligence. The candidate gene was identified by linkage analysis; truncating mutations were detected in all patients. The protein localises to the ER and is predicted to function as a protein folding catalyst. Western blot analysis and immunocytochemistry of cultivated fibroblasts of patients showed reduced amounts and/or disturbed organization of fibronectin and other ECM proteins. Deficient protein processing in the ER may not only cause autosomal recessive osteogenesis imperfecta but also other ECM disorders. Mutations in hydroxymethylbilane synthase (HMBS), the third enzyme of the haem synthesis, may induce acute intermittent porphyria (AIP). The molecular basis of the disease remains unclear and valuable information about phenotype-genotype correlations can be obtained by functional studies on the wild-type (wt) and mutants. Five mutations selected for this study (R116W, K132N, R167W, R173Wand V215E) represent: i) mutations around the active site and/or interfering with binding of the dipyrromethane-cofactor, expected to have catalytic, misfolding and/or destabilization effects and ii) mutations far from the active site predicted to affect overall folding and flexibility. Characterization of K132N and V215E has not been reported previously. We have characterized the steady-state kinetic parameters of the mutants comparative to the wt, and investigated the conformational stability by fluorescence and circular dichroism. K132N and V215E possess 87% and 54% activity, respectively, compared to wt. R116W and R167W show activity <20%, while R173W shows no activity, as expected from previous reports. Wt-HMBS shows a high thermostability (Tm=79°C). K132N, R167W and V215E reveal a wt-like conformation and stability, whereas R116W and R173W show decreased thermostability (Tm=54°C). These results together with on-going investigations will provide insights in the pathogenic mechanisms in AIP and help selecting potential therapeutic strategies.