Schimke immuno osseous dysplasia: pathophysiological investigations

Objectives: Neurologic symptoms -besides spondyloepiphyseal dysplasia, nephropathy and immunopathy – are frequent findings in Schimke immuno osseous dysplasia (SIOD, MIM 242900, defect in SMARCAL 1). Recently we could show, that premature vasoocclusive processes are a life-limiting feature of severe SIOD with vasoocclusion not being secondary to renal disease. There is evidence for local endothelial factors causing vasoocclusion; disorders in the metabolism of nitric oxide (NO) or in energy supply via mitochondrial respiratory chain complexes may be such underlying causes.

Material and Methods: In 7 SIOD-patients we determined parameters of NO-metabolism: ADMA, an endogenous inhibitor of the NO-synthase, was measured using GC-tandem-MS in plasma and urine, while concentrations of nitrate and nitrite were determined using GC/MS. As for mitochondrial parameters we spectrophotometrically measured the activities of respiratory chain complexes I-V in fibroblasts of SIOD patients and determined the concentrations of lactate, pyruvate, ketone bodies and amino acids in plasma as well as organic acids in urine. In SIOD-siblings with the same genotype we tried to elucidate a genotype- phenotype correlation.

Results: Compared with healthy controls we did not find a significant difference either in the parameters of NO-metabolism or in mitochondrial function. We could show that neither clinical nor genetic features of SIOD are predictive for appearance of neurologic symptoms in SIOD.

Conclusions: Vasoocclusive processes are a life-limiting feature in SIOD. Neither NO-metabolism nor mitochondrial function seem to be involved in the pathophysiology of the disease. Epigenetic mechanisms may have an important role in SIOD. The pathophysiology of SIOD remains unclear.