JIMD Reports, Volume 33

Grønborg, Sabine, Darin, Niklas, Miranda, Maria J, Damgaard, Bodil, Cayuela, Jorge Asin, Oldfors, Anders, Kollberg, Gittan, Hansen, Thomas V O, Ravn, Kirstine, Wibrand, Flemming, Østergaard, Elsebet, Sabine Grønborg, Niklas Darin, Maria J. Miranda, Bodil Damgaard, Jorge Asin Cayuela, Anders Oldfors, Gittan Kollberg, Thomas V. O. Hansen, Kirstine Ravn, Flemming Wibrand, Elsebet Østergaard, Miranda, Maria J., Hansen, Thomas V. O.

Isolated complex II deficiency is a rare cause of mitochondrial disease and bi-allelic mutations in SDHB have been identified in only a few patients with complex II deficiency and a progressive neurological phenotype with onset in infancy. On the other hand, heterozygous SDHB mutations are a well-known cause of familial paraganglioma/pheochromocytoma and renal cell cancer. Here, we describe two additional patients with respiratory chain deficiency due to bi-allelic SDHB mutations. The patients' clinical, neuroradiological, and biochemical phenotype is discussed according to current knowledge on complex II and SDHB deficiency and is well in line with previously described cases, thus confirming the specific neuroradiological presentation of complex II deficiency that recently has emerged. The patients' genotype revealed one novel SDHB mutation, and one SDHB mutation, which previously has been described in heterozygous form in patients with familial paraganglioma/pheochromocytoma and/or renal cell cancer. This is only the second example in the literature where one specific SDHx mutation is associated with both recessive mitochondrial disease in one patient and familial paraganglioma/pheochromocytoma in others. Due to uncertainties regarding penetrance of different heterozygous SDHB mutations, we argue that all heterozygous SDHB mutation carriers identified in relation to SDHB-related leukoencephalopathy should be referred to relevant surveillance programs for paraganglioma/pheochromocytoma and renal cell cancer. The diagnosis of complex II deficiency due to SDHB mutations therefore raises implications for genetic counselling that go beyond the recurrence risk in the family according to an autosomal recessive inheritance.