Leukoencephalopathy due to Complex II Deficiency and Bi-Allelic SDHB Mutations: Further Cases and Implications for Genetic Counselling

Abstract

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.

Genotype–phenotype associations in PPGLs in 59 patients with variants in SDHX genes

“…In family B2, no heterozygous individual with a class 5 missense variant (c.769C>G, p.Leu257Val) in exon 8 of the SDHB gene has as yet developed PPGLs. Literature, however, suggests an increased risk (20), indicating a low penetrance for this specific variant. The homozygous proband's clinical course supports the international recommendation that sequencing of SDHB, -D, and possibly -C should be performed in patients suspected for or diagnosed with multisystem mitochondrial disorder and complex II deficiency (20).…”

“…Clinical characteristics, biochemistry, and imaging results at the time of PPGL diagnosis were extracted and validated by a second observer (senior clinician). One patient had previously been described (20).…”

Genetic testing and surveillance guidelines in hereditary pheochromocytoma and paraganglioma

“…However, there are to our knowledge no such cases reported in the literature. This is probably due to the reduced penetrance for PPGL as in at least two cases, the healthy parents harboured a pathogenic variant in SDHA or SDHB known to cause PPGL .…”

Loss of sdhb in zebrafish larvae recapitulates human paraganglioma characteristics

“…Zebrafish embryos hatch externally to the mother and use maternal proteins in yolk to go through early developmental phases and this may explain why homozygous sdhb mutant zebrafish are viable, whereas Sdhb knock-out mice do not (Despic & Neugebauer 2018). In humans, bi-allelic mutations in SDHB result in Leigh-syndrome-like phenotype with largely impaired complex-II activity resulting in severe and progressive neurogeneration and myopathy with onset in infancy and poor prognosis (Alston et al 2012, Gronborg et al 2016. The lifespan of these patients usually varies between 1 and 5 years.…”

“…In humans, homozygous or compound heterozygous SDH germline mutations, causing isolated complex 2 deficiencies, lead to congenital hypotonia and leukoencephalopathy and are often lethal (Alston et al 2012, Gronborg et al 2016. Isolated deficiency of complex 2 is a rare condition, accounting for an estimated 2% of respiratory chain deficiencies (Briere et al 2005).…”