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.

Keywords: Complex II; Familial paraganglioma/pheochromocytoma; Leukoencephalopathy; SDH; SDHB.

Fig. 1

Pedigree of the family of patient 1 (arrow). Affected family members are shown with filled symbols, and heterozygotes for the p.Leu257Val variant are shown with half-filled symbols

Fig. 2

Magnetic resonance imaging (MRI) of patient 1 (a–h) at 15 months of age and patient 2 (i–n) at 10 months of age including T2-weighted (T2W) (a–e; i–k, n) and diffusion-weighted (DWI) (f–h; l, m) imaging. MRI of patient 1 demonstrates increased T2W signal intensity involving frontal, parietooccipital, and posterior temporal white matter sparing juxtacortical fibers (a–c), lateral geniculate bodies (b), corpus callosum with sparing of the inner and outer blades (c), middle cerebellar peduncles, corticospinal tracts in the anterior pons (d, e), and extensive involvement of the cervical medulla (e). Diffusion restriction is demonstrated in the periventricular white matter and corpus callosum (f), and particularly evident in the lateral geniculate bodies (g). Minimal changes are seen in the thalamic pulvinar (h) and bilateral ventral nuclei (f). MRI of patient 2 likewise reveals extensive T2 hyperintensities involving frontal, parietooccipital, and posterior temporal white matter with sparing of the juxtacortical fibers (i, k). T2 hyperintensity and restricted diffusion of the bilateral pulvinar and ventral thalamic nuclei (i, l) was prominent. Infratentorially, the pons including crossing fibers, middle cerebellar peduncles, and deep white matter of the cerebellar hemispheres (j, k) as well as medullary pyramids and central cervical medulla (n) are affected. Decreased diffusivity is demonstrated in the dorsal pons and cerebellar peduncles (m). (o) shows ¹H MR spectroscopy with short echo time and voxel of interest placed over centrum semiovale with an abnormal succinate peak at 2.4 ppm detected in patient 2

Fig. 3

Muscle histology, sequence analysis, and Western blot analysis in patients with SDHB mutations. (a) Muscle histology of patient 2: Muscle biopsy of the vastus lateralis muscle at age 1 year demonstrated reduced histochemical activity of succinate dehydrogenase (SDH) (I) compared to an age-matched control (II). Electron microscopy (III) demonstrated a few lipid droplets (L), some enlarged mitochondria with partly disrupted cristae (arrows), and abundant glycogen between the myofibrils. (b) DNA sequence analysis of SDHB in patient 1 indicates the position of homozygous missense mutation c.769C>G (p.Leu257Val) (top) compared to wild-type sequence in a control individual (bottom). (c) Alignment of a relevant stretch of amino acid sequence of SDHB in different species shows that leucine 257 (black rectangle) is evolutionary conserved. (d) Immunoblot analysis of fibroblast cells from patient 1, patient 2, and three controls with antibodies against SDHA, SDHB, and porin as loading control reveals reduced amount of SDHB and a lesser extent of SDHA in both patients