Magnetic resonance imaging spectrum of succinate dehydrogenase–related infantile leukoencephalopathy

Abstract

Background Succinate dehydrogenase-deficient leukoencephalopathy is a complex II-related mitochondrial disorder for which the clinical phenotype, neuroimaging pattern and genetic findings have not been comprehensively reviewed. Methods 19 individuals with succinate dehydrogenase deficiency-related leukoencephalopathy were reviewed for neuroradiologic, clinical and genetic findings as part of Institutional Review Board approved studies at Children's National Health System (Washington, DC) and VU University Medical Center (Amsterdam, NL). Results All individuals had signal abnormalities in the central corticospinal tracts and spinal cord where imaging was available. Other typical findings were involvement of the cerebral hemispheric white matter with sparing of the U fibers, the corpus callosum with sparing of the outer blades, the basis pontis, middle cerebellar peduncles and cerebellar white matter, and elevated succinate on MRS. The thalamus was involved in most studies with a predilection for the anterior nucleus, pulvinar and geniculate bodies. Clinically, infantile-onset neurological regression with partial recovery and subsequent stabilization was typical. All individuals had mutations in SDHA, SDHB or SDHAF1, or proven biochemical defect. Interpretation Succinate dehydrogenase deficiency is a rare leukoencephalopathy, for which improved recognition by MRI in combination with advanced sequencing technologies allows non-invasive diagnostic confirmation. The MRI pattern is characterized by cerebral hemispheric white matter abnormalities with sparing of the U fibers, corpus callosum involvement with sparing of the outer blades, and involvement of corticospinal tracts, thalami and spinal cord. In individuals with infantile regression and this pattern of MRI abnormalities, the differential diagnosis should include succinate dehydrogenase deficiency, in particular if MRS shows elevated succinate.

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

“…Information on genetic testing of other family members was not available. Both mutations have been reported previously; c.143A>T (p.Asp48Val) has been found homozygous and compound heterozygous in patients with leukodystrophy and complex II deficiency (Alston et al 2012;Helman et al 2015), whereas the c.689G>A (p.Arg230His) mutation has been reported in heterozygous form in two patients with apparently sporadic paraganglioma/pheochromocytoma (Amar et al 2005), in a family with paraganglioma/ pheochromocytoma and renal cell cancer (Ricketts et al 2012), as well as in patients with head and neck paraganglioma (Cerecer-Gil et al 2010;Peterson et al 2014). …”

“…While heterozygous SDHB mutations are a well-known cause of familial paraganglioma/pheochromocytoma (Ricketts et al 2010), 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 (Alston et al 2012;Helman et al 2015). Here, we present two further patients with bi-allelic SDHB mutations causing complex II deficiency and a progressive neurological disease with leukoencephalopathy.…”

“…More significantly, Western blot analysis showed decreased amount of SDHB protein in patient fibroblasts. The p. Asp48Val variant has been found in six out of seven reported patients with complex II deficiency due to SDHB mutations (Alston et al 2012;Helman et al 2015), whereas the p.Arg230His variant has been reported in heterozygous form in patients with familial paraganglioma/pheochromocytoma (Amar et al 2005) and/or renal cell cancer (Ricketts et al 2012). To our knowledge, 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; previously, this has exclusively been described for the c.91C>T (p.Arg31*) variant in SDHA (Renkema et al 2015).…”

“…Brain imaging with magnetic resonance (MRI) may show affection of basal ganglia, cerebellum, brain stem, white matter, and/or cortical structures. Different patterns of MRI abnormalities can support the diagnostic process (Bricout et al 2014;Helman et al 2015). Even though involvement of the basal ganglia is a frequent and wellknown feature of mitochondrial disease, white matter involvement has been increasingly recognized in more recent patient descriptions (Wong 2012;Morato et al 2014).…”

“…Complex II-related RC deficiencies show a wide clinical spectrum including presentations with isolated myopathy/cardiomyopathy as well as severe multisystem disorders with neurological manifestations. Recently, the first patients with complex II deficiency due to bi-allelic mutations in SDHB and SDHD were described and patients presented with progressive mitochondrial encephalomyopathy (Alston et al 2012;Jackson et al 2014;Helman et al 2015).…”