Guy Helman1,2, Ljubica Caldovic2, Matthew T Whitehead3, Cas Simons4, Knut Brockmann5, Simon Edvardson6, Renkui Bai7, Isabella Moroni8, J Michael Taylor9, Keith Van Haren10, Ryan J Taft4,11,12, Adeline Vanderver1,2,12, Marjo S van der Knaap13,14. 1. Department of Neurology, Children's National Health System, Washington, DC. 2. Center for Genetic Medicine Research, Children's National Health System, Washington, DC. 3. Department of Neuroradiology, Children's National Health System, Washington, DC. 4. Institute for Molecular Bioscience, University of Queensland, St Lucia, Queensland, Australia. 5. Department of Pediatrics and Pediatric Neurology, Georg-August University, Göttingen, Germany. 6. Neuropediatric Unit, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. 7. GeneDX, Gaithersburg, MD. 8. Child Neurology Unit, Foundation "Carlo Besta" Institute of Neurology-Institute of Hospitalization and Scientific Care, Milan, Italy. 9. Division of Neurology, Cincinnati Children's Hospital, Cincinnati, OH. 10. Department of Neurology, Lucile Packard Children's Hospital and Stanford University School of Medicine, Stanford, CA. 11. Illumina, San Diego, CA. 12. School of Medicine and Health Sciences, George Washington University, Washington, DC. 13. Department of Child Neurology, VU University Medical Center, Amsterdam, The Netherlands. 14. Department of Functional Genomics, Neuroscience Campus Amsterdam, Amsterdam, The Netherlands.
Abstract
OBJECTIVE: 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: Nineteen individuals with succinate dehydrogenase deficiency-related leukoencephalopathy were reviewed for neuroradiological, 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, the Netherlands). 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 magnetic resonance spectroscopy (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 magnetic resonance imaging (MRI) in combination with advanced sequencing technologies allows noninvasive 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.
OBJECTIVE:Succinatedehydrogenase-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: Nineteen individuals with succinate dehydrogenasedeficiency-related leukoencephalopathy were reviewed for neuroradiological, 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, the Netherlands). 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 magnetic resonance spectroscopy (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:Succinatedehydrogenase deficiency is a rare leukoencephalopathy, for which improved recognition by magnetic resonance imaging (MRI) in combination with advanced sequencing technologies allows noninvasive 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 succinatedehydrogenase deficiency, in particular if MRS shows elevated succinate.
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