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Abstract Details

Solving the Unsolved: Targeted Gene Panel Identifies SDH-Related Infantile Leukoencephalopathy
Child Neurology/Developmental Neurobiology
P02 - (-)
090
BACKGROUND: Succinate dehydrogenase assembly factor (SDHAF1) is integral in the formation of mitochondrial complex II (succinate dehydrogenase, SDH). Recent studies have elucidated a clinical phenotype of SDH-defective infantile leukoencephalopathy. This is a rare presentation of an uncommon mitochondrial disorder.
DESIGN/METHODS: This is a case series of a kindred evaluated at a multidisciplinary clinic for patients with unsolved leukoencephalopathies at Children's National Medical Center. Imaging and metabolic testing were reviewed and focused testing advised. A panel of mitochondrial nuclear DNA genes were sequenced for one patient. The SDHAF1 gene was then sequenced on unaffected parents and the other affected child.
RESULTS: A consanguineous kindred from Iraq are described in which 2 siblings are affected by SDHAF1 and there were several late gestational fetal demises. The index cases both presented with developmental regression following a minor physiologic stress at ages 1 and 3 years. In each patient, there was an initial marked loss of developmental ability followed by slow recovery of function. Motor disability continues to worsen, resulting in spasticity, scoliosis, and functional dependence. Cognitive function is also affected, but to a lesser degree. Magnetic resonance imaging reveals multifocal increased T2 signal involving the periventricular white matter, pons, and cervical spinal cord. Sequencing and deletion/duplication Genetic testing of 101 nuclear genes important for normal mitochondrial function revealed a c.3 G>A point mutation of SDHAF1, resulting in an isoleucine substitution for methionine at amino acid position 1. This substitution is predicted to be disease-causing. Both siblings were homozygous for this mutation, with each parent being heterozygous.
CONCLUSIONS: Mutations of SDHAF1 results in a recognizable clinical phenotype of SDH-related infantile leukoencephalopathy. Testing with targeted panels of genes is a successful approach in unsolved disorders.
Authors/Disclosures
John M. Taylor, MD (Cincinnati Children'S Hospital Medical Center)
PRESENTER 		Dr. Taylor has received personal compensation for serving as an employee of Cincinnati Children's Hospital Medical Center. Dr. Taylor has received personal compensation in the range of $10,000-$49,999 for serving as an Expert Witness for John Michael Taylor, Forensic Medical Consulting. The institution of Dr. Taylor has received research support from NINDS. The institution of Dr. Taylor has received research support from StrokeNet.
No disclosure on file
Robert C. Griggs, MD, FAAN (University of Rochester Department of Neurology) Dr. Griggs has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Strongbridge Pharmaceuticals. Dr. Griggs has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Idera Pharmaceuticals. Dr. Griggs has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Solid Biopharma. Dr. Griggs has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Santhera Pharmaceuticals. Dr. Griggs has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Elsevier. Dr. Griggs has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Lippincott. The institution of Dr. Griggs has received research support from PTC Pharmaceuticals. The institution of Dr. Griggs has received research support from Sarepta Pharmaceuticals. The institution of Dr. Griggs has received research support from National Institutes of Health. The institution of Dr. Griggs has received research support from Santhere Pharmaceuticals. Dr. Griggs has received personal compensation in the range of $500-$4,999 for serving as a Study section member with National Institutes of Health. Dr. Griggs has a non-compensated relationship as a Board of Directors;Chair Research Advisory Committee with American Brain Foundation that is relevant to AAN interests or activities.
Guy T. Helman No disclosure on file
No disclosure on file
No disclosure on file
No disclosure on file
No disclosure on file
No disclosure on file
Adeline Vanderver, MD, FAAN (Children'S Hospital of Philadelphia) An immediate family member of Dr. Vanderver has received personal compensation for serving as an employee of Maryland Physician Care. The institution of Dr. Vanderver has received research support from Takeda. The institution of Dr. Vanderver has received research support from Passage Bio. The institution of Dr. Vanderver has received research support from Homology. The institution of Dr. Vanderver has received research support from Eli Lilly. The institution of Dr. Vanderver has received research support from Myrtelle. The institution of Dr. Vanderver has received research support from SynaptixBio. The institution of Dr. Vanderver has received research support from PMD Foundation. The institution of Dr. Vanderver has received research support from Ionis. The institution of Dr. Vanderver has received research support from ISD . The institution of Dr. Vanderver has received research support from Boehringer-Ingelheim. The institution of Dr. Vanderver has received research support from Biogen. The institution of Dr. Vanderver has received research support from Sana. The institution of Dr. Vanderver has received research support from Affinia. The institution of Dr. Vanderver has received research support from BridgeBio. The institution of Dr. Vanderver has received research support from Orchard. The institution of Dr. Vanderver has received research support from Minoryx. The institution of Dr. Vanderver has received research support from Forge Biologics. The institution of Dr. Vanderver has received research support from Vigil. Dr. Vanderver has received intellectual property interests from a discovery or technology relating to health care. Dr. Vanderver has received intellectual property interests from a discovery or technology relating to health care.
Olga Ciccarelli, MD, PhD, FRCP (UCL Institute of Neurology) Prof. Ciccarelli has received personal compensation in the range of $0-$499 for serving as a Consultant for Lundebeck. Prof. Ciccarelli has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. Prof. Ciccarelli has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Prof. Ciccarelli has received personal compensation in the range of $0-$499 for serving on a Speakers Bureau for Merck. Prof. Ciccarelli has received personal compensation in the range of $10,000-$49,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for NEUROLOGY Journal.