Abstract Details

Title A Novel Mutation in the Mitochondrial DNA Cytochrome B Gene (MTCYB) in a Patient with Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke like Episodes Syndrome

Topic Child Neurology/Developmental Neurobiology

Presentation(s) P02 - (-)

Poster/Presentation
Number 088

Objective

Background BACKGROUND: Isolated mitochondrial complex III deficiency is a rare cause of respiratory chain dysfunction. It can be due to mutations in the nuclear genome or in MTCYB. Mutations in MTCYB have been commonly associated with isolated mitochondrial myopathy and exercise intolerance, rarely with multisystem disorders, and only once with a parkinsonism/MELAS overlap syndrome.

Design/Methods DESIGN/METHODS: Clinical data were collected. Muscle histochemical and biochemical analysis was performed. The most common MELAS mutations of the mtDNA were screened by restriction fragment length polymorphism (RFLP) analysis. Quantitative PCR was performed to detect any mtDNA depletion. The 22 mt tRNA, MTND1-6 genes and MTCYB gene were sequenced. Mutation load was assessed by RFLP analysis.

Results RESULTS: A 15-year-old girl presented with a history of migraines, epilepsy, sensorimotor neuropathy, strokelike episodes, and lactic acidosis, a clinical picture reminiscent of MELAS. Cytochrome c oxidase and succinate dehydrogenase stainings in muscle showed increased subsarcolemmal reactivity. Biochemistry revealed mild complex I and complex III deficiencies in muscle. Genetic tests were negative for the common MELAS mtDNA mutations, no depletion of mitochondrial DNA was detected, and direct sequencing of all 22 transfer RNAs and the ND1-6 genes did not detect any pathogenic mutations. Sequencing of the MTCYB gene revealed a novel m.14864T>C transition. The mutation, which changes a highly conserved cysteine to arginine at amino acid position 40 of cytochrome b, was heteroplasmic in muscle (39%), blood (32%), fibroblasts (42%), and urinary sediment (57%) from the patient but absent in her asymptomatic mother.

Conclusions CONCLUSIONS: This case demonstrates that MTCYB must be included in the already long list of mitochondrial DNA genes that have been associated with the MELAS phenotype.

Authors/Disclosures
Valentina Emmanuele, MD, PhD (NYP at CUIMC) PRESENTER	Dr. Emmanuele has nothing to disclose.
Evangelia Sotiriou, MD	No disclosure on file
Purificacion Gutierrez Rios, PhD (Columbia University)	No disclosure on file
	No disclosure on file
Rebecca N. Ichord, MD (Perelman School of Medicine of the Univ of Pennsylvania)	No disclosure on file
	No disclosure on file
Orhan H. Akman, PhD (Columbia University Medical Center)	No disclosure on file
Michael S. Okun, MD, FAAN (University of Florida)	Dr. Okun has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for NIH. Dr. Okun has received personal compensation in the range of $10,000-$49,999 for serving as an officer or member of the Board of Directors for Parkinson's Foundation. Dr. Okun has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for JAMA Neurology. Dr. Okun has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for NEJM Journal Watch. The institution of Dr. Okun has received research support from NIH. The institution of Dr. Okun has received research support from Parkinson's Foundation. The institution of Dr. Okun has received research support from Tourette Association of America. The institution of Dr. Okun has received research support from Michael J Fox. Dr. Okun has received publishing royalties from a publication relating to health care.
	No disclosure on file

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