title: Progressive cerebral vascular degeneration with mitochondrial encephalopathy.
abstract: MELAS (mitochondrial encephalopathy with lactic acidosis and stroke-like episodes) is a maternally inherited disorder characterized by recurrent cerebral infarctions that do not conform to discreet vascular territories. Here we report on a patient who presented at 7 years of age with loss of consciousness and severe metabolic acidosis following vomiting and dehydration. She developed progressive sensorineural hearing loss, myopathy, ptosis, short stature, and mild developmental delays after normal early development. Biochemical testing identified metabolites characteristic of medium-chain acyl-CoA dehydrogenase (MCAD) deficiency (hexanoylglycine and suberylglycine), but also severe lactic acidemia (10-25 mM) and, in urine, excess of lactic acid, intermediates of the citric cycle, and marked ketonuria, suggesting mitochondrial dysfunction. She progressed rapidly to develop temporary cortical blindness. Brain imaging indicated generalized atrophy, more marked on the left side, in addition to white matter alterations consistent with a mitochondrial disorder. Magnetic resonance angiography indicated occlusion of the left cerebral artery with development of collateral circulation (Moyamoya syndrome). This process worsened over time to involve the other side of the brain. A muscle biopsy indicated the presence of numerous ragged red fibers. Molecular testing confirmed compound heterozygosity for the common mutation in the MCAD gene (985A>G) and a second pathogenic mutation (233T>C). MtDNA testing indicated that the muscle was almost homoplasmic for the 3243A>T mutation in tRNALeu, with a lower mutant load (about 50% heteroplasmy) in blood and skin fibroblasts. These results indicate that mitochondrial disorders may be associated with severe vascular disease resulting in Moyamoya syndrome. The contribution of the concomitant MCAD deficiency to the development of the phenotype in this case is unclear.
authors.affiliation: Department of Pediatrics, Division of Medical Genetics, University of Utah Health Sciences Center, Salt Lake City, Utah 84132, USA. nicola.longo@hsc.utah.edu
authors.forename: Nicola
authors.initials: N
authors.lastname: Longo
authors.forename: Iris
authors.initials: I
authors.lastname: Schrijver
authors.forename: Hannes
authors.initials: H
authors.lastname: Vogel
authors.forename: Lynn M
authors.initials: LM
authors.lastname: Pique
authors.forename: Tina M
authors.initials: TM
authors.lastname: Cowan
authors.forename: Marzia
authors.initials: M
authors.lastname: Pasquali
authors.forename: Gary K
authors.initials: GK
authors.lastname: Steinberg
authors.forename: Gary L
authors.initials: GL
authors.lastname: Hedlund
authors.forename: Sharon L
authors.initials: SL
authors.lastname: Ernst
authors.forename: Renata C
authors.initials: RC
authors.lastname: Gallagher
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Enns
mesh_terms: D042964:Acyl-CoA Dehydrogenase / Q000172:deficiency / Q000235:genetics; D001921:Brain / Q000098:blood supply* / Q000503:physiopathology*; D002560:Cerebrovascular Circulation; D002648:Child; D005260:Female; D006801:Humans; D017241:MELAS Syndrome / Q000235:genetics*; D018810:Magnetic Resonance Angiography; D017354:Point Mutation; D012356:RNA, Transfer, Leu / Q000235:genetics
chemical_list: D012356:RNA, Transfer, Leu; D042964:Acyl-CoA Dehydrogenase