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Neurology 2003;61:648-654
© 2003 American Academy of Neurology

Membrane phospholipids and high-energy metabolites in childhood ataxia with CNS hypomyelination

S. Blüml, PhD, M. Philippart, MD, R. Schiffmann, MD, K. Seymour, PhD and B. D. Ross, MD

From the Magnetic Resonance Spectroscopy Unit (Drs. Blüml, Seymour, and Ross), Huntington Medical Research Institutes, Pasadena, CA; Rudi Schulte Research Institute (Drs. Blüml, Seymour, and Ross), Santa Barbara, CA; Brain Research Institute (Dr. Philippart), University of California, Los Angeles, CA; and Developmental and Metabolic Neurology Branch (Dr. Schiffmann), National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD.

Address correspondence and reprint requests to Dr. Brian D. Ross, Huntington Medical Research Institutes, 660 South Fair Oaks Avenue, Pasadena, CA 91105; e-mail: mrs{at}hmri.org

Background: Childhood ataxia with CNS hypomyelination (CACH) is a leukodystrophy with extreme rarefaction of white matter caused by mutations in one of the five subunits of the translation initiation factor 2B (eIF2B).

Methods: Seven children with this disease and nine age-matched control subjects were studied with proton-decoupled phosphorus magnetic resonance (MR) spectroscopy.

Results: In patients with CACH, cerebral concentrations of high-energy phosphate metabolites were abnormal. Of the metabolites involved in biosynthesis and catabolism of membrane phospholipids, glycerophosphorylethanolamine was reduced (0.24 ± 0.18 mmol/kg brain vs 0.44 ± 0.14; p < 0.02), and phosphorylethanolamine was increased (2.32 ± 0.53 vs 1.53 ± 0.22; p < 0.01), whereas the choline-containing phosphorylated metabolites were unchanged. Nucleoside triphosphate (NTP) was reduced (2.44 ± 0.34 mmol/kg brain tissue vs 3.09 ± 0.58; p < 0.01), phosphocreatine was elevated (4.11 ± 0.63 vs 3.27 ± 0.33; p < 0.01), and inorganic phosphate was reduced (0.77 ± 0.32 vs 1.06 ± 0.26; p < 0.05). Intracellular pH was elevated in patients (7.03 ± 0.04 vs 6.99 ± 0.02; p < 0.02).

Conclusions: The authors found an altered energy state of the residual cell population investigated. Together with previously identified replacement of white matter by CSF, the present findings raise the possibility that the genetic defect in eIF2B may result in impairment of myelin membrane synthesis or myelin membrane transport in the in vivo CACH brain. Ethanolamine metabolites constitute the plasmalogens, and the present findings may include a defect in plasmalogen metabolism.






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