Reduced brain choline in homocystinuria due to remethylation defects This information is current as of January 30, 2009http://www.neurology.org/cgi/content/full/71/1/44 located on the World Wide Web at:The online version of this article, along with updated information and services, is Objective:To investigate whether secondary impairment of the transmethylation pathway is a mechanism underlying the neurologic involvement in homocystinuria due to remethylation defects.Methods: Twelve patients with neurologic disease due to remethylation defects were examined by brain magnetic resonance spectroscopic imaging ( 1 H MRSI). Brain N-acetylaspartate, cholinecontaining compounds (Cho), and creatine (Cr) were quantified and compared to with controls. Metabolites of remethylation cycle and creatine biosynthesis pathway were measured in plasma and urine.Results: MRSI revealed isolated Cho deficiency in all regions examined (mean concentration units Ϯ SD, patients vs controls): frontal white matter (0.051 Ϯ 0.010 vs 0.064 Ϯ 0.010; p ϭ 0.001), lenticular nucleus (0.056 Ϯ 0.011 vs 0.069 Ϯ 0.009; p Ͻ 0.001), and thalamus (0.063 Ϯ 0.010 vs 0.071 Ϯ 0.007; p ϭ 0.006). In contrast to controls, the Cho/Cr ratio decreased with age in patients in the three brain regions examined. Low creatine urinary excretion (p Ͻ 0.005), normal urine and plasma guanidinoacetate, and a paradoxical increase in plasma S-adenosylmethionine (p Ͻ 0.005) concentrations were observed. Conclusion:Patients with homocystinuria due to remethylation defects have an isolated brain choline deficiency, probably secondary to depletion of labile methyl groups produced by the transmethylation pathway. Although biochemical studies suggest mild peripheral creatine deficiency, brain creatine is in the reference range, indicating a possible compartmentation phenomenon. Paradoxical increase of S-adenosylmethionine suggests that secondary inhibition of methylases contributes to the transmethylation defect in these conditions. Neurology GLOSSARYCblC ϭ combined homocystinuria-methylmalonic aciduria; CblG ϭ methionine synthase deficiency; CBS ϭ cystathionine ␤-synthase; Cho ϭ water-soluble choline-containing compounds; Cr ϭ creatine; DQ ϭ developmental quotient; Met ϭ plasma methionine; MR ϭ magnetic resonance; MSRI ϭ magnetic resonance spectroscopic imaging; MTHFR ϭ methylene tetrahydrofolate reductase; NA ϭ not available; NAA ϭ N-acetylaspartate; NN ϭ neonatal; NS ϭ not significant; OA ϭ optic atrophy; OMA ϭ oculomotor apraxia; OMIM ϭ Online Mendelian Inheritance in Man; PM ϭ pigmentary maculopathy; Pt ϭ patient; RD ϭ remethylation defect; RP ϭ retinitis pigmentosa; tHcy ϭ plasma total homocysteine; THF ϭ tetrahydrofolate.

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Homocysteine is a thiol-containing amino acid synthesized in mammals ⁄ humans as part of the normal metabolism of the essential amino acid methionine. Studies conducted over the past three decades have shown that high levels of homocysteine in the plasma (hyperhomocysteinemia, i.e. > 15 lmolAEL ) constitute a risk factor for cardiovascular diseases and stroke [1]. Elevated homocysteine is also a risk factor for several neurodegenerative disorders, such as dementia [2], Alzheimer's disease [3], and Parkinson's disease [4]. As elevated homocysteine is associated with an increasing number of pathologies, the regulation of homocysteine levels is of clinical importance.Several factors contribute to elevated homocysteine levels: (a) genetic disorders stemming from mutations in the enzymes involved in homocysteine remethylation to methionine (e.g. 5,10-methylenetetrahydrofolate reductase) [ Ammonium trichloro(dioxoethylene-o,o¢)tellurate (AS101) is an organotellurium compound with pleiotropic functions that has been associated with antitumoral, immunomodulatory and antineurodegenerative activities. Tellurium compounds with a +4 oxidation state, such as AS101, react uniquely with thiols, forming disulfide molecules. In light of this, we tested whether AS101 can react with the amino acid homocysteine both in vitro and in vivo. AS101 conferred protection against homocysteine-induced apoptosis of HL-60 cells. The protective mechanism of AS101 against homocysteine toxicity was directly mediated by its chemical reactivity, whereby AS101 reacted with homocysteine to form homocystine, the less toxic disulfide form of homocysteine. Moreover, AS101 was shown here to reduce the levels of total homocysteine in an in vivo model of hyperhomocysteinemia. As a result, AS101 also prevented sperm cells from undergoing homocysteine-induced DNA fragmentation. Taken together, our results suggest that the organotellurium compound AS101 may be of clinical value in reducing total circulatory homocysteine levels.Abbreviations AS101, ammonium trichloro(dioxoethylene-o,o¢)tellurate; ddw, double-deionized water; DEVD, Ac-benzyloxycarbonyl aspartyl glutamylvalylaspartic acid; DFI, DNA fragmentation index; FACS, fluorescence-activated cell sorter; Nbs 2 , 5,5¢-dithiobis(2-nitrobenzoic acid); PI, propidium iodide; pNA, p-nitroaniline; RP, reaction product; SCSA, sperm chromatin structure assay.

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