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NEUROLOGY 2008;71:44-49
© 2008 American Academy of Neurology

Reduced brain choline in homocystinuria due to remethylation defects

F. -G. Debray, MD, Y. Boulanger, PhD, A. Khiat, PhD, J. -C. Decarie, MD, J. Orquin, MD, M. -S. Roy, PhD, A. Lortie, MD, F. Ramos, MSc, N. M. Verhoeven, PhD, E. Struys, PhD, H. J. Blom, PhD, C. Jakobs, PhD, E. Levy, MD, PhD, G. A. Mitchell, MD and M. Lambert, MD

From the Divisions of Medical Genetics (F.-G.D., G.A.M., M.L.) and Neurology (A.L.), Department of Pediatrics; Departments of Medical Imaging (J.-C.D.), Ophthalmology (J.O., M.-S.R.), Psychology (F.R.), and Nutrition (E.L.), University of Montreal and Ste-Justine Hospital, Montreal, Quebec, Canada; Department of Radiology (Y.B., A.K.), University of Montreal and Hôpital Saint-Luc, Montreal, Quebec, Canada; and Metabolic Unit (N.M.V., E.S., H.J.B., C.J.), Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands.

Address correspondence and reprint requests to Dr. Marie Lambert, Division of Medical Genetics, Ste-Justine Hospital, 3175 Côte-Sainte-Catherine, Montreal, Quebec, H3T 1C5, Canada marie.lambert{at}umontreal.ca

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 (1H MRSI). Brain N-acetylaspartate, choline-containing 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 ± SD, patients vs controls): frontal white matter (0.051 ± 0.010 vs 0.064 ± 0.010; p = 0.001), lenticular nucleus (0.056 ± 0.011 vs 0.069 ± 0.009; p < 0.001), and thalamus (0.063 ± 0.010 vs 0.071 ± 0.007; p = 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 < 0.005), normal urine and plasma guanidinoacetate, and a paradoxical increase in plasma S-adenosylmethionine (p < 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.

Abbreviations: CblC = combined homocystinuria-methylmalonic aciduria; CblG = methionine synthase deficiency; CBS = cystathionine β-synthase; Cho = water-soluble choline-containing compounds; Cr = creatine; DQ = developmental quotient; Met = plasma methionine; MR = magnetic resonance; MSRI = magnetic resonance spectroscopic imaging; MTHFR = methylene tetrahydrofolate reductase; NA = not available; NAA = N-acetylaspartate; NN = neonatal; NS = not significant; OA = optic atrophy; OMA = oculomotor apraxia; OMIM = Online Mendelian Inheritance in Man; PM = pigmentary maculopathy; Pt = patient; RD = remethylation defect; RP = retinitis pigmentosa; tHcy = plasma total homocysteine; THF = tetrahydrofolate.

Supplemental data at www.neurology.org

Disclosure: The authors report no disclosures.

Received September 9, 2007. Accepted in final form March 7, 2008






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