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Recently, 3 patients with a creatine synthesis defect have been described. They presented with developmental regression, extrapyramidal movement abnormalities, and intractable epilepsy, and they improved with treatment of creatine monohydrate. We report 2 unrelated boys with a creatine synthesis defect and nonspecific presenting signs of psychomotor retardation, behavioral problems, and, in 1, mild epilepsy. Metabolic urine screening revealed elevations in all metabolites, expressed as millimoles per mole of creatinine, which suggests decreased creatinine excretion. This finding led to the correct diagnosis. We propose to include the assessment of the overall concentrations of amino acids and organic acids relative to creatinine in routine metabolic urine screening.

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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Our study describes the adult clinical and biochemical spectrum of guanidinoacetate methyltransferase (GAMT) deficiency, a recently discovered inborn error of metabolism. The majority of the previous reports dealt with pediatric patients, in contrast to the present study. A total of 180 institutionalized patients with a severe mental handicap were investigated for urine and plasma uric acid and creatinine. Patients with an increased urinary uric acid/creatinine ratio and/or decreased creatinine were subjected to the analysis of guanidinoacetate (GAA). Four patients (three related and one from an unrelated family) were identified with GAMT-deficiency. A fifth patient had died before a biochemical diagnosis could be made. They all had shown a normal psychomotor development for the first year of life, after which they developed a profound mental retardation. Three out of four had convulsions and all four totally lacked the development of speech. Their GAMT activity in lymphoblasts was impaired and two novel mutations were identified: the 59 G > C and 506 G > A missense mutations. Urinary GAA was increased, but highly variable 347-1,624 mmol/mol creat (Controls <150 mmol/mol creat). In plasma and CSF the GAA levels were fairly constant at 17.3-27.0 mumol/L (Controls 1.33-3.33) and 11.0-12.4 mumol/L, respectively (Controls 0.068-0.114). GAMT deficiency in adults is associated with severe mental retardation and absence or limited speech development. Convulsions may be prominent. The nonspecific nature of the clinical findings as well as the limited availability of GAA assays and/or in vivo magnetic resonance spectroscopy of the brain may mean that many more patients remain undiagnosed in institutions for persons with mental handicaps.