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Propionic acidemia is an inborn deficiency of propionyl-coenzyme A (CoA) carboxylase activity, which leads to mitochondrial accumulation of propionyl-CoA and its by-products. Neurologic complications are frequent, but only a few cases presenting with psychiatric symptoms have been reported so far. We report 2 cases of children with chronic psychiatric symptoms who presented with an acute psychotic episode as teenagers. Both patients had hallucinations, panic and grossly disorganized behavior, for several weeks to several months. They had signs of moderate metabolic decompensation at the beginning of the episode, although the psychiatric symptoms lasted longer than the metabolic imbalance. We propose that these episodes were at least partially imputable to propionic acidemia. Such episodes require psychiatric examination and antipsychotic treatment, which may have to be adapted in case of cardiomyopathy or long QT syndrome.

Background: Loss of function mutations in 3-Hydroxyacyl-CoA Dehydrogenase (HADH) cause protein sensitive hyperinsulinaemic hypoglycaemia (HH). HADH encodes short chain 3-hydroxacyl-CoA dehydrogenase, an enzyme that catalyses the penultimate reaction in mitochondrial β-oxidation of fatty acids. Mutations in GLUD1 encoding glutamate dehydrogenase, also cause protein sensitive HH (due to leucine sensitivity). Reports suggest a protein-protein interaction between HADH and GDH. This study was undertaken in order to understand the mechanism of protein sensitivity in patients with HADH mutations., Methods: An oral leucine tolerance test was conducted in controls and nine patients with HADH mutations. Basal GDH activity and the effect of GTP were determined in lymphoblast homogenates from 4 patients and 3 controls. Immunoprecipitation was conducted in patient and control lymphoblasts to investigate protein interactions., Results: Patients demonstrated severe HH (glucose range 1.7-3.2 mmol/l; insulin range 4.8-63.8 mU/l) in response to the oral leucine load, this HH was not observed in control patients subjected to the same leucine load. Basal GDH activity and half maximal inhibitory concentration of GTP was similar in patients and controls. HADH protein could be co-immunoprecipitated with GDH protein in control samples but not in patient samples., Conclusions: We conclude that GDH and HADH have a direct protein-protein interaction, which is lost in patients with HADH mutations causing leucine induced HH. This is not associated with loss of inhibitory effect of GTP on GDH (as in patients with GLUD1 mutations).

Background: Activating mutations in the GLUD1 gene (which encodes for the intra-mitochondrial enzyme glutamate dehydrogenase, GDH) cause the hyperinsulinism-hyperammonaemia (HI/HA) syndrome. Patients present with HA and leucine-sensitive hypoglycaemia. GDH is regulated by another intra-mitochondrial enzyme sirtuin 4 (SIRT4). Sirt4 knockout mice demonstrate activation of GDH with increased amino acid-stimulated insulin secretion., Objectives: To study the genotype-phenotype correlations in patients with GLUD1 mutations. To report the phenotype and functional analysis of a novel mutation (P436L) in the GLUD1 gene associated with the absence of HA. Patients and methods Twenty patients with HI from 16 families had mutational analysis of the GLUD1 gene in view of HA (n=19) or leucine sensitivity (n=1). Patients negative for a GLUD1 mutation had sequence analysis of the SIRT4 gene. Functional analysis of the novel P436L GLUD1 mutation was performed., Results: Heterozygous missense mutations were detected in 15 patients with HI/HA, 2 of which are novel (N410D and D451V). In addition, a patient with a normal serum ammonia concentration (21 micromol/l) was heterozygous for a novel missense mutation P436L. Functional analysis of this mutation confirms that it is associated with a loss of GTP inhibition. Seizure disorder was common (43%) in our cohort of patients with a GLUD1 mutation. No mutations in the SIRT4 gene were identified., Conclusion: Patients with HI due to mutations in the GLUD1 gene may have normal serum ammonia concentrations. Hence, GLUD1 mutational analysis may be indicated in patients with leucine sensitivity; even in the absence of HA. A high frequency of epilepsy (43%) was observed in our patients with GLUD1 mutations.

Uncoupling protein 2 (UCP2) belongs to a family of transporters of the mitochondrial inner membrane and is reported to uncouple respiration from ATP synthesis. Our observation that the amino acid glutamine specifically induces UCP2 protein expression prompted us to investigate metabolic consequences of a UCP2 knockdown (Ucp2-KO) when glutamine is offered as a substrate. We found that Ucp2-KO macrophages incubated in the presence of glutamine exhibit a lower ammonium release, a decreased respiratory rate, and an intracellular accumulation of aspartate. Therefore, we conclude that UCP2 expression is required for efficient oxidation of glutamine in macrophages. This role of UCP2 in glutamine metabolism appears independent from the uncoupling activity of UCP2.

Background: Moderate hyperhomocysteinaemia, as occurs in chronic renal failure patients, is an established independent risk factor for atherosclerotic arterial occlusive accidents, the incidence of which is abnormally high in such patients. Folic acid supplementation has been shown to reduce plasma homocysteine level in end-stage renal disease patients treated with haemodialysis or peritoneal dialysis, but its long-term effects in predialysis patients had not been assessed., Methods: We prospectively treated a total of 78 predialysis patients with folic acid for at least 1 year (range 12-74 months) together with oral pyridoxine and vitamin B12 supplements. Of the patients, 67 received 5 mg folic acid three times per week, whereas the other 11 patients who were treated with recombinant erythropoietin received 5 mg/day. Plasma fasting total homocysteine concentration was determined at baseline, after 3 months and at the end of follow-up., Results: Mean (+/-SD) plasma total homocysteine level decreased from 21.2+/-6.4 micromol/l at baseline to 14.2+/-4.6 at 3 months and remained at 12.8+/-3.7 micromol/l at the end of follow-up (average duration 2.8 years), whereas plasma creatinine rose from 268+/-129 to 399+/-234 micromol/l. Mean plasma folate concentration rose from 19+/-12 to 47+/-13 nmol/l and mean plasma vitamin B12 rose from 237+/-119 to 347+/-191 pmol/l from baseline to end of follow-up., Conclusions: Moderate folic acid supplementation (2.15 mg/day) allows a substantial (40% as a mean) and sustained (up to 6 years) reduction of plasma total homocysteine level in predialysis uraemic patients without any detectable side effect. Folic acid supplementation may thus contribute to lower the risk of accelerated atherosclerosis in such patients.

Hyperhomocysteinemia has been shown to constitute an independent risk factor for premature occlusive arterial disease. Moderate hyperhomocysteinemia is present in chronic uremic patients, who often develop premature atherosclerosis, but no direct evidence of an association between the occurrence of atherosclerotic cardiovascular accidents (CVAs) and hyperhomocysteinemia has yet been reported in such patients. We serially determined total plasma homocysteine (Hcy) levels in a cohort of 93 consecutive chronic renal failure, undialyzed patients (57 males, 36 females) with creatinine clearance (Ccr) < 50 ml/min.1.73 m2 and age > or = 50 years at start of follow-up, together with serial assessment of Ccr and blood lipid parameters. From January 1989 to December 1995, 24 patients (group 1) experienced myocardial infarction (18 cases, 13 males) or cerebral infarction (6 cases, 3 males) while the remaining 69 (group 2) remained free of CVAs. Patients in groups 1 and 2 did not differ with respect to age (66 +/- 1.8 vs. 65 +/- 1.1 years, mean +/- Se) or serum creatinine (227 +/- 24 vs. 251 +/- 36 mumol/l) at onset of a CVA (group 1) or at the end of follow-up (group 2). The mean Hcy level was significantly higher in group 1 (20.7 +/- 1.6 vs. 12.8 +/- 0.5 mumol/l, p < 0.0001), as was the proportion of patients with Hcy in excess of 14 mumol/l, the upper limit in healthy controls (83 vs. 30%, p < 0.0001). Logistic regression analysis identified Hcy as an independent risk factor for CVA, with an odds ratio of 11.4 (95% confidence interval 3.5-37.7), which remained significant after adjustment on other variables. We conclude that an elevated Hcy level is associated with a risk of occlusive arterial accidents in patients with chronic renal failure and that hyperhomocysteinemia contributes to the accelerated atherosclerosis complicating chronic uremia.

Moderate hyperhomocysteinemia, a risk factor for premature atherosclerosis, is present in chronic uremic patients. We prospectively evaluated the effects of sequential supplementation with pyridoxine (70 mg/day) and folic acid (10 mg/day) for two 3-month periods in 37 nondialyzed patients (29 males) with creatinine clearance (CCr) ranging from 10 to 80 ml/min, whose plasma vitamin B12 and folate level was in the normal range. Mean (+/- SD) baseline plasma total homocysteine (Hcy) was 14.9 +/- 5.2, 16.5 +/- 5.1 and 26.1 +/- 12.1 mumol/l (upper limit in 45 healthy controls 14.1 mumol/l) in patients with CCr 40-80, 20-40 and < 20 ml/min, respectively. Following pyridoxine Hcy did not significantly decrease whereas following folic acid Hcy decreased significantly to 9.9 +/- 2.9 (-33% vs. baseline), 10.3 +/- 3.4 (-37%) and 15.4 +/- 5.5 (-40%), respectively (Student's paired t test, p < 0.001) in the 3 groups. We conclude that folate (but not pyridoxine) pharmacologic supplementation is effective in lowering elevated plasma Hcy in chronic renal failure patients, thus suggesting that enhancing the Hcy remethylation pathway may overcome hyperhomocysteinemia in such patients. In view of the potential atherogenic effects of hyperhomocysteinemia, long-term folate supplementation should be considered in uremic patients.

Serum levels of total homocysteine were studied in the following: 26 healthy adults; 79 hospitalised patients in whom serum cobalamin, serum folate, and erythrocyte folate were greater than 230 pmol/L, 12 nmol/L, and 600 nmol/L, respectively; 32 hospitalised patients whose serum cobalamin was less than 147 pmol/L, compared to 25 patients whose serum cobalamin was greater than 147 pmol/L but unmatched in any other parameter; and 194 patients in whom samples were sent for determination of cobalamin and folate from a neurological service. None of this last group had megaloblastic anaemia. There was a relationship between the elevated concentrations of total homocysteine in serum and low concentrations of serum cobalamin and of erythrocyte folate. This relationship was most evident in samples with serum cobalamin < 86 pmol/L and erythrocyte folate < 335 nmol/L, although elevated homocysteine levels were found in some samples where serum cobalamin and erythrocyte folate levels were greater than these. Serum folate correlated poorly with serum total homocysteine. There was only a poor-to-fair correlation of neutrophil lobe counts to total serum homocysteine.

Prenatal diagnosis of methylenetetrahydrofolate reductase (MTHFR) deficiency and family studies were performed because of a severely affected first child in this family. The fetus at risk was found to be heterozygous as confirmed by the enzymatic activity assay performed several times after birth. In the father, MTHFR activity was normal in lymphocytes and decreased in fibroblasts, whereas in the asymptomatic mother, the activity was not detectable in fibroblasts and was very low in lymphocytes. The absence of any clinical symptoms in the mother despite a clear MTHFR deficiency and hyperhomocystinemia emphasizes the heterogeneity of this disease.

Hyperhomocysteinemia has been shown to constitute an independent risk factor for premature occlusive arterial disease (N Engl J Med 324:1149), a frequent complication in chronic uremic patients in whom homocysteine (Hcy) accumulation has been reported to occur. We prospectively determined fasting plasma level of total, protein-bound Hcy in 118 adult chronic uremic patients, either dialyzed or not. In 79 non-dialyzed patients (47 male) with various degrees of chronic renal failure (RF) assessed by creatinine clearance (CCr), none receiving folate, B6 or B12 vitamin supplementation, mean (+/- 1 SD) plasma Hcy level was 16.2 +/- 8.1 mumol/liter in 28 patients with mild RF (CCr 30 to 75 ml/min), 23.3 +/- 14.7 in 29 patients with moderate RF (CCr 10 to 29.9), and 29.5 +/- 14.4 in 22 patients with advanced RF (CCr < 10), a significant difference (P < 0.01 for all groups) compared to 45 healthy controls (8.2 +/- 2.2 mumol/liter). Linear regression analysis showed a significant correlation between plasma creatinine and Hcy concentrations (r = 0.49, P < 0.0001). Hcy was significantly higher in 20 patients (16 males) who had past histories of occlusive arterial disease than in the 59 (31 males) who did not (30.9 +/- 19.1 vs. 19.6 +/- 9.7 mumol/liter, P < 0.001) and all of the former had Hcy level > 14.1 mumol/liter (the upper limit in healthy controls) versus 35 of 59 in the latter.(ABSTRACT TRUNCATED AT 250 WORDS)

Homocystinuria is a rare inherited metabolic disease. Arterial and venous thromboembolic events represent frequent and life-threatening complications in homocystinuric patients. It has been suggested that mild homocysteinemia could be a risk factor for vascular disease. We have therefore measured total plasma homocysteine (HCy) concentrations by radioisotopic assay in 50 subjects with venous or arterial thrombosis and studied the relationship between HCy, coagulation and fibrinolytic parameters. Values were considered abnormal if they were higher than 2.7 standard deviations (SD) above the mean, i.e., 14.1 mmol/l. Thus, eighteen of the 50 patients with thrombosis were classified in the hyperhomocysteinemia group. Nine of these subjects had only this isolated risk factor. No correlations were found between HCy and antithrombin III, protein C, protein S and plasminogen levels, or plasma plasminogen activator inhibitor activity. Nevertheless, the correlation between tissue-plasminogen activator antigen and total plasma HCy was significant (r = 0.61, p < 0.001). Increased homocysteinemia seems to be a risk factor for thrombotic events especially knowing that HCy presents a direct cytotoxic effect. Vitamin therapy, already used in homozygote homocystinuric patients, might be beneficial in the prevention of thromboembolic disease in heterozygous patients.

Since moderate hyperhomocysteinemia is associated with premature occlusive arterial disease, a frequent complication in uremic patients, we prospectively determined fasting plasma concentration of total homocysteine (Hcy) in 79 nondialyzed patients (47 males) with chronic renal failure. None received folate supplementation. Mean (+/- SD) Hcy concentrations were 16.2 +/- 8.1, 23.3 +/- 14.7 and 29.5 +/- 14.4 mumol/l in patient groups with creatinine clearance (Ccr) of, respectively, 30-75, 10-30 and < 10 ml/min, and significantly higher (p < 0.01) than in 45 healthy controls (8.2 +/- 2.2 mumol/l). Linear regression analysis showed a significant negative correlation between Ccr and Hcy (r = 0.40, p < 0.01). Among 37 male patients aged > or = 50 years, Hcy was significantly higher in 15 who had clinical evidence of occlusive arterial disease than in 22 who did not (28.9 +/- 13.3 vs. 17.8 +/- 8.9 mumol/l, p < 0.01). We conclude that hyperhomocysteinemia is present from the early stage of chronic renal failure and may constitute a risk factor for premature arteriosclerosis in uremic patients.

We report the results of 23 prenatal diagnoses performed at the 11th or 12th week of gestation by the simultaneous analysis of chorionic villi (for direct or indirect enzymatic analysis) and cell-free amniotic fluid (for search of accumulated catabolites). For six cases of citrullinaemia, four cases of argininosuccinic aciduria, seven cases of propionic acidaemia, and six cases of methylmalonic acidaemia, three discrepancies were observed between the two methods used. The amniotic fluid analysis for accumulated catabolites seems to be a safe method and should always be used in conjunction with the enzymatic assays performed for the prenatal diagnosis of these diseases.

Three patients from a single family of six siblings had homocystinemia and homocystinuria due to 5,10-methylenetetrahydrofolate reductase deficiency and had severe recurrent strokes in adult life. Two of the patients died 1 year after clinical onset.

Homocystinuria is a rare inherited metabolic disease transmitted as an autosomal recessive trait. Arterial and venous thromboembolic events are frequent and life-threatening complications in homocystinuric patients. It has been suggested that mild homocysteinemia could be a risk factor for vascular disease. We measured total plasma L-homocysteine concentrations by radioisotopic assay in 32 subjects with arterial (n = 15) or venous (n = 17) thrombosis. Twelve subjects exceeded the upper normal limit (2.70 SD above the mean), i.e. 14.1 mumol/l. Seven had arterial thrombotic disease and five had deep vein thrombosis. In 18 subjects thrombosis developed in the absence of any of the hitherto recognized risk factors; 6 of these subjects had mild homocysteinemia. Thus, homocysteine metabolism must be investigated in patients with thromboembolism. An increase of homocysteinemia could be a risk factor for thromboembolic events, and the possible benefit of vitamin therapy should be discussed.

Arterial and venous thromboembolic events represent frequent and life-threatening complications in homocystinuric patients and are responsible for their early deaths. Reduced levels of antithrombin III activity in homocystinuric patients have recently been reported. So, high plasma L-homocysteine concentration could play a role in the low antithrombin III activity level. In the present study, we have studied the relationship between total plasma homocysteine and inhibitors of blood coagulation levels in 16 patients with malignancies who received bone marrow grafts. There were no correlations between homocysteine values and inhibitors of blood coagulation levels. So, while the defect in amino acid transsulfuration that is responsible for homocystinuria can directly affect the synthesis or activity of some clotting factors, homocysteine concentration is not responsible for this effect.

Organic acids were studied in amniotic fluids taken by early amniocentesis between 6 to 12 weeks in control pregnancies. The prenatal diagnosis of methylmalonic acidemia and propionic acidemia could be made by the measurement of methylmalonic and methylcitric acid respectively in the amniotic fluid taken simultaneously with chorionic villi at the 11th week of gestation.

The authors report here a simple radioenzymatic determination of total L-homocysteine in plasma and urine. L-homocysteine-containing disulfides were reduced with dithioerythritol. L-homocysteine was then condensed by S-adenosyl L-homocysteine hydrolase to 14C-adenosine to form S-14C adenosyl L-homocysteine that was separated from 14C-adenosine by paper descendant chromatography. The concentration of the total plasma L-homocysteine of 45 normal subjects was 8.04 +/- 0.26 (mean +/- SEM) mumol/l and total L-homocysteine concentration in urine was 0.59 +/- 0.06 mumol/mmol of creatinine (25 subjects). This method is as sensitive than the other methods described in the literature but more rapid and less expensive.

Seven defects of the urea cycle enzymes were obtained in 48 hours at-risk pregnancies. A new method for measuring ornithine transcarbamylase and carbamylphosphate synthetase-I was used for prenatal diagnosis of the related enzymopathies in chorionic villi.

Mosaic tetrasomy 12p is a dysmorphic syndrome which has been described under the name of Pallister mosaic syndrome and Teschler-Nicola/Killian syndrome and has sometimes been incorrectly interpreted as tetrasomy 21. Here we report the first case to be diagnosed prenatally and confirmed by enzyme assays, and we summarize the clinical and biological characteristics of all the cases reported so far under various names.

The enzymatic activity of cystathionine beta synthase has been studied in fibroblasts of nine patients with regular trisomy 21. An excess of CBS activity was found in trisomy 21 with a trisomy 21/normal ratio equal to 1.66. A 1.04 ratio was found in 21q21----21 p ter monosomy; a 1.04 and 0.99 ratio was found in two 21 qter----21q22.3 monosomies; a 1.14 ratio in 21 qter----21q22 monosomy; a 0.89 ratio in a 21q21----21 pter trisomy; an excess of CBS activity was found in a 21q22.1 ----21q21 trisomy with a 1.57 ratio. These results show a gene dosage effect in human fibroblasts trisomic for chromosome 21 and suggest the assignment of human CBS locus between 21q22.1 and 21q21.

Prenatal diagnosis of propionic acidemia was achieved by the direct assay of propionyl CoA carboxylase in chorionic villi. The diagnosis was confirmed by determination of methylcitrate in amniotic fluid and measurement of propionyl CoA carboxylase in the liver from the abortion. Discrepancy between [14C]-propionate incorporation into protein of chorionic villi or cultured chorionic cells and propionyl CoA carboxylase activity is reported.

A patient with the phenotype of trisomy 21 (Down syndrome) was found to have a normal karyotype in blood lymphocytes and fibroblasts. Assessment of the chromosome 21 markers SOD1, CBS, ETS2, D21S11, and BCEI showed partial trisomy by duplication of a chromosome segment carrying the SOD1, CBS, and ETS2 loci and flanked by the BCEI and D21S11 loci, which are not duplicated. This submicroscopic duplication at the interface of 21q21 and 21q22.1 reduces to about 2000-3000 kb the critical segment the trisomy of which is responsible for the phenotype of trisomy 21.

In two cases, first interpreted as mosaic tetrasomy 21, the R banding and the gene dosage studies lead us to conclude to a mosaic tetrasomy 12 p. In Pallister mosaic syndrome and in Teschler-Nicola/Killian syndrome, the very similar clinical signs and the identical abnormal chromosome, missing in leucocytes, led us to conclude that Pallister and Teschler-Nicola/Killian syndrome, as well as mosaic tetrasomy 21 are one and the same syndrome tetrasomy 12 p. This tissue limited mosaic is probably more frequent than it is assumed. Prenatal diagnosis can be made since the supernumerary chromosome is found in amniocytes. The distinctive tissue distribution is probably a selective process due to cellular differentiation gene, CD9 (or Alb 6) located to 12 p.

The enzymatic activity of phosphoribosylglycinamide synthetase (GARS) has been studied in several cases of partial monosomies and full and partial trisomies 21. An excess of GARS activity was found in regular trisomy 21 with a trisomy 21/normal ratio equal to 1.55. A 0.99 ratio was found in 21q21----21pter monosomy; a 0.54 ratio was found in 21qter----21q22 monosomy; a 0.88 ratio, in 21q21----21pter trisomy, and a 1.46 ratio, in 21q22.1 trisomy. Consequently, the GARS gene locus, assigned to chromosome 21, could be localized in subband 21q22.1.

Among several cases of partial monosomies and full and partial trisomies 21, the enzymatic activity of phosphofructokinase (PFK) is increased only in 21q21----21pter trisomy with a (T21/N) ratio equal to 1.35 and decreased in monosomy 21q21----21pter. These results suggest that the human gene for liver-type PFK is located between 21q21 and 21pter.