Acute psychosis in propionic acidemia: 2 case reports.

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.

Sustained reduction of hyperhomocysteinaemia with folic acid supplementation in predialysis patients.

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 is associated with atherosclerotic occlusive arterial accidents in predialysis chronic renal failure 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.

Long-term folic acid (but not pyridoxine) supplementation lowers elevated plasma homocysteine level in chronic renal failure.

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.

Homocysteine: relationship to serum cobalamin, serum folate, erythrocyte folate, and lobation of neutrophils.

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.

Methylenetetrahydrofolate reductase deficiency: prenatal diagnosis and family studies.

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, a risk factor for atherosclerosis in chronic uremic patients.

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)

Elevated total plasma homocysteine, a risk factor for thrombosis. Relation to coagulation and fibrinolytic parameters.

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.

Increased plasma homocysteine concentration in patients with chronic renal failure.

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.

Eleventh week amniocentesis for prenatal diagnosis of some metabolic diseases.

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.

Homocystinuria due to 5,10-methylenetetrahydrofolate reductase deficiency revealed by stroke in adult siblings.

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.

[Plasma homocysteine assay in the exploration of thrombosis in young subjects]. / Dosage de l'homocystéine plasmatique dans l'exploration des thromboses du sujet jeune.

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.

Antithrombin III activity is not related to plasma homocysteine concentrations.

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.

Early amniocentesis and amniotic fluid organic acid levels in the prenatal diagnosis of organic acidemias.

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.

[Radioisotopic assay of total L-homocysteine in plasma and urine: application to serial determinations]. / Dosage radioisotopique de la L-homocystéine totale dans le plasma et l'urine: application à des dosages en séries.

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.