Long term outcome of organic acidurias: Survey of 105 French cases (1967–1983)

The French experience in the long term follow-up of 105 cases of organic aciduria (45 maple syrup urine disease, 12 isovaleric acidaemia, 19 propionic acidaemia, 24 methylmalonic aciduria and some rare allied disorders) is reported. Main conclusions drawn from this survey are the poor overall prognosis and the slow improvement in the outcome of such disorders over the last 15 years. In MSUD, while early diagnosis and early management remain a basic requirement, intellectual development did not improve as much as expected. In propionic and methylmalonic acidaemia modern treatment does not prevent a fatal outcome in the classical neonatal forms. It should be also emphasized that in the rare cases where a coenzyme deficiency has been demonstrated, vitamin therapy is very often ineffectivein vivo.     

Plasma total odd-chain fatty acids in the monitoring of disorders of propionate,methylmalonate and biotin metabolism

Summary Total plasma odd-numbered long-chain fatty acids were analysed in patients with methylmalonic acidaemia (vitamin B₁₂-responsive and unresponsive), combined methylmalonic acidaemia/homocystinuria (CblC), propionic acidaemia (both neonatal-onset and late-onset), biotinidase deficiency and holocarboxylase synthase deficiency, as well as in hospital controls. Total odd-numbered long-chain fatty acids (C_15:0, C_17:1 and C_17:0) were expressed as a percentage of total C₁₂–C₂₀ fatty acids. Control values were 0.72%±0.31% (n=12). Normalization of the percentage of odd-chain fatty acids occurred in all vitamin-responsive patients, following the institution of vitamin treatment. In general the neonatal-onset propionic acidaemia and B₁₂-unresponsive methylmalonic acidaemia patients had the highest plasma odd-chain fatty acid concentrations, which correlated with the clinical condition but not with the urinary excretion of methylcitrate or methylmalonate. Plasma odd-chain fatty acid concentrations and methylmalonate excretions in CblC patients reacted very well to vitamin B₁₂ treatment, but with no clinical response. Measurement of plasma odd-chain fatty acids is of no value for the monitoring of defects of biotin metabolism.     

The management and long term outcome of organic acidaemias

We review the outcome of patients with maple syrup urine disease (14 classical patients and three variants), biotinidase deficiency (two patients) and non-cofactor-responsive variants of methylmalonic acidaemia (eight patients), propionic acidaemia (eight patients) and isolated 3-methylcrotonyl CoA carboxylase deficiency (three patients). Their survival, growth, intellectual development and other clinical problems are analysed. With the exception of isolated 3-methylcrotonyl CoA carboxylase deficiency the outcome of patients with disorders that are not cofactor responsive is disappointing. Twelve patients have died (five maple syrup urine disease, two methylmalonic acidaemia, five propionic acidaemia) and many of the survivors are developmentally retarded. The outlook is worst for patients with propionic acidaemia presenting in the neonatal period but a good outcome is possible for patients with maple syrup urine disease if the diagnosis is made early.     

Infantile mitochondrial DNA depletion syndrome associated with methylmalonic aciduria and 3-methylcrotonyl-CoA and propionyl-CoA carboxylase deficiencies in two unrelated patients: A new phenotype of mtDNA depletion syndrome

Mitochondrial DNA (mtDNA) depletion refers to a quantitative defect in mtDNA and is heterogeneous with regard to causal genotypes and the associated clinical phenotypes. We report two unrelated infants with mtDNA depletion. A diagnosis of methylmalonic aciduria was initially raised in both on the basis of high urine methylmalonic acid and related organic acids and elevated propionylcarnitine and methylmalonylcarnitine. Carboxylase assay with skin fibroblasts revealed low propionyl-CoA and 3-methylcrotonyl-CoA carboxylase and normal pyruvate carboxylase activities. Quantitative Southern blot analysis of mitochondrial and nuclear DNA with muscle tissues revealed the patients' mtDNA to be depleted to 24% and 39% of normal controls. Our two patients showed multiple mitochondrial dysfunction including respiratory chain defects and deficiencies in the two nuclear DNA encoded carboxylases resulting in abnormal urine organic acids. To our knowledge, there is no obvious connection between the defective pathways other than their mitochondrial locations. These two cases may represent a new entity of mitochondrial disease that might be due to a defective common mechanism, such as assembly, maintenance and transport, affecting various mitochondrial enzymes and functions. Mitochondrial depletion should be considered in infants with atypical organic aciduria that may resemble methylmalonic aciduria, propionic acidaemia, or 3-methylcrotonyl-CoA carboxylase deficiency. This revised version was published online in September 2006 with corrections to the Cover Date.     

Breastfeeding experience in inborn errors of metabolism other than phenylketonuria

Summary Breastfeeding has been recommended for the dietary treatment of infants with phenylketonuria, but studies documenting clinical experience in other inborn errors of metabolism are very few. Seven infants diagnosed with methylmalonyl-CoA mutase deficiency (n=2), ornithine carbamoyltransferase deficiency (n=1), propionic acidaemia (n=1), isovaleric acidaemia (n=1), maple syrup urine disease (n=1) and glutaric acidemia type I (n=1) were tried with breastfeeding over two years. After the control of acute metabolic problems, an initial feeding period with a measured volume of expressed breast milk plus a special essential amino acid mixture was continued with breastfeeding on demand and with the addition of a special essential amino acid mixture. Two patients with methylmalonic acidaemia and one patient with glutaric acidaemia type I tolerated breastfeeding on demand very well, with good growth and metabolic control for periods of 18, 8 and 5 months, respectively. In the patient with propionic acidaemia, on-demand breastfeeding continued for 3 months but was terminated after two acute metabolic episodes. The patient with isovaleric acidaemia had insufficiency of breast milk and formula supplementation ended with breast milk cessation. In the patient with severe ornithine carbamoyltransferase deficiency, breastfeeding was stopped owing to poor metabolic control. The patient with maple syrup urine disease also experienced problems, both in metabolic control and in insufficiency of breast milk, resulting in termination of breastfeeding. Breastfeeding of infants with inborn errors of protein catabolism is feasible, but it needs close monitoring with attention to such clinical parameters as growth, development and biochemistry, including amino acids, organic acids and ammonia. This revised version was published online in May 2005 with corrections to the authors’ names.     

Stable-isotope selected-ion monitoring quantification of methylmalonic acid in dried filter-paper urine samples

Summary Urea and creatinine were measured by Kodak Ektachem methods and methylmalonic acid by stable-isotope gas chromatography—mass spectrometry in 24 urine samples from patients with methylmalonic acidaemia. For each sample analyses were performed both directly on the liquid urine and on an aliquot which had been blotted onto filter paper and dried. There was good correlation between the methylmalonate/creatinine ratios in liquid and dried urine (r ²=0.983). Urine dried on filter paper can be used advantageously for monitoring treatment in patients with this disorder.     

Propionic acidaemia presenting with pancytopaenia in infancy

A 2-month-old infant presented with vomiting, lethargy and pancytopaenia. She was found to have propionic acidaemia, and the activity of propionyl-CoA carboxylase in cultured fibroblasts was defective (McKusick 23200). Abnormal amounts of glycine, 3-hydroxypropionate, methylcitrate, tiglyglycine, propionylglycine, 2-methylacetoacetate, 2-methyl-3-hydroxybutyrate, 3-oxovalerate and 3-hydroxyvalerate were found in body fluids. It appears that the organic acidaemia leads to an inhibition in the maturation of cells in the bone marrow.     

Propionic acidaemia presenting with pancytopaenia in infancy

A 2-month-old infant presented with vomiting, lethargy and pancytopaenia. She was found to have propionic acidaemia, and the activity of propionyl-CoA carboxylase in cultured fibroblasts was defective (McKusick 23200). Abnormal amounts of glycine, 3-hydroxypropionate, methylcitrate, tiglylglycine, propionylglycine, 2-methylacetoacetate, 2-methyl-3-hydroxybutyrate, 3-oxovalerate and 3-hydroxyvalerate were found in body fluids. It appears that the organic acidaemia leads to an inhibition in the maturation of cells in the bone marrow.     

Possible explanation for hyperglycinaemia in propionic acidaemia and methylmalonic acidaemia: Propionate and methylmalonate inhibit liver and brain mitochondrial glycine transport

The effect of propionate and methylmalonate on the transport of glycine into rat liver and brain mitochondria was investigated. Both propionate and methylmalonate markedly inhibited mitochondrial glycine transport. These compounds also inhibited¹⁴CO₂ production from [¹⁴C]glycine by isolated brain and liver mitochondria and glycine metabolism in rat brain cortex slices. These results are discussed with reference to hyperglycinaemia associated with propionic acidaemia and methylmalonic acidaemia and as a possible contributory factor to the pathological mechanisms in these conditions.     

Possible explanation for hyperglycinaemia in propionic acidaemia and methylmalonic acidaemia: Propionate and methylmalonate inhibit liver and brain mitochondrial glycine transport

The effect of propionate and methylmalonate on the transport of glycine into rat liver and brain mitochondria was investigated. Both propionate and methylmalonate markedly inhibited mitochondrial glycine transport. These compounds also inhibited¹⁴CO₂ production from [¹⁴C]glycine by isolated brain and liver mitochondria and glycine metabolism in rat brain cortex slices. These results are discussed with reference to hyperglycinaemia associated with propionic acidaemia and methylmalonic acidaemia and as a possible contributory factor to the pathological mechanisms in these conditions.     

Absolute configuration of <Emphasis Type="Italic">N</Emphasis>-acetylaspartate in urine from patients with Canavan disease

Summary High-resolution ¹H and ¹³C NMR of N-acetylaspartic acid as its 2-(S)-butyl diester allows the two enantiomers to be unambiguously identified. Analysis of urine samples from five patients with Canavan disease (N-aspartoacylase deficiency) showed that more than 95% of the excreted N-acetylaspartate had the S-configuration.     

Effect of docosahexaenoic acid administration on plasma lipid profile and metabolic parameters of children with methylmalonic acidaemia

Summary Aim. To evaluate the effect of administration of docosahexaenoic acid (DHA) on dyslipidaemia, plasma fatty acid composition and metabolic parameters of children with isolated methylmalonic acidaemia (MMA) (McKusick 25100). Methods. Four children (3 male, 1 female) with MMA (mut(0)), participated in a crossover, randomized study of DHA administration (25 mg/kg per day, divided into three daily doses). The control group comprised 56 healthy children, aged 10± 2.7 years, (51 male, 5 female), who were followed in our clinic owing to possible familial risk of cardiovascular disease. Results. The comparison of plasma fatty acid composition of children with MMA versus control children demonstrated that the patients had significantly higher values for oleic acid (p = 0.004) and linolenic acid (p = 0.008). No differences were observed in the levels of DHA and arachidonic acid. Plasma concentrations of insulin, glycine, ammonia, total cholesterol and cholesterol fractions did not change with DHA administration. No significant changes were observed in urinary excretion of methylmalonic acid. As expected, the percentage of DHA and n−3 fatty acids in plasma increased significantly after therapy (p = 0.005 and 0.014, respectively). The most remarkable result was a decrease of plasma levels of triglycerides after DHA therapy (p = 0.014). Conclusion. As previously found in normal children, dietary supplementation with DHA decreases the triglyceride levels, normalizing the hypertriglyceridaemia of these children without any evidence of short-term adverse effects. Communicating editor: Georg Hoffmann Competing interests: None declared     

Breast feeding in organic acidaemias

Summary Breast feeding has been recommended for the dietary treatment of infants with organic acidaemias, but studies documenting clinical experience are still very few. Nine infants, diagnosed with methylmalonic acidaemia (n = 4), propionic acidaemia (n = 1), isovaleric acidaemia (n = 2) and glutaric acidaemia type I (n = 2) were breast fed after diagnosis. The age of the patients was 28.9± 13.4 months (mean ± SD) (range 10–57 months). Eight patients were diagnosed with clinical symptoms and one because of an affected sibling. After the control of acute metabolic problems, an initial period with a measured volume of expressed breast milk was continued with on-demand breast feeding with the addition of a special essential amino acid mixture and energy supplements. Breast feeding was well tolerated in seven infants with good growth, metabolic control and neurological outcome. The duration of breast feeding was 12.3± 7.4 months (mean ± SD) (range 4–24 months) in these patients. Breast feeding was terminated in the patient with propionic acidaemia because of two acute metabolic episodes requiring hospitalization, and could not be continued in one of the patients with isovaleric acidaemia owing to shortage of breast milk. A decrease in the frequency of infections, acute metabolic episodes and hospital admissions was observed in breast-fed infants. Breast feeding of infants with organic acidaemias is feasible with close monitoring of clinical parameters such as growth, development and biochemistry, including amino acids, organic acids and ammonia. Presented at the 42nd Annual Meeting of the SSIEM, Paris, 6–9 September 2005. Competing interests: None declared     

Multiple OXPHOS deficiency in the liver of a patient with CblA methylmalonic aciduria sensitive to vitamin B12

Summary  An adult patient with methylmalonic aciduria due to defective cobalamin synthesis (CblA) responsive to vitamin B₁₂ presented suddenly with severe visual impairment ascribed to optic atrophy followed by a fatal multiorgan failure and lactic acidosis but low methylmalonic acid in plasma and urine. Multiple deficiency of oxidative phosphorylation was found in the patient’s liver. We suggest that patients with B₁₂-sensitive methylmalonic aciduria who have a milder clinical course should be carefully monitored for long-term complications. Competing interests: None declared References to electronic databases: Methylmalonic aciduria (MMA): OMIM 251000, 277400, 251100 (CblA), 277410 (CblD), 251110 (CblB), 277380, 606169. Adenosylcobalamin: EC 2.7.7.62. Methylmalonyl-coenzyme A mutase (MUT): EC 5.4.99.2. Citrate synthase: EC 2.3.3.1. Succinate-CoA ligase (GDP-forming): EC 6.2.1.4. Succinate-CoA ligase (ADP-forming): EC 6.2.1.5. Succinate dehydrogenase (ubiquinone): EC 1.3.5.1. Fumarate hydratase: EC 4.2.1.2. ATP citrate synthetase: EC 2.3.3.8. Pyruvate dehydrogenase: EC 1.2.4.1. Pyruvate carboxylase: EC 6.4.1.1. Nucleoside-diphosphate kinase: EC 2.7.4.6. Presented at the Annual Symposium of the SSIEM, Lisbon, Portugal, 2–5 September 2008.     

Management of methylmalonic acidaemia by combined liver–kidney transplantation

Summary Methylmalonic acidaemia (MMA) is a rare autosomal recessive inborn error of metabolism that typically presents in infancy with recurrent episodes of metabolic acidosis, developmental delay and failure to thrive. The disease course is complicated by the development of chronic tubulointerstitial nephritis progressing to end-stage renal disease in adolescence. We describe two adolescents with cobalamin-nonresponsive MMA (mut ⁰ ) who developed polyuria, chronic tubulointerstitial nephritis, dystonia but normal synthetic liver function. Both patients received combined liver–kidney transplantation (CLKT), preceded by a single pretransplant haemodialysis for clearance of methylmalonic acid. Post CLKT there was 95–97% reduction in serum and urine methylmalonic acid, leading to significant liberalization of dietary protein intake and a consequent increase in body mass index, muscle strength and energy. In addition, renal function normalized and clinical neurological status stabilized. We propose that CLKT be considered as a therapeutic option early in the course of cobalamin-nonresponsive MMA. Progressive tubulointerstitial nephritis with disabling polyuria is a confounder in patient management even in the absence of end-stage renal disease. Successful CLKT restores methylmalonyl-CoA mutase enzyme levels in the liver and kidney, improves clearance of methylmalonic acid with resultant dietary protein liberalization, and offers excellent graft and patient outcomes with improvement in quality of life.     

Renal transplantation in a patient with methylmalonic acidaemia

Renal insufficiency is frequently reported in mutase-deficient methylmalonic acidaemia. We present a case report of a patient with mut– methylmalonic acidaemia who developed chronic tubulointerstitial nephropathy during adolescence. At 24 years of age, she developed end-stage renal failure and underwent renal transplantation. Both plasma and urine methylmalonic acid levels decreased significantly with improved renal function following transplantation. Complications included cyclosporin toxicity and development of diabetes. Renal, metabolic, and clinical status remained improved at 3 years after the kidney transplant.     

Deranged isoleucine metabolism during ketotic attacks in patients with methylmalonic acidaemia

Two patients with methylmalonic acidaemia due to methylmalonyl-CoA mutase deficiency were studied for several years. Both exhibited at least two attacks of severe ketoacidosis, during which they excreted, in addition to methylmalonic acid, a number of abnormal compounds: 3-hydroxypropionic acid, 2-methyl-3-hydroxybutyric acid, 3-hydroxy-n-valeric acid, 3-oxo-n-valeric acid, 2-methyl-3-oxobutyric acid, citraconic acid andN-tiglylglycine. These compounds represent partly intermediary metabolites from the isoleucine degradation pathway and partly secondary metabolites of propionyl-CoA and tiglyl-CoA.     

<Emphasis Type="Italic">N</Emphasis>-Carbamylglutamate protects patients with decompensated propionicaciduria from hyperammonaemia

Summary In patients with propionic aciduria, the accumulating metabolite propionyl-CoA causes a disturbance of the urea cycle via the inhibition of N-acetylglutamate synthesis. Lack of this allosteric activator results in an inhibition of carbamoylphosphate synthase (CPS). This finally leads to hyperammonaemia. In two patients with decompensated propionic aciduria the CPS activator carbamylglutamate was tested for its ability to antagonize the propionyl-CoA associated hyperammonaemia. Oral carbamyl glutamate administration resulted in a significant increase in ammonia detoxification and could avoid further dialysis therapy. Safe, fast and easy to administer, carbamyl glutamate improves the acute therapy of decompensated propionic aciduria by increasing ammonia detoxification and avoiding hyperammonaemia.     

Abnormal tricarboxylic acid cycle metabolites in isovaleric acidaemia

Summary Background  Although a number of abnormal diagnostic metabolites have previously been described in the urine of patients with isovaleric acidaemia (IVA), they do not fully explain the clinical symptoms associated with this disease. Methods  On the basis of our current understanding of the TCA cycle and IVA, we predicted a number of abnormal methylated TCA cycle metabolites, initiated by methylsuccinic acid. We subsequently obtained characteristic gas chromatography–mass spectrometry elution times and mass spectra of the chemically synthesized predicted compounds and screened the urine of 6 IVA patients and 24 age-matched controls. Further proof for our findings was generated from a series of in vitro enzyme reactions using the chemically synthesized standards as substrates to their respective TCA cycle enzymes. Results  Apart from the previously described methylsuccinic and methylfumaric acid, 3-methylmalic acid, (2R,3S)- and (2R,3R)-methylcitric acid and 2-methyl-cis-aconitic acid were detected in the urine of all 6 IVA patients in increased amounts. Additionally, although not directly determined, the in vitro enzyme reaction using of 3-methylmalic acid and malate dehydrogenase, in conjunction with the detection of 2-ketobutyric acid in the urine of all 6 IVA patients, strongly suggests an additional synthesis of 3-methyloxaloacetic acid by the same cycle. Conclusion  Not only do these newly identified metabolites serve as additional diagnostic markers to those previously identified in IVA, but due to the structural arrangements of the (2R,3R)-methylcitric acid and 2-methyl-cis-aconitinic acid-derived 2-methylisocitric acid, inhibition of normal TCA cycle metabolism results at citrate synthase and isocitrate dehydrogenase, respectively. Synopsis  Methylsuccinic acid acts as the initiating substrate to a series of abnormal, potentially harmful, methylated tricarboxylic acid cycle metabolites in isovaleric acidaemia. Competing interests: None declared References to electronic databases: Isovaleric acidaemia: OMIM #243500. Isovaleryl-CoA dehydrogenase: EC 1.3.99.10.     

Stimulation of ketogenesis by propionate in isolated rat hepatocytes: An explanation for ketosis associated with propionic acidaemia and methylmalonic acidaemia?

The effect of propionate on ketone body production from oleate and octanoate in isolated rat hepatocytes was studied. Propionate (5 mmol/l) stimulated ketogenesis from oleate and octanoate, although the effect was more pronounced when octanoate was used as substrate. Propionate decreased CO₂ production from fatty acids, suggesting that propionate inhibited the oxidation of free fatty acid carbons through the tricarboxylic acid cycle. Our results suggest that propionate enhanced ketogenesis as a consequence of the decrease in the rate of the tricarboxylic acid cycle, caused by propionate and/or its derivatives. The stimulation of ketogenesis caused by propionate is discussed as the possible cause of ketosis associated with propionic acidaemia and methylmalonic acidaemia.