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P Rinaldo

Publications and source records attributed to P Rinaldo.

At least 73 records · Page 4Linked to original sources
PubMed1994

A novel mutation in medium chain acyl-CoA dehydrogenase causes sudden neonatal death.

Medium chain acyl-CoA dehydrogenase (MCAD) deficiency is the most common known genetic disorder of fatty acid oxidation. Most (approximately 80%) cases are homozygous for a single mutation: A to G replacement at nucleotide 985 (A985G). MCAD deficiency typically presents in the second year of life as hypoketotic hypoglycemia associated with fasting and may progress to liver failure, coma, and death. Prompt diagnosis and management may prevent long-term sequelae. MCAD deficiency was verified by analysis of urinary acylglycine and serum acylcarnitine species from two neonates referred for diagnosis. Full-length cDNA and MCAD exon 7 and 11 genomic clones were prepared for sequence analysis. Normal and mutant cDNAs were expressed in bacteria, and enzymatic activity was assayed by the ferricenium hexaflurophosphate method. Four compound heterozygote individuals from two unrelated families with A985G on one allele and a novel G to A mutation at nucleotide 583 (G583A) as the second mutant allele presented with MCAD deficiency in the first week of life. The expressed G583A mutant protein lacks enzymatic activity. This novel mutation, G583A, is associated with severe MCAD deficiency causing hypoglycemia or sudden, unexpected neonatal death. This previously unrecognized phenotype of MCAD deficiency may contribute significantly to preventable infant deaths.

Acyl-CoA Dehydrogenase↗
PubMed1994

Acute fatty liver of pregnancy and long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency.

The pathogenesis of acute fatty liver of pregnancy is unknown, but similarities in the clinical presentation and the histological appearance of the liver with those found in children with metabolic defects in the intramitochondrial beta-oxidation pathway of the liver suggest that a disturbance in hepatic fatty acid oxidation may play a role. We report a woman with acute fatty liver of pregnancy who gave birth to a seemingly normal full-term infant who was seen at 4 mo of age with hypoglycemia, coma and profound hepatic steatosis. The infant had a defect in fatty acid oxidation, long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency, and the mother proved to be heterozygous for this metabolic condition. We hypothesize that the interaction of an affected fetus with a female heterozygous for this defect in fatty acid oxidation in the late third trimester accounts for some cases of acute fatty liver of pregnancy.

3-Hydroxyacyl CoA Dehydrogenases↗
PubMed1993

Short-term response to dietary therapy in molybdenum cofactor deficiency.

Molybdenum cofactor deficiency was diagnosed in a 3-month-old girl who presented with microcephaly, developmental delay, severe irritability, and lactic acidosis. Dietary methionine restriction, with cysteine supplementation, was associated with moderate short-term clinical improvement, including a resumption in predicted head growth, modest developmental progress, and a reduction in irritability. Clinical relapse was associated with noncompliance of dietary therapy 2 months later. Urinary sulfite levels measured by commercial dipsticks were useful in following therapy. Molybdenum cofactor deficiency is probably frequently underdiagnosed due to the lack of specific clinical or laboratory features. Screening of infants at risk for the presence of urinary sulfites or serum hypouricemia, or both, is both rapid and inexpensive.

Acidosis, Lactic↗
PubMed1993

Reliable prenatal diagnosis of Canavan disease (aspartoacylase deficiency): comparison of enzymatic and metabolite analysis.

Prenatal diagnosis has been undertaken in 17 pregnancies in 15 families at risk for aspartoacylase deficiency. Amniocentesis was at 14-18 weeks gestation followed by measurement of amniotic fluid N-acetyl-L-aspartate (NAA) levels in all pregnancies and amniocyte aspartoacylase activity in most pregnancies. In one case amniocentesis was performed at 11 weeks gestation in conjunction with chorionic villus sampling. At 14-18 weeks of gestation, control levels of NAA were 0.30-2.55 mumol/L. The fetus was predicted to be affected in 8 of the pregnancies, 4 of which were confirmed by enzyme analysis on fetal tissue and 2 by the clinical and metabolic expression of Canavan disease in a newborn. In two cases there was no fetal tissue available for enzyme confirmation. One of these had the highest amniotic fluid NAA level (8.68 mumol/L) and in the other pregnancy there were two amniocenteses, both with markedly elevated levels. Of 9 fetuses predicted to be normal, 8 newborns were clinically and biochemically normal. A single case with amniotic fluid NAA in the normal range (1.56 mumol/L, measured in one laboratory only) resulted in an aborted fetus in whom aspartoacylase was deficient in cultured skin fibroblasts. We propose that amniotic fluid NAA levels remain the best predictor of an affected fetus and recommend that the assay be performed in multiple laboratories.

Amniotic Fluid↗
PubMed1993

Effect of treatment with glycine and L-carnitine in medium-chain acyl-coenzyme A dehydrogenase deficiency.

To assess the relative contribution of glycine and carnitine conjugation pathways to total acyl-group excretion, we investigated the excretion of C6 to C10 dicarboxylic acids, C6 to C8 acylglycines, and C6 to C8 acylcarnitines in five symptom-free patients with medium-chain acyl-coenzyme A dehydrogenase deficiency during sequential 1-week periods as follows: (1) no treatment, (2) oral supplementation with glycine, 250 mg/kg per day, (3) oral supplementation with L-carnitine, 100 mg/kg per day, and (4) oral supplementation with both combined. In untreated patients, acylglycines and acylcarnitines represented 60% and less than 1% of the total metabolite excretion, respectively; the average acylglycine/acylcarnitine ratio was 70:1. Oral supplementation with glycine did not alter the excretion of acylglycines or acylcarnitines. L-Carnitine supplementation increased the acylcarnitine excretion sixfold and caused a 60% reduction in acylglycine excretion (p < 0.001); however, even with carnitine supplementation, acylglycine excretion was still 10 times greater than that of acylcarnitines. The results suggest that glycine conjugation was the major pathway for the disposal of C6 to C8 acyl moieties and that oral L-carnitine supplements may inhibit glycine conjugation. The findings cast doubt on the value of long-term treatment of medium-chain acyl-coenzyme A dehydrogenase deficiency with L-carnitine.

Acyl-CoA Dehydrogenase↗
PubMed1993

Impaired fatty acid oxidation in children on valproic acid and the effect of L-carnitine.

Fatty acid oxidation was studied in 12 patients (aged 3 to 19 years) receiving valproic acid (VPA), predominantly as monotherapy, before and after 1 month of L-carnitine supplementation (50 mg/kg/day po) in order to determine whether L-carnitine plays a role in preventing the hepatotoxic effects of this drug. Five of these patients were also studied prior to VPA treatment. Only one patient taking VPA had an abnormally low plasma free carnitine. Acyl-/free carnitine ratios were elevated in five patients on VPA and normalized after L-carnitine supplementation. Mean plasma concentrations of free fatty acids, beta-OH-butyrate, and cumulative excretion of 13CO2 after administration of 1-13C-octanoic acid were not changed by VPA or L-carnitine treatment. Urinary dicarboxylic acids, acylglycines, and octanoylcarnitine were elevated during VPA therapy and unaltered by L-carnitine. These results suggest that, in patients at low risk for VPA-induced hepatotoxicity (patients aged > 2 years and taking VPA as monotherapy), VPA causes metabolic abnormalities resembling those found in inborn errors of mitochondrial beta-oxidation which are not corrected by L-carnitine.

Adolescent↗
PubMed1993

Metabolic disease of the neonate and young infant.

The inborn errors of metabolism must always be considered when a newborn presents with neurological distress, feeding difficulties, or a family history of neonatal or unexplained death. Clinical suspicion combined with prompt sophisticated laboratory evaluation is crucial if infants affected with this group of disorders are to be rescued.

Amino Acid Metabolism, Inborn Errors↗
PubMed1992

Intentional infantile ethylene glycol poisoning presenting as an inherited metabolic disorder.

A 6-month-old girl was hospitalized on three occasions for irritability, vomiting, acidosis, and hypotonia. During the third hospitalization hyperglycinemia and urinary glycolic acid were detected. Ethylene glycol was discovered in the infant's blood and bottled formula. Clinicians must consider ethylene glycol intoxication as a cause of recurrent infantile metabolic acidosis.

Acidosis↗
PubMed1992

Urinary medium-chain acylcarnitines in medium-chain acyl-CoA dehydrogenase deficiency, medium-chain triglyceride feeding and valproic acid therapy: sensitivity and specificity of the radioisotopic exchange/high performance liquid chromatography method.

To determine the sensitivity and specificity of detecting urinary medium-chain acylcarnitines for the diagnosis of MCAD deficiency, 114 urine specimens from 75 children with metabolic diseases and controls were analyzed in a blinded fashion using a radioisotopic exchange/HPLC method. All 47 patients with MCAD deficiency were correctly diagnosed using the criterion hexanoylcarnitine or octanoylcarnitine peak areas larger than those of other medium-chain acylcarnitines. The majority of them were tested during the asymptomatic state without L-carnitine loading. Four patients with other defects of fatty acid oxidation and three patients receiving valproic acid had a similar acylcarnitine excretion pattern. To further examine the specificity of the method, eight infants receiving a diet enriched with medium-chain triglycerides and 13 additional patients receiving valproic acid were studied. Most of these also tested positive for MCAD deficiency by the above criterion. Analysis by a new gas chromatographic-mass spectrometric procedure revealed that octanoylcarnitine, not valproylcarnitine, was the most abundant medium-chain carnitine ester excreted by a patient treated with valproic acid. Quantitation of urinary hexanoylcarnitine and octanoylcarnitine showed considerable overlap among patients with MCAD deficiency and those receiving valproic acid or a medium-chain triglyceride-enriched diet. MCAD deficiency can be reliably detected in urine specimens by this method without the need for prior carnitine loading. However, other defects in fatty acid oxidation must be differentiated from MCAD deficiency, and a history of medium-chain triglyceride or valproic acid administration must be considered if the diagnosis of MCAD deficiency is sought through analysis of urinary acylcarnitines.

Acyl-CoA Dehydrogenase↗
PubMed1992

Detection and quantitation of acylcarnitines in plasma and blood spots from patients with inborn errors of fatty acid oxidation.

Acylcarnitine profiling in plasma and dried blood spots by radioisotopic exchange/HPLC demonstrates that MCAD deficiency can be reliably detected in the asymptomatic state without L-carnitine therapy. The OC/AcC ratio differentiates MCAD deficiency from normal controls. A longer chain acylcarnitine (r.t. 43 min.) was detected in all 3 patients with a defect in long chain fatty acid oxidation. Detection of C4- and C5-acylcarnitine isomers in plasma helped characterize a metabolic defect affecting branched chain acyl-CoA oxidation in 3 patients. Quantitative data in 2 patients with MCAD deficiency showed that plasma concentrations of OC and AcC are dependent on both the availability of free carnitine and the severity of metabolic decompensation.

Acyl-CoA Dehydrogenase↗
PubMed1991

Mass spectrometric analysis of metabolite excretion in five Japanese patients with the late-onset form of glutaric aciduria type II.

The variability of clinical and biochemical features in five Japanese patients with the late-onset form of glutaric aciduria type II (GAII) was studied using mass spectrometric procedures. The age at onset ranged from 5 months to five years, presenting acute episodes such as lethargy, hypotonia, hyperammonaemia, hypoglycaemia or Reye's syndrome-like illness, while one of the five cases was asymptomatic at 1 year of age. Organic acid analysis as oxime-trimethylsilyl derivatives by gas chromatography/mass spectrometry revealed the presence of several abnormalities characteristic of GAII in clinically asymptomatic conditions of three patients but not of the two others. Quantitative acylglycine analysis using a stable isotope dilution method and qualitative acylcarnitine analysis by fast atom bombardment mass spectrometry provided diagnostic information in all five patients, regardless of their clinical conditions. However, significant differences in the respective metabolite profiles as well as in their clinical pictures were noted. Although an increased excretion of both isovalerylglycine and isovalerylcarnitine was found in four patients, the fifth showed normal isovalerylglycine excretion during both the acute stage and in remission, despite the increased amount of isovalerylcarnitine in urine. From these results, it was suggested that the variations in clinical severity and metabolite excretion among GAII patients may be attributed not only to the residual enzyme activity at the defective site but also to differences in the capability to conjugate accumulated acyl-coenzyme A.

Acids↗
PubMed1991

Ethylmalonic/adipic aciduria: effects of oral medium-chain triglycerides, carnitine, and glycine on urinary excretion of organic acids, acylcarnitines, and acylglycines.

A 9-y-old girl with ethylmalonic/adipic aciduria was hospitalized to determine the possible therapeutic efficacy of oral carnitine and glycine supplementation. To provoke a mild metabolic stress, her diet was supplemented with 440 mg/kg/d of medium-chain triglycerides. She was treated successively with carnitine (100 mg/kg/d) for 5 d, neither carnitine nor glycine for 2 d, and then glycine (250 mg/kg/d) for 6 d. Consecutive 12-h urine collections were obtained throughout the entire period. The urinary excretion of eight organic acids, four acylglycines, and four acylcarnitines, which accumulate as a result of a metabolic block of five mitochondrial acyl-CoA dehydrogenases, were quantitatively determined by capillary gas chromatography, stable isotope dilution gas chromatography/mass spectrometry, and radioisotopic exchange HPLC, respectively. The excretion of each group of metabolites was calculated as the mean percentage of total output (mumol/24 h) during the four phases of the protocol (organic acids/acylglycines/acylcarnitines = 100.0%): 1) regular diet (3 d); 88.1/10.8/1.1; 2) medium-chain triglyceride supplementation (4); 82.5/15.6/1.9; 3) medium-chain triglycerides plus carnitine (5); 79.2/8.2/12.6; and 4) medium-chain triglycerides plus glycine (6); 81.0/18.7/0.3. Comparison between total and individual excretion of acylglycines and acylcarnitines indicates that oral glycine supplementation enhanced the conjugation and excretion of fatty acyl-CoA intermediates as efficiently as carnitine. We propose that oral glycine supplementation should be considered in the treatment of other inborn errors of metabolism associated with abnormal urinary excretion of acylglycines.

Acylation↗
PubMed1991

Prenatal diagnosis and neonatal monitoring of a fetus with glutaric aciduria type II due to electron transfer flavoprotein (beta-subunit) deficiency.

The prenatal diagnosis of a male fetus with glutaric aciduria type II and the time course of metabolite urinary excretion, starting immediately after birth, are described. Prenatal diagnosis was undertaken at the 17th wk of gestation by immunoblot analysis and pulse labeling experiments of amniocytes and, retrospectively, by stable isotope dilution analysis of six metabolites in amniotic fluid. The results were as follows: 1) The immunochemical analysis on cultured amniocytes showed that the fetus, as the previous index case in this family, was affected with a deficiency of the beta-subunit of electron transfer flavoprotein. 2) Glutarate concentration was significantly increased in the cell-free supernatant of the amniotic fluid. In the postnatal period, most of the organic acids and acylglycines characteristic of the disorder appeared in urine within a week, although an increased excretion of hexanoylglycine was the only biochemical abnormality detectable in the first urine sample collected at 9 h after birth. Growth and development of this infant were normal during the following 6 mo of life, when he was receiving oral supplementation with L-carnitine and riboflavin. It should be underscored that transient abnormalities in routine blood tests (glutamic oxaloacetic transaminase, lactate dehydrogenase, and creatine phosphokinase) were present soon after birth, despite his asymptomatic clinical course. Early detection and aggressive treatment could be effective in such a form of glutaric aciduria type II.

Amniotic Fluid↗
PubMed1991

Molecular survey of a prevalent mutation, 985A-to-G transition, and identification of five infrequent mutations in the medium-chain Acyl-CoA dehydrogenase (MCAD) gene in 55 patients with MCAD deficiency.

Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is an inborn error of fatty-acid oxidation that is characterized by fasting intolerance and recurrent episodes of hypoglycemic coma which can be fatal. Its incidence is one of the highest among genetic metabolic disorders. Using a modified PCR and NcoI digestion method, we have surveyed 46 additional, unrelated MCAD-deficient patients for a prevalent mutation, an 985A-to-G transition (985A----G), that we previously identified in nine MCAD-deficient patients. Among the total of 55 studied, 44 were homozygous and 10 were heterozygous for the 985G allele, whereas one did not carry this mutant allele, indicating that the prevalence of the 985G allele is 89.1%. Furthermore, we identified five other types of mutation: one each in three of the compound heterozygotes and two in the single non-985G patient. An RFLP study of 12 985G-homozygotes showed that all 24 alleles fell into a single haplotype. A questionnaire regarding the ethnic and national origin of their patients was sent to all referring investigators. All 41 patients for whom this information was provided were Caucasians. Of 29 patients whose country of origin was specified, 19 and five were from the British Isles and Germany, respectively. These data suggest that 985A----G may have occurred in a single person in an ancient Germanic tribe.

Acyl-CoA Dehydrogenase↗