Plasma homocyst(e)ine or homocysteine?
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Homocysteine↗
Biomedical subjects
H L Levy
Publications and source records attributed to H L Levy.
Comparison of erythrocyte uridine sugar nucleotide levels in normals, classic galactosemics, and patients with other metabolic disorders.
By limiting galactosylation mechanisms, a cellular deficiency of the uridine sugar nucleotide, UDPgalactose, has been implicated as a cause of the long-term complications seen in patients with classic galactosemia despite dietary treatment. As a result, great interest has been generated in the accurate assessment of UDPgalactose, as well as UDPglucose, from which UDPgalactose may be derived by the function of a ubiquitous, active UDPgalactose-4-epimerase. Since several series of values for the concentration of these compounds in red blood cells (RBCs) of galactosemics have been flawed by the use of methods subsequently shown to be unsuitable, we have quantified erythrocyte UDPgalactose and UDPglucose levels by an accurate high-performance liquid chromatography (HPLC) assay in 116 normals, 76 galactosemics, and 39 patients with other metabolic disorders. These large groups have permitted the evaluation of age, diet, and genotype as influential factors in the steady-state RBC levels of the sugar nucleotides. The data show that age is an important determinant of RBC levels, with children younger than 10 years having higher values than individuals older than 10 years. Mean UDPgalactose levels in galactosemic children younger than 10 years and those older than 10 years were 30% and 18% lower, respectively, than levels in comparable normals. Although the mean differences were highly significant, there was considerable overlap of individual values. There was no difference in UDPglucose levels between galactosemics and normals.(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
Molecular mechanisms of an inborn error of methionine pathway. Methionine adenosyltransferase deficiency.
Methionine adenosyltransferase (MAT) is a key enzyme in transmethylation, transsulfuration, and the biosynthesis of polyamines. Genetic deficiency of alpha/beta-MAT causes isolated persistent hypermethioninemia and, in some cases, unusual breath odor or neural demyelination. However, the molecular mechanism(s) underlying this deficiency has not been clearly defined. In this study, we characterized the human alpha/beta-MAT transcription unit and identified several mutations in the gene of patients with enzymatically confirmed diagnosis of MAT deficiency. Site-directed mutagenesis and transient expression assays demonstrated that these mutations partially inactivate MAT activity. These results establish the molecular basis of this disorder and allow for the development of DNA-based methodologies to investigate and diagnose hypermethioninemic individuals suspected of having abnormalities at this locus.
Amino Acid Metabolism, Inborn Errors↗
Psychosocial factors in maternal phenylketonuria: women's adherence to medical recommendations.
OBJECTIVES: This study identified factors predicting adherence to medical recommendations in maternal phenylketonuria, which can result in severe fetal damage. METHODS: Sixty-nine women with phenylketonuria, 68 of their acquaintances, and 69 women with diabetes mellitus were interviewed annually for 5 years. A model in which each stage in the maternal phenylketonuria life cycle represented a treatment-related goal provided a means to assess adherence. RESULTS: At the stages of prevention of unplanned pregnancy, treatment initiation, and diet continuation throughout pregnancy, attitudes and social support were associated with adherence to medical recommendations. No specific variables were associated with outcome at reproductive decision making, but women with phenylketonuria were more likely to delay making a decision, resulting in unplanned and, hence, untreated or late-treated pregnancy. CONCLUSIONS: Women with phenylketonuria differed from their acquaintances and diabetic women in many respects, suggesting that special programs are needed. Greater emphasis on reproductive decision making is especially needed. Interventions that focus on improving social support networks and attitudes about treatment may increase adherence to recommendations.
Adult↗
Isolated persistent hypermethioninemia.
New information has been obtained on 30 patients with isolated persistent hypermethioninemia, most of them previously unreported. Biopsies to confirm the presumptive diagnosis of partially deficient activity of ATP: L-methionine S-adenosyltransferase (MAT; E.C.2.5.1.6) in liver were not performed on most of these patients. However, none showed the clinical findings or the extreme elevations of serum folate previously described in other patients with isolated hypermethioninemia considered not to have hepatic MAT deficiency. Patients ascertained on biochemical grounds had no neurological abnormalities, and 27/30 had IQs or Bayley development-index scores within normal limits or were judged to have normal mental development. Methionine transamination metabolites accumulated abnormally only when plasma methionine concentrations exceeded 300-350 microM and did so more markedly after 0.9 years of age. Data were obtained on urinary organic acids as well as plasma creatinine concentrations. Patterns of inheritance of isolated hypermethioninemia were variable. Considerations as to the optimal management of this group of patients are discussed.
Adolescent↗
A missense mutation (I278T) in the cystathionine beta-synthase gene prevalent in pyridoxine-responsive homocystinuria and associated with mild clinical phenotype.
Cystathionine beta-synthase (CBS) deficiency is an autosomal recessive disorder characterized by homocystinuria and multisystem clinical disease. Patients responsive to pyridoxine usually have a milder clinical phenotype than do nonresponsive patients, and we studied the molecular pathology of this disorder in an attempt to understand the molecular basis of the clinical variation. We previously reported a T833C transition in exon 8 causing a substitution of threonine for isoleucine at codon 278 (I278T). By PCR amplification and sequencing of exon 8 from genomic DNA we have now detected the I278T mutation in 7 of 11 patients with in vivo pyridoxine responsiveness and in 0 of 27 pyridoxine-nonresponsive patients. Two pyridoxine-responsive patients are homozygous and five are heterozygous for I278T. We have now observed the I278T mutation in 41% (9 of 22) of the independent alleles in pyridoxine-responsive patients of varied ethnic backgrounds. In two of the compound heterozygotes we identified a novel mutation (G139R and E144K) in the other allele. The finding that the two patients who are homozygous for I278T have only ectopia lentis and mild bone demineralization suggests that this mutation is associated with both in vivo pyridoxine responsiveness and mild clinical disease. Compound heterozygous patients who have one copy of this missense mutation are likely to retain some degree of pyridoxine responsiveness.
Adult↗
Mutation analysis in families with discordant phenotypes of phenylalanine hydroxylase deficiency. Inheritance and expression of the hyperphenylalaninaemias.
Neonatal hyperphenylalaninaemia caused by mutations in the gene encoding phenylalanine hydroxylase (PAH) represents a wide spectrum of metabolic phenotypes, ranging from classical phenylketonuria (PKU) to mild hyperphenylalaninaemia (MHP). The marked interindividual heterogeneity is due to the expression of multiple PAH mutations in genetic compounds. We have investigated four unusual families in which both PKU and MHP were present. In each family three different mutations in the PAH gene were identified, including two associated with PKU and one associated with MHP. The unexpected outcome of discordant phenotypes within the families described is explained by previously unrecognized parental MHP. By mutation analysis we have also predicted the phenotypical outcome in a hyperphenylalaninaemic infant born to a mother who before pregnancy had been diagnosed as having MHP. Our results demonstrate the utility of nucleic acid analysis in follow-up in PKU screening programmes.
Amino Acid Metabolism, Inborn Errors↗
Comparison of phenylketonuric and nonphenylketonuric sibs from untreated pregnancies in a mother with phenylketonuria.
Two children, one with phenylketonuria (PKU) and the other nonphenylketonuric, from untreated pregnancies in a mother with PKU provided the opportunity to compare the degree of damage from maternal PKU between these genotypically different fetuses. Both the phenylketonuric offspring and her nonphenylketonuric sib were microcephalic at birth and had congenital anomalies, esophageal atresia in the former and congenital dislocation of the hip in the latter. However, the phenylketonuric child also had intrauterine growth retardation while the nonphenylketonuric sib had normal weight and length at birth. Both children are mentally retarded with an IQ below 50 in the phenylketonuric child despite early dietary treatment for PKU and an IQ of 54 in the nonphenylketonuric sib. Both children also have hypoplasia of the corpus callosum and enlarged cerebral ventricles. This experience and review of the literature indicates that the residual liver phenylalanine hydroxylase activity of a nonphenylketonuric fetus offers little or no protection from damage in untreated maternal PKU. Consequently, the outcome in maternal PKU is likely to depend on control of the maternal biochemical abnormalities in the mother regardless of whether the fetus has or does not have PKU.
Abnormalities, Multiple↗
Molecular characterization of two galactosemia mutations and one polymorphism: implications for structure-function analysis of human galactose-1-phosphate uridyltransferase.
We report here the molecular characterization of two galactosemia mutations, L74P and F171S, and one polymorphism, S135L, in human galactose-1-phosphate uridyltransferase (GALT). Both galactosemia mutations result in reduced enzymatic activity when reconstructed in the cDNA and overexpressed. The polymorphism, in contrast, has near normal activity. Both mutations affect evolutionarily conserved residues, suggesting that they are functionally important, while the polymorphism occurs in a nonconserved domain which is presumably not critical for enzymatic function. The F171S mutation is close to the putative active-site nucleophile. Our data further support the notion of molecular heterogeneity of galactosemia and suggest that galactosemia mutations and GALT polymorphisms may be useful tools in highlighting different functional domains in human GALT.
Base Sequence↗
Prenatal diagnosis of non-ketotic hyperglycinaemia.
Non-ketotic hyperglycinaemia (NKH) is a devastating neurological disease for which there is no effective therapy. Consequently, most couples with a pregnancy known to be at risk for NKH request prenatal diagnosis. We have applied the combination of chorionic villus (CVS) assay for glycine cleavage enzyme activity and determination of amniotic fluid glycine concentration to increase the reliability of prenatal diagnosis for this disorder beyond that of each of these methods alone. All 15 of the at-risk pregnancies monitored had CVS glycine cleavage assay and five also had amniotic fluid glycine measurements. Two cases had no detectable cleavage activity in CVS and one gave uninterpretable enzyme results. Amniotic fluid glycine concentration was increased in all three and NKH was confirmed by abortus tissue assays for cleavage activity and amino acids. The remaining 12 case had activity in CVS (two also had normal amniotic fluid glycine levels) and delivered unaffected infants. Four of these 12 cases had cleavage activities below or at the low end of the normal range, perhaps indicating carrier status. We believe that the combination of CVS glycine cleavage assay and amniotic fluid glycine measurement is currently the best approach to the prenatal diagnosis of NKH.
Amino Acid Metabolism, Inborn Errors↗
Characterization of two missense mutations in human galactose-1-phosphate uridyltransferase: different molecular mechanisms for galactosemia.
We report the molecular characterization of two novel galactosemia mutations that exhibit different molecular phenotypes. Both are of the missense type with low or no residual enzyme activity. The R148W mutation results in an unstable protein, although messenger RNA is still produced. In contrast, the L195P mutation produces stable but inactive immunoreactive protein. The R148W mutation alters an amino acid that is not evolutionarily conserved, while the L195P mutation affects a well-conserved residue nine amino acids down-stream from the putative active site nucleophile. These mutations provide evidence that different mechanisms can result in galactosemia: destabilizing mutations in any given area of the protein and missense mutations in conserved domains of the enzyme resulting in low or no activity. These two mutant alleles represent the fifth and sixth galactosemia mutations and confirm the hypothesis that galactosemia results from a multiplicity of mutations at the molecular level.
Amino Acid Sequence↗
Maternal phenylketonuria collaborative study, obstetric aspects and outcome: the first 6 years.
OBJECTIVE: The purpose of this study was to evaluate the efficacy of a phenylalanine-restricted diet in reducing fetal morbidity associated with maternal hyperphenylalaninemia in women of childbearing age with blood phenylalanine levels greater than 240 mumol/L (greater than 4 mg/dl) on an unrestricted diet. STUDY DESIGN: Two hundred thirteen pregnant women with hyperphenylalaninemia that resulted in 134 live births have been enrolled in the study. Outcome measures were subject to the chi 2 test, Fisher exact test, analysis of variance, t test, or Wilcoxon nonparametric test for analysis. RESULTS: Optimal fetal outcome appeared to occur when blood phenylalanine levels less than 600 mumol/L (less than 10 mg/dl) were achieved by 8 to 10 weeks' gestation and maintained throughout pregnancy (trimester averages of less than or equal to 360 mumol/L (less than or equal to 6 mg/dl). Initiation of dietary therapy during the third trimester of pregnancy appears to have little beneficial effect on the fetus. CONCLUSIONS: Preconceptual counseling and early entrance into a prenatal care program is essential in achieving optimal fetal outcome in women with hyperphenylalaninemia.
Congenital Abnormalities↗
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↗
Neonatal hemochromatosis: diagnosis with MR imaging.
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Family↗
Do children benefit from mass screening for neuroblastoma? Consensus Statement from the American Cancer Society Workshop on Neuroblastoma Screening.
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Age Factors↗
Agoraphobia in phenylketonuria.
We describe agoraphobia as a complication of phenylketonuria (PKU) in young adults. The five patients have classic PKU and received phenylalanine-restricted diet only in childhood. Only one has normal intelligence. All but one were also depressed. All were anxious. Three of the five had initiated the phenylalanine-restricted diet after 3 months of age. Two returned to the phenylalanine-restricted diet with dramatic reduction of symptoms. The frequency of manifestations of agoraphobia was also examined in 50 young women with PKU enrolled in a longitudinal study of psychosocial factors in maternal PKU, 47 of their acquaintances and 49 women with diabetes. All were administered a test of agoraphobic-avoidant behaviour. The women with PKU appeared to be more prone to social withdrawal and fear of leaving home. Twenty per cent were within the agoraphobia range of the Mobility Inventory. Those still on diet and those with non-PKU hyperphenylalaninaemia reported less avoidant behaviour than those who had terminated the diet in childhood. These results suggest that young adults with PKU are at risk for agoraphobia but that return to the phenylalanine-restricted diet may be an effective treatment.
Adult↗
Characterization of a novel biochemical abnormality in galactosemia: deficiency of glycolipids containing galactose or N-acetylgalactosamine and accumulation of precursors in brain and lymphocytes.
Classic galactosemia, an inborn error of human galactose metabolism, is characterized by a deficiency of the enzyme galactose-1-phosphate uridyltransferase (GALT). The current model for the pathophysiology of this disease ascribes most of its symptoms to the toxicity of intracellular galactose-1-phosphate (Gal-1-P), one of the substrates of GALT which accumulates in the untreated disease state. Recently, a reduction in the intracellular concentration of UDP-Gal (uridine diphosphogalactose), one of the products of GALT, has been described in treated galactosemic patients. We investigated whether galactosemic patients might also have reduced amounts of those macromolecules that depend on UDP-Gal for their biosynthesis. We report a reduction in glycolipids that contain either galactose or its derivative N-acetylgalactosamine and an accumulation of the precursors to these compounds in the brain of a neonate with galactosemia. We also found an imbalance in glycolipids in galactosemic lymphoblasts. This novel biochemical abnormality observed in galactosemic patients is not addressed by dietary galactose-restriction therapy and could explain some of the chronic neurologic and other complications of galactosemia.
Acetylgalactosamine↗
Paternal phenylketonuria.
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Benzene Derivatives↗