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Biomedical subjects

S Milstien

Publications and source records attributed to S Milstien.

At least 91 records · Page 5Linked to original sources
PubMed1987

Folinic acid therapy in treatment of dihydropteridine reductase deficiency.

We gave folinic acid to three siblings, and to a fourth child, who have or had dihydropteridine reductase (DHPR) deficiency. The youngest began folinic acid therapy in addition to neurotransmitter precursors and a phenylalanine-restricted diet at age 2 months, and at 2 years of age has near normal development without evidence of neurologic impairment. His older brother began similar treatment at 5 1/2 months of age, when early neurologic findings were evident. At age 6 years his mental retardation and neurologic impairment are less severe than reported in most patients with DHPR deficiency. Little improvement occurred in their sister, who first received treatment at 2 years of age, when she already had severe neurologic impairment. An unrelated boy with profound neurologic impairment showed subtle signs of improvement after he began treatment with folinic acid alone at age 9 years. These results provide evidence that folinic acid is important in the treatment of DHPR deficiency and, if begun early in infancy, may prevent irreversible neurologic damage. The mechanism of folinic acid action in DHPR deficiency may be to increase indirectly the synthesis of 5-methyltetrahydrofolate.

5-Hydroxytryptophan↗
PubMed1987

Structure and expression of human dihydropteridine reductase.

Dihydropteridine reductase (DHPR; EC 1.6.99.7) catalyzes the NADH-mediated reduction of quinonoid dihydrobiopterin and is an essential component of the pterin-dependent aromatic amino acid hydroxylating systems. A cDNA for human DHPR was isolated from a human liver cDNA library in the vector lambda gt11 using a monospecific antibody against sheep DHPR. The nucleic acid sequence and amino acid sequence of human DHPR were determined from a full-length clone. A 112 amino acid sequence of sheep DHPR was obtained by sequencing purified sheep DHPR. This sequence is highly homologous to the predicted amino acid sequence of the human protein. Gene transfer of the recombinant human DHPR into COS cells leads to expression of DHPR enzymatic activity. These results indicate that the cDNA clone identified by antibody screening is an authentic and full-length cDNA for human DHPR.

Amino Acid Sequence↗
PubMed1987

Cerebrospinal fluid monoamines in Down's syndrome adults at different ages.

Markers of monoamine metabolism in lumbar cerebrospinal fluid (CSF) and plasma were determined in nine young, healthy adults with trisomy 21 Down's syndrome (DS), 21-34-years-old, and in three DS subjects over 45 years, two of whom were demented, as well as in two groups of age-matched controls. Test scores of general intelligence, visuospatial ability, visual discrimination and verbal intelligence were reduced significantly in the old as compared to the young DS subjects. Dementia in DS was evident from a history of mental deterioration, disorientation and hallucinations. In the young DS adults, as compared to the controls, CSF 5-HIAA and norepinephrine were significantly elevated but plasma levels were unchanged. HVA, MHPG and biopterin did not differ between the DS groups and age-matched controls, or with relation to age in the DS or control subjects. These results suggest an increased turnover of monoamines in young adults with DS but that alterations in monoamine metabolism are unrelated to the cognitive decline with age in DS.

Adult↗
PubMed1986

Cerebrospinal fluid biopterin is decreased in Alzheimer's disease.

Tetrahydrobiopterin is the cofactor in the hydroxylation of phenylalanine, tyrosine, and tryptophan leading to the eventual synthesis of the monoaminergic neurotransmitters, dopamine, norepinephrine, and serotonin, respectively. Total biopterin (90% of which is in the tetrahydro form) was measured in cerebrospinal fluid (CSF) and plasma of 30 patients with Alzheimer's disease and of 19 healthy controls. Plasma and CSF biopterin concentrations were not significantly correlated, but the mean CSF biopterin concentration in patients with Alzheimer's disease was significantly less than in age-matched controls, 13.5 pmol/mL as compared with 18.9 pmol/mL. The CSF biopterin concentration was not correlated with ventricular volume, as estimated by quantitative computed tomography, nor with the severity of dementia, as measured by various cognitive tests. The results suggest that a central biopterin deficiency exists in Alzheimer's disease.

Adult↗
PubMed1986

A modified ferrozine method for the measurement of enzyme-bound iron.

A general procedure for the determination of the iron content of enzymes by digestion with methanesulfonic acid to release protein-bound iron has been developed. This procedure replaces the tedious and potentially hazardous method of wet ashing with concentrated nitric-sulfuric-perchloric acids. The method has been used to determine the stoichiometry of iron for nanomole quantities of heme-iron proteins, iron-sulfur proteins, complex iron-sulfur proteins, as well as in phenylalanine hydroxylase, an enzyme with iron in an undetermined coordination.

Catalase↗
PubMed1985

Biosynthesis of tetrahydrobiopterin: conversion of dihydroneopterin triphosphate to tetrahydropterin intermediates.

It is known that the first step in the de novo synthesis of tetrahydrobiopterin from GTP is the conversion of GTP to dihydroneopterin triphosphate. Recent evidence supports the conclusion that beyond this first step, the pterin intermediates in the pathway are all at the tetrahydro level of reduction. We have now shown that partially purified fractions from rat liver, rat brain and bovine adrenal medulla catalyze the conversion of dihydroneopterin triphosphate to tetrahydrobiopterin, as well as to the putative intermediates in the pathway, 6-pyruvoyl-tetrahydropterin and 6-lactoyl-tetrahydropterin. Results of both enzymatic and chemical studies support the assigned structures for the latter two tetrahydropterins. We have also purified extensively from brain an enzyme, distinct from sepiapterin reductase, that catalyzes the TPNH-dependent reduction of 6-pyruvoyl-tetrahydropterin to 6-lactoyl-tetrahydropterin. The role of this reductase in tetrahydrobiopterin synthesis has not yet been established.

Adrenal Medulla↗
PubMed1984

Dystonia in 61-year-old identical twins: observations over 45 years.

We examined 61-year-old identical twin women of Jewish extraction with a probable autosomal recessive form of torsion dystonia. The dystonia in each was relatively mild and discovered only because a young relative developed dystonia. The twins were said to be discordant for dystonia, but personal evaluation led to the diagnosis of dystonia in both. Their slow course, with prolonged spontaneous remission in one twin, is in contrast to that described in most published reports. Although similar in mode of onset and initial course, the twins were dissimilar in age at onset, influence of pregnancy, diurnal variation in symptoms, need for medication, later course, and degree of disability at age 61. Normal plasma levels of norepinephrine and dopamine-beta-hydroxylase are consistent with autosomal recessive hereditary torsion dystonia. The importance of personal evaluation of key family members in establishing the correct genetic basis for a heterogeneous group of disorders, such as the hereditary dystonias, is stressed.

Chromosome Aberrations↗
PubMed1984

Biopterin synthesis defect. Treatment with L-dopa and 5-hydroxytryptophan compared with therapy with a tetrahydropterin.

We have identified a generalized deficiency of monoamine neurotransmitters in a patient with a defect in biopterin synthesis. Neurotransmitter precursors (L-3,4-dihydroxyphenylalanine [L-dopa]; 5-hydroxytryptophan [5-HTP] and a tetrahydropterin [6-methyltetrahydropterin (6MPH4)] were investigated for their ability to normalize monoamine neurotransmitter metabolism. Before treatment, the concentrations of dopamine (DA), norepinephrine, epinephrine, and six monoamine metabolites were very low or undetectable in plasma, cerebrospinal fluid, or urine. L-Dopa and 5-HTP replacement was begun at age 7 mo. This therapy generally corrected the deficiency of monoamines and their metabolites, and improved neurological development until the age of 25 mo. Despite these benefits, the intermittent administration of L-dopa could not produce a stable improvement of acute neurological function or DA metabolism. In the 3 h after L-dopa administration, plasma DA and the motor activity and alertness of the patient rose and fell in parallel. Doses of L-dopa that were clinically optimal produced normal plasma levels of norepinephrine and epinephrine, but excessive concentrations of DA and its metabolites. Furthermore, the clinical and biochemical effects of L-dopa were inhibited by phenylalanine and 5-HTP, respectively, demonstrating that these amino acids have antagonistic pharmacological effects. Physiological correction of the monoamine deficit and the hyperphenylalaninemia of this disorder was attempted at age 35 mo using high doses (8-38 mg/kg per d) of 6MPH4. 6MPH4, a synthetic analogue of tetrahydrobiopterin, controlled the hyperphenylalaninemia. Significant concentrations of 6MPH4 were obtained in the cerebrospinal fluid; no neurological improvement or stimulation of monoamine synthesis in the central nervous system was detected. These findings indicate the complexity in replacement therapy with L-dopa and 5-HTP, but suggest that this treatment may be partially effective in biopterin-deficient patients who are unresponsive to high doses of tetrahydropterins.

5-Hydroxytryptophan↗
PubMed1984

Biopterin synthesis defects: problems in diagnosis.

Hyperphenylalaninemia due to a biopterin synthesis defect was detected in an infant with decreased biopterin and increased neopterin levels in plasma and urine. Tetrahydrobiopterin (BH4) administration normalized plasma phenylalanine levels. CSF biopterin and neurotransmitter metabolite levels were normal and with the infant's normal growth and development suggest that the defect in biopterin synthesis did not affect CNS biopterin metabolism. Comparison of plasma and urine pterin levels from this patient with levels reported in patients who have neurologic complications fails to reveal differences that would distinguish patients at risk for neurologic problems. CSF pterin and neurotransmitter levels may correlate with neurologic function in these patients. CSF pterin and neurotransmitter determinations should be performed prior to initiation of neurotransmitter precursor and BH4 replacement therapies in patients who were determined to have biopterin synthesis defect(s).

Biopterins↗
PubMed1983

Tetrahydro-sepiapterin is an intermediate in tetrahydrobiopterin biosynthesis.

7,8-Dihydrobiopterin is not an intermediate in the de novo biosynthesis of tetrahydrobiopterin, the cofactor required for aromatic amino acid hydroxylations. However, N-acetyl-serotonin inhibition of sepiapterin reductase, an enzyme whose previously only known function was the reduction of sepiapterin to 7,8-dihydrobiopterin, completely inhibited biosynthesis of tetrahydrobiopterin by bovine adrenal medulla extracts. We have now shown that sepiapterin reductase catalyzes the reduction of tetrahydro-sepiapterin to tetrahydrobiopterin and that this reaction is N-acetyl-serotonin-sensitive. A new pathway for tetrahydrobiopterin biosynthesis is proposed which takes these observations into account and which involves tetrahydro intermediates.

Adrenal Medulla↗
PubMed1980

Neopterin and biopterin levels in patients with atypical forms of phenylketonuria.

The pattern of unconjugated pterins in liver tissue and in urine from patients with atypical forms of phenylketonuria with hyperphenylalaninemia (HPA) has been investigated with a high performance liquid chromatographic technique. Two patients with defects in the biosynthesis of biopterin have been shown to have higher than normal levels of neopterin and lower than normal levels of biopterin. In contrast, a patient with HPA due to a deficiency of dihydropteridine reductase has the reverse urinary pattern, i.e., high biopterin, low neopterin. These results indicate that the ratio of neopterin to biopterin in urine can be of value in discriminating between HPA due to a deficiency of phenylalanine hydroxylase (classic PKU), HPA due to dihydropteridine reductase deficiency, and HPA due to a block in the biosynthesis of biopterin.

Amino Acid Metabolism, Inborn Errors↗
PubMed1980

Hyperphenylalaninemia due to dihydropteridine reductase deficiency: diagnosis by measurement of oxidized and reduced pterins in urine.

Hyperphenylalaninemia due to dihydropteridine reductase deficiency results from the inability to maintain the aromatic amino acid hydroxylase cofactor, tetrahydrobiopterin, in its reduced or active form. Diagnosis of the disease is usually made by direct enzymatic assay on liver biopsies or in cultured skin fibroblasts. Evidence is presented that normal children and classic phenylketonuric children excrete mainly tetrahydrobiopterin in their urines, whereas children with dihydropteridine reductase deficiency excrete only oxidized forms of biopterin. Details of a rapid high performance liquid chromatographic assay for the measurement of the various forms of biopterin in urine are presented. This assay can be used to screen for suspected dihydropterine reductase mutants.

Adult↗
PubMed1979

The mechanism of the irreversible inhibition ofrat liver phenylalanine hydroxylase due to treatment with p-chlorophenylalanine. The lack of effect on turnover of phenylalanine hydroxylase.

The administration of a single dose of p-chlorophenylalanine (360 mg/kg) to rats leads to the irreversible loss of 90% of hepatic phenylalanine hydroxylase activity after 24 h. This loss of activity is not the result of either an alteration in the overall structure of the enzyme, as determined by its antigenicity, or in the total immunologically reactive protein in the liver, as tested with a specific antiserum prepared against native phenylalanine hydroxylase. Neither the rate of synthesis nor the rate of degradation of phenylalanine hydroxylase is changed by p-chlorophenylalanine (pClPhe) treatment. The half-life for the enzyme is about 2 days in control and in pClPhe-treated rats. In addition, there is no detectable incorporation of pClPhe into the phenylalanine hydroxylase molecule itself.

Animals↗
PubMed1979

Dihydropteridine reductase deficiency associated with severe neurologic disease and mild hyperphenylalaninemia.

A deficiency of hepatic dihydropteridine reductase (DHPR) activity was found in a neurologically impaired infant with mild hyperphenylalaninemia and normal levels of hepatic phenylalanine hydroxylase. DHPR is required for the regeneration of tetrahydrobiopterin, an essential cofactor in aromatic amino acid hydroxylation, a necessary step in the biosynthesis of the neurotransmitters, dopamine and serotonin. Evidence for decreased synthesis of these transmitters in this patient was provided by the finding of reduced levels of homovanillic acid and 5-hydroxyindole acetic acid, metabolites of dopamine and serotonin, respectively, in the cerebrospinal fluid and urine. Treatment with dopamine and serotonin precursors, L-3,4 dihydroxyphenylalanine and 5-hydroxytryptophan, respectively, was associated with improvement in temperament and motor tone and less frequent seizures. However, there was no improvement in gross motor function or language development.

5-Hydroxytryptophan↗
PubMed1978

Hyperphenylalaninemia due to a deficiency of biopterin. A variant form of phenylketonuria.

We studied the components of the hepatic phenylalanine hydroxylating system in a child with phenylketonuria who showed substantial neurologic impairment despite early dietary control of elevated blood phenylalanine levels. Phenylalanine hydroxylase, dihydropteridine reductase and dihydrofolate reductase activities were normal. In contrast the level of hydroxylation cofactor, tetrahydrobiopterin, in liver was only 10 per cent of normal. In addition to this hepatic deficiency, serum and urinary levels of biopterin-like compounds were low, and the serum biopterin did not increase in response to a phenylalanine load as it does in normal and phenylketonuric subjects. The phenylalanine hydroxylase activity in this child, as determined by an in vivo tritium-release assay, was 2.3 per cent of the normal value. These results indicate that the child suffers from a variant form of phenylketonuria--a deficiency of a functional phenylalanine hydroxylating system secondary to a defect in biosynthesis of biopterin.

Administration, Oral↗
PubMed1978

Hyperphenylalaninaemia due to dihydropteridine reductase deficiency.

Two siblings with increased levels of serum phenylalanine were detected by newborn screening. The older sibling deteriorated neurologically and mentally, despite early dietary control, and died at the age of 6 1/2 years. In the younger sibling phenylalanine hydroxylase activity in liver tissue was normal. Further investigations revealed increased concentrations of biopterin derivatives in the blood, a low excretion of 5-hydroxyindole acetic acid in the urine, and a dihydropteridine reductase deficiency as the cause of hyperphenylalaninaemia. The parents of the siblings showed 50% of the normal dihydropteridine reductase activity in their fibroblasts grown in culture. Neurotransmitter therapy was started in the second child at the age of 6 months and this was followed by distinct neurological and mental improvement.

Amino Acid Metabolism, Inborn Errors↗