A disorder of biogenic amines in dihydropteridine reductase deficiency
Corresponding Author
Dr. Ian J. Butler MB, FRACP
Department of Neurology and Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD
Butler, Department of Neurology, University of Texas Medical School at Houston, 6301 Almeda Rd, Houston, TX 77021Search for more papers by this authorStephen H. Koslow PhD
Department of Neurology and Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD
Laboratory of Preclinical Pharmacology, National Institute of Mental Health, St. Elizabeth's Hospital, Washington, DC
Laboratory of Neurochemistry, National Institute of Mental Health, Bethesda, MD
Search for more papers by this authorAllan Krumholz MD
Department of Neurology and Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD
Laboratory of Preclinical Pharmacology, National Institute of Mental Health, St. Elizabeth's Hospital, Washington, DC
Laboratory of Neurochemistry, National Institute of Mental Health, Bethesda, MD
Search for more papers by this authorNeil A. Holtzman MD
Department of Neurology and Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD
Laboratory of Preclinical Pharmacology, National Institute of Mental Health, St. Elizabeth's Hospital, Washington, DC
Laboratory of Neurochemistry, National Institute of Mental Health, Bethesda, MD
Search for more papers by this authorSeymour Kaufman PhD
Department of Neurology and Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD
Laboratory of Preclinical Pharmacology, National Institute of Mental Health, St. Elizabeth's Hospital, Washington, DC
Laboratory of Neurochemistry, National Institute of Mental Health, Bethesda, MD
Search for more papers by this authorCorresponding Author
Dr. Ian J. Butler MB, FRACP
Department of Neurology and Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD
Butler, Department of Neurology, University of Texas Medical School at Houston, 6301 Almeda Rd, Houston, TX 77021Search for more papers by this authorStephen H. Koslow PhD
Department of Neurology and Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD
Laboratory of Preclinical Pharmacology, National Institute of Mental Health, St. Elizabeth's Hospital, Washington, DC
Laboratory of Neurochemistry, National Institute of Mental Health, Bethesda, MD
Search for more papers by this authorAllan Krumholz MD
Department of Neurology and Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD
Laboratory of Preclinical Pharmacology, National Institute of Mental Health, St. Elizabeth's Hospital, Washington, DC
Laboratory of Neurochemistry, National Institute of Mental Health, Bethesda, MD
Search for more papers by this authorNeil A. Holtzman MD
Department of Neurology and Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD
Laboratory of Preclinical Pharmacology, National Institute of Mental Health, St. Elizabeth's Hospital, Washington, DC
Laboratory of Neurochemistry, National Institute of Mental Health, Bethesda, MD
Search for more papers by this authorSeymour Kaufman PhD
Department of Neurology and Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD
Laboratory of Preclinical Pharmacology, National Institute of Mental Health, St. Elizabeth's Hospital, Washington, DC
Laboratory of Neurochemistry, National Institute of Mental Health, Bethesda, MD
Search for more papers by this authorAbstract
A severe deficiency of dihydropteridine reductase (DHPR) in liver, brain, and cultured skin fibroblasts was demonstrated in a child with hyperphenylalaninemia and an atypical form of phenylketonuria. DHPR is required for regeneration of the cofactor, tetrahydrobiopterin. The cofactor is essential in hydroxylation of aromatic amino acid precursors in the biosynthesis of neurotransmitters, serotonin, dopamine, and norepinephrine. In gray tissue at brain biopsy, dopamine was low at 3 ng per gram of tissue, serotonin was barely detected, and norepinephrine appeared high at 1600 ng per gram. In cerebrospinal fluid, homovanillic acid (HVA) was low normal at 33 ng/ml, 5-hydroxyindoleacetic acid (5-HIAA) was low at 4.2 ng/ml, and after a high dose of oral probenecid there was impaired accumulation of HVA to 128 ng/ml and 5-HIAA to 22.4 ng/ml. When the patient was 22 months of age, treatment with hydroxylated aromatic amino acid precursors was initiated, and after three months HVA and 5-HIAA levels were increased in CSF. The apparent restoration of biogenic amines in brain appears to have delayed the rate of neurological deterioration. DHPR activity in cultured skin fibroblasts of children with persistent hyperphenylalaninemia should permit early diagnosis and early treatment of this disorder.
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