GTP cyclohydrolase I deficiency, a new enzyme defect causing hyperphenylalaninemia with neopterin, biopterin, dopamine, and serotonin deficiencies and muscular hypotonia

Abstract

A 4-year-old patient is described with hyperphenylalaninemia, severe retardation in development, severe muscular hypotonia of the trunk and hypertonia of the extremities, convulsions, and frequent episodes of hyperthermia without infections. Urinary excretion of neopterin, biopterin, pterin, isoxanthopterin, dopamine, and serotonin was very low, although the relative proportions of pterins were normal. In lumbar cerebrospinal fluid, homovanillic acid, 5-hydroxyindoleacetic acid, neopterin and biopterin were low. Oral administration of L-erythro tetrahydrobiopterin normalized the elevated serum phenylalanine within 4 h, serum tyrosine was increased briefly and serum alanine and glutamic acid for a longer time. Urinary dopamine and serotonin excretion were also increased. Administration of an equivalent dose of D-erythro tetrahydroneopterin was ineffective and demonstrated that this compound is not a cofactor in vivo and cannot be transformed into an active cofactor. GTP cyclohydrolase I activity was not detectable in liver biopsies from the patient. The presence of an endogenous inhibitor in the patient's liver was excluded. This is the first case of a new variant of hyperphenylalaninemia in which the formation of dihydroneopterin triphosphate and its pterin metabolites in liver is markedly diminished. Normal activities of xanthine oxidase and sulfite oxidase were apparent since uric acid levels were normal and no increase in hypoxanthine, xanthine, and S-sulfocysteine concentrations could be observed in urine. It is concluded that the molybdenum cofactor of these enzymes may not be derived from dihydroneopterin triphosphate in man. Also, since no gross abnormalities in the patient's immune system could be found, it seems unlikely that dihydroneopterin triphosphate metabolites, such as neopterin, participate actively in immunological processes, as postulated by others. See Note added in proof.

Structural Basis of Biopterin-induced Inhibition of GTP Cyclohydrolase I by GFRP, Its Feedback Regulatory Protein

“…GTP cyclohydrolase I (GTPCHI) 1 (EC. 3.5.4.16), which is a 260-kDa decamer of homologous subunits, catalyzes the conversion of GTP to dihydroneopterin triphosphate, the first and rate-limiting step involved in the de novo synthesis of tetrahydrobiopterin (BH 4 ) in animals.…”

Crystal structure of the stimulatory complex of GTP cyclohydrolase I and its feedback regulatory protein GFRP

“…1). Genetic defects affecting GTPCHI activity cause hyperphenylalaninemia and severe neurological disorders such as 3,4-dihydroxyphenylalanine-responsive dystonia (1)(2)(3)(4). The BH 4 deficiency that occurs because of abnormalities in the control mechanisms of GTPCHI have been found in a variety of diseases ranging from vascular diseases such as diabetes, hypertension, and atherosclerosis (5)(6)(7)(8) to neurological diseases such as Parkinson's and Alzheimer's (9,10).…”

Conversion of 6-substituted tetrahydropterins to 7-isomers via phenylalanine hydroxylase-generated intermediates.

“…The most prevalent form of this disease, called classical PKU, has been shown to be caused by a lack of phenylalanine hydroxylase (6). Variant forms ofPKU have also been described that are caused by either a deficiency of BH4 (7)(8)(9)(10)(11)(12)(13)(14) or a defect in the pathway required to reduce this cofactor, which is oxidized during catalysis (15). All of these variant forms of PKU result in a BH4 deficiency, hyperphenylalaninemia, and a biogenic amine neurotransmitter deficiency, since BH4 is also required for the conversion of tyrosine and tryptophan to catecholamines and serotonin, respectively (16).…”