Defect in Dihydropteridine Reductase

Defect in dihydropteridine reductase

Author: Professor Jean-Louis Dhondt1 Creation Date: April 2001 Updates: May 2003 February 2005

Scientific Editor: Professor Jean-Marie Saudubray

1Centre régional de dépistage néonatal, 68 Rue Sylvere Verhulst, 59000 Lille, France. [email protected]

Abstract Keywords Disease name and synonyms Excluded diseases Diagnostic criteria / definition Differential diagnosis Prevalence Clinical description Management including treatment Diagnostic methods Genetic counseling Antenatal diagnosis References

Abstract Dihydropteridine reductase (DHPR) deficiency, an autosomal recessive genetic disorder, is one of the causes of malignant hyperphenylalaninemia due to tetrahydrobiopterin deficiency. Not only does tetrahydrobiopterin deficiency cause hyperphenylalaninemia, it is also responsible for defective neurotransmission of monoamines because of malfunctioning tyrosine and tryptophan hydroxylases, both tetrahydrobiopterin-dependent hydroxylases. DHPR deficiency should be suspected in all infants with a positive neonatal screening test for phenylketonuria, especially when hyperphenylalaninemia is moderate. DHPR activity can be measured by means of a technique adapted to dry blood samples. When left untreated, DHPR deficiency leads to neurological signs at age 4 or 5 months, although clinical signs are often obvious from birth. The principal symptoms include: psychomotor retardation, tonicity disorders, drowsiness, irritability, abnormal movements, hyperthermia, hypersalivation, and difficult swallowing. The treatment attempts to bring phenylalaninemia levels back to normal (diet with restricted phenylalanine intake or prescription of tetrahydrobiopterin) and to restore normal monoaminergic neurotransmission by administering precursors (L-dopa/carbidopa and 5-hydroxytryptophane). Folic acid intake prevents progressive deficits of cerebral folates, while antifolates, such as cotrimoxazole are dangerous.

Keywords tetrahydrobiopterin deficiency, malignant hyperphenylalaninemia, defective neurotransmission, folic acid intake

Disease name and synonyms Excluded diseases • Dihydropteridine reductase (DHPR) Other hyperphenylalaninemias (phenylketonuria deficiency (EC.1.6.99.7), (PKU), mild hyperphenylalaninemia), other • Tetrahydrobiopterin deficiency, tetrahydrobiopterin deficiencies (GTP- • Malignant hyperphenylalaninemia. cyclohydrolase (GTPch) deficiency, 6-pyruvoyl-

Dhont J.L. Defect in dihydropteridine reductase; Orphanet encyclopedia, February 2005. http://www.orpha.net/data/patho/GB/uk-dhpr.pdf 1 tetrahydropterin synthase (PTPS) pterin-4 alpha- EEG was normal in 38% of DHPR-deficient carbinolamine dehydratase (PCD) patients, paroxysmal activity (hypsarrhythmia, sharp waves, epileptic discharges) was Diagnostic criteria / definition observed in 46%. Neuroanatomical DHPR deficiency is one of the etiologies of investigations (CT scan & MRI) showed frequent "malignant hyperphenylalaninemia" which results and rather early brain atrophy. from tetrahydrobiopterin deficiency. In addition to DHPR deficiency may produce progressive being hyperphenylalaninemic, patients lacking intracranial calcifications, most evident in the tetrahydrobiopterin are deficient in the basal ganglia but also present in other areas of neurotransmitters whose syntheses depend on cerebral white and gray matter. These the normal activity of tetrahydrobiopterin- calcifications are thought to arise as a result of dependent tyrosine and tryptophan hydroxylases the decrease of cerebral folic acid. (EC.1.14.16.2 and EC.1.14.16.4). Some authors suggest that a partial deficiency of DHPR activity may also exist. That could explain Differential diagnosis a few reports of patients who had other Although the incidence of tetrahydrobiopterin manifestations. deficiencies remains low, it is important to be sure that patients with hyperphenylalaninemia Management including treatment are not tetrahydrobiopterin deficient so that good The goal is to control hyperphenylalaninemia by results with a low phenylalanine diet can be dietary restriction of phenylalanine intake or confidently predicted. tetrahydrobiopterin administration, and to restore It is recommended to that all infants with neurotransmitter homeostasis by oral hyperphenylalaninemia be screened for defects administration of amine precursors L-dopa and 5 in tetrahydrobiopterin metabolism even in the hydroxy-tryptophan (5HT). Carbidopa, an absence of neurological symptoms, and inhibitor of peripheral aromatic aminoacid regardless of the degree of the decarboxylase, enables the lowering of the hyperphenylalaninemia (mild, transient, therapeutic dose of L-dopa. persistent, etc.) The doses usually given are L-dopa/carbidopa : 5-10 mg/kg body weight (b;w)/day, 5HT: 5-10 Prevalence mg/kg bw/day. However, doses can vary, and DHPR deficiency is one of the most frequent indeed have to be tailored for each individual. conditions resulting in tetrahydrobiopterin The daily neurotransmitter dose is usually deficiency: 110 cases are known (32% of them divided into three equal proportions. However, are tetrahydrobiopterin-deficient patients), in diurnal fluctuations are often observed and France: 8 cases in 6 families. require changes in the schedule of drug Consanguinity exists in 2/3 of cases and administration. The optimal dose should be explains the higher prevalence in some countries adjusted to the requirements of each patient with (Turkey, southern Italy, North Africa, etc). monitoring for adverse effects and possible disappearance of neurological symptoms when Clinical description they exist. Unfortunately, no biochemical The median age at which clinical signs became parameters measurable in the periphery (except evident was 4-5 months, but symptoms do not hyperprolactinemia which is a good indicator of necessarily correlate with age at diagnosis, even the hypothalamic dopamine deficiency) in a given family. However, during the neonatal adequately monitor; consequently, analyzing of period, abnormal signs (poor sucking, fewer neurotransmitter metabolites in cerebrospinal spontaneous movements, floppy baby) can be fluid (CSF) represents the most direct way to observed. The common symptoms were: mental evaluate its efficacy, at least from a biochemical retardation, convulsions, disturbances of tonicity point of view. and posture, drowsiness, irritability, abnormal Although tetrahydrobiopterin-deficient subjects movements, recurrent hyperthermia without exhibit higher dietary phenylalanine tolerance infection, hypersalivation, swallowing difficulties. than classical phenylketonuria (PKU) patients, a Diurnal fluctuation of alertness and neurological factor limiting in the response to neurotransmitter symptoms are often reported. Microcephaly precursor therapy might be the plasma (head circumference less than the mean minus 2 phenylalanine fluctuations, which could alter the standard deviation for age) is observed in 1/3 of dose-effect relationships of these substances, by the cases. interfering with their membrane transport or by The neuroradiological and electrophysiological competitive inhibition of tyrosine and tryptophan abnormalities were often less severe than would hydroxylases. Blood phenylalanine has to be be expected from the clinical picture. EEG more strictly controlled than for other tracings and changes with age are not specific. hyperphenylalaninemias, some patients on Considering data obtained before 1 year of age, neurotransmitter treatment have developed

Dhont J.L. Defect in dihydropteridine reductase; Orphanet encyclopedia, February 2005. http://www.orpha.net/data/patho/GB/uk-dhpr.pdf 2 neurological problems with phenylalanine common. The gene (QDPR) has been located concentrations as low as 6 mg/dl. on chromosome 4q15.3 (7 exons), 26 mutations In contrast to PTPS deficiency, have been reported recently. tetrahydrobiopterin therapy alone for DHPR deficiency does not seem feasible because Antenatal diagnosis sufficiently high amounts cannot be given in to The option of prenatal diagnosis is likely to be maintain an adequate pool of tetrahydrobiopterin taken seriously, since the prognosis of these in the absence of the endogenous reducing conditions is subject to much uncertainty. system maintained by DHPR. DHPR activity can be measured in amniocytes. The picture is also more complicated as a DNA analysis can also be used. gradual folate deficit may occur within the central nervous system. A direct relationship between of References folic acid administration and clinical improvement Blau N, Barnes I., Dhondt J.L. International has been observed. Database of Tetrahydrobiopterin Deficiencies. J On the contrary, folic acid (oxidized form) Inherit Metab Dis 1996, 19, 8-14 administration aggravates the symptoms. The Butler I .J., Holtzman N.A., Kaufman S., Koslow adverse effect of cotrimoxazole has been shown. S.H., Krumholz A., Mielstien S. Phenylketonuria The potential danger of using other folate due to deficiency of dihydropteridine reductase. analogs is likely. Pediatr. Res. 1975, 9, 348 Dhondt J.L. Strategy for the screening of Diagnostic methods tetrahydrobiopterin deficiency among The diagnosis has to be considered in all hyperphenylalaninemic patients: 15 years conditions with hyperphenylalaninemia. experience. J.Inherit .Metab. Dis. 1991, 14, 117- DHPR deficiency can be suspected from 127 measurements of related metabolites in urine, Dhondt J.L. Tetrahydrobiopterin deficiencies. blood and CSF; but it can be confirmed only by Lessons from the compilation of 200 patients. specific assay of the enzyme's activity. Owing to Developmental Brain Dysfunction 1993, 6, 139- the lack of tetrahydrobiopterin, the absence of 155 feedback inhibition of GTPch results in activation Dhondt J.L., Meyer M., Malpuech G. Problems of pterin biosynthesis, which explains the high in the diagnosis of tetrahydrobiopterin deficiency. amounts of biopterin in body fluids. However and Eur. J. Pediatr. 1988, 147, 332-335 particularly in very young patients, the Scriver CR, Kaufman S, Eisensmith RC, Woo neopterin/biopterin ratio which is expected to be SLC. The hyperphenylalaninemias. In: Scriver low, is close to values found in PKU patients. CR, Beaudet AL, Sly WS, Valle D, eds. The High CSF biopterin levels are also found. Metabolic and Molecular Bases of Inherited The distribution of CSF 5-hydroxyindolacetic Disease, 7th edn, vol.1 New York: McGraw-Hill, acid (5-HIAA) and homovanillic acid (HVA) are 1995, 1015-1075 similar to those observed in PTPS deficiency. International register of tetrahydrobiopterin The 5-HIAA decrease is more important than deficiencies (J.L. Dhondt, N. Blau): that of HVA and both metabolites decrease with www.bh4.org (BIODEF (patients database) and age in parallel to normal control levels. BIOMDB (mutations database). Diagnosis of DHPR deficiencies also can be missed by a tetrahydrobiopterin-loading test,(2- 20 mg/kg) and the persistence of hyperphenylalaninemia during the assay can be misinterpreted as phenylalanine hydroxylase (PAH) deficiency (PKU). The lack of efficacy of tetrahydrobiopterin administration on blood phenylalanine is presumably due to the dose of tetrahydrobiopterin, which is insufficient to maintain repeated cycles of hydroxylation. To overcome these diagnostic difficulties, DHPR measurement is strongly recommended. DHPR assay in erythrocytes of dried blood spots has been shown reliable for this purpose and is now used for detection of the disease.

Genetic counseling DHPR deficiency is a genetic disorder with autosomal recessive inheritance, the disease occurs in both sexes and consanguinity is

Dhont J.L. Defect in dihydropteridine reductase; Orphanet encyclopedia, February 2005. http://www.orpha.net/data/patho/GB/uk-dhpr.pdf 3