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Other entities represented in this entry:
SNOMEDCT: 23447005; ORPHA: 2102, 238583; DO: 0112225;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 14q22.2 | Hyperphenylalaninemia, BH4-deficient, B | 233910 | Autosomal recessive | 3 | GCH1 | 600225 |
A number sign (#) is used with this entry because tetrahydrobiopterin (BH4)-deficient hyperphenylalaninemia (HPA) B (HPABH4B) is caused by mutation in the gene encoding GTP cyclohydrolase I (GCH1; 600225). An autosomal recessive form of dopa-responsive dystonia with or without hyperphenylalaninemia is caused by mutation in the same gene.
Dopa-responsive dystonia-5 (DYT5; 128230) is an allelic disorder resulting from heterozygous mutations in the GCH1 gene.
For a general phenotypic description and a discussion of genetic heterogeneity of BH4-deficient hyperphenylalaninemia, see HPABH4A (261640).
Niederwieser et al. (1984) reported a 4-year-old girl with hyperphenylalaninemia, severe developmental retardation, severe muscular hypotonia of the trunk and hypertonia of the extremities, convulsions, and frequent episodes of hyperthermia without infection. Urinary excretion of neopterin, biopterin, pterin, isoxanthopterin, dopamine, and serotonin were very low, although their relative proportions were normal. Spinal fluid showed low concentrations of homovanillic acid, 5-hydroxyindoleacetic acid, neopterin, and biopterin. Oral administration of L-erythro-tetrahydrobiopterin (but not the dextroisomer) normalized the serum phenylalanine level within 4 hours. No defect of the immune system was found. The patient's parents were first cousins, suggesting autosomal recessive inheritance. Liver biopsy showed a deficiency of GTP cyclohydrolase I. Phytohemagglutinin-stimulated lymphocytes of the parents showed levels of enzyme activity intermediate between zero (in the child's lymphocytes) and normal.
Naylor et al. (1987) made the diagnosis of GTP cyclohydrolase I deficiency in a 4-month-old infant in whom a positive Guthrie test for phenylketonuria (PKU; 261600) at birth led to institution of dietary therapy. Urinary pteridine screening for cofactor variants, however, revealed extremely low levels of both neopterin and biopterin. The diagnosis was confirmed by BH4-loading studies and assay of GTP cyclohydrolase I activity in the liver.
Ichinose et al. (1995) reported a female infant with BH4-dependent hyperphenylalaninemia due to GTP1 deficiency. She developed feeding problems, poor sucking, and poor muscle tone in the first week of life, and later showed delayed development. By the age of 2 years, she was unable to walk and developed seizures and choreoathetosis. Urinary pterins showed a profound deficiency in neopterin and biopterin. She died at age 10 years.
Blau et al. (1995) described a male infant in whom GCH1 deficiency was not detected in the newborn PKU screening program. The characteristic clinical phenotype developed at the age of 5 months: elevated plasma phenylalanine, undetectable urinary pterins, and absence of GCH1 enzyme activity in a liver biopsy. Developmental delay was first noted in the patient at 4 months of age. At that time, neurologic findings included generalized hypotonia and clonic movements. After 4.5 months, examination revealed developmental delay with generalized hypotonia and dystonic Parkinson-like movements with wide-ranging tremors, especially of the upper limbs and the head. When the patient was 9 months of age, BH4 and neurotransmitter replacement therapy was started, and the low-phenylalanine diet was stopped. One month later, a reduction in the intention tremors and dystonic movements was observed, but axial hypotonia persisted. When the patient was 15 months of age, after he had undergone therapy for 6 months, slight axial hypotonia persisted, but the intention tremors and the dystonic movements had completely disappeared. Administration of L-DOPA and 5-hydroxytryptophan was used to control the cerebrospinal fluid neurotransmitter levels.
Autosomal Recessive Dopa-Responsive Dystonia with or without Hyperphenylalaninemia
Furukawa et al. (1998) described a phenotype, which they called 'dystonia with motor delay,' that showed a severity intermediate between the severe autosomal recessive hyperphenylalaninemia with neopterin deficiency and the milder Segawa dystonia-parkinsonism with diurnal fluctuation (DYT5; 128230). In this intermediate phenotype, there is marked motor delay, but no mental retardation and only minimal, if any, hyperphenylalaninemia. Furukawa et al. (1998) reported a 6-year-old girl with dystonia with motor delay who was found to be compound heterozygous for 2 mutations in the GCH1 gene (600225.0010; 600225.0011). The maternal allele was also found in her mother, maternal grandmother, and great-grandmother, all of whom had progressive dystonia with diurnal variation. The second mutation was inherited from her asymptomatic father. The proband responded to treatment with tetrahydrobiopterin and levodopa. A second unrelated 17-year-old male with dystonia with motor delay was also found to be compound heterozygous for GCH1 mutations (600225.0012; 600225.0013). He could not walk until age 4, at which time language was normal except for mild dysarthria. Between the ages of 4 and 6 years, the patient's previously acquired motor and speech functions deteriorated, and he subsequently became wheelchair bound and mute.
Hwu et al. (1999) described a girl with progressive dopa-responsive dystonia with diurnal fluctuation beginning at age 2 years and 8 months. Plasma phenylalanine was normal. Genetic analysis identified a homozygous mutation in the GCH1 gene (R249S; 600225.0016). Both unaffected parents were heterozygous for the mutation. The data suggested that patients with recessive GCH1 mutations do not necessarily have hyperphenylalaninemia, although they can develop a movement disorder.
Nardocci et al. (2003) reported monozygotic twin girls who showed rigidity and tremors of the extremities, with diurnal fluctuation, from the first months of life associated with a homozygous mutation in the GCH1 gene (P199A; 600225.0022). One girl also had prolonged generalized dystonic spasms, with opisthotonus, hyperextension of lower limbs, and hyperpronation of the arms, also with diurnal fluctuation. Cognitive development was normal. At age 6 months, the girls showed delayed motor development with normal cognitive abilities, rigidity, irregular and arrhythmic hyperkinesias involving the limbs, and symmetric hyperreflexia without extensor plantar responses. Laboratory results were normal and neither had hyperphenylalaninemia. Treatment with L-DOPA resulted in marked clinical improvement, and both had almost normal neurologic examination at age 15, except for slight hyperreflexia and low-normal IQ. Neither parent had any signs or symptoms suggesting a GCH1 deficiency. Nardocci et al. (2003) interpreted the findings as expanding the clinical phenotype associated with recessive GCH1 mutations to include patients with neonatal onset of a movement disorder without hyperphenylalaninemia.
BH4-deficient Hyperphenylalaninemia B
In a male infant with HPA due to GCH1 deficiency, Blau et al. (1995) identified a homozygous mutation in the GCH1 gene (600225.0017).
In a female infant with BH4-deficient HPA, Ichinose et al. (1995) identified a homozygous mutation in the GCH1 gene (600225.0020).
Autosomal Recessive Dopa-Responsive Dystonia with or without Hyperphenylalaninemia
Furukawa et al. (1998), Hwu et al. (1999), and Nardocci et al. (2003) identified homozygous or compound heterozygous mutations in patients with dopa-responsive dystonia with or without hyperphenylalaninemia (see, e.g., 600225.0010, 600225.0016, and 600225.0022).
The hph1 mouse exhibits hyperphenylalaninemia and a reduction in GTP cyclohydrolase I activity (McDonald et al., 1988). Hyland et al. (2003) found that hph1 mice have low brain levels of BH4, catecholamines, serotonin, and their metabolites, together with low levels of tyrosine hydroxylase protein within the striatum. These findings are similar to the neurochemical findings in human patients with mutations in the GCH1 gene, suggesting that the hph1 mouse is a good model system of GCH1 deficiency.
Blau, N., Ichinose, H., Nagatsu, T., Heizmann, C. W., Zacchello, F., Burlina, A. B. A missense mutation in a patient with guanosine triphosphate cyclohydrolase I deficiency missed in the newborn screening program. J. Pediat. 126: 401-405, 1995. [PubMed: 7869202] [Full Text: https://doi.org/10.1016/s0022-3476(95)70458-2]
Curtius, H.-C., Heintel, D., Ghisla, S., Kuster, T., Leimbacher, W., Niederwieser, A. Biosynthesis of tetrahydrobiopterin in man. J. Inherit. Metab. Dis. 8 (suppl. 1): 28-33, 1985. [PubMed: 3930838] [Full Text: https://doi.org/10.1007/BF01800656]
Dhondt, J.-L., Farriaux, J.-P., Boudha, A., Largilliere, C., Ringel, J., Roger, M.-M., Leeming, R. J. Neonatal hyperphenylalaninemia presumably caused by guanosine triphosphate-cyclohydrolase deficiency. J. Pediat. 106: 954-956, 1985. [PubMed: 3873535] [Full Text: https://doi.org/10.1016/s0022-3476(85)80251-1]
Furukawa, Y., Kish, S. J., Bebin, E. M., Jacobson, R. D., Fryburg, J. S., Wilson, W. G., Shimadzu, M., Hyland, K., Trugman, J. M. Dystonia with motor delay in compound heterozygotes for GTP-cyclohydrolase I gene mutations. Ann. Neurol. 44: 10-16, 1998. [PubMed: 9667588] [Full Text: https://doi.org/10.1002/ana.410440107]
Hwu, W.-L., Wang, P.-J., Hsiao, K.-J., Wang, T.-R., Chiou, Y.-W., Lee, Y.-M. Dopa-responsive dystonia induced by a recessive GTP cyclohydrolase I mutation. Hum. Genet. 105: 226-230, 1999. [PubMed: 10987649] [Full Text: https://doi.org/10.1007/s004390051093]
Hyland, K., Gunasekara, R. S., Munk-Martin, T. L., Arnold, L. A., Engle, T. The hph-1 mouse: a model for dominantly inherited GTP-cyclohydrolase deficiency. Ann. Neurol. 54: S46-S48, 2003. [PubMed: 12891653] [Full Text: https://doi.org/10.1002/ana.10695]
Ichinose, H., Ohye, T., Matsuda, Y., Hori, T., Blau, N., Burlina, A., Rouse, B., Matalon, R., Fujita, K., Nagatsu, T. Characterization of mouse and human GTP cyclohydrolase I genes: mutations in patients with GTP cyclohydrolase I deficiency. J. Biol. Chem. 270: 10062-10071, 1995. [PubMed: 7730309] [Full Text: https://doi.org/10.1074/jbc.270.17.10062]
Kaufman, S. Hyperphenylalaninaemia caused by defects in biopterin metabolism. J. Inherit. Metab. Dis. 8 (suppl. 1): 20-27, 1985. [PubMed: 3930837] [Full Text: https://doi.org/10.1007/BF01800655]
McDonald, J. D., Cotton, R. J. H., Jennings, I., Ledley, F. D., Woo, S. L. C., Bode, V. C. Biochemical defect of hph-1 mouse mutant is a deficiency in GTP-cyclohydrolase activity. J. Neurochem. 50: 655-657, 1988. [PubMed: 3335865] [Full Text: https://doi.org/10.1111/j.1471-4159.1988.tb02961.x]
Nardocci, N., Zorzi, G., Blau, N., Alvarez, E. F., Sesta, M., Angelini, L., Pannacci, M., Invernizzi, F., Garavaglia, B. Neonatal dopa-responsive extrapyramidal syndrome in twins with recessive GTPCH deficiency. Neurology 60: 335-337, 2003. [PubMed: 12552057] [Full Text: https://doi.org/10.1212/01.wnl.0000044049.99690.ad]
Naylor, E. W., Ennis, D., Davidson, A. G. F., Wong, L. T. K., Applegarth, D. A., Niederwieser, A. Guanosine triphosphate cyclohydrolase I deficiency: early diagnosis by routine urine pteridine screening. Pediatrics 79: 374-378, 1987. [PubMed: 3822637]
Niederwieser, A., Blau, N., Wang, M., Joller, P., Atares, M., Cardesa-Garcia, J. GTP cyclohydrolase I deficiency, a new enzyme defect causing hyperphenylalaninemia with neopterin, biopterin, dopamine, and serotonin deficiencies and muscular hypotonia. Europ. J. Pediat. 141: 208-214, 1984. [PubMed: 6734669] [Full Text: https://doi.org/10.1007/BF00572762]
Niederwieser, A., Ponzone, A., Curtius, H.-C. Differential diagnosis of tetrahydrobiopterin deficiency. J. Inherit. Metab. Dis. 8 (suppl. 1): 34-38, 1985. [PubMed: 3930839] [Full Text: https://doi.org/10.1007/BF01800657]