Hyperphenylalaninemia, Bh4-Deficient, A
A number sign (#) is used with this entry because tetrahydrobiopterin (BH4)-deficient hyperphenylalaninemia due to PTS deficiency (HPABH4A) is caused by mutation in the gene encoding 6-pyruvoyl-tetrahydropterin synthase (PTS; 612719).
DescriptionTetrahydrobiopterin (BH4)-deficient hyperphenylalaninemia (HPA) comprises a genetically heterogeneous group of progressive neurologic disorders caused by autosomal recessive mutations in the genes encoding enzymes involved in the synthesis or regeneration of BH4. BH4 is a cofactor for phenylalanine hydroxylase (PAH; 612349), tyrosine hydroxylase (TH; 191290) and tryptophan hydroxylase (TPH1; 191060), the latter 2 of which are involved in neurotransmitter synthesis. The BH4-deficient HPAs are characterized phenotypically by hyperphenylalaninemia, depletion of the neurotransmitters dopamine and serotonin, and progressive cognitive and motor deficits (Dudesek et al., 2001).
HPABH4A, caused by mutations in the PTS gene, represents the most common cause of BH4-deficient hyperphenylalaninemia (Dudesek et al., 2001). Other forms of BH4-deficient HPA include HPABH4B (233910), caused by mutation in the GCH1 gene (600225), HPABH4C (261630), caused by mutation in the QDPR gene (612676), and HPABH4D (264070), caused by mutation in the PCBD1 gene (126090). Niederwieser et al. (1982) noted that about 1 to 3% of patients with hyperphenylalaninemia have one of these BH4-deficient forms. These disorders are clinically and genetically distinct from classic phenylketonuria (PKU; 261600), caused by mutation in the PAH gene.
Two additional disorders associated with BH4 deficiency and neurologic symptoms do not have overt hyperphenylalaninemia as a feature: dopa-responsive dystonia (612716), caused by mutation in the SPR gene (182125), and autosomal dominant dopa-responsive dystonia (DYT5; 128230), caused by mutation in the GCH1 gene. Patients with these disorders may develop hyperphenylalaninemia when stressed.
Clinical FeaturesKaufman et al. (1978) studied a boy with what appeared to be classic phenylketonuria who showed neurologic abnormalities, including hypotonia and delayed motor development, despite good dietary control of blood levels of phenylalanine from the age of 25 days. Tetrahydrobiopterin was only 10% of normal in liver, and serum and urinary levels of biopterin-like compounds were low. Furthermore, serum biopterin did not increase with phenylalanine load, as it would in both normal individuals and in patients with PKU. A defect in biopterin synthesis was postulated. Phenylalanine loading showed the mother to be a heterozygote. The father was considered to be intermediate between normal and heterozygous. Similar cases were reported by Rey et al. (1977) and Milstien et al. (1977).
Using an assay for PTS activity in red blood cells, Niederwieser et al. (1987) identified 4 patients in 3 families with 'peripheral' tetrahydrobiopterin deficiency. They were characterized biochemically by a BH4-responsive hyperphenylalaninemia, a high neopterin:biopterin ratio in urine and plasma, but normal or even elevated concentrations of neurotransmitter metabolites in the cerebrospinal fluid (CSF). The authors concluded that although residual PTS activity was sufficient to cover modest BH4 requirements of tyrosine hydroxylase and tryptophan hydroxylase in the brain, it was not enough to cover the much higher BH4 requirements of PAH in the liver, depending on the phenylalanine intake, protein turnover, and age. Thus, the so-called peripheral form results in hyperphenylalaninemia with only mild or no neurologic symptoms.
Scriver et al. (1987) reported deficient red cell PTS activity as the cause of persistent postnatal hyperphenylalaninemia in 4 probands and 1 sib. The metabolic findings were associated with a benign clinical presentation and normal biopterin levels in cerebrospinal fluid in the newborn period. Impaired development was apparent at 3 months in 1 proband not treated early. Treatment with oral BH4 restored adequate phenylalanine hydroxylase activity; it also maintained or improved CNS function. Red cell activity of PTS in homozygotes or compound heterozygotes was less than 10% of normal. Obligatory heterozygotes in some instances showed levels of enzyme activity lower than expected, suggesting genetic heterogeneity at the PTS locus.
Dhondt et al. (1988) described a patient with clinical features similar to those of the peripheral form of BH4 deficiency: hyperphenylalaninemia with an increase in neopterin to biopterin ratio in the urine, decrease in blood phenylalanine levels on tetrahydrobiopterin loading, biopterin and neurotransmitter metabolite levels within the normal range in the CSF, and a clinically normal appearance at 9 months with minimal neurologic signs on elevation of the plasma phenylalanine levels. In this patient, an unidentified pteridine-like compound was found in the urine and in the CSF, leading the authors to suggest the existence of an unidentified block in the biopterin biosynthetic pathway.
Dudesek et al. (2001) reported long-term follow-up information on 5 patients with PTS deficiency from 4 different families and provided a review of the disorder. Patients with BH4 deficiency resulting from a defect in the PTS gene presented with neurologic signs linked to impaired catecholamines and serotonin synthesis. Most infants were born small for gestational age, and most were seen at an average age of 4 months, although symptoms sometimes became evident in the first weeks of life. Frequent symptoms of PTS deficiency resembled those of Parkinson disease (PD; 168600), indicating a lack of dopamine in the basal ganglia. Extrapyramidal signs included characteristic truncal hypotonia, increased limb tone, postural instability, hypokinesia, choreatic or dystonic limb movements, gait difficulties, hypersalivation due to swallowing difficulties, and oculogyric crises. There were 2 main phenotypes. The more common was the severe 'central' form, accompanied by abnormalities of biogenic amines in the CSF. These patients required a combined treatment of BH4 and neurotransmitter precursors, and needed monotherapy with BH4 in order to maintain normal plasma phenylalanine levels. In contrast, the rare mild 'peripheral' (atypical) form of PTS deficiency was characterized by normal neurotransmitter homeostasis and moderate or transient hyperphenylalaninemia. In patients with the mild peripheral form, hyperphenylalaninemia did not recur when BH4 therapy was discontinued.
Clinical ManagementNiederwieser et al. (1982) found that treatment with L-sepiapterin (see 182125) was more effective than tetrahydrobiopterin therapy, and pointed to evidence that biopterin biosynthesis in the kidney and liver proceeds via a dioxo compound and L-sepiapterin.
McInnes et al. (1984) presented studies that indicated the complexity in replacement therapy with L-DOPA and 5-hydroxytryptophan (5-HTP). The treatment may be partially effective, however, in biopterin-deficient patients who are unresponsive to high doses of BH4. McInnes et al. (1984) used a lipophilic analog of BH4, 6-methyltetrahydropterin (6MPH4), which crosses the blood-brain barrier. Although the hyperphenylalaninemia was controlled and significant concentrations of 6MPH4 in cerebrospinal fluid were obtained, neurologic improvement and stimulation of monoamine synthesis in the nervous system were not achieved.
In 10 Chinese patients with BH4 deficiency due to PTS mutations, Chien et al. (2001) found that BH4 supplementation with restriction of high-protein foods gave control of plasma phenylalanine within the normal range, and administration of L-DOPA itself prevented seizures. However, the average IQ of these patients was only 76 +/- 14, with a range of 56 to 98. Statistically, the age of starting medication, including 5-hydroxytryptophan, was inversely correlated with IQ scores of these patients. Chien et al. (2001) suggested that the combination of BH4, L-DOPA, and 5-HTP as the standard protocol for the treatment of BH4 deficiency be started as early as possible, although prenatal brain damage may already exist.
Lee et al. (2006) reported long-term follow-up of 10 PTS-deficient Taiwanese patients who had delayed treatment with tetrahydrobiopterin, L-DOPA, and 5-HTP. The patients included 2 pairs of sibs. Five patients had severe psychomotor retardation with central hypotonia, were bedridden, lacked eye contact, and were in a vegetative-like state. Two other patients had psychomotor retardation and central hypotonia, but were not as severely affected as the first 5 patients. They were able to articulate single words and walked with unstable gait. These 8 patients had multiple seizures per day and were classified as severe. The remaining 2 patients had mild mental retardation, milder spasticity, and were in special educational schools. All patients showed marked improvements in neurologic signs and symptoms after initiation of treatment. Patients with recurrent seizures showed a marked decrease in the frequency of seizures, and oculogyric spasm improved gradually after 3 to 5 days. Other neurologic manifestations, including limb spasticity, hypotonia, dysphagia, and hypersalivation gradually improved over a 6- to 12-month period. The 2 patients with milder spasticity had resolution of spasticity after initiation of therapy. Eight of the patients showed increases in IQ scores after many years. One patient began walking and talking after 4 years of treatment. Most patients discontinued 5-HTP treatment due to a drug shortage, without significant adverse effects. Lee et al. (2006) concluded that treatment is beneficial in all cases.
Molecular GeneticsThony et al. (1994) identified mutations in the PTS gene (e.g., 612719.0001) in patients with BH4-deficient hyperphenylalaninemia.
Oppliger et al. (1997) identified 4 novel mutations in 4 Italian families with PTS deficiency.
Thony and Blau (1997) reviewed the spectrum of mutations in the PTS gene resulting in tetrahydrobiopterin deficiency. They stated that compound heterozygous or homozygous mutations spread over all 6 exons of the gene can cause an autosomal recessive variant of hyperphenylalaninemia, mostly accompanied by a deficiency of dopamine and serotonin.
Population GeneticsLiu et al. (1998) identified 7 single-base mutations in Chinese cases of PTS-deficient hyperphenylalaninemia. In all, 38 PTS mutant alleles from 19 unrelated Chinese families were studied. Two common mutations, N52S (612719.0004) and P87S (612719.0005), accounted for 71% of the mutant alleles. The N52S mutation accounted for 48% of the southern Chinese PTS mutations, but only 1 (9%) of the northern Chinese PTS mutant alleles was found to be N52S. Clinically, the V56M (612719.0006) mutation was found to be associated with the mild form of PTS deficiency, whereas R25G (612719.0001), N52S, P87S, and D96N (612719.0009) were found mainly in patients with severe clinical symptoms.
Chien et al. (2001) reported 10 cases of BH4 deficiency among 1,337,490 newborns screened in a Chinese population in Taiwan. They postulated that the high incidence in the Taiwanese population may be explained by a founder effect, since all of the patients were found to have PTS gene mutations, and grouping the common N52S and P87S mutations together constituted 88.9% of the disease alleles.
NomenclatureDanks et al. (1978, 1979) referred to the BH4-dependent HPA disorders as 'malignant hyperphenylalaninemia' since all untreated patients showed severe cerebral deterioration and often died at an early age compared to patients with classic PKU. However, these disorders are no longer fatal with proper treatment; thus, the term 'malignant' should not be used (Dudesek et al., 2001).
Animal ModelSumi-Ichinose et al. (2001) established mice unable to synthesize BH4 by disrupting the Pts gene. Homozygous mice were born almost at the expected mendelian ratio, but died within 48 hours of birth. In the brains of homozygous mutant neonates, levels of biopterin, catecholamines, and serotonin were extremely low. Tyrosine hydroxylase (TH; 191290) activity was severely impaired by BH4 depletion, and TH immunoreactivity was reduced in the nerve terminals, but not in the cell bodies. The catecholaminergic, serotonergic, and nitric oxide (see NOS1, 163731) systems were differentially affected by BH4 starvation and were variably rescued by BH4 administration.