Hyperphenylalaninemia (HPA), a disorder of phenylalanine catabolism, is caused primarily by a deficiency of the hepatic phenylalanine-4-hydroxylase (PAH) or by one of the enzymes involved in its cofactor tetrahydrobiopterin (BH4) biosynthesis (GTP cyclohydrolase I (GTPCH) and 6- pyruvoyl-tetrahydropterin synthase (PTPS)) or regeneration (dihydropteridine reductase (DHPR) and pterin- 4acarbinolamine dehydratase (PCD)) (Blau et al. 2001). BH4 is known to be the natural cofactor for PAH, tyrosine-3- hydroxylase, and tryptophan-5-hydroxylase as well as all three isoforms of nitric oxide synthase (NOS) (Werner et al. 2011), the latter two being the key enzymes in the biosynthesis of the neurotransmitters dopamine and serotonin. Thus, with two exceptions (see below) any cofactor defect will result in a deficiency of biogenic amines accompanied by HPA. Because phenylalanine is a competitive inhibitor of the uptake of tyrosine and tryptophan across the blood-brain barrier and of the hydroxylases of tyrosine and tryptophan, depletion of catecholamines and serotonin occurs in untreated patients with PAH deficiency. Both groups of HPA (PAH and BH4 deficiency) are heterogeneous disorders varying from severe, e.g., classical phenylketonuria (PKU), to mild and benign forms Because of the different clinical and biochemical severities in this group of diseases, the terms “severe” or “mild” will be used based upon the type of treatment and involvement of the CNS. For the BH4 defects, symptoms may manifest during the first weeks of life but usually are noted within the first half year of life. Birth is generally uneventful, except for an increased incidence of prematurity and lower birth weights in severe PTPS deficiency (Opladen et al. 2012).
Two disorders of BH4 metabolism may present without HPA. These are dopa-responsive dystonia (DRD; Segawa disease) (Segawa 2011) and sepiapterin reductase (SR) deficiency (Friedman et al. 2012). While DRD is caused by mutations in the GTPCH gene and is inherited in an autosomal dominant manner, SR deficiency is an autosomal recessive trait. Both diseases evidence severe biogenic amine deficiencies. DRD usually presents with a dystonic gait and diurnal variation, while many patients with SR deficiency have an initial diagnosis of cerebral palsy. At least two reports describe heteroallelic patients with DRD suggesting a wide spectrum of GTPCH variants.
A diagnosis of HPA is usually based upon the confirmation of an elevated blood phenylalanine level obtained on a normal diet, following a positive newborn screening test. Normal breast milk or formula feeding for only 24 h is sufficient to raise the baby’s blood phenylalanine sufficiently to trigger a positive test level (>120 μmol/l). In general, an infant will be found to have a positive screening test 12 h postnatal. The tandem mass spectrometry (TMS) is today the method of choice for newborns screening. A detection as early as possible is essential in order to introduce appropriate treatment to prevent effects on mental development.
In PAH and BH4 deficiencies, factors like a relatively high phenylalanine intake or catabolic situations may be responsible for high phenylalanine concentrations in blood. Once HPA has been detected, a sequence of quantitative tests enables the differentiation between variants, i.e., BH4-non-responsive PKU (usually the patients with the most severe PAH deficiency), BH4-responsive PKU (Heintz et al. 2013), and BH4 deficiencies. Because the BH4 deficiencies are actually a group of diseases which may be detected because of HPA, but not simply and routinely identified by neonatal mass screening, selective screening for a BH4 deficiency is essential in every newborn with even slightly elevated phenylalanine levels. Differential testing for BH4 deficiencies should be done in all newborns with plasma phenylalanine levels greater than 120 μmol/l (2 mg/dl), as well as in older infants and children with neurological signs and symptoms.
BH4 deficiencies presenting without HPA are detectable only by investigations for neurotransmitter metabolites and pterins in CSF or by clinical signs and symptoms. In DRD, a phenylalanine loading test, a trial with l -dopa, and enzyme activity measurement in cytokine-stimulated fibroblasts and molecular testing are confirmatory for the diagnosis. SR deficiency can be definitely diagnosed by an enzyme assay of cultured fibroblasts or DNA testing, but phenylalanine loading test is also positive.
The goals of treatment are to control HPA in PAH and BH4 deficiencies and to restore CNS neurotransmitter homeostasis in BH4 deficiencies (Blau et al. 2010). To that aim, dietary restriction in phenylalanine intake, supplementation with BH4, and oral administration of dopamine and serotonin precursors (l-dopa/carbidopa and 5- hydroxytryptophan, respectively), as well as some other drugs are available (Opladen et al. 2012). In this respect, it should be taken into account that some patients with PAH deficiency, historically only treated by diet, can be treated with BH4 (sapropterin dihydrochloride). At the same time, in patients with DPHR deficiency, in whom historically the HPA was not treated with BH4, the diet restricting phenylalanine intake is the treatment of choice. Only about 20 % of DHPR-deficient patients are on BH4 treatment (Opladen et al. 2012).
Late detection of PAH or BH4 deficiencies and late introduction of treatment lead to irreversible brain damage. In contrast to early and continuously treated patients with PAH deficiency, some patients with BH4 deficiencies show progressive neurological deterioration despite treatment. Patients with PCD deficiency are at risk of developing early-onset diabetes in puberty.
This text is an extract from “Physician´s Guide to the Diagnosis, Treatment and Follow-Up of Inherited Metabolic Diseases”, Editors: Nenad Blau, Marinus Duran, K. Michael Gibson, Carlos Dionisi-Vici, Publisher: Springer
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