Outcome and long-term follow-up of 36 patients with tetrahydrobiopterin deficiency

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Abstract

We describe the treatment, the clinical, and biochemical findings and the outcome of 26 patients with 6-pyruvoyl-tetrahydropterin synthase (PTPS) deficiency and 10 patients with dihydropteridine reductase (DHPR) deficiency. These are the two most common forms of the autosomal-recessively inherited tetrahydrobiopterin (BH4) deficiency. Time of diagnosis, dosage of BH4 and neurotransmitter precursors, folinic acid substitution, and levels of 5-hydroxyindoleacetic acid (5HIAA) and homovanillic acid (HVA) in cerebrospinal fluid (CSF) are essential parameters in the follow-up of patients. Unfortunately, treatment protocols vary greatly among patients and clinical centers, and CSF investigations and outcome assessments are not always available. Seventeen patients with PTPS deficiency and four patients with DHPR deficiency were diagnosed within 2 months after birth. In 14 patients with PTPS deficiency (54%; 9 early and 5 late diagnosed) and 2 patients with DHPR deficiency (20%; all early diagnosed) no developmental delay is observed, while in 10 patients with PTPS deficiency (38%; 6 early and 4 late diagnosed) and 8 patients with DHPR deficiency (80%; 2 early and 6 late diagnosed) development was delayed. Two PTPS-deficient patients died in the newborn period. DHPR deficiency seems to be more severe than PTPS deficiency and it is clearly the onset of treatment that determines the outcome. Our data suggest that diagnosis within the first month of life is essential for a good outcome and that low CSF5 HIAA and HVA values in CSF could be an indicator for the ongoing developmental impairment, even in the absence of neurological symptoms.

Introduction

Tetrahydrobiopterin (BH4) deficiency represents a heterogeneous group of metabolic disorders caused by autosomal recessively inherited enzyme defects of the BH4 synthesis or regenerating pathway [1]. BH4 is the cofactor for phenylalanine hydroxylase (PAH) (EC 1.14.16.1), tryptophan hydroxylase (TPH) (EC 1.14.16.4), tyrosine hydroxylase (TH) (EC 1.14.16.2) and nitric oxide synthase (NOS) (EC 1.14.13.39) [2], [3]. It is synthesized in a three-step pathway from guanosine triphosphate (GTP) trough GTP cyclohydrolase 1 (EC 3.5.4.16), 6-pyruvoyl-tetrahydropterin synthase (PTPS) (EC 4.6.1.10), and sepiapterin reductase (SR) (EC 1.1.1.153). After coupling as an active cofactor to the aromatic amino acid hydroxylases, it is regenerated by pterin-4a-carbinolamine dehydratase (PCD) (EC 4.2.1.96) and dihydropteridine reductase (DHPR) (EC 1.6.99.7) [4].

BH4 deficiency, formerly known as malignant or atypical phenylketonuria (PKU), results in hyperphenylalaninemia (HPA), and decreased neurotransmitter and folate levels in cerebrospinal fluid. Infants affected by PTPS deficiency, the most common form of BH4 deficiency, are frequently born small for gestational age [5]. In the neonatal period they may show abnormal signs such as poor sucking, impaired tone and microcephaly. Later they present characteristic extrapyramidal symptoms due to lack of dopamine in the basal ganglia [6] including truncal hypotonia, increased limb tone, postural instability, hypokinesia, choreatic or dystonic limb movements, gait difficulties, hypersalivation due to swallowing difficulties, and oculogyric crises. Ataxia, hyperreflexia, hypothermia as well as episodes of hyperthermia (in the absence of infections), drowsiness, irritability, disturbed sleep patterns, and convulsions (grand mal or myoclonic) are often seen [7], [8]. The clinical course of illness in DHPR deficiency is similar to that seen in severe forms of PTPS deficiency. In addition, extensive neuronal loss, calcifications, and abnormal vascular proliferation were noted in cortex, basal ganglia, and thalamus [9].

Screening tests for BH4 deficiencies are available (urinary pterins, DHPR activity in dried blood, and BH4 loading test) and performed in most developed countries in patients with HPA detected in newborn screening [10], [11].

The treatment of BH4 deficiency consists of regulating phenylalanine (Phe) levels in blood either by oral administration of BH4 (in GTPCH and PTPS deficiency) or low Phe diet (mainly in DHPR deficiency) and substitution of the neurotransmitter precursors l-dopa and 5-hydroxytryptophan (5HTRP) [12]. It has been shown that addition of Selegiline (MAO-B inhibitor) or Entacapone (COMT inhibitor) allowed a lower dosage of l-dopa and 5HTRP, preventing overdosing [13], [14], [15]. Folinic acid substitution is essential in DHPR-deficient patients and also in some PTPS-deficient patients with low 5-methyltetrahydrofolate (5MTHF) levels in cerebrospinal fluid (CSF).

Reports of long-term follow-up of patients with BH4 deficiency are still scarce [16], [17], [18] and therapeutic strategies or treatment guidelines are vague and far from clinically based evidence. In this article we describe the long-term follow-up and outcome of 26 patients with PTPS deficiency and 10 patients with DHPR deficiency.

Section snippets

Case reports

Detailed information about BH4-deficient patients is tabulated in the BIODEF database (www.bh4.org). All patients presented with elevated blood Phe levels at newborn screening or at the time of the diagnosis. Initial biochemical data are summarized in Table 1. Mutation analysis was performed in very few patients (Table 1). The clinical information is illustrated in Table 2. Additional information is included in following reports:

BIODEF ID#47 (PTPS deficiency). Despite different treatment

Results

We retrospectively investigated the medical records of 36 patients with the diagnosis of BH4 deficiency (26 with PTPS deficiency and 10 with DHPR deficiency). The patients originate from Germany, Italy, Hungary, Turkey, Saudi Arabia, Georgia, Afghanistan, Pakistan, Sri Lanka, and Albania and they were diagnosed between one week (#372, #450) and 27 years (#478) of age. Only 11 patients had consanguineous parents. Mean birth weight was 2841 g and 6 patients were born prematurely between 33 and 37

Discussion

Today selective screening for BH4 deficiencies is performed in most parts of the world in patients with even slight HPA detected in PKU screening. By means of a BH4 loading test and measurement of urinary pterins and DHPR activity an exact diagnosis of the type of BH4 deficiency can be made in the first weeks of life [10], [11]. This led in most countries to an early onset of therapy and prevention of the severe mental and physical disability reported of untreated patients [33], [34]. Early

Acknowledgments

We thank Prof. Felix Sennhauser, Medical Director of the University Children’s Hospital in Zürich for his continuous support. This work was supported by the Swiss National Science Foundation Grant No. 3100000-107500/1.

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