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1 Introduction

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-4a-carbinolamine 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 (see Sect. 1.4). 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 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 (see Sect. 1.8) 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 for developing early-onset diabetes in puberty.

2 Nomenclature

No.

Disorder

Alternative Name

Abbreviation

Gene Symbol

Chromosomal Localization

Affected Protein

OMIM No.

Sub Type

1.1

Phenylalanine hydroxylase deficiency

Classic phenylketonuria

Classic PKU

PAH

12q22-24.1

Phenylalanine hydroxylase

261600

Mild to severe

1.2

GTP cyclohydrolase deficiency

 

arGTPCH

GCH1

14q22.1-22.2

GTP cyclohydrolase I

233910

Autosomal recessive

1.3

6-Pyruvoyl-tetrahydropterin synthase deficiency

 

PTPS

PTS

11q22.3-23.3

6-Pyruvoyl-tetrahydropterin synthase

261640

 

1.4

Dihydropteridine reductase deficiency

 

DHPR

QDPR

4p15.3

Dihydropteridine reductase

261630

Moderate and severe

1.5

Pterin-4a-carbinolamine dehydratase deficiency

Primapterinuria

PCD

PCBD1

10q22

Pterin-4a-carbinolamine dehydratase

264070

Benign HPA Early-onset diabetes

1.6

Dopa-responsive dystonia

Segawa disease

adGTPCH, DRD

GCH1

14q22.1-22.2

GTP cyclohydrolase I

600225

 

1.7

Sepiapterin reductase deficiency

 

SR

SPR

2p14-p12

Sepiapterin reductase

182125

 

3 Metabolic Pathway

Fig. 1.1
figure 1

Biosynthesis and regeneration of tetrahydrobiopterin (BH4) including possible metabolic defects in hyperphenylalaninemia (HPA) and catabolism of phenylalanine. 1.1 phenylalanine-4-hydroxylase (PAH), 1.2/1.6 GTP cyclohydrolase I, 1.3 6-pyruvoyl-tetrahydropterin synthase (PTPS), 1.4 dihydropteridine reductase (DHPR), 1.5 pterin-4a-carbinolamine dehydratase (PCD), 1.7 sepiapterin reductase, carbonyl reductase (CR), aldose reductase (AR), dihydrofolate reductase (DHFR), aromatic amino acid decarboxylase (AADC), tyrosine hydroxylase (TH), and tryptophan hydroxylase (TPH). 7,8-BH2: 7,8-dihydrobiopterin; PTP: 6-pyruvoyl-tetrahydropterin; HVA: homovanillic acid; 5HIAA: 5-hydroxyindoleacetic acid. Pathological metabolites used as specific markers in the differential diagnosis are marked in squares

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4 Signs and Symptoms

Table 1.1 Phenylalanine hydroxylase deficiency, classic PKU
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Table 1.2 GTP cyclohydrolase deficiency
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Table 1.3 6-Pyruvoyl-tetrahydropterin synthase deficiency
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Table 1.4 Dihydropteridine reductase deficiency
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Table 1.5 Pterin-4a-carbinolamine dehydratase deficiency
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Table 1.6 Dopa-responsive dystonia
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Table 1.7 Sepiapterin reductase deficiency
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5 Reference Values

Table 9 Serum, urine, and dried blood spots
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Table 10 CSF
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Table 11 Amniotic fluid, amniocytes, and fibroblasts
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Table 12 Enzymes
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6 Pathological Values/Differential Diagnosis

Table 13 Plasma
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Table 14 Plasma, urine, DBS, and CSF
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7 Loading Tests

Loading test with BH4

Fig. 1.2
figure 2

Proposed algorithms for the BH4 (sapropterin dihydrochloride; Kuvan) challenge, screening, and initiating treatment in BH4-responsive PKU patients. (a) Initial screening test with blood Phe monitoring on the first day and BH4 (sapropterin dihydrochloride) administration (20 mg/kg) on two following days. (b) Efficiency testing in BH4-reponsive patients over several weeks with BH4 doses adjusted individually according to Phe tolerance and therapeutic blood Phe levels. Combined Phe (100 mg/kg) and BH4 (20 mg/kg) loading test is sometimes difficult to interpret and is therefore not recommended (Blau et al. 2011)

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Loading tests with Phe

Fig. 1.3
figure 3figure 3

Oral phenylalanine loading with 100 mg Phe/kg body weight is performed, as previously described by Hyland et al. (1997). Samples were collected at time T-0, T-1h, T-2h, T-4h, and T-6h. Plasma was frozen immediately and kept in the dark; DBS were kept in dry conditions at 4 °C. The clearest differentiation measured by the standardized mean difference between the patients and controls was seen 2 h after Phe administration (Opladen et al. 2010). See also the flowchart with cut-off values. (a) Means and standard deviations (SDs) of phenylalanine/tyrosine (Phe/Tyr) ratios in pediatric patients after Phe loading [open circles dopa-responsive dystonia (DRD) patients; black squares controls; * p < 0.05; **p < 0.01] (b) Means and standard deviations (SDs) of biopterin concentration in pediatric patients after phenylalanine loading [open circles dopa-responsive dystonia (DRD) patients; black squares controls; **p < 0.01] (Opladen et al. 2010)

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8 Diagnostic Flowcharts

Differential diagnosis of HPAs

Fig. 1.4
figure 4

Diagnostic flowchart for the laboratory diagnosis of PKU and BH4 deficiencies (Blau et al. 2011). Dried blood spots (DBS) or random urine (U) can be used for the differential diagnosis and depending on the profile of neopterin (Neo), biopterin (Bio), and primapterin (Pri) and dihydropteridine reductase (DHPR) activity in DBS, diagnosis of following BH4 deficiencies can be established: GTP cyclohydrolase I (GTPCH) deficiency (low or no detectable neopterin and biopterin), 6-pyruvoyl-tetrahydropterin synthase (PTPS) deficiency (high neopterin and low or no detectable biopterin), dihydropteridine reductase (DHPR) deficiency (normal neopterin and normal or elevated biopterin and no DHPR activity), and pterins-4acarbinolamine dehydratase (PCD) deficiency (elevated neopterin, low-normal biopterin, and elevated primapterin). N normal (Blau et al. 2011)

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Screening for a BH4 deficiency should be done in all newborns and children with even slight HPA (plasma Phe >120 μmol/l) as well as in older children without HPA but with neurological symptoms suggestive of a neurotransmitter deficiency. The following protocol is suggested:

  1. 1.

    Analysis of pterins in urine

  2. 2.

    Measurement of DHPR activity in blood from a Guthrie card

  3. 3.

    Analysis of phenylalanine and tyrosine in serum or plasma before and after a BH4 challenge

  4. 4.

    DNA testing

The first two tests are essential and will allow the differentiation between all variants with BH4 deficiencies. With some limitations (DHPR def.), the BH4 loading test is an additional useful diagnostic tool for the rapid discrimination between classical PKU and biopterin variants. This test is also useful for identifying the recently described BH4-responsive PAH deficiency. For the interpretation and determination of the various disorders based upon loading tests, see Sect. 1.6.

Biochemical and loading test data are summarized in Fig. 1.5 (Blau et al. 2010):

Fig. 1.5
figure 5

Flow-chart for the differential diagnosis of BH4 responsive PKU and BH4 deficiencies. Phe phenylalanine, DBS dried blood spots, DHPR dihydropteridine reductase, Neo neopterin, Bio biopterin, Pri primapterin, GTPCH GTP-cyclohydrase I, PTPS 6-pyruvoyl-tetrahydropterin synthase, PCD pterin-4a-carbinolamine dehydratase, BH4 tetrahydrobiopterin. (Blau et al. 2010)

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Interpretation of the Phe loading test

Fig. 1.6
figure 6

Phenylalanine (Phe) loading in children: revised shortened test procedure and test interpretation (Bio biopterin, Phe/Tyr Phe/tyrosine ratio, DBS dried blood spot, P plasma, BW body weight, dd diagnostic decision) (Opladen et al. 2010)

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9 Diagnostic Flowchart in the Differential Diagnosis of Non-HPA Variants

Fig. 1.7
figure 7

Diagnostic algorithm for patients with a possible disorder of neurotransmitter metabolism. Sepiapterin reductase (SR) deficiency and other disorders of neurotransmitter metabolism should be considered in patients with (1) developmental delay with hypotonia, (2) suspect but unexplained cerebral palsy (CP) or CP with atypical features, and (3) uncharacterized l-dopa-responsive motor disorders. (1) In a patient with developmental delay and hypotonia, if oculogyric crises, diurnal fluctuation, sleep disturbance, or extrapyramidal or autonomic signs exist, a disorder of neurotransmitter biosynthesis is likely and cerebrospinal fluid (CSF) analysis should be done. If no other signs are present, CSF analysis should be considered if standard workup for hypotonia is unrevealing. If CSF analysis is abnormal, then mutational screening and/or measurement of enzymatic activity can be targeted to confirm the specific disorder suggested by the pattern of CSF abnormalities. If CSF evaluation is impractical, alternative evaluation may include l-dopa trial and/or phenylalanine load. If negative, CSF analysis must still be done to exclude a disorder of neurotransmitter metabolism. If l-dopa trial and/or phenylalanine loading are positive, CSF analysis will allow targeted mutational screening; however, one should keep in mind that phenylalanine (Phe) load can be positive in heterozygote carriers for phenylketonuria. Alternatively, CSF analysis may be skipped and broad mutational screening undertaken. Mutational and gene dosage screening may be time-consuming and costly, and false negatives may still occur. Therefore, this alternative evaluation route should be reserved for cases in which CSF analysis is not available or is declined, or in which other clinical features lead to suspicion of a specific diagnosis. (2) In a patient with unexplained CP or CP with atypical features, a disorder of neurotransmitter metabolism should be considered and diagnostic algorithm, as outlined above, should be followed. Atypical or unexplained features suggesting need for further metabolic investigation in a child with possible CP include lack of adequate antecedent, nondiagnostic magnetic resonance imaging, progressive symptoms, familial occurrence, episodic encephalopathy, and features not expected in the CPs such as diurnal variation, sleep disturbance, autonomic symptoms, or oculogyric crises. (3) All patients with an l-dopa-responsive motor disorder should be evaluated for a disorder of neurotransmitter metabolism. CSF analysis (after discontinuation of l-dopa therapy for at least 10 days) is the recommended first step. If l-dopa withdrawal is impractical, the results of CSF analyses may still be informative if either pterins or 5-hydroxyindoleacetic acid levels are abnormal. Alternatively, molecular investigations can be done, guided either by results of phenylalanine loading test or clinical symptoms with caveats as noted above.1 CSF analysis should consist of homovanillic acid, 5-hydroxyindoleacetic acid (5HIAA), pterins (neopterin, biopterin, and sepiapterin), and 5-methyltetrahydrofolate (Blau et al. 2010)

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10 Specimen Collection

Test

Preconditions

Material

Handling

Pitfalls

Phe

Free diet

Guthrie card, serum/plasma, CSF

Keep cool (−20 °C) for serum or plasma

 

Guthrie card at RT

Neo

Free diet, Phe in plasma high enough

Random urine, spotted urine

Keep cool, dark (−20 °C)

Infections (Neo ↑)

Bio

Oxidized sample, dark, RT

  

Serum/plasma

Keep cool, dark (−20 °C)

 
  

CSF

EDTA tube (−20 °C)

 

BH4, BH2

 

CSF

DTE/DETAPAC tube (−80 °C)

 

HVA

1 h before medication, withdraw first 0.5 ml

CSF

(−80 °C)

 

5HIAA

5-CH3-THF

DHPR

 

Erythrocytes from heparinized blood

Frozen (−20 °C)

 
  

Guthrie card

RT

 
  

Fibroblasts

RT

 
 

Min. 50 mg

Chorionic villi

Frozen (−80 °C)

 

PTPS

Before medication, no BH4

Erythrocytes from heparinized blood

frozen (−20 °C)

 
 

Min. 50 mg

Chorionic villi

Frozen (−80 °C)

 

GTPCH

 

Fibroblasts

RT

 

SR

 

Fibroblasts

RT

 
  1. RT room temperature

11 Prenatal Diagnosis

Disorder

Material

Timing, Trimester

1.1

Fetal DNA

I

1.2

Amniotic fluid, liver, DNA

II

1.3

Amniotic fluid, liver, erythrocytes, amniocytes, DNA

II

CV

I

1.4

Amniotic fluid, liver, erythrocytes, amniocytes, DNA

II

CV

I

12 DNA Analysis

DNA analysis is possible for PAH and all BH4 deficiencies

Disorder

Material

Method

1.1

Genomic DNA

PCR/RFLP/SSCP/ sequencing

1.2

Genomic DNA/FB

PCR/DGGE/sequencing

1.3

Genomic DNA/FB

PCR/DGGE/sequencing

1.4

Genomic DNA/FB

PCR/RFLP/DGGE/sequencing

1.5

Genomic DNA

PCR/sequencing

1.6

Genomic DNA/FB

PCR/DGGE/sequencing

1.7

Genomic DNA/FB

PCR/sequencing

13 Treatment

PAH or BH4 deficiency present either with or without HPA. In those presenting with HPA (1.1–1.5; see below), the main goal of treatment is to reduce or normalize blood phenylalanine levels without causing deficiencies of other amino acids and other nutrients that are usually received by intake of natural intake (Belanger-Quintana et al. 2011). This can be done by introduction of the low-phenylalanine (or low-natural protein) diet; in some patients administration of the synthetic cofactor BH4 can relax or even replace the diet (Keil et al. 2013). In such cases it is important to be sure that patients use normal amounts of natural protein and not causing deficiencies of amino acids.

In PAH deficiency, one of the areas that need consensus is whether to start treatment at blood phenylalanine levels above 360–600 μmol/l (van Spronsen et al. 2011). Treatment targets have not reached consensus yet, but for the first decade, more or less every center will try to keep phenylalanine below 360 μmol/l or even lower (Blau et al. 2010). Very recent data even show that outcome is even better when phenylalanine is kept below 240 μmol/l (Jahja R et al., J Pediatr, in press). The next issue to decide on is the search for BH4-responsive patients. To this end we refer to paragraph 1.7. All three existing methods (i.e., DNA, 7–24 days BH4 loading test (Levy 2007), and the 48-h BH4 loading test (Blau et al. 2011; Anjema et al. 2013)) have their own considerations. For all tests, long-term data are necessary to proof the predictive correctness of the method. Other issues that need attention are the amount of total protein (natural protein plus amino acids), giving extra tyrosine in case of low tyrosine concentrations (especially in case of pregnancy), and the question how strict treatment should be during adulthood (especially in males and in females after reproductive age).

One should be aware that there are individuals with “severe” PKU mutations that have escaped severe mental retardation despite high blood phenylalanine levels and very poor dietary control. One explanation for this phenomenon is that they have near normal brain phenylalanine levels, despite high blood phenylalanine levels. A number of studies have now demonstrated considerably variability in blood versus brain phenylalanine levels in PKU patients. Outcome in PKU appears to be related to both blood and brain phenylalanine levels. This, in all probability, will assume greater importance in making decisions about the strictness and duration of dietary control in the future.

In BH4 deficiencies, the mode of treatment depends on the type of disease, may differ with the patient’s age, and the policies in various countries and centers (Opladen et al. 2012). In addition, patients with HPA due to a cofactor defect need more strict blood phenylalanine control and additional supplementations with neurotransmitter precursors l-dopa and 5-hydroxytryptophan in a combination with the peripheral decarboxylase inhibitor carbidopa. Patients with dihydropteridine reductase deficiency (DHPR, 1.4) need additional folinic acid substitution. In patients revealing levodopa-induced peak-dose dyskinesia, slow-release forms of drugs can be used, and reaching the upper therapeutic limits of l-dopa may be an indication for the use of MAO and/or COMT inhibitors.

Patients with dopa-responsive dystonia (DRD, dominant GTPCH cyclohydrolase I deficiency, 1.6) and sepiapterin reductase deficiency (SR, 1.7) respond to low dosage l-dopa/carbidopa therapy and patients with SR deficiency need additional supplementation with 5-hydroxytryptophan and probably also BH4 (Friedman et al. 2012).

Prognosis and outcome strongly depend on the age when the diagnosis is made and treatment introduced but also on the type of mutation (Jäggi et al. 2008).

Recommendations for treatment and monitoring are not completely uniform worldwide. Therefore, where possible and necessary, recommendations have been combined and ranges of values indicating lower and upper limits are reported.

1.1 Phenylalanine hydroxylase deficiency (PKU)

Age

Protein requirement (g/kg BW/day)a

Phe tolerance (mg/day)

Target blood Phe (μmol/l)

Phe-free AAM

Germany

Netherlands

UK

USA

Type

g/dayb

0–3 months

2.1–2.7

~130–400

40–240

120–360

120–360

120–360

1

3–10

4–12 months

2.1–2.0

~130–400

40–240

120–360

120–360

120–360

1

3–10

1–2 years

1.7

~130–400

40–240

120–360

120–360

120–360

2

20–50

2–3 years

1.7

~200–400

40–240

120–360

120–360

120–360

2

20–50

4–6 years

1.6

~200–400

40–240

120–360

120–360

120–360

2

20–50

7–9 years

1.4

~200–400

40–240

120–360

120–480

120–360

2

20–50

10–12 years

1.1

~350–800

40–900

120–360

120–480

120–360

2

50–90

13–15 years

1.0

~350–800

40–900

120–600

120–700

120–600

2

50–90

>16 years

0.9

~450–1,000

40–1,200

120–600

120–700

120–900

3

60–150

  1. Protein requirement for PKU diet is assigned higher than recommendations for healthy people since bioavailability of amino acid mixtures is equivalent to natural protein
  2. aDGE 1985; RDA; WHO
  3. bSpread as evenly as possible through the 24 h

Non-PKU Hyperphenylalaninemia

Treatment only necessary for pregnant women with blood Phe levels >250–360 μmol/l (see below). Clinical monitoring is advised for all patients with Phe >360 μmol/l

Tetrahydrobiopterin (BH4)-Responsive PKU/HPA

There are no specific recommendations for the treatment of this group of HPA. The following table summarizes the current knowledge based on several experimental trials.

Age

Protein requirement

g/kg BW/day

Phe tolerance

mg/day

Target blood Phe

μmol/l

mg BH4/kg BWa

All ages

See 1.1

Near normal

See 1.1

5–20

  1. aThis applies to BH4 responsive PKU, but there it is not necessary to distribute in >1 time daily (usually); no long-term clinical experience; BH4 tablets contain (per 100 mg BH4) 100 mg ascorbic acid

Maternal PKU/HPA

Trimester

Protein requirement

g/kg BW/day

Phe tolerance

mg/day

Target blood Phe

μmol/l

Phe-free AAM

Type

g/daya

1

1.1

~180–1,600

120–360

3

60–150

2–3

1.3–1.5

~180–1,600

120–360

3

60–150

  1. aSpread as evenly as possible through the 24 h

1.2 GTP cyclohydrolase I deficiency and 1.3 6-Pyruvoyl-tetrahydropterin synthase deficiency (severe form)

No.

Symbol

Age

Medication/diet

Dosage (mg/kg/day)

Dosages per day

1.2

GTPCH

Newborn

l-Dopa

1–3

3–6

1.3

PTPS (severe)

Carbidopa

10–25 %a

3–6

5-Hydroxytryptophan

1–2

3–6

Tetrahydrobiopterin (BH4)

5–10

3

  

<1–2 years

l-Dopa

4–7

3–6

Carbidopa

10–25 %a

3–6

5-Hydroxytryptophan

3–5

3–6

Tetrahydrobiopterin (BH4)

5–10

2

  

>1–2 years

l-Dopa

8–15

3–6

Carbidopa

10–25 %a

3–6

5-Hydroxytryptophan

6–9

3–6

Tetrahydrobiopterin (BH4)

5–10

2

  1. aPercentage compared to l-dopa

Beware/Pitfalls

  1. 1.

    Patients are on an unrestricted (i.e., protein-rich) diet.

  2. 2.

    BH4 may significantly reduce plasma and CSF tyrosine levels. Consider nutrition and tyrosine supplementation.

  3. 3.

    l-Dopa/carbidopa/5-hydroxytryptophan therapy should be introduced slowly but continuously increased according to the clinical picture in steps of 1 mg/kg/day per week. 5-Hydroxytryptophan may not be tolerated due to gastrointestinal side effect. In these cases monotherapy with l-dopa/carbidopa may be sufficient.

  4. 4.

    l-Dopa/carbidopa/5-hydroxytryptophan therapy may reduce CSF folates (CH3-group trapping by l-dopa to 3-O-methyl-dopa). Determine 5-methyltetrahydrofolate in CSF. Consider folinic acid (5-formyltetrahydrofolate, leucovorin) substitution (10–20 mg/day).

  5. 5.

    Drugs like trimethoprim-sulfamethoxazoles or methotrexate may induce hyperphenylalaninemia by inhibiting DHPR.

1.3 6-Pyruvoyl-tetrahydropterin synthase deficiency (mild form)

No.

Symbol

Age

Medication/diet

Dosage (mg/kg/day)

Dosages per day

1.3

PTPS (mild)

All ages

Tetrahydrobiopterin (BH4)a

5–10

2

  1. aBH4 tablets contain (per 100 mg BH4) 100 mg ascorbic acid

1.4 Dihydropteridine reductase deficiency

No.

Symbol

Age

Medication/diet

Dosage (mg/kg/day)

Dosages per day

1.4

DHPR

Newborn

l-Dopa

1–3

3–6

Carbidopa

10–25 %a

3–6

5-Hydroxytryptophan

1–2

3–6

Folinic acid

15–20 mg/day

1–2

Diet (see 1.1 PKU)

  
  

<1–2 years

l-Dopa

4–7

3–6

Carbidopa

10–25 %a

3–6

5-Hydroxytryptophan

3–5

3–6

Folinic acid

15–20 mg/day

1–2

Diet (see 1.1 PKU)

  
  

>1–2 years

l-Dopa

8–15

3–6

Carbidopa

10–25 %a

3–6

5-Hydroxytryptophan

6–9

3–6

Folinic acid

15–20 mg/day

1–2

Diet (see 1.1 PKU)

  
  1. aPercentage compared to l-dopa

Beware/Pitfalls

  1. 1.

    Patients are on low-Phe diet (see Table 1.1); however, blood Phe levels should be close to normal. These patients are more sensitive to high Phe levels than other PKU.

  2. 2.

    l-Dopa/carbidopa/5-hydroxytryptophan therapy should be introduced slowly but continuously increased according to the clinical picture in steps of 1 mg/kg/day per week. 5-Hydroxytryptophan may not be tolerated due to gastrointestinal side effect. In these cases monotherapy with l-dopa/carbidopa may be sufficient.

  3. 3.

    Drugs like trimethoprim-sulfamethoxazoles or methotrexate may induce hyperphenylalaninemia by inhibiting DHPR.

1.5 Pterin-4a-carbinolamine dehydratase deficiency

No.

Symbol

Age

Medication/diet

Dosage (mg/kg/day)

Dosages per day

1.5

PCD

Newborn

Tetrahydrobiopterin (BH4)a

5–10

2

  

>1 years

No treatmentb

  
  1. aBH4 tablets contain (per 100 mg BH4) 100 mg ascorbic acid
  2. bDue to the possible development of diabetes type MODY3-like, periodic control necessary

Beware/Pitfalls

  1. 1.

    Patients are on an unrestricted (i.e., protein-rich) diet.

  2. 2.

    BH4 may significantly reduce plasma and CSF tyrosine levels. Consider tyrosine supplementation.

  3. 3.

    Drugs like trimethoprim-sulfamethoxazoles or methotrexate may induce hyperphenylalaninemia by inhibiting DHPR.

1.6 Dopa-responsive dystonia/autosomal dominant GTPCH deficiency

No.

Symbol

Age

Medication/diet

Dosage (mg/kg/day)

Dosages per day

1.6

DRD

Newborn

l-Dopa

1–3

3–4

Carbidopa

10–25 %a

3–4

  

>1 years

l-Dopa

4–12

3–4

Carbidopa

10–25 %a

3–4

  1. aPercentage compared to l-dopa

Beware/Pitfalls

  1. 1.

    l-Dopa/carbidopa therapy should be introduced slowly but continuously increased according to the clinical picture in steps of 1 mg/kg/day per week.

1.7 Sepiapterin reductase deficiency

No.

Symbol

Age

Medication/diet

Dosage (mg/kg/day)

Dosages per day

1.7

SR

Newborn

l-Dopa

1–3

3–4

Carbidopa

10–25 %a

3–4

5-Hydroxytryptophan

1–2

3–4

  

>1 years

l-Dopa

4–10

3–4

Carbidopa

10–25 %a

3–4

5-Hydroxytryptophan

3–9

3–4

  1. aPercentage compared to l-dopa

Beware/Pitfalls

  1. 1.

    l-Dopa/carbidopa/5-hydroxytryptophan therapy should be introduced slowly and increased in steps of not more than 1 mg/kg over days/weeks.

Alternative therapies/experimental trials

No.

Deficiency symbol

Age

Medication

Dosage (mg/kg/day)

Dosages per day

1.1

BH4-responsive PKU

>4 years

BH4a

10–20

1–2

1.3–1.5

GTPCH, PTPS, DHPR

All ages

Deprenylb

0.1–0.3

3–4

Entacaponec

~30

1–2

1.7

SR

All ages

Deprenylb

0.07–0.14

3–4

Sertralined

0.71–2.14

2–3

Melatonine

0.01–0.03

1–2

Bromocriptine

Not reported

Not reported

  1. aTetrahydrobiopterin (BH4; sapropterin dihydrochloride, Kuvan®) treatment has been recently introduced as a standard therapy for children with phenylalanine hydroxylase deficiency that showed a decrease of Phe levels after BH4 loading (see above)
  2. bMAO-B inhibitor (Selegiline)
  3. cCOMT inhibitor
  4. dSerotonin reuptake inhibitor
  5. eProduct of serotonin metabolism

Beware/Pitfalls

  1. 1.

    Administration of MAO-B or COMT inhibitors allows a 30 % reduction of the daily dosage of neurotransmitter precursors.

14 Follow-Up/Monitoring

1.1. PAH deficiency

Age

Biochemical monitoring Phe and Tyr

Clinical monitoringa

Intellectual and personality development

0–3 months

Weekly

1–3 monthly

 

4–12 months

Weekly

1–3 monthly

X

1–2 years

Weekly

2–6 monthly

 

2–3 years

Weekly

2–6 monthly

X

4–6 years

Fortnightly

3–6 monthly

X

7–9 years

Fortnightly

6 monthly

 

10–12 years

Monthly

6 monthly

X

13–15 years

Monthly

6 monthly

X

Adolescents/adults

Monthly

6–12 monthly

X

Maternal PKU

Weeklyb

Bimonthlyc

 
  1. aNutrient intake, body growth, general health, as well as laboratory tests: blood count, calcium, phosphate, magnesium, iron, liver and kidney function tests, alkaline phosphatase, total protein, albumin, pre-albumin, cholesterol, triglycerides, vitamins
  2. bPlasma AA, albumin, cholesterol, ferritin, folate, vitamin B12
  3. cNutrient intake including micronutrients, body growth, general health

Standard protocol for intercurrent illness

Aim the best possible intake of fluid, energy, and Phe-free AAM, with special attention for higher need of energy, while taking AAM in these periods may be a real.

1.2–1.7. BH 4 deficiencies

Plasma Phe and Tyr are monitored in all forms of HPA, CSF investigations only in disorders affecting BH4 metabolism with and without HPA (1.2–1.7).

Test

Age

Frequency

Comments

Phe and Tyr (blood)

1–3 years

Weekly to fortnightly

Phe levels: 40–240 (360) μmol/la

 

4–10 years

Fortnightly to monthly

 

11–16 years

Monthly

Phe levels: 40–900 μmol/la

 

>16 years

Every 2–3 months

Phe levels: 40–1,200 μmol/la

Neopterin

<1 month

Fortnightly

Close to normal range

Biopterin

5HIAA

HVA

Folates (CSF)b

 

1 month–1 years

Every 4–8 weeks

Close to normal range

 

<1 years

Monthly to yearly

Close to normal range

Glucose (P)

>5 years

Yearly

Only in PCD-deficient patients

  1. aIn DHPR-deficient patients, Phe levels should be close to 240–360 μmol/l at all ages
  2. bLumbar puncture in the morning before medication. Discard first 0.5 ml and collect the next 1–2 ml (−80 °C)