Consensus guideline for the diagnosis and treatment of tetrahydrobiopterin (BH4) deficiencies

Abstract

Background: Tetrahydrobiopterin (BH₄) deficiencies comprise a group of six rare neurometabolic disorders characterized by insufficient synthesis of the monoamine neurotransmitters dopamine and serotonin due to a disturbance of BH₄ biosynthesis or recycling. Hyperphenylalaninemia (HPA) is the first diagnostic hallmark for most BH₄ deficiencies, apart from autosomal dominant guanosine triphosphate cyclohydrolase I deficiency and sepiapterin reductase deficiency. Early supplementation of neurotransmitter precursors and where appropriate, treatment of HPA results in significant improvement of motor and cognitive function. Management approaches differ across the world and therefore these guidelines have been developed aiming to harmonize and optimize patient care. Representatives of the International Working Group on Neurotransmitter related Disorders (iNTD) developed the guidelines according to the SIGN (Scottish Intercollegiate Guidelines Network) methodology by evaluating all available evidence for the diagnosis and treatment of BH₄ deficiencies.

Conclusion: Although the total body of evidence in the literature was mainly rated as low or very low, these consensus guidelines will help to harmonize clinical practice and to standardize and improve care for BH₄ deficient patients.

Keywords: 6-pyruvoyltetrahydropterin synthase deficiency; BH4; Consensus guidelines; Dihydropteridine reductase deficiency; Guanosine triphosphate cyclohydrolase deficiency; Hyperphenylalaninemia; Neurotransmitter; SIGN; Sepiapterin reductase deficiency, pterin-4-alpha-carbinolamine dehydratase deficiency; Tetrahydrobiopterin deficiency; iNTD.

Fig. 1

Biosynthesis and regeneration of tetrahydrobiopterin (BH₄) and its functions as cofactor in the synthesis of serotonin, dopamine, and other catecholamines as well as the catabolism of phenylalanine. Simplified scheme of the biosynthesis and regeneration of tetrahydrobiopterin (BH₄) in the presynaptic axonal end. BH₄ serves as essential cofactor of the aromatic amino acid hydroxylases phenylalanine hydroxylase (PAH), tyrosine hydroxylase (TH), and tryptophan hydroxylase (TPH) which catalyse key reactions in the synthesis of the monoamines dopamine, serotonin, norepinephrine, and epinephrine. Note that AGMO and NOSs are not depicted in this overview. 5-HIAA, 5-hydroxyindoleacetic acid; 5-HIAL, 5-hydroxyindoleacetaldehyde; 7,8-BH₂, 7,8-dihydrobiopterin; BH₄, tetrahydrobiopterin; DOPAC, 3,4-dihydroxyphenylacetic acid; DOPAL, 3,4-dihydroxyphenylacetaldehyde; DTDS, dopamine transport deficiency syndrome; GTP, guanosine-5′-triphosphate; HVA, homovanillic acid; Oxo-PH41, oxo-2-hydroxy-tetrahydropterin; PLP, pyridoxal 5′-phosphate; PTP, 6-pyruvoyltetrahydropterin; qBH₂, quinonoid dihydrobiopterin; VLA, vanillyllactic acid; VMA, vanillylmandelic acid; VMAT 2, vesicular monoamine transporter

Fig. 2

Diagnostic flowchart for differential diagnosis of BH₄Ds with and without HPA. ¹Consider genetic HPA workup depending on availability and financial resources. The gene panel should include the QDPR, GCH1, PTS PCBD1, SPR genes as well as DNAJC12. For GCH1, consider MLPA if Sanger sequencing is negative. ²The analysis in urine is more sensitive than in DBS and pathological patterns suggestive for PCDD and SRD can only be detected in urine but not in DBS. ³Primapterin measurement in urine is only elevated in PCDD. ⁴Aminoacids in CSF are not required for diagnosis of BH₄Ds. ⁵CSF analysis should always include standard measurements (cell count, proteins, glucose and lactate). ⁶Recommendation against measurements of HVA, 5-HIAA, 5-MTHF, and pterins in CSF in the case of PCDD. (*) A diagnostic L-Dopa trial should be limited to children with symptoms suggestive of dopa-responsive dystonia or to situations where biochemical and genetic diagnostic tools are not available. If the diagnostic L-Dopa trial is positive but the results of CSF biochemical and/or molecular genetic testing are not compatible with AD-GTPCHD or SRD, further aetiologies for dopa responsive dystonia should be considered (e.g. juvenile parkinsonism (PARK2gene)). (**) Can be considered if available. See text for more detailed information. Abbreviations: 5-HIAA, 5-hydroxyindoleacetic acid; 5-MTHF, 5-methyltetrahydrofolate; AA: amino acids; AD−/AR- GTPCHD: guanosine triphosphate cyclohydrolase I deficiency; BH₄, tetrahydrobiopterin; Bio: biopterin; CSF: cerebrospinal fluid; DBS: dry blood spot; DHPR: q-dihydropteridine reductase; DHPRD, dihydropteridine reductase deficiency; HVA, homovanillic acid; MRI, magnetic resonance imaging; N: normal; NBS: newborn screening; Neo: neopterin; NR: not reported; PAH: phenylalanine hydroxylase; Phe: phenylalanine; PKU: phenylketonuria; Prim: primapterin; PTPSD, 6-pyruvoyltetrahydropterin synthase deficiency; SRD: sepiapterin reductase deficiency; Tyr: tyrosine; u: urine; (+) = positive effect; (−) = no or no clear effect