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

Abstract

Background: Tetrahydrobiopterin (BH 4) 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 BH 4 biosynthesis or recycling. Hyperphenylalaninemia (HPA) is the first diagnostic hallmark for most BH 4 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 BH 4 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 BH 4 deficient patients.

BH4-deficient hyperphenylalaninemia in Russia

“…Phe restricted diet as a monotherapy is ineffective for HPABH 4 patients as it does not solve the problem of neurotransmitter deficit. The most effective method for those patients is BH 4 replacement therapy combined with levodopa and 5-hydroxytryptophan [ 7 – 9 ]. Other treatment options are folinic acid, melatonin, and dopamine agonists [ 7 ].…”

“…The most effective method for those patients is BH 4 replacement therapy combined with levodopa and 5-hydroxytryptophan [ 7 – 9 ]. Other treatment options are folinic acid, melatonin, and dopamine agonists [ 7 ]. The most common disorder in this group is HPABH 4 A caused by mutations in the PTS gene: it accounts for 65.3% of all HPABH 4 cases in Europe which in turn make around 2% of all HPA cases.…”

A Proposed Diagnostic Algorithm for Inborn Errors of Metabolism Presenting With Movements Disorders

“…Quite apart from the fact that many of these report do not provide in-depth characterization of the MD. Some studies that include large series of patients with IEMs and MD are: Tetrahydrobiopterin (BH4) deficiencies (37), cobalamin-related remethylation disorders (38), SERAC1 deficiency (39), mitochondrial disorders (22), PLA2G6associated neurodegeneration (24), lysosomal storage disorders (40), cerebrotendinous xanthomatosis (9), and congenital disorders of glycosylation (41). IEMs with MD as a primary or prominent feature and treatable causes should always be in mind.…”

“…Spectroscopy can be useful in some cases: Creatine transporter deficiency (43), SLC13A5-Epileptic encephalopathy, early infantile (143), 25, Pyruvate dehydrogenase complex deficiency (58)(59)(60)(61), thiamine pyrophosphokinase deficiency, biotin-thiamine-responsive basal ganglia disease, mitochondrial thiamine pyrophosphate transporter deficiency (54), and many other mitochondrial disorders (Figure 4). Detection of intracerebral or basal ganglia calcification is also suggestive of certain IEMs (Table 5, Figure 3): Dihydropteridine reductase deficiency (37), folate receptor alpha deficiency, dihydrofolate reductase deficiency, hereditary folate malabsorption (144), phenylketonuria (144), Krabbe disease (145) and Aicardi-Goutières syndrome (146). Figure 3 and Figure 4 present the radiological pattern and MR Spectroscopy of some IEMs and Table 5 shows a list of IEMs with disease-specific treatment classified according to the neuroradiological pattern.…”

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

“…Following the original article's publication [ 1 ] the authors asked for the correction of Fig. 2 , since the names of the disease genes [ GCH1 and PCBD1 ] in the figure published did not match the listed diseases [AR-GTPCHD and PCDD].…”