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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.

SUBMITTER: Opladen T

PROVIDER: S-EPMC7251883 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Consensus guideline for the diagnosis and treatment of tetrahydrobiopterin (BH<sub>4</sub>) deficiencies.

Opladen Thomas T López-Laso Eduardo E Cortès-Saladelafont Elisenda E Pearson Toni S TS Sivri H Serap HS Yildiz Yilmaz Y Assmann Birgit B Kurian Manju A MA Leuzzi Vincenzo V Heales Simon S Pope Simon S Porta Francesco F García-Cazorla Angeles A Honzík Tomáš T Pons Roser R Regal Luc L Goez Helly H Artuch Rafael R Hoffmann Georg F GF Horvath Gabriella G Thöny Beat B Scholl-Bürgi Sabine S Burlina Alberto A Verbeek Marcel M MM Mastrangelo Mario M Friedman Jennifer J Wassenberg Tessa T Jeltsch Kathrin K Kulhánek Jan J Kuseyri Hübschmann Oya O

Orphanet journal of rare diseases 20200526 1

<h4>Background</h4>Tetrahydrobiopterin (BH<sub>4</sub>) 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<sub>4</sub> biosynthesis or recycling. Hyperphenylalaninemia (HPA) is the first diagnostic hallmark for most BH<sub>4</sub> deficiencies, apart from autosomal dominant guanosine triphosphate cyclohydrolase I deficiency and sepiapterin reductase deficie ...[more]

PMID: 32456656

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Project description:To improve awareness and recognition of chronic bacterial prostatitis (CBP) and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) among non-specialists and patients. To provide guidance to healthcare professionals treating patients with CBP and CP/CPPS, in both non-specialist and specialist settings. To promote efficient referral of care between non-specialists and specialists and the involvement of the multidisciplinary team (MDT).The guideline population were men with CBP or CP/CPPS (persistent or recurrent symptoms and no other urogenital pathology for ?3 of the previous 6 months). Consensus recommendations for the guidelines were based on a search to identify literature on the diagnosis and management of CBP and CP/CPPS (published between 1999 and February 2014). A Delphi panel process was used where high-quality, published evidence was lacking.CBP and CP/CPPS can present with a wide range of clinical manifestations. The four main symptom domains are urogenital pain, lower urinary tract symptoms (LUTS - voiding or storage symptoms), psychological issues and sexual dysfunction. Patients should be managed according to their individual symptom pattern. Options for first-line treatment include antibiotics, ?-adrenergic antagonists (if voiding LUTS are present) and simple analgesics. Repeated use of antibiotics, such as quinolones, should be avoided if there is no obvious symptomatic benefit from infection control or cultures do not support an infectious cause. Early use of treatments targeting neuropathic pain and/or referral to specialist services should be considered for patients who do not respond to initial measures. An MDT approach (urologists, pain specialists, nurse specialists, specialist physiotherapists, general practitioners, cognitive behavioural therapists/psychologists, and sexual health specialists) is recommended. Patients should be fully informed about the possible underlying causes and treatment options, including an explanation of the chronic pain cycle.Chronic prostatitis can present with a wide variety of signs and symptoms. Identification of individual symptom patterns and a symptom-based treatment approach are recommended. Further research is required to evaluate management options for CBP and CP/CPPS.

Project description:BackgroundTetrahydrobiopterin (BH4) is an essential cofactor in multiple metabolic processes and plays an essential role in maintaining the inflammatory and neurovascular homeostasis. In this study, we have investigated the deleterious effects of BH4 deficiency on retinal vasculature during development.Methodshph-1 mice, which display deficiency in BH4 synthesis, were used to characterize the inflammatory effects and the integrity of retinal microvasculature. BH4 levels in retinas from hph-1 and wild type ?(WT)? mice were measured by LC-MS/MS. Retinal microvascular area and microglial cells number were quantified in hph-1 and WT mice at different ages. Retinal expression of pro-inflammatory, anti-angiogenic, and neuronal-derived factors was analyzed by qPCR. BH4 supplementation was evaluated in vitro, ex-vivo, and in vivo models.ResultsOur findings demonstrated that BH4 levels in the retina from hph-1 mice were significantly lower by ~?90% at all ages analyzed compared to WT mice. Juvenile hph-1 mice showed iris atrophy, persistent fetal vasculature, significant increase in the number of microglial cells (p < 0.01), as well as a marked degeneration of the retinal microvasculature. Retinal microvascular alterations in juvenile hph-1 mice were associated with a decreased expression in Norrin (0.2-fold) and its receptor Frizzled-4 (FZD4; 0.51-fold), as well as with an augmented expression of pro-inflammatory factors such as IL-6 (3.2-fold), NRLP-3 (4.4-fold), IL-1? (8.6-fold), and the anti-angiogenic factor thrombospondin-1 (TSP-1; 17.5-fold). We found that TSP-1 derived from activated microglial cells is a factor responsible of inducing microvascular degeneration, but BH4 supplementation markedly prevented hyperoxia-induced microglial activation in vitro and microvascular injury in an ex-vivo model of microvascular angiogenesis and an in vivo model of oxygen-induced retinopathy (OIR).ConclusionOur findings reveal that BH4 is a key cofactor in regulating the expression of inflammatory and anti-angiogenic factors that play an important function in the maintenance of retinal microvasculature.

Dataset Information

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

Publications

Consensus guideline for the diagnosis and treatment of tetrahydrobiopterin (BH<sub>4</sub>) deficiencies.

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