Dataset Information

Tetrahydrobiopterin (BH4) deficiency is associated with augmented inflammation and microvascular degeneration in the retina.

ABSTRACT:

Background

Tetrahydrobiopterin (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.

Methods

hph-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.

Results

Our 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).

Conclusion

Our 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.

SUBMITTER: Rivera JC

PROVIDER: S-EPMC5586016 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Publications

Tetrahydrobiopterin (BH4) deficiency is associated with augmented inflammation and microvascular degeneration in the retina.

Rivera José Carlos JC Noueihed Baraa B Madaan Ankush A Lahaie Isabelle I Pan Jingyi J Belik Jaques J Chemtob Sylvain S

Journal of neuroinflammation 20170906 1

<h4>Background</h4>Tetrahydrobiopterin (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.<h4>Methods</h4>hph-1 mice, which display deficiency in BH4 synthesis, were used to characterize the inflammatory effects and the integrity of retinal microvasculature. BH4 levels in reti ...[more]

PMID: 28874201

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Project description:BackgroundInherited phenylalanine hydroxylase deficiency, also known as phenylketonuria (PKU), causes poor growth and neurologic deficits in the untreated state. After ascertainment through newborn screen and dietary phenylalanine (Phe) restriction to achieve plasma Phe in the range of 120-360 μmol/L, these disease manifestations can be prevented. Poor compliance with protein restricted diets supported by medical food is typical in later years, beginning in the late toddler and teenage years. Pharmacologic doses of oral tetrahydrobiopterin (BH4; sapropterin dihydrochloride) is effective in reducing plasma Phe in about 40-50% of PKU patients but effectiveness is highly variable.ObjectiveTo assess the maximal responsiveness to 20 mg/kg/day oral BH4 as it affects plasma Phe and dietary Phe allowance in PKU patients.Materials and methodsThis was a single-center, retrospective observational study, combining case reports of individual patients. We reported an outcome of 85 patients with PKU who were trialed on BH4. Phe levels and dietary records of 19 BH4 "super-responders" were analyzed.ResultsOverall, 63.5% of the patients (54/85) were considered BH4 responders. However, we quantitated the dietary liberalization of 19 of our responsive patients (35%), those with at least a 2-fold increase in dietary Phe and maintenance of plasma Phe in treatment range. In these "super-responders", the mean plasma Phe at baseline was 371 ± 237 μmol/L and decreased to 284 ± 273 μmol/L after 1 year on BH4. Mean dietary Phe tolerance increased significantly from 595 ± 256 to 2260 ± 1414 mg/day (p ≤0.0001), while maintaining mean plasma Phe levels within treatment range. Four patients no longer required dietary Phe restriction and could discontinue medical food. The majority of patients had at least one BH4-responsive genotype.ConclusionThis cohort demonstrates the maximally achievable dietary liberalization which some PKU patients may expect with BH4 therapy. Health benefits are considered to accrue in patients with increased intact protein.

Project description:Background and purposeSevere and progressive neurologic disease remains a problem for patients with hyperphenylalaninemia due to a deficiency of tetrahydrobiopterin (BH4), even with early diagnosis and despite treatment with BH4 and neurotransmitter precursors. Few reports have included the associated imaging characteristics. Our purpose was to describe the imaging features of BH4-deficient patients identified by neonatal screening in a Taiwanese population and to correlate the imaging features with the treatment.MethodsThis study analyzed the cases of eight BH4-deficient patients who were examined by MR imaging and MR spectroscopy. Analysis of the findings was correlated with the clinical findings.ResultsOne patient whose intelligence quotient score was lower than those of the other seven patients experienced seizures in conjunction with central white matter signal changes on MR images and a lactate peak on MR spectroscopy. Lactate peak was revealed in another patient who had marked elevations of N-acetylaspartate:creatine and N-acetylaspartate:choline ratios. Although most patients had a higher than average N-acetylaspartate:creatine or N-acetylaspartate:choline ratio, the patient who had decreases of both ratios possessed the highest intelligence quotient scores among the eight patients. In addition, the myoinositol:choline ratio correlated positively with the average BH4 dosage (P =.027, r = 0.027) and the choline:creatine ratio correlated negatively with the average 5-hydroxytryptophan dosage (P =.035, r = -0.742).ConclusionCompared with classical phenylketonuria, patients with BH4 deficiency have fewer white matter changes revealed by MR imaging but more changes revealed by MR spectroscopy. MR spectroscopy is a potential method with which to monitor the dosages of supplements used to treat this disorder. In addition, MR spectroscopy may be helpful in gaining understanding of the neurophysiological changes that occur in association with this disease.

Project description:BackgroundPeople with Phenylketonuria (PKU) who respond to tetrahydrobiopterin (BH4) often decrease dependence on medical food (MF) following increased phenylalanine (phe) tolerance. Responders to BH4 may experience a reduction in certain nutrients if not compensated through intact foods or supplements. This study investigated B6, B12, folate, and iron status based on blood levels and dietary intake in patients with PKU responsive to BH4 over 1 year.MethodsFifty-eight patients with PKU, ages 4-50 years were recruited and initiated on BH4 therapy. Patients were monitored for BH4 response, and nutritional status was recorded at regular intervals over 12 months. The analysis included 33 patients with known BH4 response status and complete nutritional data. Nutrient intake was determined by National Data System for Research (NDSR) analysis of self reported 3 day diet records and compared to Dietary Reference Intakes (DRIs). Blood biomarkers were analyzed by Quest Diagnostics and compared to laboratory reference ranges. Patient laboratory values were compared to controls from the National Health and Examination Survey (NHANES). Differences in nutrient intakes across time points were examined, stratified by age, using nonparametric methods. Statistical analyses were completed with SAS 9.4, with significance set at α = 0.05.ResultsMedical food intake declined among pediatric (p < 0.01) and adult (p = 0.06) BH4 responders over 1 year. Among those < 18 years of age, mean percent of calories obtained from MF declined from 21.3 to 4.7%. In adults, percent calories from MF dropped from 19.5 to 4.0%. Though maintaining laboratory and dietary values within reference ranges, responders < 18 years experienced a significant decline in serum B12 (p = 0.01), dietary folate (p = 0.006), and dietary iron (p = 0.004) over the study.ConclusionAlthough mean dietary and laboratory values for B12, B6, folate, and iron in BH4 responders and non-responders were adequate at baseline and 12-month follow-up, responders experienced a significant decline in serum B12 over 1 year, which may be explained by decreased intake of fortified MF. Both response groups had lower serum B12 than NHANES controls at baseline and 12 months. Results indicate a need to monitor B12 concentrations and consider micronutrient supplementation, with special attention to pediatric patients with PKU.

Dataset Information

Tetrahydrobiopterin (BH4) deficiency is associated with augmented inflammation and microvascular degeneration in the retina.

Background

Methods

Results

Conclusion

Publications

Tetrahydrobiopterin (BH4) deficiency is associated with augmented inflammation and microvascular degeneration in the retina.

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