Birth prevalence of tetrahydrobiopterin deficiency in China: data from the national newborn screening program, 2013–2019

Background Tetrahydrobiopterin deficiency (BH4D), a less common form of hyperphenylalaninemia (HPA), can lead to severe developmental retardation if untreated. Little has been reported on the prevalence of BH4D among live births worldwide. This study examined its prevalence across China and between geographical areas within the country. Methods We analyzed data from the Chinese national screening program for HPA in newborns between 2013 and 2019. BH4D prevalence was examined by province, region and the entire country. Provincial-level prevalence was estimated from the number of confirmed BH4D cases and screened newborns, after adjusting for HPA-positive recall rate. Regional- and national-level prevalences were estimated by summing provincial-level prevalences after weighting them by the number of live births. A Poisson distribution was assumed in order to calculate 95% confidence intervals (CIs) for prevalence. Results Among 107,078,115 newborns screened for HPA in China, 380 with BH4D were identified, corresponding to a total prevalence of 3.8 per 1,000,000 live births. Prevalence was higher in eastern regions (5.9 per 1,000,000) and northern regions (4.1 per 1,000,000) of China than in southern regions (1.6 per 1,000,000) or northwestern regions (1.7 per 1,000,000). Across the entire country, 3.9% cases of HPA were diagnosed as BH4D, and this proportion reached as high as 15.1% in the southern part of the country. Conclusions These first insights into BH4D prevalence across China suggest slightly higher prevalence than in other countries, and it varies substantially by region. More attention should be paid to early diagnosis and timely treatment of BH4D.

Tetrahydrobiopterin deficiency in schizophrenia as a new target for personalized medicine

Summary. Tetrahydrobiopterin (BH4) is an important cofactor, that involved in the synthesis of dopamine, norepinephrine, and serotonin, as well as affecting the production of nitric oxide (NO) and regulating the activity of the glutamatergic system. A few foreign studies have shown, that patients with schizophrenia had a markedly reduced level of BH4 compared to the healthy population. The aim of this work was to study the association of BH4 deficiency with the risk of schizophrenia among Russian patients by comparison with a group of healthy volunteers.Materials and methods: 50 patients with schizophrenia and 36 healthy volunteerswere randomly selected and underwent a biochemical study of the BH4 level using the method of competitive enzyme immunoassay (ELISA) on a spectrophotometer (Sunrise, Tecan) with a set of CEG421Ge (CloudClone Corp).Results: it was found that the BH4 level was significantly lower in patients than in the controlgroup (3684.75 [1283.00; 4815.00] versus 4260.60 [4057.40; 5236.85] pmol / l, respectively, p = 0 , 0016). The proportion of patients with a BH4 level below the lower limit of the interquartile range in healthy volunteers (4057.40 pmol / l) is 30/50 (60%), the proportion of healthy volunteers with a BH4 level below this border is 9/36 (25%), the difference is statistically significant, χ2 = 10.35; p = 0.002; OR = 4.5; 95% CI [1.75; 11.56](CI — confidence interval). The correlation of BH4 level with the duration of the disease, gender, age of the subjects is very weak and not statistically significant.Conclusion: further interdisciplinary studies are required to identify the causes and molecular mechanisms for the development of BH4 deficiency in schizophrenia and to develop approaches to personalized pharmacological intervention.

DIAGNOSIS AND TREATMENT OF PHENYLKETONURIA: OPPORTUNITIES AND PROSPECTS

A review of current data on phenylketonuria (PKU) and the differential diagnosis of various forms of hyperphenylalaninemia (HFA) is presented. There are considered existing worldwide recommendations for the treatment of patients with classical PKU and HFA. Neonatal screening has been shown to provide an early diagnosis of classical PKU and HFA, and the timely appointment and commitment of patients with a hypophenylalanine diet remains to be the main method for preventing CNS damage. Molecular diagnosis of PKU helps to confirm the results of laboratory screening of newborns and facilitates the choice of treatment tactics. Drug therapy with sapropterin is vital for HFA, due to tetrahydrobiopterin deficiency, and may also be applicable in patients with classical PKU.

Molecular genetics of tetrahydrobiopterin deficiency in Chinese patients

BackgroundThe overall incidence of hyperphenylalaninemia (HPA) in China is 1:11,763, with tetrahydrobiopterin (BH4) deficiency accounting for 8.55% of patients with HPA in the mainland. Much progress has been made in the diagnosis and treatment of BH4 deficiency with the introduction of neonatal screening in China. However, the screening rate is still low and screening is not universally available.MethodsA total of 44 BH4-deficient patients were enrolled in this study, of which 39 were diagnosed with BH4 deficiency, while the remaining five showed typical characteristics of BH4 deficiency at a later period. The entire coding regions and adjacent intronic regions ofGCH1,PTS,PCBD1andQDPRgenes were analyzed using target sequencing.ResultsNineteen (n=19) different mutations in thePTSgene including four novel mutations and one mutation inQDPRwere identified. p.P87S, p.D96N, IVS1-291A>G, p.N52S, p.K91R, p.V56M, p.T106M and p.F40GfsX53 inPTSwere the prevalent mutations with ≥3% relative frequency. The mutation p.R221X in theQDPRgene was found with relatively lower frequencies (2.27%). The remaining 12 mutations inPTSwere found at relative frequencies of 1.14%.ConclusionsThe results could be of value for genetic counseling and prenatal diagnosis in the patients’ families and for the molecular diagnosis of BH4 deficiencies. Furthermore, four novel mutations expand and improve thePTSmutation database.