BH4-deficient hyperphenylalaninemia in Russia

Area of Science:

• Genetics
• Biochemistry
• Pediatrics

Background:

• Timely detection of tetrahydrobiopterin (BH4)-deficient hyperphenylalaninemia (HPABH4) is essential for effective patient management and complication avoidance.
• HPABH4 patients are often initially treated similarly to phenylalanine hydroxylase (PAH)-deficient phenylketonuria patients, delaying specific BH4 substitutive therapy until molecular confirmation.
• Accurate diagnosis is critical to differentiate HPABH4 from other forms of hyperphenylalaninemia (HPA).

Purpose of the Study:

• To characterize the genetic spectrum and prevalence of HPABH4 in a Russian cohort.
• To identify common and novel genetic variants in genes associated with HPABH4.
• To inform the integration of differential diagnostics for HPABH4 into neonatal screening programs in Russia.

Main Methods:

• Analysis of a cohort of 30 Russian patients with HPABH4.
• Family-based genetic diagnostics.
• Biochemical analysis of urinary pterin spectrum.

Main Results:

• Tetrahydrobiopterin deficiency type A (HPABH4A) was the predominant form, accounting for 83.3% of cases.
• The most frequent mutations in the PTS gene in Russia were p.Thr106Met (32%), p.Asn72Lys (20%), p.Arg9His (8%), and p.Ser32Gly (6%).
• Seven novel PTS variants and three novel QDPR variants were identified. HPABH4 prevalence in Russia was estimated at 0.5-0.9% of all HPA cases, lower than in other regions.

Conclusions:

• The study defines the mutation spectrum for PTS in the Russian population and identifies novel variants.
• HPABH4 prevalence in Russia is lower compared to European countries, China, and Saudi Arabia.
• Implementing differential diagnostics for HPABH4 in neonatal screening is necessary for timely and appropriate patient care.