PTS – BH4-deficient hyperphenylalaninemia A

6-Pyruvoyl-tetrahydropterin synthase (PTPS), encoded by PTS (HGNC:9689), catalyzes the second step in tetrahydrobiopterin (BH4) biosynthesis, a critical cofactor for phenylalanine hydroxylase and monoamine neurotransmitter synthesis. Loss-of-function variants in PTS cause BH4-deficient hyperphenylalaninemia A (MONDO:0009863), manifesting as hyperphenylalaninemia and central neurotransmitter deficiencies. Early diagnosis via newborn screening and prompt BH4 plus neurotransmitter precursor treatment mitigate neurologic sequelae.

Autosomal recessive inheritance is confirmed in multiple cohorts. A Saudi Arabian tribal study described 10 affected individuals from seven unrelated families presenting severe early neurologic deterioration and hyperphenylalaninemia, with enzyme assays confirming PTPS deficiency (PMID:2027491). Italian families (n=4) harbored five distinct PTS alleles—including missense (Thr67Met, Lys129Glu, Asp136Val), a triplet deletion (Val57del), and a splice-site mutation—each segregating with disease and abrogating enzyme function in recombinant expression studies (PMID:9222757). A Beijing cohort of 11 PTPS-deficient patients further expanded the spectrum with seven missense, one splicing, and one deletion variant, demonstrating hot-spot intronic mutation c.84-291A>G in multiple alleles (PMID:36212127). A population-based mutation spectrum from Jiangxi (53 families, 106 alleles) highlighted recurrent c.259C>T (p.Pro87Ser) and c.84-291A>G variants, accounting for 47.2% and 19.8% of alleles respectively (PMID:36583021).

Case series and long-term follow-up studies reinforce phenotypic variability by genotype. Five patients across four families showed compound heterozygosity or homozygosity for combinations of L26F, T67M, P87L, V124L, D136G, and frameshift mutations, with outcomes correlating to treatment initiation age and residual enzyme activity (PMID:11388593). In 19 Italian patients, seven novel alleles were identified, and genotype–phenotype correlation revealed that milder forms retained partial in vitro enzyme activity and exhibited normal neurological development when treated early (PMID:20059486).

Functional assays validate pathogenic mechanisms. Recombinant expression of human PTPS mutants (Arg16Cys, Arg25Gln) in E. coli and COS-1 cells demonstrated residual activities of 7–14% of wild type, while frameshift and nonsense alleles abolished activity completely (PMID:8178819). Structural studies and phosphorylation assays implicate Ser19 modification and hexamer assembly in enzymatic stability and activity (PMID:7493990). Antisense morpholino rescue of deep-intronic pseudoexon inclusion confirmed restoration of normal splicing and enzyme function in patient fibroblasts, highlighting therapeutic potential (PMID:21542064).

No credible conflicting evidence has been reported. The extensive replication of genetic findings across diverse populations, clear segregation in multiple families, and concordant functional data establish a definitive gene–disease relationship.

Clinical integration of genetic and functional data supports precision diagnosis of BH4-deficient hyperphenylalaninemia A. Early identification of PTS variants through newborn screening or targeted sequencing enables timely BH4 and neurotransmitter replacement, preventing irreversible neurologic injury. Key take-home: PTS genetic testing is essential for infants with hyperphenylalaninemia to guide life-saving BH4-focused therapy.

References

• Neurology • 1991 • Biopterin-dependent hyperphenylalaninemia due to deficiency of 6-pyruvoyl tetrahydropterin synthase. PMID:2027491
• Human mutation • 1997 • Identification of mutations causing 6-pyruvoyl-tetrahydrobiopterin synthase deficiency in four Italian families. PMID:9222757
• Human mutation • 2000 • Isolated central form of tetrahydrobiopterin deficiency associated with hemizygosity on chromosome 11q and a mutant allele of PTPS. PMID:10874306
• European journal of pediatrics • 2001 • Molecular analysis and long-term follow-up of patients with different forms of 6-pyruvoyl-tetrahydropterin synthase deficiency. PMID:11388593
• Frontiers in genetics • 2022 • Identification and molecular analysis of 11 cases of the PTS gene variants associated with tetrahydrobiopterin deficiency. PMID:36212127
• Frontiers in genetics • 2022 • Mutation spectrum of PTS gene in patients with tetrahydrobiopterin deficiency from jiangxi province. PMID:36583021
• Clinical genetics • 2010 • Phenotypic variability, neurological outcome and genetics background of 6-pyruvoyl-tetrahydropterin synthase deficiency. PMID:20059486
• American journal of human genetics • 1994 • Hyperphenylalaninemia due to defects in tetrahydrobiopterin metabolism: molecular characterization of mutations in 6-pyruvoyl-tetrahydropterin synthase. PMID:8178819
• The Journal of biological chemistry • 1995 • Structural and functional consequences of mutations in 6-pyruvoyltetrahydropterin synthase causing hyperphenylalaninemia in humans. Phosphorylation is a requirement for in vivo activity. PMID:7493990
• Human mutation • 2011 • Pseudoexon exclusion by antisense therapy in 6-pyruvoyl-tetrahydropterin synthase deficiency. PMID:21542064

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