QDPR – Dihydropteridine Reductase Deficiency

QDPR encodes dihydropteridine reductase (DHPR), an enzyme critical for regeneration of tetrahydrobiopterin (BH4), the cofactor for aromatic amino acid hydroxylases. Pathogenic biallelic variants in QDPR cause autosomal recessive dihydropteridine reductase deficiency, presenting with hyperphenylalaninemia and neurotransmitter deficiency due to impaired PAH, tyrosine, and tryptophan hydroxylation (PMID:14705166).

Genetic evidence includes homozygous or compound heterozygous loss-of-function and missense variants in over 150 patients worldwide (PMID:14705166). A large consanguineous Tunisian family exhibited seven homozygous siblings and two affected cousins carrying a frameshift allele, with parental heterozygosity confirmed by segregation analysis (n=9 probands) (PMID:9796752). Case reports also describe single-nucleotide deletions causing exon skipping and premature termination in homozygous patients with parental carrier status (PMID:7783174).

The variant spectrum encompasses frameshift, nonsense, splice-site, missense, in-frame duplications, and structural inversions. A recurrent in-frame duplication, c.366_368dup (p.Thr123dup), was identified in multiple unrelated patients and abolishes DHPR activity in fibroblasts (PMID:2116088).

Functional assays demonstrate severely reduced or absent DHPR enzyme activity in patient erythrocytes and recombinant expression systems. In vitro characterization of missense alleles shows loss of enzymatic kinetics, impaired dimerization, and increased protease susceptibility (e.g., p.Gly23Asp, p.His158Tyr) (PMID:8518287). A homozygous 9-Mb inversion disrupting QDPR further underscores the role of structural variants in this disorder (PMID:32022462).

Clinically, DHPR deficiency presents in infancy with hyperphenylalaninemia (HP:0004923), progressive microcephaly, developmental regression (HP:0002376), seizures (HP:0001250), and movement disorders. Early diagnosis via newborn screening and prompt treatment with BH4, levodopa, 5-HTP, and folinic acid can prevent irreversible neurologic damage.

Integration of robust genetic, segregation, and functional data yields a Definitive gene–disease association. The availability of molecular testing and biochemical assays supports precise diagnosis, genetic counseling, and tailored therapy. Key Take-home: QDPR testing should be included in hyperphenylalaninemia panels to enable early management and optimize neurodevelopmental outcome.

References

• Medicinal research reviews • 2004 • Dihydropteridine reductase deficiency in man: from biology to treatment. PMID:14705166
• Journal of child neurology • 1998 • Dihydropteridine reductase deficiency in a large consanguineous Tunisian family: clinical, biochemical, and neuropathologic findings. PMID:9796752
• Journal of medical genetics • 1995 • A mutation causing DHPR deficiency results in a frameshift and a secondary splicing defect. PMID:7783174
• American journal of human genetics • 1990 • Insertion of an extra codon for threonine is a cause of dihydropteridine reductase deficiency. PMID:2116088
• Biochemistry • 1993 • Identification and in vitro expression of mutations causing dihydropteridine reductase deficiency. PMID:8518287
• Molecular genetics & genomic medicine • 2020 • Genome sequencing identifies a homozygous inversion disrupting QDPR as a cause for dihydropteridine reductase deficiency. PMID:32022462

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