Dihydropteridine reductase deficiency

Dihydropteridine reductase (DHPR) deficiency, also known as BH4-deficient hyperphenylalaninemia type C or atypical phenylketonuria (PKU), is a rare autosomal recessive disorder caused by mutations in the QDPR gene located on chromosome 4p15.32. It is one of the tetrahydrobiopterin (BH4) deficiency disorders and represents a severe form of hyperphenylalaninemia. DHPR is the enzyme responsible for regenerating tetrahydrobiopterin (BH4) from quinonoid dihydrobiopterin. BH4 is an essential cofactor not only for phenylalanine hydroxylase but also for tyrosine hydroxylase and tryptophan hydroxylase, which are critical for the synthesis of the neurotransmitters dopamine and serotonin. As a result, DHPR deficiency leads to both elevated blood phenylalanine levels and profound central nervous system neurotransmitter deficiencies. Clinical features typically present in infancy, often within the first few months of life, and include progressive neurological deterioration, intellectual disability, seizures, abnormal movements (dystonia, choreoathetosis), microcephaly, hypotonia, irritability, and swallowing difficulties. Without treatment, the disease follows a severe and progressive course. Affected infants may initially be identified through newborn screening programs that detect elevated phenylalanine, but further testing (including measurement of urinary pterins and blood DHPR activity) is essential to distinguish this condition from classic PKU, as treatment strategies differ significantly. Treatment involves a multifaceted approach including a phenylalanine-restricted diet, oral BH4 supplementation, and neurotransmitter precursor replacement therapy with L-DOPA/carbidopa and 5-hydroxytryptophan to restore dopamine and serotonin levels. Folinic acid supplementation is also critical, as DHPR deficiency leads to cerebral folate deficiency, which can cause additional neurological damage if untreated. Early diagnosis and prompt initiation of comprehensive therapy are essential to improve neurological outcomes, though even with treatment, some degree of developmental impairment may persist.

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