Dihydropteridine reductase deficiency (DHPRD) is a genetic disorder affecting the tetrahydrobiopterin (BH4) synthesis pathway, inherited in the autosomal recessive pattern. It is one of the six known disorders causing tetrahydrobiopterin deficiency, and occurs in patients with mutations of the QDPR gene. The disease presents with such symptoms as elevated levels of phenylalanine ( hyperphenylalaninemia), microcephaly, hypotonus, mental retardation and epileptic seizures.

Diagnostics

Besides the traditional analysis of symptoms and investigation of

phenylalanine Phenylalanine (symbol Phe or F) is an essential α-amino acid with the formula . It can be viewed as a benzyl group substituted for the methyl group of alanine, or a phenyl group in place of a terminal hydrogen of alanine. This essential amino a ...

concentrations, patients suspected for DHPRD undergo the assessment of enzymatic activity using the

dried blood spot Dried blood spot testing (DBS) is a form of biosampling where blood samples are blotted and dried on filter paper. The dried samples can easily be shipped to an analytical laboratory and analysed using various methods such as DNA amplification or ...

method - this permits to distinguish DHPR deficiency from the other forms of BH4 deficiency.

Treatment

Patients are prescribed a phenylalanine-reduced diet, with regular monitoring of phenylalanine levels in the blood. Besides the diet, a patient may be prescribed

sapropterin Tetrahydrobiopterin (BH4, THB), also known as sapropterin (INN), is a cofactor of the three aromatic amino acid hydroxylase enzymes, used in the degradation of amino acid phenylalanine and in the biosynthesis of the neurotransmitters serotonin ...

, a synthetic analogue of tetrahydrobiopterin. In order to restore dopamine levels in the central nervous system, patients are given L-dopa in conjunction with an inhibitor of aromatic amino acid decarboxylase that acts outside the nervous system, so as to promote the transformation of L-dopa into dopamine inside the central nervous system, and thus to improve the efficiency of the treatment. Since the insufficient levels of BH4 inhibit the transformation of tryptophan into 5-hydroxytryptophan in a reaction in which BH4 serves as a cofactor of the enzyme tryptophane hydroxylase 2, patients suffer from a lack of serotonin in their CNS. In order to correct this deficiency, they are given

5-hydroxytryptophan 5-Hydroxytryptophan (5-HTP), also known as oxitriptan, is a naturally occurring amino acid and chemical precursor as well as a metabolic intermediate in the biosynthesis of the neurotransmitter serotonin. Uses 5-HTP is sold over the counter i ...

. In patients with DHPR deficiency, a pronounced lack of

5-methyltetrahydrofolate Levomefolic acid (INN, also known as L-5-MTHF, L-methylfolate and L-5-methyltetrahydrofolate and (6''S'')-5-methyltetrahydrofolate, and (6''S'')-5-MTHF) is the primary biologically active form of folate used at the cellular level for DNA reprodu ...

(5-MTHF) is observed in the central nervous system. This condition, termed cerebral folate deficiency, (CFD) is more severe in DHPRD patients than in patients with other forms of BH4 deficiency. CFD is corrected by treating patients with folinic acid, a form of folate that efficiently passes the hematoencephalic barrier.(2013) Emery and Rimoin's Principles and Practice of Medical Genetics
Chapter 92. Amino Acid Metabolism. 92.1.7. DHPR Deficiency
by Raymond Y.Wang, William R.Wilcox, and Stephen D.Cederbaum The use of '' folic acid'', the synthetic form of folate employed in food fortification, should be avoided because folic acid tightly binds to the folate receptor alpha and may inhibit the transport of folate into the central nervous system.

References

{{Reflist Metabolic disorders