What is DHPR deficiency?
What is DHPR deficiency?
Dihydropteridine reductase deficiency (DHPR) is a severe form of hyperphenylalaninemia (high levels of the amino acid phenylalanine in the blood) due to impaired renewal of a substance known as tetrahydrobiopterin (BH4).
Does BH4 deficiency cause PKU?
BH4 deficiencies are grouped with phenylketonuria (PKU), which is an inborn error of protein metabolism that results from an impaired ability to metabolize the essential amino acid Phe. Similar to PKU, BH4 deficiencies negatively affect developmental function.
How is BH4 deficiency treated?
Treatment of BH4 deficiencies consists of BH4 supplementation (2-20 mg/kg per day) or diet to control blood phenylalanine concentration and replacement therapy with neurotransmitters precausers (L-dopa/CarbiDOPA and 5-hydroxytryptophan), and supplements of folinic acid in DHPR deficiency.
What does Dihydropteridine reductase do?
Dihydropteridine reductase (DHPR) is an enzyme essential for the regeneration of tetrahydrobiopterin, itself a co-factor necessary for the hydroxylation reactions in the brain leading to the synthesis of tyrosine, dopa, noradrenaline and 5-hydroxytryptophan (Fig. 1).
How does Dhpr work?
The dihydropyridine receptor (DHPR), normally a voltage-dependent calcium channel, functions in skeletal muscle essentially as a voltage sensor, triggering intracellular calcium release for excitation-contraction coupling.
What does Hyperphenylalaninemia mean?
Hyperphenylalaninemia is broadly defined as the presence of blood phenylalanine levels that exceed the limits of the upper reference range (2 mg/dL or 120 µmol/L) without treatment but that are below the level found in patients with phenylketonuria (PKU).
What is BH4 supplement?
Abstract. Tetrahydrobiopterin (BH4) is an essential cofactor of nitric oxide synthetase (1, 2) as well as of aromatic amino acid hydroxylases of phenylalanine (3), tyrosine (4), and tryptophan (5, 6). BH4-supplement has been used effectively to treat many cases of neuronal dysfunctions caused by BH4 deficiency.
What is SPR disease?
SPR deficiency. Sepiapterin reductase deficiency is an inherited pediatric disorder characterized by movement problems, and most commonly displayed as a pattern of involuntary sustained muscle contractions known as dystonia.
Where is BH4 from?
BH4 is made from the molecule GTP (guanosine triphosphate). GTP is converted into BH4 in three stages, which are catalysed (in order) by the enzymes GTPCH, PTPS and SR. These enzymes are coded for, respectively, by the GCH1, PTS and SR genes. Interestingly, rare mutations in these genes can lead to deficiency of BH4.
What is malignant PKU?
A small percentage of children with elevated phenylalanine levels exhibit normal PAH levels but have a deficiency in synthesis or recycling of BH4 known as tetrahydrobiopterin deficiency. This condition is sometimes termed malignant PKU and can result from biallelic mutations in the GCH1, PCB1, PTS, or QDPR genes.
How is DHPR activated?
Skeletal muscle excitation–contraction (EC) coupling is initiated by sarcolemmal depolarization, which is translated into a conformational change of the dihydropyridine receptor (DHPR), which in turn activates sarcoplasmic reticulum (SR) Ca2+ release to trigger muscle contraction.
Why is it called dihydropyridine?
A protein called the dihydropyridine receptor (DHPR) senses the membrane potential on the T-tubule membrane and relays this to another protein, the Ryanodine receptor (RyR), on the SR membrane inside the fiber. The RyR is so named because it binds a plant alkaloid, ryanodine, with high affinity.
