Autosomal recessive GTP cyclohydrolase I deficiency (AR-GTPCHD) is a disorder associated with the deficient operation of the enzyme

GTP cyclohydrolase I GTP cyclohydrolase I (GTPCH) () is a member of the GTP cyclohydrolase family of enzymes. GTPCH is part of the folate and biopterin biosynthesis pathways. It is responsible for the hydrolysis of guanosine triphosphate (GTP) to form 7,8-dihydro ...

. The condition leads to insufficient production of the cofactor

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

necessary for the proper synthesis of

dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. It is an amine synthesized ...

and

serotonin Serotonin (), also known as 5-hydroxytryptamine (5-HT), is a monoamine neurotransmitter with a wide range of functions in both the central nervous system (CNS) and also peripheral tissues. It is involved in mood, cognition, reward, learning, ...

and for maintenance of adequate levels of

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

. As of 2020, autosomal recessive GTP cyclohydrolase I deficiency was one of the six known causes of

tetrahydrobiopterin deficiency Tetrahydrobiopterin deficiency (THBD, BH4D) is a rare metabolic disorder that increases the blood levels of phenylalanine. Phenylalanine is an amino acid obtained normally through the diet, but can be harmful if excess levels build up, causing int ...

. It is also considered part of the spectrum of dopa-responsive dystonias.

Symptoms and signs

Patients may present with developmental delay, axial hypotonia, delayed development of speech, or dysarthria. The list of possible motor disturbances includes dystonia,

oculogyric crises Oculogyric crisis (OGC) is a rare sudden, paroxysmal, dystonic reaction that may manifest in response to specific drugs, particularly neuroleptics, or medical conditions, such as movement disorders. This neurological phenomenon is characterized by ...

parkinsonism Parkinsonism is a clinical syndrome characterized by tremor, bradykinesia (slowed movements), Rigidity (neurology), rigidity, and balance disorder, postural instability. Both hypokinetic features (bradykinesia and akinesia) and hyperkinetic f ...

/hypokinesia. Patients may have a number of psychiatric symptoms. Biochemically, patients present with

hyperphenylalaninemia Hyperphenylalaninemia is a medical condition characterized by mildly or strongly elevated concentrations of the amino acid phenylalanine in the blood. Phenylketonuria (PKU) can result in severe hyperphenylalaninemia. Phenylalanine concentrat ...

, and usually have decreased levels of

biopterin Biopterins are pterin derivatives which function as endogenous enzyme cofactors in many species of animals and in some bacteria and fungi. The prototypical compound of the class is biopterin (6-(1,2-dihydroxypropyl)-pterin), as shown in the infobo ...

and

neopterin Neopterin is an organic compound belonging to the pteridine class of heterocyclic compounds. Neopterin belongs to the chemical group known as pteridines. It is synthesised by human macrophages upon stimulation with the cytokine interferon-gamma an ...

in urine and in dry blood spots.

Cause

Diagnosis

Treatment

According to a consensus guideline published in 2020, patients may be put on a phenylalanine-restricted diet to help bring down their elevated phenylalanine levels. To the same effect, and to normalise their production of neurotransmitters, they may be prescribed sapropterin, an artificially produced analogue of

. Another first-line drug in this disease is

L-DOPA -DOPA, also known as -3,4-dihydroxyphenylalanine and used medically as levodopa, is made and used as part of the normal biology of some plants and animals, including humans. Humans, as well as a portion of the other animals that utilize -DO ...

. Prescription of

5-hydroxytryptophan 5-Hydroxytryptophan (5-HTP), used medically as oxitriptan, is a naturally occurring amino acid and chemical precursor as well as a metabolic intermediate in the biosynthesis of the neurotransmitter serotonin. 5-HTP can be manufactured and use ...

is also possible. Prolonged therapy with large doses of L-DOPA may lead to the development of

cerebral folate deficiency Cerebral may refer to: * Of or relating to the brain * Cerebrum, the largest and uppermost part of the brain * Cerebral cortex, the outer layer of the cerebrum * Retroflex consonant, also referred to as a cerebral consonant, a type of consonant so ...

, therefore patients with decreased concentrations of

5-MTHF 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 ...

in their

cerebrospinal fluid Cerebrospinal fluid (CSF) is a clear, colorless Extracellular fluid#Transcellular fluid, transcellular body fluid found within the meninges, meningeal tissue that surrounds the vertebrate brain and spinal cord, and in the ventricular system, ven ...

may be prescribed

folinic acid Folinic acid, also known as leucovorin, is a medication used to decrease the toxic effects of methotrexate and pyrimethamine. It is also used in combination with 5-fluorouracil to treat colorectal cancer and pancreatic cancer, may be used to ...

, which efficiently penetrates the blood-cerebrospinal fluid barrier and helps restore the folate status.

References

{{Reflist

External links

Hyperphenylalaninemia, BH4-deficient, B
description in the

OMIM Online Mendelian Inheritance in Man (OMIM) is a continuously updated catalog of human genes and genetic disorders and traits, with a particular focus on the gene-phenotype relationship. , approximately 9,000 of the over 25,000 entries in OMIM ...