What are the other Names for this Condition? (Also known as/Synonyms)

• BH4-Deficient Hyperphenylalaninemia B
• Tetrahydrobiopterin-Deficient Hyperphenylalaninemia due to GTP Cyclohydrolase 1 Deficiency

What is GTP Cyclohydrolase I Deficiency Disorder? (Definition/Background Information)

• GTP-Cyclohydrolase I Deficiency Disorder, an autosomal recessive genetic disorder, is one of the causes of malignant hyperphenylalaninemia due to tetrahydrobiopterin deficiency
• Not only does tetrahydrobiopterin deficiency cause hyperphenylalaninemia, it is also responsible for defective neurotransmission of monoamines because of malfunctioning tyrosine and tryptophan hydroxylases, both tetrahydrobiopterin-dependent hydroxylases
• GTP-Cyclohydrolase I Deficiency should be suspected in all infants with a positive neonatal screening test for phenylketonuria, especially when hyperphenylalaninemia is moderate
• The principal symptoms include psychomotor retardation, tonicity disorders, convulsions, drowsiness, irritability, abnormal movements, hyperthermia, hypersalivation, and difficulty swallowing
• The treatment attempts to bring phenylalaninemia levels back to normal (diet with restricted phenylalanine intake or prescription of tetrahydrobiopterin) and to restore normal monoaminergic neurotransmission by administering precursors (L-dopa/carbidopa and 5-hydroxytryptophane)

(Source: GTP Cyclohydrolase I Deficiency Disorder; Orphanet, National Institute of Health and Medical Research (INSERM), Paris.)

Who gets GTP Cyclohydrolase I Deficiency Disorder? (Age and Sex Distribution)

• GTP Cyclohydrolase I Deficiency Disorder is a very rare congenital disorder. The presentation of symptoms may occur at birth
• Both males and females may be affected
• Worldwide, individuals of all racial and ethnic groups may be affected

What are the Risk Factors for GTP Cyclohydrolase I Deficiency Disorder? (Predisposing Factors)

• A positive family history may be an important risk factor, since GTP Cyclohydrolase I Deficiency Disorder can be inherited
• Children born to consanguineous parents may bear an increased risk for the disorder

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases one’s chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of GTP Cyclohydrolase I Deficiency Disorder? (Etiology)

• GTP Cyclohydrolase I Deficiency Disorder is caused by mutation(s) in the GCH1 gene
• This gene codes for the enzyme GTP cyclohydrolase I
• The disorder is inherited in an autosomal recessive manner

Autosomal recessive inheritance: Autosomal recessive conditions are traits or disorders that occur when two copies of an abnormal gene have been inherited on a non-sex chromosome. If both parents have an autosomal recessive condition, there is a 100% likelihood of passing on the mutated genes to their children. If, however, only one mutant copy of the gene is inherited, the individual will be a carrier of the condition, but will not be present with any symptoms. Children born to two carriers, have a 25% chance of being homozygous dominant (unaffected), a 50% chance of being heterozygous (carrier), and a 25% chance of being homozygous recessive (affected).

What are the Signs and Symptoms of GTP Cyclohydrolase I Deficiency Disorder?

The signs and symptoms of GTP Cyclohydrolase I Deficiency Disorder may include:

• Abnormality of eye movement
• Choreoathetosis
• Dysphagia
• Dystonia
• Episodic fever
• Excessive salivation
• Global developmental delay
• Hyperkinesis
• Hyperphenylalaninemia
• Intellectual disability, progressive
• Irritability
• Lethargy
• Limb hypertonia
• Progressive neurologic deterioration
• Rigidity
• Severe muscular hypotonia
• Tremor

(Source: GTP Cyclohydrolase I Deficiency Disorder; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

How is GTP Cyclohydrolase I Deficiency Disorder Diagnosed?

GTP Cyclohydrolase I Deficiency Disorder is diagnosed on the basis of the following information:

• Complete physical examination
• Thorough medical history evaluation
• Assessment of signs and symptoms
• Imaging tests
• Biopsy, if necessary
• Laboratory tests, including measurement of pteridine levels in urine, followed by confirmation by measuring neurotransmitters (5-hydroxyindolacetic acid and homovanillic acid) in cerebrospinal fluid and with an oral tetrahydrobiopterin-loading test (20 mg/kg)

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of GTP Cyclohydrolase I Deficiency Disorder?

The complications of GTP Cyclohydrolase I Deficiency Disorder may include:

• Poor feeding
• Severe developmental retardation
• Inability to walk due to muscle weakness and rigidity
• Severe intellectual disability

Complications may occur with or without treatment, and in some cases, due to treatment also.

How is GTP Cyclohydrolase I Deficiency Disorder Treated?

There is no cure for GTP Cyclohydrolase I Deficiency Disorder, since it is a genetic condition. The treatment is usually given to manage the signs and symptoms and any complication that develops. The treatment options may include:

• Diet restriction of phenylalanine and prescription for tetrahydrobiopterin to normalize the levels of phenylalanine
• Restoring monoaminergic neurotransmission by administration of precursors, such as L-dopa/carbidopa and 5-hydroxytryptophane

How can GTP Cyclohydrolase I Deficiency Disorder be Prevented?

Currently, GTP Cyclohydrolase I Deficiency Disorder may not be preventable, since it is a genetic disorder.

• Genetic testing of the expecting parents (and related family members) and prenatal diagnosis (molecular testing of the fetus during pregnancy), if available, may help in understanding the risks better during pregnancy
• If there is a family history of the condition, then genetic counseling will help assess risks, before planning for a child
• Active research is currently being performed to explore the possibilities for treatment and prevention of inherited and acquired genetic disorders

Regular medical screening at periodic intervals with tests and physical examinations are recommended.

What is the Prognosis of GTP Cyclohydrolase I Deficiency Disorder? (Outcomes/Resolutions)

• The prognosis of GTP Cyclohydrolase I Deficiency Disorder is dependent upon the severity of the signs and symptoms and associated complications, if any
• Individuals with mild conditions have better prognosis than those with severe symptoms and complications
• If left untreated, the neurological signs may become apparent by 5 months of age
• Typically, the prognosis may be assessed on a case-by-case basis

Additional and Relevant Useful Information for GTP Cyclohydrolase I Deficiency Disorder:

The following DoveMed website link is a useful resource for additional information:

http://www.dovemed.com/diseases-conditions/rare-disorders/