GTP-cyclohydrolase I (GTPCH I) deficiency ..., (Segawa disease, Dystonia 5 -DYT5-; DOPA responsive Dystonia) - GCH1 gene

GTP cyclohydrolase deficiency I is an inherited, progressive disorder that encompasses a broad spectrum of clinical manifestations. This process is different denominations, such as, Segawa disease, dystonia 5 (DYT 5) or dystonia response to Dopa (DRD).

In general, the signs and symptoms associated GTP cyclohydrolase deficiency I usually begin to manifest at the age of 6 years, although some patients have their onset in adulthood. It starts with gait disturbances caused by lower limb dystonia, parkinsonism and further development of fluctuating daytime symptoms that worsen throughout the day and with the effort, and improve with sleep or rest. Sometimes, the first symptoms may include upper limb dystonia with postural hand tremor and slowness of movement, but usually appear later, at the age of 10 years.

The degree of rigidity worsens progressively. In fact, postural dystonia of the lower extremities during childhood expands to all extremities, generalized dystonia developing during adolescence. The diurnal fluctuation, at this stage, usually begins to decline. The quake, with onset during adolescence, all the limbs and trunk expands during the second decade of life, in many cases requiring wheelchair after a few years of disease onset. Milder cases have focal dystonia, generally as abnormal foot position. However, in severe cases, symptoms described above may be accompanied by mental retardation, seizures, difficulty swallowing, excessive salivation, abnormal muscle tone trunk hypotonia and limb hypertonia, abnormal movements, etc.

This process is due to mutations in the gene GCH1, located on the long arm of chromosome 14 (14q22.1-q22.2). This gene encodes an enzyme called GTP cyclohydrolase I. This enzyme is involved in the first three stages in encoding a molecule called tetrahydrobiopterin (BH4). Tetrahydrobiopterin plays a critical role in the processing of amino acids in the body. For example, it acts with the enzyme phenylalanine hydroxylase to convert the amino acid phenylalanine at amino acid tyrosine. Tetrahydrobiopterin is also involved in the reactions encoding neurotransmitters. Specifically, tetrahydrobiopterin is involved in encoding dopamine and serotonin. Among its many functions, the dopamine transmits signals within the brain to perform physical movements, and serotonin regulates mood, emotion, sleep and appetite.

Mutations in the gene result GCH1 encoding a GTP cyclohydrolase I enzyme with reduced activity. Most mutations change the amino acids in GTP cyclohydrolase enzyme 1. As a result, the reduction of GTP cyclohydrolase 1 functional results in coding less dopamine and serotonin, causing problems of movement and other features of the disease.

This disease is inherited as an autosomal dominant, which means that a copy of the altered gene in each cell is sufficient for the disease to be expressed.

Tests in IVAMI: in IVAMI perform detection of mutations associated with GTP cyclohydrolase I deficiency, by complete PCR amplification of the exons of the gene GCH1, and subsequent sequencing.

Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).