A novel mutation in GCH-1 gene in a case of dopa-responsive dystonia

Abstract

Sirs: Dopa-responsive dystonia (DRD) is an autosomal dominant disorder characterized by earlyonset dystonia, diurnal fluctuations with worsening toward the evening and after exercise, and sustained response to small doses of L-dopa without side effects [1]. DRD has incomplete penetrance and high variability of phenotipic expression. Females are affected two to four times more often than males [2]. Linkage analysis mapped the DRD locus on the chromosome 14q11-4.3 [3] and mutations in the GTP cyclohydrolase I gene (GCH-1) have been found in about 50% of cases [2]. GCH-1 is the rate-limiting enzyme in the synthesis of tetrahydrobyopterin (BH4) from GTP. BH4 is an essential cofactor for tyrosine-hydroxilase to convert Ldopa to dopamine. A 11-year-old girl presented an acute right hemidystonia after one intramuscular administration of 10 mg of metoclopramide. The antiemetic treatment was withdrawn and the symptomatology disappeared spontaneously after one day from the drug discontinuation. After one year she developed walking difficulties, stiffness, cramps, and abnormal posturing in the right arm. Symptoms improved after the nocturnal sleep and worsened toward the afternoon and after exercise. Her disturbance was first related to orthopedic postural abnormalities and later to a conversion disorder. At the age of 14 years she was admitted to our department. Her motor and development milestones had been normal and medical history was unremarkable. Her parents and sister were asymptomatic (Fig. 1A). Neurological examination showed dystonia at right arm and both legs. Unified Dystonia Rating Scale (UDRS) score was 15/112. The patient also presented scoliosis and bilateral pes cavus. Ceruloplasmine, anti-nuclear antibodies, thyroid function, and MRI brain were normal. Neurological examinations of her parents and sister were normal. A pharmacological test with 100 mg of L-dopa plus 25 mg of benserazide resulted in a dramatic improvement of all symptoms of the patient. After two years, she is still on a daily L-dopa treatment, at the same dosage with constant benefit and without side effects. Oral loading with 100 mg/kg of phenylalanine was performed as previously described [4]. Phe/Tyr ratios at 1, 2, 3, and 4 hours from capillary blood samples were outside the normal range, confirming a GCH1 activity decrease. The molecular study revealed a novel missense mutation within the GCH-1 gene at position c.630C > G (Fig. 1B). This mutation, which causes an amino acid change from histidine to glutamine (H210Q) in exon 6, was carried in heterozygosis by the proband and her mother, and it was not found in 100 normal chromosomes. The residue mutated in our patient is located in the enzyme active site that appears to be essential for the catalysis [5, 6] and is conserved among species from human to yeast. As a matter of fact, in the proposed reaction mechanism of the GCH-1, Histidine 210 assists the catalysis acting as a proton donor to a reaction intermediate. Given the different acid-base properties of a glutamine residue, the H210Q substitution certainly abolishes the enzymatic activity, as clearly shown by biochemical studies on GCH-1 mutants of the active site (Fig. 1C) [6, 7]. In our patient, the first dystonic manifestation followed intramuscular metoclopramide administration. Dystonic reactions due to metoclopramide, in absence of a dose-effect correlation, are known, especially in teenager girls [8]. In our patient, the antidopaminergic effect of the drug probably preA. De Rosa AE E. Xhoxhi AE C. Criscuolo S. Striano AE A. Filla AE G. De Michele (&) Dept. of Neurological Sciences Federico II University Via Pansini 5 80131 Naples, Italy Tel.: +39-081/7463711 Fax: +39-081/5469861 E-Mail demichel@unina.it