Dystonia, Dopa-Responsive

A number sign (#) is used with this entry because dopa-responsive dystonia, or autosomal dominant Segawa syndrome, is caused by heterozygous mutation in the gene encoding GTP cyclohydrolase I (GCH1; 600225) on chromosome 14q13. GTP cyclohydrolase I is rate-limiting in the conversion of GTP to tetrahydrobiopterin (BH4), the cofactor for tyrosine hydroxylase, which in turn is the rate-limiting enzyme for dopamine synthesis.

See 233910 for a discussion of BH4-deficient hyperphenylalaninemia B (HPABH4B) and autosomal recessive dopa-responsive dystonia with or without hyperphenylalaninemia, allelic disorders caused by homozygous or compound heterozygous mutations in the GCH1 gene.

An autosomal recessive form of Segawa syndrome (605407) is caused by mutation in the tyrosine hydroxylase gene (TH; 191290).

Clinical Features

Segawa et al. (1976) reported 9 patients in 6 families with postural and motor disturbances showing marked diurnal fluctuation. Dystonic posture or movement of one limb appeared insidiously between ages 1 and 9 years. All limbs were involved within 5 years of onset. Torsion of the trunk was unusual. Rigidity, resting tremors, or cerebellar, pyramidal and sensory changes were not found, and intelligence was normal. Symptoms were remarkably alleviated after sleep and aggravated gradually toward evening.

Allen and Knopp (1976) observed a family in which 3 females had dopa-responsive dystonia: the proband, her paternal grandmother, and her niece. The proband's father had died at age 34 years. A disorder of gait ('walking on the ball of her foot') started in the proband at age 6 years and tremor in the hands at age 10. Achilles tenotomy was performed at age 11. In her thirties, striking improvement occurred with L-DOPA and anticholinergic medication. The paternal grandmother had onset of tremors at age 13 years. Flexion dystonia of the fingers and fixed facial expression were evident by age 54. She became immobile and bedridden after age 64 and died at age 80. The niece, aged 15 at the time of report, showed dystonic movements of the right hand and a longstanding disturbance of gait. L-DOPA resulted in improvement. Although these patients were earlier thought to have had juvenile Parkinson disease (168100), Nygaard et al. (1988) concluded that they had dopa-responsive dystonia.

Nygaard and Duvoisin (1986) studied a family with an extrapyramidal disorder characterized by childhood onset of lower limb and axial dystonia, followed by parkinsonism. Dramatic response to levodopa therapy and minimal progression in adulthood were features. A family described by de Yebenes et al. (1988) had childhood onset of a dopa-responsive form of dystonia involving legs, gait, and balance. Diurnal fluctuation of symptoms and features of parkinsonism were common. Nygaard et al. (1990) described the spectrum of clinical manifestations in this large English/American family. The dystonia was nearly completely ameliorated by levodopa therapy. Penetrance of the dystonia gene was estimated to be 35% in this family. Four persons carrying the dystonia gene (2 affected and 2 obligate gene carriers) manifested parkinsonism later in life. A somewhat higher frequency than in the general population suggested that parkinsonism is a manifestation of this disorder.

In a study of 66 patients with DRD, including 47 with familial disease and 19 with sporadic disease, Nygaard et al. (1991) found that levodopa was the most effective treatment, with an excellent response lasting as long as 10 to 22 years. The authors noted that the coexistence of parkinsonian features and the dramatic responsiveness to levodopa are two clinical features of DRD that separate it from other forms of idiopathic torsion dystonia. In addition, the sustained nature of the levodopa responsiveness, free from the complications of therapy that typically occur in Parkinson disease (wearing-off, 'on-off,' and unpredictable dose response), distinguish DRD from other causes of childhood-onset dystonia-parkinsonism such as cerebral palsy or spastic diplegia.

Harwood et al. (1994) described a family in which 6 members of 4 generations had dopa-responsive dystonia. The disorder presented in childhood with dystonia of the legs, progressing to parkinsonism and pseudo-pyramidal deficits, or in adult life with parkinsonism and pseudo-pyramidal signs. The pseudo-pyramidal signs included exaggerated tendon reflexes and extensor plantar responses. Remarkably, in the 3 family members with childhood onset, the symptoms and signs of the condition were abolished 36 to 52 years later by small doses of levodopa. No long-term side effects of levodopa had appeared after 15 years of treatment.

Steinberger et al. (1998) demonstrated marked variation in expressivity, even between affected members of the same kindred. Whereas one of their index cases had difficulty walking from age 3 years and was wheelchair-bound from age 6, the only demonstrable sign in her 43-year-old mother was tightening of the legs while she wrote with her left hand.

Brique et al. (1999) reported a family with DRD in which 4 of 9 sibs were affected; DNA was available on 3 of the affected individuals. Two sisters were 7 and 8 years of age when dystonia appeared. A simultaneous parkinsonism developed in 1, whereas it occurred after the age of 54 years in the second sister. Levodopa therapy was effective in both. In the 2 brothers, dystonia began at age 13 and 15 years. Parkinsonism (rest tremor) appeared at age 15 in 1 brother. Dystonia and parkinsonism spontaneously disappeared at age 40 and age 44, respectively, in the 2 brothers. For 17 years the brothers were free of symptoms; parkinsonism then reappeared in both of them, but was dramatically improved by levodopa. Genetic analysis revealed a mutation in the GCH1 gene (600225.0015).

Hahn et al. (2001) described a family with clinically variable neurologic and psychiatric manifestations and a novel mutation in the GCH1 gene. The proband was a young boy with variable foot dystonia and fatigue. Eleven additional members of the family were found to have the same mutation, of which 2 members were unaffected. Of the 9 affected members, there was a wide range of clinical phenotypes, including dystonia, torticollis, brisk deep tendon reflexes, and levodopa-responsive parkinsonism. Clinical deafness was found in 50% of affected family members. The father of the proband had a long history of anxiety and depression. Based on CSF analysis, Hahn et al. (2001) suggested that the mutation may produce a defect in cerebral dopamine, serotonin, and norepinephrine biosynthesis, contributing to psychiatric manifestations. Detailed histories revealed that the family had multiple members with psychiatric symptoms, including depression, anxiety, obsessive-compulsive traits, and eating disorders. Hahn et al. (2001) concluded that the range of neuropsychiatric features may be related to mutation in the GCH1 gene and should be included in diagnostic criteria.

Chaila et al. (2006) reported 4 adult female sibs from Ireland with DRD confirmed by genetic analysis late in life. All had childhood-onset dystonia and pyramidal tract signs, 3 had additional extrapyramidal signs, including tremor, bradykinesia, or rigidity, and 2 had definite signs of cerebellar dysfunction. All had mild horizontal gaze-evoked nystagmus. Treatment with levodopa therapy resulted in marked clinical improvement of dystonia and cerebellar signs. The authors concluded that some patients with DRD may show cerebellar signs.

Grotzsch et al. (2002) reported a 3-generation Swiss family with dopa-responsive dystonia in which 7 members were definitely affected and 4 members were possibly affected. The pattern of inheritance was autosomal dominant. The proband was a 77-year-old woman who had developed dystonia of the lower limbs by age 3 years, leading to gait and postural abnormalities which worsened by the end of the day. The condition progressed, leaving her wheelchair-bound and with generalized dystonia and parkinsonism. Treatment with levodopa markedly improved symptoms. Brain autopsy of an affected patient showed severe depigmentation (hypomelanization) of the large neurons of the substantia nigra and the locus ceruleus, although the number of these neurons appeared unaffected. The defect was asymmetric, with the lateral areas more severely depigmented than the medial areas.

Inheritance

The pedigree patterns in the families of Segawa et al. (1976) were consistent with irregular dominant inheritance.

Nygaard and Duvoisin (1986) reported a family which included 5 generations of affected persons with instances of male-to-male transmission in an autosomal dominant pattern.

Furukawa et al. (1998) found the penetrance of GCH1 gene mutations in women to be 2.3 times higher than in men but there was no difference in penetrance in affected children who received the mutation from the mother or father.

Mapping

Locus Exclusions

Kwiatkowski et al. (1991) identified a highly polymorphic (GT)n repeat VNTR within the argininosuccinate synthetase locus (603470), which maps to 9q34, and used it to study the large family reported by Nygaard et al. (1990). They demonstrated that the gene is not located in this region of the genome and is therefore not an allele of the torsion dystonia locus (128100), which has been mapped to 9q32-q34. Schuback et al. (1991) excluded dopamine beta-hydroxylase (223360) and Fletcher et al. (1989) excluded tyrosine hydroxylase as candidate genes. Nygaard (1993) excluded the TH locus in his families and, according to him, the TH locus was excluded by Segawa in his families. Bartholome et al. (1993) demonstrated linkage of the Segawa syndrome to the gene for tyrosine hydroxylase. Furthermore, in 1 family with 2 affected children, they identified a point mutation in exon 11 of the TH gene resulting in an amino acid exchange. Gorke and Bartholome (1990) suggested the existence of an autosomal dominant and an autosomal recessive form of Segawa syndrome. It is the recessive form that shows linkage to the tyrosine hydroxylase gene on chromosome 11; see 191290.0001 and 191290.0003.

Linkage to 14q22

In a linkage study of 3 families, Nygaard et al. (1993) mapped the DRD gene to chromosome 14. They found a maximum 2-point lod score of 4.67 at 8.6 cM from D14S63. They found a maximum multipoint lod score greater than 6 for the intervals D14S47-D14S52 and D14S52-D14S63. The multipoint analyses gave equal support for localizing DRD in either of these intervals. The flanking loci D14S47 and D14S63 defined a region of about 22 cM as containing the DRD gene. In an addendum, Nygaard et al. (1993) cited evidence for support of the linkage of DRD to 14q in a Japanese family, a large French-Canadian family, and 4 smaller English families.

In the family originally reported by Grotzsch et al. (2002), Wider et al. (2008) performed linkage analysis on 32 individuals, including 6 affected family members, and found linkage to a region on chromosome 14q that included the GCH1 gene.

Nomenclature

The dopa-responsive dystonia in the family reported by Grotzsch et al. (2002) was originally thought to be at a locus on chromosome 14 separate from the DYT5 locus and was designated dystonia-14 (DYT14). Wider et al. (2008) restudied the family reported by Grotzsch et al. (2002) and determined that the disorder was indeed DYT5 caused by mutation in the GCH1 gene.

Pathogenesis

In a neuropathologic examination of a patient with DRD, Rajput et al. (1994) found normal numbers of hypopigmented neurons with reduced levels of dopamine in the substantia nigra, as well as normal TH activity and normal TH protein levels in the substantia nigra. In the striatum, there was no evidence of a degenerative process, but there was a reduction of dopamine (8% of control in the putamen and 18% of control in the caudate), and a reduction of TH protein and activity. The authors concluded that disturbed dopamine synthetic capacity or a reduced arborization of striatal dopamine terminals may be the underlying pathophysiology in DRD.

In DRD, Nygaard et al. (1993) described decreased melanin content in the substantia nigra, with normal neuronal cell counts and morphology, suggesting a developmental reduction in the number of dopaminergic nerve endings in the striatum.

In neuropathologic examination of 2 patients with DRD, Furukawa et al. (1999) found a substantial decrease in brain tetrahydrobiopterin (BH4), reduced brain neopterin, and low levels of the tyrosine hydroxylase protein, which are likely secondary to BH4 deficiency.

There is a 4:1 female predominance in dopa-responsive dystonia. Ichinose et al. (1994) found higher GTP cyclohydrolase I activities in males than in females, a possible explanation for the difference in frequency of the disorder. The diurnal fluctuations that are characteristic of this disorder may be explained by the relatively short half-life of tetrahydrobiopterin. The patients may synthesize tetrahydrobiopterin at a low rate that is not high enough to compensate for the consumption of the cofactor during the day, thus leading to aggravation of symptoms toward evening.

In a detailed review of the disorder, Segawa et al. (2003) presented neuroimaging, neurophysiologic, and biochemical evidence to confirm the normal preservation of the structure of nigrostriatal dopaminergic neurons. The findings suggested that decreased striatal dopamine and a decreased level of tyrosine hydroxylase is the main pathology of autosomal dominant DRD.

Diagnosis

Hyland et al. (1997, 1999) demonstrated that oral phenylalanine loading can identify both symptomatic and asymptomatic carriers of the gene for autosomal dominant GTP cyclohydrolase deficiency. Patients with heterozygous mutations showed significantly increased plasma phenylalanine after loading compared to controls. The findings indicated decreased hepatic PAH (612349) activity due to defective synthesis of BH4 resulting from GCH1 mutations, and suggested that patients with heterozygous mutations can show hyperphenylalaninemia if stressed.

Molecular Genetics

In affected members of 4 families with DRD, Ichinose et al. (1994) identified 4 different mutations in the GCH1 gene (600225.0001-600225.0004).

In 58 patients with dopa-responsive dystonia, Steinberger et al. (2000) identified mutations in the GCH1 gene in 30 individuals from 22 families. Thirteen of the mutations were familial, 3 occurred de novo, and inheritance could not be determined in 6 cases. Since there was no difference in therapeutic doses of L-DOPA between patients with or without a GCH1 mutation, the authors suggested that the phenotype in those without a GCH1 mutation may be caused by other genes involved in the synthesis of dopamine.

Hagenah et al. (2005) identified mutations in the GCH1 gene in 20 (87%) of 23 unrelated individuals with dopa-responsive dystonia. Two patients had large deletions of more than 1 exon, which were detected only by quantitative PCR testing. Hagenah et al. (2005) stated that 85 different mutations had been reported in the GCH1 gene.

Using multiple ligation-dependent probe amplification (MLPA), Steinberger et al. (2007) identified 3 different deletions in the GCH1 gene in multiple affected members of 3 unrelated families with DRD. Previous analysis had excluded single basepair changes in the GCH1 gene. The findings demonstrated that DRD is most likely due to haploinsufficiency of the GCH1 gene, rather than a dominant-negative effect. All patients showed characteristic signs and symptoms of DRD.