Dystonia, DOPA-responsive

Bandmann O., Valente E., Holmans P. el al. (1998). Dopa-responsive dystonia a clinical and molecular genetic study. Ann. Neurol. 44, 649-56. 

Nygaard T., Marsden C., Duvoisin R. (1988). Dopa-responsive dystonia. Adv. Neurol. 50, 377-84. 

The pharmacologic basis of these disorders is unknown, and there is no satisfactory medical treatment for them. A subset of patients respond well to levodopa medication (dopa-responsive dystonia), which is therefore worthy of trial. Occasional patients with dystonia may respond to diazepam, amantadine, antimuscarinic drugs (in high dosage), carbamazepine, baclofen, haloperidol, or phenothiazines. A trial of these pharmacologic approaches is worthwhile, though often not successful. Patients with focal dystonias such as blepharospasm or torticollis often benefit from injection of botulinum toxin into the overactive muscles. The role of deep brain stimulation for the treatment of these conditions is being explored. 

DHPR Dihydropteridine reductase, DRD dopa-responsive dystonia, GTPCH GTP cyclohydrolase I, n normal, PCD pterin-4a-carbinolamine dehydratase, PTPS 6-pyruvoyltetrahydrobiopterin synthase, SR sepiapterin... 

Bonafe L, Thony B, Leimbacher W, Kierat L, Blau N (2001) Diagnosis of Dopa-responsive dystonia and other tetrahydrobiopterin disorders by the study of biopterin metabolism in fibroblasts. Clin Chem 47 477-485... 

Blau N, Bonafe L, Thony (2001) Tetrahydrobiopterin deficiencies without hyperphenyl-alaninemia diagnosis and genetics of Dopa-responsive dystonia and sepiapterin reductase deficiency. Mol Genet Metab 74 172-185... 

Two types of inherited disorders caused by mutations of genes related to BH4 are known. Autosomal dominant mutations in the GCH gene are causative for DOPA-responsive dystonia (DRD) [157,158]. Malignant hyperphenylalaninemia or atypical phenylketonuria (PKU) is caused by recessive mutations of genes encoding BH4-biosynthetic or recycling enzymes [159]. 

DOPA-responsive dystonia (DRD) is a disorder characterized by childhood or adolescent onset dystonia and by the dramatic response to low-dose l-DOPA, a precursor of dopamine. DRD is a hereditary disorder in an autosomal dominant trait with reduced penetrance, and constitutes approximately 5 to 10% of primary dystonia in childhood and adolescence. DRD is caused by the dysfunction of nigro-striatal dopaminergic neurons, as indicated by the dramatic effect of l-DOPA. Although Parkinson s disease is also caused by the dysfunction of nigro-striatal dopaminergic neurons due to the degeneration of the dopaminergic neurons, the differences in symptoms, i.e. dystonia in DRD and parkinsonism in Parkinson s disease, has not yet been clarified. 

Bandmann O, Wood NW. 2002. Dopa-responsive dystonia—The story so far. Neuropediatrics 33 1-5... 

Genetic disorders (not included above) tyrosine hydroxylase deficiency dopa-responsive dystonia dihydropteridine reductase deficiency aromatic L-amino acid decarboxylase deficiency Menkes disease monoamine oxidase deficiency. 

Deficiencies of tyrosine hydroxylase or of enzymes involved in production of tetrahydrobiopterin cofactor (e.g., dopa-responsive dystonia) usually result in presentation of severe neurological abnormalities in early childhood. Depending on the exact mutation, deficiencies of tyrosine hydroxylase can involve moderate to severe loss of enzyme activity, most accurately diagnosed by low cerebrospinal fluid levels of catecholamine metabolites, such as MHPG and HVA, but normal levels of In the autosomal... 

IWo disorders of BH4 metabolism may present without hyperphenylalaninemia. These are Dopa-responsive dystonia (DRD Segawa disease) and sepiapterin reductase (SR) deficiency. While DRD is caused by a mutation in the GTPCH gene and is inherited in an autosomal dominant manner, SR deficiency is an autosomal recessive trait. Both diseases evidence severe biogenic amines deficiencies. DRD usually presents with a dystonic gait and diurnal variation. At least two reports describe heteroallelic patients with DRD suggesting a wide spectrum of GTPCH variants. 

Table 1.6. Dopa-responsive dystonia (DRD) autosomal dominant GTPCH 1 deficiency (>400 patients)...

Segawa M, Nomura Y. Hereditary progressive dystonia with marked diurnal fluctuation and dopa-responsive dystonia Pathognomonic clinical features. In Segawa M, Nomura Y, eds. Age Related Dopamine Dependent Disorders. Basel Karger, 1995 10-24. 

Bartholome K, Ludecke B. Mutations in the tyrosine hydroxylase gene cause various forms of L-dopa-responsive dystonia. Adv Pharmacol 1998 42 48-49. 

Segawa M. Dopa-responsive dystonia. Handb. Clin. Neurol. 2011 100 539-557. 

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