The following disorders are discussed: dopa-responsive Dystonia, aromatic L-amino acid decarboxylase deficiency, and monoamine oxidase A deficiency (MAO-A). Dopamine β-hydroxylase deficiency is not dealt with because it has only been diagnosed in adults (orthostatic hypotension), and defects of tetrahydrobiopterin are discussed in the chapter by Smith and Brenton. Dopa-responsive dystonia was first reported in 1976. At least 130 patients are presently known. Nygaard at al, have reported 66 personally examined patients.
Disorders of Neurotransmitters Diseases
Clinical Presentation Dopa-Responsive Dystonia
Age at onset of the dystonia is mostly between 1 and 10 years. There is a great variability in the severity of the disorder. The dystonia starts in the lower extremities, mostly with gait difficulties, and often remains limited to the extremities (e.g., writer’s cramp) with no or minimal axial dystonia. About 25% of affected children have clinical signs suggestive of spastic diplegia. In most patients there is a marked diurnal fluctuation of symptoms characterized by worsening of symptoms and increasing fatigue throughout the day and marked benefit of sleep. Symptoms noted in
a minority of patients are scoliosis, opisthotonus, dysarthria, dysphagia, postural tremor, and/or
intermittent abnormal eye movements. The disorder may be expressed as pure ‘parkinsonism’ in some adults without any dystonia in childhood.
Disorders of Neurotransmitters Diseases
Metabolic Derangement Dopa-Responsive Dystonia
The precise biochemical defect is still unknown. Most evidence points to a defect in striatal dopamine production. CSF levels of homovanillic acid, a dopamine metabolite, tend to be reduced. Levels of neopterin and its metabolite biopterin (a cofactor for tyrosine hydroxylase, the rate-limiting enzyme in dopamine production) are reduced.
Disorders of Neurotransmitters Diseases
Diagnostic Tests Dopa-Responsive Dystonia
The only diagnostic test is the dramatic responsiveness to levodopa which distinguishes dopa-responsive dystonia from other causes of childhood-onset dystonia-parkinsonism.
Disorders of Neurotransmitters Diseases
Treatment and Prognosis Dopa-Responsive Dystonia
Low doses of L-dopa (5-30 mg/kg per day), associated with a decarboxylase inhibitor such as in prolopa or sinemet, cause a marked improvement with complete or almost complete remission of symptoms usually within days or weeks. Progressive improvement continues to occur for months in some cases without increase in dosage. On withdrawal of L-dopa, there is immediate recurrence of symptoms. The effect of levodopa is sustained and free from the complications which occur in Parkinson disease, such as wearing off and unpredictable dose response.
Disorders of Neurotransmitters Diseases
Genetics Dopa-Responsive Dystonia
Available data strongly suggest autosomal dominant inheritance with sex-related reduced penetrance. Girls are more frequently and severely affected than boys. Moreover, it seems that the age of onset is earlier in girls. The disorder occurs worldwide. Recently, the gene for dopa-responsive dystonia has been mapped to chromosome 14q by linkage analysis.
Disorders of Neurotransmitters Diseases
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