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Autosomal recessive dopa-responsive dystonia
Autosomal recessive dopa-responsive dystonia (DYT5b) is a very rare neurometabolic disorder characterized by a spectrum of symptoms ranging from those seen in dopa-responsive dystonia (DRD; see this term) to progressive infantile encephalopathy.
The estimated European prevalence of DRD ranges from 1/1,000,000-1/200,000. DYT5b is much less frequent than autosomal dominant DRD (DYT5a; see this term); fewer than 50 patients have been described worldwide to date.
Disease presents in infancy (most frequently in the first year of life) with a progressive hypokinetic-rigid syndrome with generalized dystonia, involuntary jerky movements, postural tremor, or gait disturbances that may fluctuate during the day and show good or excellent responsiveness to levodopa (L-dopa) in most cases (>80%). Eye-rolling movements and/or mild, non-progressive intellectual deficit may be present in some cases. Less frequently, a more severe phenotype of complex encephalopathy can present before the age of 6 months, with marked hypokinesia and progressive truncal hypotonia, combined with focal or generalized dystonia, sometimes with dystonic crises over several days and (often excessive) jerky movements like myoclonus and tremor without diurnal fluctuations. Autonomic disturbances are frequent, such as excessive salivation and sweating, lethargy, constipation, poor feeding and ''pyrexia of unknown origin''. Intellectual deficit, developmental motor delay, bilateral ptosis and oculogyric crises are also frequent.
DYT5b is caused by mutations in the tyrosine hydroxylase TH gene (11p15.5) encoding tyrosine hydroxylase, an enzyme responsible for catalyzing the conversion of L-tyrosine to L-dopa, the precursor of dopamine. For the two most common missense mutations (c.698G>A and c.707T>C) and for heterozygous truncating mutations, no genotype-phenotype correlation has been observed, but mutations in the promoter region are apparently associated with a milder phenotype.
Diagnosis is based on clinical findings and the improvement of symptoms with the administration of oral L-dopa. The finding of homozygous TH mutations confirms diagnosis. Low levels of the dopamine metabolite homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA) and 3-methoxy-4-hydroxyphenylethylene glycol (MHPG) are found in the cerebrospinal fluid (CSF) of patients with DYT5b. HVA concentrations and the HVA/5-HIAA ratio in CSF appear to correlate with the age of onset and the severity of the phenotype.
Differential diagnoses include different forms of DRD (e.g. autosomal dominant DRD), early onset torsion dystonia, myoclonic dystonia (see these terms) and other types of early-onset parkinsonism. It can also be mistaken for cerebral palsy or spastic paraplegia. Differential diagnoses that need to be considered for the more severe, encephalopathy-like phenotype include febrile infection-related epilepsy syndrome, neonatal hypoxic and ischemic brain injury (see these terms), other tetrahydrobiopterin (BH4)-related enzyme deficiencies and mitochondrial disorders.
Prenatal diagnosis is possible in families with a known TH mutation.
DYT5b is inherited in an autosomal recessive manner. Genetic counseling is possible and recommended.
Management and treatment
L-dopa, usually in combination with carbodopa, is the treatment of choice. The less severe phenotype typically shows a significant positive and quick response, but patients with the more severe phenotype frequently show hypersensitivity to L-dopa, with only moderate or no benefit, even after prolonged treatment and careful dosage adjustment, and are more prone to side effects. Dosage should be monitored for side effects and adjusted as necessary. Inhibitors of dopamine degradation like selegiline may be considered alternatively or in addition to L-dopa, but are rarely used in clinical practice.
Prognosis depends on the severity of the disease and if/when patients receive treatment.