PracticeUpdate: Conference Series - The Best of ICIEM 2017

NoMutations in the Three Genes Involved in BH4 Biosynthesis and Recycling were Identified in a Cohort of Patients with Dopa-Responsive Dystonia No mutations in the three genes involved in tetrahydrobiopterin (BH4) biosynthesis and recycling were identified in a cohort of patients with dopa-responsive dystonia.

J im Black, MD, of the University of Birmingham, UK, explained that dopa-responsive dystonia is a child- hood-onset dystonic disorder (onset usually age 5–8 years) characterized by a dramatic response to low doses of levodopa. Dopa-responsive dystonia is very rare, affecting one in two million individuals. It is more common in females than in males. Several hundred cases are in the US, 25 known cases in the UK, and fewer in Australia and New Zealand. Characteristic symptoms are increased muscle tone and Parkinsonian features, typically absent in the morning or after rest but worsening during the day and with exertion. Owing to the rarity of the disease, children with dopa-responsive dystonia are often misdiagnosed as suffering with cerebral palsy. This mis- diagnosis results in patients often living their entire childhood with the condition untreated. When left untreated, patients often need Achilles tendon surgery by age 21 years. They will also struggle with walking, which degrades throughout the day. Power napping can provide temporary relief in untreated patients. Improvement with sleep, with relative freedom from symptoms in the morning, and increasingly severe symptoms as the day progresses has led to the disorder being referred to as progressive heredi- tary dystonia with diurnal fluctuations. Yet

not all patients experience such diurnal fluctuations, causing many researchers to prefer other terms for the disease. Dopa-responsive dystonia also impairs development into adulthood, reduces balance, and reduces calf muscle development. Socially, it can result in depression, lack of social skills, and ina- bility to find employment. The diagnosis of dopa-responsive dys- tonia can be made from a typical history, a trial of dopamine medications, and genetic testing. Not all patients show mutations in the GCH1 gene (GTP cyclohy- drolase I), which renders genetic testing imperfect. Lumbar puncture is sometimes performed to measure concentrations of biopterin and neopterin, which can help determine the exact form of dopamine-responsive movement disorder. Forms are early onset parkinsonism (reduced biopterin and normal neopterin), GTP cyclohydrolase I

deficiency (both decreased), and tyrosine hydroxylase deficiency (both normal). In approximately half of cases, a phenyla- lanine loading test can be used to show decreased conversion from the amino acid phenylalanine to tyrosine. This pro- cess uses BH4 as a cofactor. Decreased twitching may be noticed during REM sleep during a sleep study. Brain MRI scanning can be used to look for conditions that can mimic dopa- responsive dystonia. For example, metal deposition in the basal ganglia can indicate Wilson’s disease or pantothenate kinase-associated neurodegeneration. Nuclear imaging of the brain using position emission tomography (PET scanning) shows normal radiolabeled dopamine uptake in dopa-responsive dystonia, contrary to the decreased uptake of Parkinson's disease. Other differential diagnoses include:

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