Dopamine-responsive dystonia (DRD) also known as Segawa syndrome (SS), is a genetic movement disorder which usually manifests itself during early childhood at around ages 5–8 years (variable start age).
Characteristic symptoms are increased muscle tone (dystonia, such as clubfoot) and Parkinsonian features, typically absent in the morning or after rest but worsening during the day and with exertion. Children with dopamine-responsive dystonia are often misdiagnosed as having cerebral palsy. The disorder responds well to treatment with levodopa.
Signs and symptoms
The disease typically starts in one limb, typically one leg. Progressive dystonia results in clubfoot and tiptoe walking. The symptoms can spread to all four limbs around age 18, after which progression slows and eventually symptoms reach a plateau. There can be regression in developmental milestones (both motor and mental skills) and failure to thrive in the absence of treatment.
In addition, dopamine-responsive dystonia is typically characterized by signs of parkinsonism that may be relatively subtle. Such signs may include slowness of movement (bradykinesia), tremors, stiffness and resistance to movement (rigidity), balance difficulties, and postural instability. Approximately 25 percent also have abnormally exaggerated reflex responses (hyperreflexia), particularly in the legs. These symptoms can result in a presentation similar to that of Parkinson's disease.
Many patients experience improvement with sleep, are relatively free of symptoms in the morning, and develop increasingly severe symptoms as the day progresses (i.e., diurnal fluctuation). Accordingly, this disorder has sometimes been referred to as "progressive hereditary dystonia with diurnal fluctuations." Yet some people with dopamine-responsive dystonia do not experience such diurnal fluctuations, causing many researchers to prefer other disease terms.
Other symptoms - footwear
excessive wear at toes, but little wear on heels, thus replacement of shoes every college term/semester.
Other symptoms - handwriting
near normal handwriting at infants/kindergarten (ages 3–5 school) years. poor handwriting at pre-teens (ages 8–11 school) years. very poor (worse) handwriting during teen (qv GCSE/A level-public exams) years. bad handwriting (worsening) during post-teen (qv university exams) years. very bad handwriting (still worsening) during adult (qv post-graduate exams) years. worsening pattern of sloppy handwriting best observed by school teachers via termly reports. child sufferer displays unhappy childhood facial expressions (possibly depression).
Genetics
Autosomal dominant and autosomal recessive forms of the disease have been reported. Mutations in five genes have been shown to cause dopamine-responsive dystonia. These mutations, according to a review published in 2021, are associated with the following conditions:
Autosomal dominant GTP cyclohydrolase I deficiency (autosomal dominant Segawa syndrome) Autosomal recessive GTP cyclohydrolase I deficiency Tyrosine hydroxylase deficiency (autosomal recessive Segawa syndrome) 6-Pyruvoyltetrahydropterin synthase deficiency Sepiapterin reductase deficiency Dihydropteridine reductase deficiency
The precursor of the neurotransmitter dopamine, L-dopa, is synthesised from tyrosine by the enzyme tyrosine hydroxylase and utilises tetrahydrobiopterin (BH4) as a cofactor. A mutation in the gene GCH1, which encodes the enzyme GTP cyclohydrolase I, disrupts the production of BH4, decreasing dopamine levels (hypodopaminergia). This autosomal-dominant condition is the most frequent cause of dopamine-responsive dystonia. Mutations in the gene for tyrosine hydroxylase may lead to tyrosine hydroxylase deficiency, a rare form of dopamine-responsive dystonia inherited in an autosomal recessive manner. The activity of dopaminergic neurons in the nigrostriatal pathway normally peaks during the morning and also decreases with age until after age 20, which explains why the symptoms worsen during the course of the day and with increasing age until the third decade of life.
Diagnosis
Due to the condition's rarity, it is frequently misdiagnosed, often as cerebral palsy. This results in patients often living their entire childhood with the condition untreated.
The diagnosis of dopamine-responsive dystonia 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 cyclohydrolase I), which makes genetic testing imperfect.