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Dopamine-responsive dystonia (DRD), also known as hereditary progressive dystonia with diurnal fluctuation, Segawa's disease, or Segawa's dystonia, 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 DRD are often misdiagnosed as having cerebral palsy. The disorder responds well to treatment with levodopa.
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, DRD 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 that is similar in appearance 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 DRD patients do not experience such diurnal fluctuations, causing many researchers to prefer other disease terms.
For example, in those with DRD, symptoms typically dramatically improve with low-dose administration of levodopa (L-dopa). L-DOPA exists as a biochemically significant metabolite of the amino acid phenylalanine, as well as a biological precursor of the catecholamine dopamine, a neurotransmitter. (Neurotransmitters are naturally produced molecules that may be sequestered following the propagation of an action potential down a nerve towards the axon terminal, which in turn may cross the synaptic junction between neurons, enabling neurons to communicate in a variety of ways.) Low-dose L-dopa usually results in near-complete or total reversal of all associated symptoms for these patients. In addition, the effectiveness of such therapy is typically long term, without the complications that often occur for those with Parkinson's disease who undergo L-dopa treatment. Thus, most experts indicate that this disorder is most appropriately known as dopa-responsive dystonia (DRD).
In severe, early autosomal recessive forms of the disease, patients have been known to pass away during childhood, but in other cases survival past age 50 has been reported. Girls seem to be somewhat more commonly affected. The disease less commonly begins during puberty or after age 20, and very rarely, cases in older adults have been reported.
Genetics and disease mechanism
Autosomal dominant and autosomal recessive forms of the disease have been reported. Mutations in several genes have been shown to cause dopamine-responsive dystonia. The neurotransmitter dopamine is synthesised from tyrosine by the enzyme tyrosine hydroxylase, which uses 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 results in autosomal-dominant DRD. Mutations in the genes for tyrosine hydroxylase and sepiapterin reductase result in autosomal-recessive forms of the disease. When the latter enzyme is affected, the condition tends to be more severe. 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.
The diagnosis of DRD can be made from a typical history, a trial of dopamine medications, and genetic testing. Not all patients show mutations in the GCH1 gene, which makes genetic testing imperfect.
Sometimes a lumbar puncture is performed to measure concentrations of biopterin and neopterin, which can help determine the exact form of dopamine-responsive movement disorder: early onset parkinsonism (reduced biopterin and normal neopterin), GTP cyclohydrolase I deficiency (both decreased) and tyrosine hydroxylase deficiency (both normal).
An MRI scan of the brain can be used to look for conditions that can mimic DRD (for example, metal deposition in the basal ganglia can indicate Wilson's disease or pantothenate kinase-associated neurodegeneration). Nuclear imaging of the brain using positron emission tomography (PET scan) shows a normal radiolabelled dopamine uptake in DRD, contrary to the decreased uptake in Parkinson's disease.
Other differential diagnoses include metabolic disorders (such as GM2 gangliosidosis, phenylketonuria, hypothyroidism, Leigh disease) primarily dystonic juvenile parkinsonism, autosomal recessive early onset parkinsonism with diurnal fluctuation, early onset idiopathic parkinsonism, focal dystonias, dystonia musculorum deformans and dyspeptic dystonia with hiatal hernia.
The disease is named after Dr. Segawa, who provided an early clinical description.
- Diagnosis - main
- typically referral by GP to specialist Neurological Hospital e.g. National Hospital in London.
- very hard to diagnose as condition is dynamic w.r.t. time-of-day AND dynamic w.r.t. age of patient.
- correct diagnosis only made by a consultant neurologist with a complete 24-hour day-cycle observation(with video/film) at a Hospital i.e. morning(day1)->noon->afternoon->evening->late-night->sleep->morning(day2).
- patient with suspected DRD required to walk in around hospital in front of Neuro'-consultant at selected daytime intervals to observe worsening walking pattern coincident with increased muscle tension in limbs.
- throughout the day, reducing leg-gait, thus shoe heels catching one another.
- diurnal affect of condition: morning(fresh/energetic), lunch(stiff limbs), afternoon(very stiff limbs), evening(limbs worsening), bedtime(limbs near frozen).
- muscle tension in thighs/arms: morning(normal), lunch(abnormal), afternoon(very abnormal), evening(bad), bedtime(frozen solid).
- Diagnosis - additional
- lack of self-esteem at school/college/University -> eating disorders in youth thus weight gains.
- lack of energy during late-daytime (teens/adult) -> compensate by over-eating.
- Other symptoms - footwear
- excessive wear at toes, but little wear on heels, thus replacement 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 teens (qv GCSE/A level-public exams) years.
- bad handwriting (worsening) during post-teens (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 (depression.?)
- Consequences if untreated
- if untreated before early teens may necessitate additional corrective surgery to achiles tendons to lengthen such tendons at age 21.
- walking: morning(near normal), lunch(abnormal), afternoon(very abnormal), evening(bad), bedtime(almost impossible).
- Mis-diagnosis conditions
- Several: Spastic, Spastic Diaplega, Stiff-man syndrome, etc.
- Temporary relief
- power-napping at lunchtime or afternoon provides temporary relief from muscle tension.
- 1 in 2million(approx)
- affects females more than males
- 25 known cases in UK(pop=60m)
- 100's known cases in USA(pop=300m)
- few known cases in Australia(pop=30m)
- fewer cases in New Zealand(pop=l.t.10m)
- Other Aspects - marriage/parenting
- Highly likely that condition is hereditary being on-passable to offspring but data to support this are scarce, but some evidence from USA.
- Other Aspects - adult life
- if untreated then childhood psychological development into mature adult(hood) impaired.
- lack of success at all sports at school/.../adult->depression/disillusionment with life/etc.
- reduced employability as an adult.
- lack of social skills as adult from incomplete child experiences (playground interactions with both sexes).
- lack of balance skills.
- reduced development of leg-calf muscles to enable running skills in adulthood.
- LevoDopa - (anhydrous) white round tablets (now discontinued)
- Sinemet - coloured lozenge shaped tablets (current-2010)
- Sinemet types: "62.5"=yellow; "110"=blue; "Plus"=yellow; "275"=blue.
- Post-Treatment aspects - face
- permanent inability to convey state of mind(e.g. happy) to facial expression(e.g. smile).
- difficult to interpret, "blank" face
- via dystonia societies (various bodies around the world) who have information brochures.
- GeneReview/NCBI/NIH/UW entry on GTP Cyclohydrolase 1-Deficient Dopa-Responsive Dystonia
- GeneReview/NCBI/NIH/UW entry on Tyrosine Hydroxylase Deficiency
- ↑ Segawa M, Hosaka A, Miyagawa F, Nomura Y, Imai H (1976). Hereditary progressive dystonia with marked diurnal fluctuation. Advances in neurology 14: 215–33.
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