Dopamine-responsive dystonia
Encyclopedia
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
.
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.
s in several gene
s 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.
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).
In approximately half of cases, a phenylalanine
loading test can be used to show decreased conversion from the amino acid
phenylalanine to tyrosine. This process uses BH4 as a cofactor.
During a sleep study (polysomnography
), decreased twitching may be noticed during REM sleep.
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 dystonia
s, dystonia musculorum deformans and dyspeptic dystonia with hiatal hernia.
Diagnosis - additional
Other symptoms - footwear
Other symptoms - handwriting
Consequences if untreated
Mis-diagnosis conditions:
Temporary relief
Incidence
Other Aspects - marriage/parenting
Other Aspects - adult life
Treatment
Post-Treatment aspects - face
Genetic disorder
A genetic disorder is an illness caused by abnormalities in genes or chromosomes, especially a condition that is present from before birth. Most genetic disorders are quite rare and affect one person in every several thousands or millions....
movement disorder
Movement disorder
Movement disorders include:* Akathisia * Akinesia * Associated Movements * Athetosis...
which usually manifests itself during early childhood at around ages 5–8 years (variable start age).
Characteristic symptoms are increased muscle tone (dystonia
Dystonia
Dystonia is a neurological movement disorder, in which sustained muscle contractions cause twisting and repetitive movements or abnormal postures. The disorder may be hereditary or caused by other factors such as birth-related or other physical trauma, infection, poisoning or reaction to...
, such as clubfoot) and Parkinsonian features
Parkinsonism
Parkinsonism is a neurological syndrome characterized by tremor, hypokinesia, rigidity, and postural instability. The underlying causes of parkinsonism are numerous, and diagnosis can be complex...
, 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
Cerebral palsy
Cerebral palsy is an umbrella term encompassing a group of non-progressive, non-contagious motor conditions that cause physical disability in human development, chiefly in the various areas of body movement....
. The disorder responds well to treatment with levodopa
Levodopa
L-DOPA is a chemical that is made and used as part of the normal biology of some animals and plants. Some animals including humans make it via biosynthesis from the amino acid L-tyrosine. L-DOPA is the precursor to the neurotransmitters dopamine, norepinephrine , and epinephrine collectively...
.
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 thriveFailure to thrive
Failure to thrive is a medical term which is used in both pediatric and adult human medicine, as well as veterinary medicine ....
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
Parkinson's disease
Parkinson's disease is a degenerative disorder of the central nervous system...
.
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. MutationMutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
s in several gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
s have been shown to cause dopamine-responsive dystonia. The neurotransmitter
Neurotransmitter
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...
dopamine
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
is synthesised from tyrosine
Tyrosine
Tyrosine or 4-hydroxyphenylalanine, is one of the 22 amino acids that are used by cells to synthesize proteins. Its codons are UAC and UAU. It is a non-essential amino acid with a polar side group...
by the enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
tyrosine hydroxylase
Tyrosine hydroxylase
Tyrosine hydroxylase or tyrosine 3-monooxygenase is the enzyme responsible for catalyzing the conversion of the amino acid L-tyrosine to dihydroxyphenylalanine . It does so using tetrahydrobiopterin as a coenzyme. DOPA is a precursor for dopamine, which, in turn, is a precursor for norepinephrine ...
, which uses tetrahydrobiopterin
Tetrahydrobiopterin
Tetrahydrobiopterin or sapropterin is a naturally occurring essential cofactor of the three aromatic amino acid hydroxylase enzymes, used in the degradation of amino acid phenylalanine and in the biosynthesis of the neurotransmitters serotonin , melatonin, dopamine, norepinephrine ,...
(BH4) as a cofactor
Cofactor (biochemistry)
A cofactor is a non-protein chemical compound that is bound to a protein and is required for the protein's biological activity. These proteins are commonly enzymes, and cofactors can be considered "helper molecules" that assist in biochemical transformations....
. A mutation in the gene GCH1, which encodes the enzyme GTP cyclohydrolase I
GTP cyclohydrolase I
GTP cyclohydrolase I is a member of the GTP cyclohydrolase family of enzymes. GTPCH is part of the folate and biopterin biosynthesis pathways. It is responsible for the hydrolysis of guanosine triphosphate to form 7,8-dihydroneopterin 3'-triphosphate .GTPCH is encoded by the gene GCH1...
, 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
Sepiapterin reductase
In enzymology, a sepiapterin reductase is an enzyme that catalyzes the following chemical reaction:Thus, the two substrates of this enzyme are 7,8-dihydrobiopterin and NADP+, whereas its three products are tetrahydrobiopterin or sepiapterin, NADPH, and a single hydrogen ion .This enzyme belongs...
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
Nigrostriatal pathway
The nigrostriatal pathway is a neural pathway that connects the substantia nigra with the striatum. It is one of the four major dopamine pathways in the brain, and is particularly involved in the production of movement, as part of a system called the basal ganglia motor loop.Loss of dopamine...
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
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
Biopterin
Biopterin is a coenzyme that is produced within the body.It is an oxidized degradation product of tetrahydrobiopterin.Defects in biopterin synthesis or regeneration can cause a form of hyperphenylalaninemia ....
and neopterin
Neopterin
Neopterin is a catabolic product of guanosine triphosphate , a purine nucleotide.Neopterin belongs to the chemical group known as pteridines. It is synthesised by macrophages upon stimulation with the cytokine interferon-gamma and is indicative of a pro-inflammatory immune status...
, 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).
In approximately half of cases, a phenylalanine
Phenylalanine
Phenylalanine is an α-amino acid with the formula C6H5CH2CHCOOH. This essential amino acid is classified as nonpolar because of the hydrophobic nature of the benzyl side chain. L-Phenylalanine is an electrically neutral amino acid, one of the twenty common amino acids used to biochemically form...
loading test can be used to show decreased conversion from the amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
phenylalanine to tyrosine. This process uses BH4 as a cofactor.
During a sleep study (polysomnography
Polysomnography
Polysomnography , also known as a sleep study, is a multi-parametric test used in the study of sleep and as a diagnostic tool in sleep medicine. The test result is called a polysomnogram, also abbreviated PSG...
), decreased twitching may be noticed during REM sleep.
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
Wilson's disease
Wilson's disease or hepatolenticular degeneration is an autosomal recessive genetic disorder in which copper accumulates in tissues; this manifests as neurological or psychiatric symptoms and liver disease...
or pantothenate kinase-associated neurodegeneration
Pantothenate kinase-associated neurodegeneration
Pantothenate kinase-associated neurodegeneration , also known as neurodegeneration with brain iron accumulation 1 and formerly called Hallervorden-Spatz syndrome Pantothenate kinase-associated neurodegeneration (PKAN), also known as neurodegeneration with brain iron accumulation 1 (NBIA1) and...
). Nuclear imaging of the brain using positron emission tomography
Positron emission tomography
Positron emission tomography is nuclear medicine imaging technique that produces a three-dimensional image or picture of functional processes in the body. The system detects pairs of gamma rays emitted indirectly by a positron-emitting radionuclide , which is introduced into the body on a...
(PET scan) shows a normal radiolabelled dopamine uptake in DRD, contrary to the decreased uptake in Parkinson's disease.
Other differential diagnoses
Differential diagnosis
A differential diagnosis is a systematic diagnostic method used to identify the presence of an entity where multiple alternatives are possible , and may also refer to any of the included candidate alternatives A differential diagnosis (sometimes abbreviated DDx, ddx, DD, D/Dx, or ΔΔ) is a...
include metabolic disorders (such as GM2 gangliosidosis, phenylketonuria
Phenylketonuria
Phenylketonuria is an autosomal recessive metabolic genetic disorder characterized by a mutation in the gene for the hepatic enzyme phenylalanine hydroxylase , rendering it nonfunctional. This enzyme is necessary to metabolize the amino acid phenylalanine to the amino acid tyrosine...
, hypothyroidism
Hypothyroidism
Hypothyroidism is a condition in which the thyroid gland does not make enough thyroid hormone.Iodine deficiency is the most common cause of hypothyroidism worldwide but it can be caused by other causes such as several conditions of the thyroid gland or, less commonly, the pituitary gland or...
, Leigh disease) primarily dystonic juvenile parkinsonism, autosomal recessive early onset parkinsonism with diurnal fluctuation, early onset idiopathic parkinsonism, focal dystonia
Focal dystonia
Focal dystonia is a neurological condition that affects a muscle or group of muscles in a part of the body and causes an involuntary muscular contraction or twisting...
s, dystonia musculorum deformans and dyspeptic dystonia with hiatal hernia.
Additional Notes
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.
Incidence
- 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.
Treatment
- 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
- "Parkinsonian-face-mask"
- permanent inability to convey state of mind(e.g. happy) to facial expression(e.g. smile).
- difficult to interpret, "blank" face
Contact Information
- via dystonia societies (various bodies around the world) who have information brochures.