Segawa disease

Dopamine-responsive dystonia (DRD), 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.

It is a progressive inherited disorder affecting dopamine synthesis in the basal ganglia. This deficit of dopamine synthesis in the basal ganglia is the pathological behavior driving the symptomatology of Parkinsonian conditions. This Parkinson’s Disease Spectrum Variant causes fluctuating movement symptoms, dystonia, and Parkinson’s-like features that improve with dopamine-based medications following its pathophysiological behavior of dopamine activity in the basal ganglia.^[1]

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"(Segawa, 2000). 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 (National Organization for Rare Disorders, 2015).
• 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).

Symptoms can include stiffness, tremor, and abnormal posture, symptoms fluctuate during the day following dopamine activity resting states and this directly impacts expression of symptoms. Symptoms are typically worse in the afternoon-nighttime as extracellular dopamine levels are naturally lower resulting in frequent dystonia in the feet and painful contractions. The symptomology of the disorder primarily responds strongly to levodopa or dopamine agonist medication.^[2]

Motor features:

• dystonia (focal → Generalized progression)
• parkinsonism (rigidity, bradykinesia w/ or w/o decrement, Gait impairment/Parkinsonain Gait.

Examples of Parkinsonian Gait include but are not limited to “hunched-over posture” , “shuffling gait” , “forward posture” , “running-propulsion/festinating gait” , “lack of arm swing while walking” these are all examples of Parkinsonian Gait and any of these can be happening in tandem with each other when patient is presenting, however not all of these are required for it to be Parkinsonian Gait.^[3]

• postural instability

^[4]

Examples of postural instability can include but are not limited to “falling backward after attempting to get up from a seated position” , “falling backward while in a crouched position” , “inability to maintain a sitting up straight position without slouching forward” , “difficulties orienting oneself after performing a turn”, “leaning against walls or tables to support oneself's own weight”.^[5]

^[6]

• tremor (postural/action predominant)

Contrary to popular belief rest tremor is quite rare to be observed in this patient population despite the Parkinsonian symptoms present in the corroborating patient population. With rest tremor occasionally showing up in some patients: The most frequent tremor that these patients will present with is an action tremor, that worsens with attempts to be more precise in motor coordination. A Dystonic Postural tremor is the second most common type of tremor in this patient population. Both of these tremors are responsive to dopamine, supporting the pathology of the disease; however this usually requires dialing in the dose of levodopa to the patient's individual needs.^[4]

• freezing of gait (later stage or wearing-off states)^[7]

In patients with certain variants of dopamine responsive dystonia they can be quite different from typical Segawa’s Syndrome, often requiring much higher doses of levodopa comparatively even if both are a result of dopamine synthesis deficiency. The required treatment doses of carbidopa/levodopa in some cases have even reached as high as 900mg a day before adequate symptom control is reached in one case of confirmed dopamine-responsive dystonia. ^[8]

Non-motor features present in cases of Dopamine-Responsive Dystonia can be a result of loss of adequate synthesis of norepinephrine and serotonin which results in a functional loss of autonomic function. With orthostatic hypotension and syncope being extremely common in this patient populace. Reduction of serotonergic synthesis in this patient population can also result in symptoms such as depression, sleep disruption, anxiety, and cognitive/behavioral changes.^[8]

As dopaminergic tone begins to slowly decrease nearing towards the afternoon - nighttime period of the day fluctuations begin to occur in motor symptoms in this patients differentiating the condition from its other Parkinsonian conditions, this effect is called Diurnal Variation a key feature of Dopamine-Responsive Dystonia.^[8]

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:^[9]

• 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.^[9] 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.^[10] 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.^[11]

Patients may also have comorbidities which can include excessive daytime sleepiness, exercise induced dystonia, depression, anxiety, extreme Charley horse/hypertonic muscle spasm, foot dystonia, ptosis, NMS like symptoms from antipsychotics, writers cramp/focal hand dystonia, Oromandibular dystonia, blepharospasm, Meige's syndrome, Periodic limb movement disorder, restless leg syndrome, clonus.

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.

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 dopamine-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 positron emission tomography (PET scan) shows a normal radiolabelled dopamine uptake in dopamine-responsive dystonia, 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.

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 dopamine-responsive dystonia 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.

May phenotypically overlap with:

• dopamine transporter disorders
• atypical parkinsonian syndromes (MSA-P/CBD-like features in some domains)

^[12]

Classic DRD (Segawa’s Syndrome)

• childhood onset
• dystonia > parkinsonism
• dramatic low dose levodopa response
• No progression

^[13]

“DRD” - spectrum disorder

Includes:

• adult-onset GCH1 phenotypes
• parkinsonism-predominant forms
• Diurnal Response Activity

^[14]

“DRD” - plus (+)

Usually implies:

• broader monoamine involvement (dopamine + serotonin + norepinephrine)
• more complex phenotype

^[15]

Treatment

In those with dopamine-responsive dystonia, symptoms typically dramatically improve with low-dose administration of levodopa, which is 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.

No data are available on mortality associated with dopamine-responsive dystonia, but patients surviving beyond the fifth decade with treatment have been reported. However, in severe, early autosomal recessive forms of the disease, patients have been known to pass away during childhood. 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.

Due to commonly being misdiagnosed, it is common for the disease to remain untreated. When left untreated, patients often need Achilles' tendon surgery by the age of 21. They will also struggle with walking, an ability that will degrade throughout the day. Power napping can provide temporary relief in untreated patients. It also impairs development into adulthood, reduces balance, and reduces calf muscle development. Socially, it can result in depression, lack of social skills, and inability to find employment.^[16]

Patients with this disorder, typically experience very strong levodopa responsiveness when the appropriate dose for the individual is reached that adequately controls their symptoms. Especially when this levodopa is combined with a dopamine decarboxylase inhibitor such as benzadamide and or carbidopa.^[17]

Apomorphine has shown efficacy in the disorder as well in the treatment of short term dystonic reactions. As well as alleviating the Parkinsonian Gait and tremors when present in these patients.^[17]

MAO-B inhibitors specifically Deprenyl have shown transient benefit in the condition but this effect is brief and only present while the drug is active in the patients system. But this has shown efficacy in treating the depressive element that can be comorbid with the condition, likely a result of catecholamine enhancing activity present in the metabolites of Deprenyl. Key players of this enhancement of catecholamine activity being Amphetamine, and Methamphetamine.^[18]

Other dopamine agonists such as lysergic-acid diethylamide, rotigotine, pramiprexole, cabergoline, ropinirole; and partial agonists such as aripiprazole, cariprazine, and brexpiprazole have shown mixed results in the condition. Some improving and some worsening the dystonic condition present in these patients and care must be taken when evaluating patients taking these drugs as they may hide or reduce the symptoms of the disease.^[19]

Epidemiology

This condition is very rare, only affecting one in two million people. It is more common in females than in males. There are several hundred cases in the United States, 25 known cases in the United Kingdom, and less than that in Australia and New Zealand.

Research

Response to treatment is variable and the long-term and functional outcome is unknown. To provide a basis for improving the understanding of the epidemiology, genotype/phenotype correlation and outcome of these diseases their impact on the quality of life of patients, and for evaluating diagnostic and therapeutic strategies a patient registry was established by the noncommercial International Working Group on Neurotransmitter Related Disorders.

Contrary to popular belief, and despite being labeled a progressive illness many seem to believe that dopa-responsive dystonia is always Segawa’s Syndrome where there is a lack of neurodegeneration and a lack of progressive disability. Recent studies have shown that the condition especially in “DRD”- Plus (+) cases has been shown to be neurodegenerative and does result in progressive disability. In some cases patients may become confined to a wheelchair unable to walk, and move. Especially when the condition is left untreated the resulting striatal dysfunction and dopamine synthesis failure begins to stress the system. Reactive oxygen species, and triggering latent fenton-chemistry in dopaminergic neurons and this can result in neurodegeneration of the striatum primarily exerting toxicity to the basal ganglia. Further worsening of the condition is to be expected when treatment is delayed or discontinued.^[13]

Patients often typically do not display Hyperphenylalaninemia and because of this the conditions genetic link is often missed during newborn screenings of physical health and often don’t show Hyperphenylalaninemia even when phenylalanine stressor trailed.^[20]

History

The disease is named after Dr. Masaya Segawa, who provided an early clinical description in 1976.^[21]

References

External links

• Furukawa, Yoshiaki (1993). "GTP Cyclohydrolase 1-Deficient Dopa-Responsive Dystonia". GeneReviews®. University of Washington, Seattle.
• Furukawa, Yoshiaki; Kish, Stephen (1993). "Tyrosine Hydroxylase Deficiency". GeneReviews®. University of Washington, Seattle.