OVERVIEW
Dopa-responsive dystonia (DRD) refers to a rare genetic disorder with dystonia or gait abnormalities as the first symptom, also known as Segawa’s disease, that is prevalent in children or adolescents. The clinical picture is characterized by diurnal fluctuations in symptoms, with rapid and significant efficacy of small doses of dopa preparations.
Questions you may be concerned about
What is the Doba-responsive dystonia test?
Dopa-responsive dystonia testing generally involves the use of small doses of dopa preparations on patients to monitor the effectiveness of their treatment.
Dopa-responsive dystonia is a chromosomal dominant disorder with reduced dopamine levels, which is usually normal when blood tests, cerebrospinal fluid tests, and liver function tests and imaging tests are done and cannot be directly diagnosed by testing.
Patients with dopa-responsive dystonia are treated with dopamine preparations with significant results and good symptomatic relief, so the diagnosis of the disease is usually made by observing the patient’s results of treatment through clinical symptoms and the use of small doses of dopa preparations, and in combination with some common tests to rule out other diseases.
If dopa-responsive dystonia is suspected, it should be actively cooperated with the examination and treatment, and diagnosed as early as possible.
Etiology
Half of the cases are sporadic, and half are autosomal dominant.The main cause of DRD is a decrease in dopamine synthesis due to a deficiency of GCHⅠ, an isoenzyme of GTP cyclization hydrolase.The cerebrospinal fluid levels of homovanillic acid, and biotinamide and neotinamide are lower than normal in patients with DRD.The main cause of the disease is a deficiency of GCHⅠ, an isoenzyme of GTP cyclization hydrolase. Positron emission tomography (PET) scanning found that striatal 18F-dopa uptake was normal, suggesting that dopa decarboxylase and dopamine receptors are normal in this disease, so the continuous administration of exogenous dopa preparations can relieve the symptoms.
Overseas scholars have found that 60% to 70% of DRD patients have mutations in the coding region of GCHⅠ at 14q32.1. Since GCHⅠ is an important rate-limiting enzyme for the synthesis of tetrahydrobiopterin, which is an essential cofactor for catecholamine biosynthesis, the lack of GCHⅠ in dopaergic neurons of the nigral striatal system will inevitably lead to the reduction of tyrosine hydroxylase synthesis, which will ultimately lead to the decrease of dopamine level. Some scholars have tested the content of homovanillic acid and biotransferrin in the cerebrospinal fluid of DRD patients, and found that both levels are lower than normal, and positron emission tomography (PET) scanning found that the uptake of 18F-dopa in the striatum is normal, which suggests that the dopa decarboxylase and the dopamine receptor in this disease are normal, and therefore, continuous administration of a small amount of exogenous dopa preparations can make up for the lack of dopamine and alleviate the symptoms.
Symptoms
Reactive dystonia is common in childhood and is more common in females than males. The age of onset is usually between 4 and 8 years, but can be as early as infancy and as late as adulthood. Infantile onset is rare and often misdiagnosed as cerebral palsy or spastic paraplegia, while adult onset has symptoms similar to Parkinson’s disease. Initial symptoms tend to be clubfoot and gait abnormalities due to lower limb dystonia. Later, the disease progressively worsens, and stiffness of the limbs, bradykinesia, and expressionlessness can occur. Half of the patients have an 8-10 Hz positional, intentional tremor (different from the 4-5 Hz resting tremor of Parkinson’s disease), which is usually relatively stable in adulthood. In some mild cases, patients only have difficulty walking and fatigue in the afternoon, and have writing spasms when holding a pen for a slightly longer period of time. On physical examination, ankle clonus and Babinski’s sign can be detected in some children. 75% of children with dystonia have characteristic diurnal changes, i.e., the dystonia is mild in the early morning when they first wake up, and then gradually worsens, and is most pronounced at dusk. The dystonia may improve slightly after daytime rest, but worsens after activity and exercise.
1.Age of onset
The age of onset of DRD is from 1 to 12 years old, accounting for 10% of children with dystonia, and a few patients may have onset at the age of 50 to 60 years old. The incidence of DRD is more common in females than males, with the ratio of male to female being 1:4. The disease starts slowly and usually begins in the lower limbs, manifesting as dystonia of the upper limbs or lower limbs and abnormal postures or gaits, with gaits manifesting as stiffness of the legs, flexion of the feet, or exostoses, and in severe cases, it may involve the neck. In a few patients, the first symptom may be tremor. Dystonia can also be combined with bradykinesia, cogwheel muscle ankylosis, postural reflex disorder and other manifestations of Parkinson’s syndrome. Symptoms fluctuate from day to day, usually being mild in the morning or late afternoon and worsening after exercise or in the evening. This phenomenon will become less obvious with age, generally within 20 years after the onset of the disease progression is obvious, 20 to 30 years tend to moderate, to 40 years the disease is almost stable.
2. Children
The first symptom at the onset of the disease is often abnormal muscle tone of one side of the lower limbs, and the children appear to have strange gait, stiffness of the lower limbs, unsteady gait, and clubfoot, etc. Sometimes they only walk late. Sometimes the child only walks late and falls easily. With the development of the disease, dystonia abnormalities can affect other limbs, head and neck and the central axis of the body, and even spasmodic cervical tilt, torsion spasm. Children have limb tremor, myotonia, and Babinske’s sign, but speech and intelligence are often not affected.
3. Adults
The onset of the disease is characterized by involuntary tremor and rigidity of the limbs similar to Parkinson’s syndrome. They are slow to move, easily fatigued, have high muscle tone in the limbs, hyperreflexia, and positive pathologic signs. Most of the patients have diurnal fluctuation of symptoms, and the symptoms will be reduced or even disappear after waking up in the morning or resting, and will be aggravated in the afternoon or after exertion.
4. Most patients
The course of the disease is progressive, and untreated patients eventually cannot take care of themselves. Dramatic and long-lasting response to small doses of levodopa is a significant clinical feature. All symptoms, including fatigue, dystonia, postural abnormalities, and tremor, disappear completely after administration of the drug. In contrast, long-term administration of levodopa does not require dose increases and there are no motor complications of levodopa.
Examination
1. Blood, urine and stool routine, usually normal.
2. Cerebrospinal fluid test
Cerebrospinal fluid may be normal, and the content of homovanillic acid and biotin may be reduced.
3. Liver function tests
Normal, with differential diagnostic significance.
4. Electroencephalogram, evoked potentials, cranial CT, MRI and PET are normal.
Diagnosis
The disease should be highly suspected based on the fact that children or adults start the disease with unexplained abnormal limb dystonia, tremor, and strange gait as the first symptom, with morning lightness and twilight heaviness as the main clinical features, especially those with a family genetic history, and the efficacy of small-dose dopa preparations.
Differential diagnosis
DRD should be differentiated from the following diseases:
1. Cerebral palsy
The disease is characterized by abnormally high muscle tone and spasticity, often accompanied by mental retardation, convulsions and mood disorders, with no fluctuation of symptoms and no response to dopa preparations.
2. Juvenile Parkinson’s disease
Rarely occurs in children under 8 years old, PET examination shows that 18F-dopa uptake is decreased, long-term application of dopa preparation needs to gradually increase the dose, easy to appear side effects.
3.Hepatomegaly
Hepatomegaly is often accompanied by hepatic impairment and mental and psychiatric abnormalities, and K-F ring can be seen in the cornea.
4. Spastic paraplegia
Very few patients have initial signs and symptoms similar to those of spastic paraplegia, and the dramatic response to small doses of dopa may be the most important point of differentiation.
Complications
The clinical manifestations of epidemic dystonia are characterized by transient dystonic episodes in the muscles of the mouth, eyes, tongue, and neck, which may involve the trunk muscles of the limbs. The episodes are characterized by turning of the neck, extension of the tongue, staring or upward rolling of the eyes to the side, and persistent extension or flexion of the limbs, and rapid shaking may also occur. Usually, each seizure lasts for several minutes to several hours, and there are one to two to more than ten seizures per day. After the attack, the patient feels dizziness, headache and generalized pain.
Treatment
Small doses of dopa preparations are dramatically effective in DRD. Half of the patients see results on the same day the drug is administered, and the onset of effects usually does not exceed 7 days. The medication is administered as soon as the disease is suspected and can be diagnostic. Levodopa/benserazide (methyldopa) can be used continuously for long periods of time with few side effects; symptoms reappear if the drug is discontinued.
Prognosis
The cause of DRD is a reduction in dopamine synthesis due to mutations in the GCHⅠ gene, which needs to be replenished over a long period of time without increasing the dosage, and there are no side effects such as switching off phenomenon or reduced efficacy of the drug.
Prevention
Prevention is more important when there are genetic factors. Preventive measures include: avoidance of marriage of close relatives, genetic counseling, genetic testing of carriers, prenatal diagnosis and selective abortion to prevent the birth of affected children. Early diagnosis, early treatment and strengthening clinical care are important to improve the quality of life of patients.