Segawa syndrome is a rare neurometabolic disease of a genetic nature caused by insufficient dopamine production in the central nervous system. The basis of the clinical symptom complex is dopa-dependent muscular dystonia, more pronounced in the lower extremities. Involuntary movements, pathological postures, hypokinesia, hyperreflexia are characteristic. Diagnosis is carried out by assessing the neurological status, electromyography data, cerebral MRI, determining the level of catecholamines. DNA diagnostics is possible. The treatment requires constant intake of small doses of levodopa drugs, which, with an early start of therapy, leads to the complete disappearance of clinical symptoms.
ICD 10
G24.1 Idiopathic familial dystonia
General information
Segawa syndrome (dopa-dependent dystonia) is a genetic pathology that leads to a decrease in the production of dopamine necessary for the full exercise of motor function. The disease was originally described by pediatric neurologist Masaya Segawa in 1971, who provided observations of two patients with dystonia of the feet and hypertonicity of the leg muscles. According to some data, the prevalence of the syndrome is in the range of 0.5-1 case per 1000000. The variability of the mutant gene expression causes the variability of the clinical picture and difficulties in early diagnosis. Studies show a greater incidence of female individuals, probably due to a more pronounced penetrance.
Causes
Dopa-dependent dystonia is the result of mutations of genes encoding metabolites involved in the synthesis of DOPA. The most common autosomal dominant inherited mutation of the GCH1 gene located on the 14th chromosome. The result is a violation of the synthesis of guanosine triphosphate cyclo-hydrolase I. In some cases, Segawa syndrome is caused by autosomal recessive mutations affecting the coding sites of dopamine hydroxylase, 6-pyrivoyl-tetrahydrobiopterin synthetase, glucose-6-phosphate transferase. Among the etiofactors of spontaneous mutations of these genes , the leading ones are:
- Physical. They include all types of ionizing, infrared and ultraviolet radiation.
- Chemical. Exposure to mutagenic substances entering the body with inhaled air, food, water, substance abuse, chronic alcoholism, drug use also have a mutagenic effect.
- Biological. Currently, the main cause of most gene disorders are viruses whose genomes are capable of embedding in human DNA. Non-viral agents (bacteria, protozoa) act as chemical mutagens, producing toxic metabolites in the course of their vital activity.
Pathogenesis
Genetically determined disorders of the synthesis of enzymes and cofactors involved in the production of DOPA lead to a reduced content of the latter in the substantia nigra and striatum. The result is a disorder of the functioning of the nigrostriatal pathway and the extrapyramidal system of the brain, which regulate muscle tone and motor activity.
The different penetrance of the altered gene even within the same family leads to a variable severity of these disorders in patients. Morphologically, subcortical ganglia remain intact. The number of dopamine receptors and their sensitivity are usually not reduced, which causes a good response to the administration of levodopa drugs.
Classification
Segawa syndrome includes several genetic abnormalities, as a result of which there is a pathological decrease in dopamine synthesis by dopaminergic neurons. In modern neurology, various forms of dopa-dependent dystonia are classified according to the nature of their inheritance:
- Autosomal dominant. These include most cases of Segawa syndrome. The probability of transmission of the disease to children is 50%. However, incomplete penetrance and different expressiveness significantly reduce the likelihood of clinical manifestations in a child who has inherited a pathological genome. There are cases of asymptomatic carriage of the CGH1 gene mutation.
- Autosomal recessive. Rare forms of dopa-dependent dystonia. Phenotypic signs of the disease appear only when the altered gene is inherited from both parents. The probability of illness in a child born from parents who carry the anomaly is 25%.
Symptoms
The symptom complex of Segava syndrome manifests at the age of 1 to 9 years. The main clinical sign is muscular dystonia, which leads to the appearance of involuntary motor acts, pathological installation of limbs. At the onset of Segawa’s disease at a younger age, muscle hypotension occurs. For patients older than 3 years, muscle hypertonus is characteristic, plastic tone is observed after 9 years. Changes in tone occur in the muscles of one leg, and over the course of a couple of years, the second leg is also captured. Then the dystonia spreads to the upper extremities. Torsion dystonia is possible, which is moderate in nature.
Typical is the fluctuation of dystonia during the day, the increase in its severity by the evening. There is a pathological flexor foot position, flexion of the hands with thumb retraction, pronation of the forearms, hyperkinesis. Patients complain of weakness in the limbs, difficulty walking, discomfort and awkwardness of movements in the hands. Pathological changes are more pronounced in the legs, they are asymmetric. Moderate dysarthria, symptoms of Parkinsonism are noted: rest tremor, slowness of movements, impoverishment of facial expressions.
Autosomal recessive forms of Segawa syndrome make their debut in the first months of life. In the perinatal period, distress syndrome, hypoglycemia is possible. Children have hypokinesia, delayed motor development, hypotension of the trunk muscles. In some cases, ptosis is noted. The clinical symptoms of Segawa syndrome, the degree of severity of manifestations have significant variability in different patients.
Complications
In the absence of pathogenetic treatment, Segava syndrome proceeds with a steady progression of symptoms, which leads to the fixation of pathological poses, the development of muscle contractures, the appearance of deformities of the spinal column and chest. As a result, children lose the ability to walk, they cannot serve themselves independently. There is a slowdown in growth, body weight is below the age norm. Speech disorders progress, dysphagia appears. There is a deep disability of the child.
Diagnostics
Differences in the manifestations of the syndrome, the similarity of its early stages with other neurological pathology significantly complicate timely diagnosis. If DNA diagnostics are not possible, the trial administration of L-dopa drugs helps to finally determine the diagnosis of Segava syndrome. The list of necessary studies includes:
- Neurological examination. The neurological status shows muscular dystonia, spastic hypertension, plasticity, and hypotension in children under 3 years of age. It is possible to reduce muscle strength in the extremities to 3.5-4 points. Tendon reflexes are increased, sensitivity is not changed. There is tremor at rest, pathological postural activity in the extremities, instability in the Romberg pose, dysarthria. Mental development corresponds to the age norm.
- Analysis for catecholamines. It reveals a reduced concentration of dopamine, serotonin, homovanilinic acid in the blood and urine.
- Electromyography. It does not detect pathology on the part of muscle tissue, neuromuscular transmission is normal. Allows to exclude hereditary myasthenia gravis, various forms of myopathy.
- MRI of the brain. It is necessary for differential diagnosis. In Segawa syndrome, it does not reveal pathological changes in cerebral tissues.
- Molecular genetic research. Detection of mutations in the genes GCH1 (14q22.1-q22.2), SPR (2p14-p12), TH (11p15.5) gives full confirmation of the diagnosis.
Differential diagnosis
Dystonia in Segava syndrome requires differentiation from Huntington’s juvenile chorea, juvenile form of parkinsonism, spinocerebellar atrophy. Chorea is characterized by a later manifestation, the predominance of hyperkinetic syndrome. Parkinsonism has largely similar symptoms, differential diagnosis is based on the results of genetic research.
Differential diagnosis with neuromuscular diseases is achieved by performing electromyography. Segawa’s disease with an early onset, accompanied by muscle hypotension, is often perceived as a delay in motor development or myopathy. The appearance of dystonic dopa-dependent disorders over time makes it possible to make the correct diagnosis.
Treatment
The only and most effective method of therapy is the constant intake of levadopa. A significant positive effect is observed after a few days of taking small doses of the drug. With the timely initiation of treatment of Segava syndrome, clinical symptoms completely disappear, functional activity is restored in full. Autosomal recessive variants of the disease are less amenable to therapy, require higher dosages.
Since dopamine receptors are preserved in patients, long-term use of levadopa is not addictive, and an increase in the dose over time is not required. Side effects in the form of pyramidal disorders, mental disorders are not observed. The appearance of transient choreic hyperkinesis in a child indicates the need to reduce the dose. Discontinuation of levadopa medications leads to the resumption of symptoms.
Prognosis and prevention
Dominant variants of the disease with timely diagnosis have a favorable prognosis with a complete regression of manifestations against the background of ongoing treatment. At the late start of therapy, after the development of pathological fixation, contractures and deformities, taking levadopa does not lead to the reverse development of these symptoms, but prevents their aggravation. Recessive forms of Segawa’s disease, as a rule, have a more serious prognosis. Disease prevention includes all ways to prevent chronic exposure to mutagenic triggers.