Juvenile parkinsonism is a genetically determined form of early Parkinsonism, manifesting before the age of 25. Typical features of the clinical picture are symmetry of manifestations, static and kinetic trembling, pyramidal signs, elements of dyskinesia, intellectual preservation. Instrumental diagnostics includes EEG, EMG, brain MRI, PET. Genetic research is carried out: genealogical analysis, DNA diagnostics. Treatment is lifelong, levodopa preparations, dopamine receptor agonists, MAO inhibitors, cholinolytics, metabolic pharmaceuticals are used.
ICD 10
G20 Parkinson’s Disease
General information
Juvenile parkinsonism (JP) is a hereditary disease of the central nervous system with an autosomal recessive transmission mechanism. A clear hereditary character distinguishes this pathology from classical Parkinson’s disease, which has a multifactorial etiology and is realized against the background of a genetically determined predisposition.
Previously, the juvenile variant was diagnosed at the onset of Parkinsonian symptoms at the age of 20-25 years. The discovery of the Parkin gene in 1998 and the introduction of DNA diagnostic methods for its defects into practical medicine allowed specialists in the field of neurology to identify later cases of the disease. Juvenile parkinsonism is widespread everywhere, it is more common in females.
Causes
Any primary and secondary parkinsonism is based on the dysfunction of dopaminergic neurons producing dopamine, a neurotransmitter involved in the regulation of motor activity. In JP, the pathology of dopamine-synthesizing neurons is caused by defects in the Parkin gene localized at the 6q25.2-q27 locus. Variable morphological rearrangements are possible: duplications, triplications, deletions, point mutations of the gene. Genetic aberrations are inherited autosomal recessive. The disease develops when a pathological gene is received from each parent.
If both parents are healthy carriers of the mutation, then the probability of having a sick child is 25%. When a defective gene is present in the genome of one parent, there is no danger of JP in children, 50% of descendants become carriers of the genetic defect. Recent studies of heterozygous carriers of parkin mutations using PET have revealed the presence of dopaminergic dysfunction in the form of reduced capture of fluorodope in the striatum, which indicates the possibility of developing the disease in heterozygotes.
Pathogenesis
The 6q25.2-q27 locus is responsible for the synthesis of the Parkin protein involved in the exchange of alpha-synuclein, which ensures its inclusion in the formation of Levi bodies. Mutations of the gene cause the absence of protein in cerebral neurons, which leads to dysmetabolism and accumulation of alpha-synuclein, blocks the formation of Levi’s bodies, presumably performing a protective function in neurodegenerative processes.
Changes in metabolism, accumulation of synuclein lead to degeneration, death of dopamine-producing nerve cells located mainly in the substantia nigra. Dopamine has an inhibitory effect on the neurons of the caudate nucleus. Its deficiency causes the predominance of excitatory (acetylcholine) effects. Excessive activation of the caudate nucleus causes an increase in its inhibitory effect on motor skills, which is clinically manifested by the main symptom of parkinsonism — a decrease in motor activity (hypokinesia).
The pathomorphological picture is characterized by the absence of Levi’s bodies in the neurons of the midbrain. Neurofibrillary glomeruli — filamentous intra-neuronal inclusions typical of a number of degenerative processes are detected in the cells of the substantia nigra, red nuclei, bluish nucleus, and cerebral cortex. Histochemical studies determine the absence of Parkin protein in neurons.
Classification
Juvenile parkinsonism is characterized by a triad of major clinical manifestations: tremor, hypokinesia, muscle rigidity. Depending on the predominance and combination of these manifestations, 5 forms of JP are distinguished. The classification is identical to the clinical variants of Parkinson’s disease. The following forms are distinguished:
- Tremulous. The fine-pitched trembling of the head, tongue, lower jaw, and limbs prevails. Tremor occurs at rest and in motion, increases with excitement. Muscle tone has not been changed, motor activity has been preserved.
- Tremor-rigid. At the onset of the disease, a tremor is observed, then gradually muscle tone disorders are added. Tremor of the distal extremities is combined with stiffness. Bradykinesia is weakly expressed, due to muscle hypertonicity (rigidity).
- Rigid-tremulous. The disease manifests itself by an increase in the tone of the muscles of the extremities, followed by a tremor. Hypokinesia develops due to severe hypertonicity, which leads the limbs to a flexor position.
- Akinetic-rigid. Hypokinesia prevails in the clinic with a significant decrease in the volume of voluntary movements. There is an increase in muscle tone. There is no shaking.
- Mixed. It is a combination of several of the above forms. Often, three main symptoms are observed simultaneously in the clinical picture: tremor, bradykinesia, rigidity.
Symptoms
The clinical manifestation of the disease occurs in the age period up to 25 years, in 20% of cases there is a later onset. A distinctive feature is the bilateral development of symptoms, the absence of a period of hemiparkinsonism characteristic of the debut of ordinary Parkinson’s disease. Hypokinetic syndrome includes slowness of motor skills, decreased gesticulation, small amplitude of movements, hypomimia of the face.
In the initial stage, difficulties arise with the rapid performance of motor acts that require the participation of fine motor skills. The child has difficulty buttoning buttons, tying shoelaces, and cannot assemble a mosaic. The patient is slow, his movements are characterized by impoverishment, stiffness. A shuffling gait with small steps is characteristic, there are no friendly hand movements when walking (achaeirokinesis). Speech slows down, becomes expressionless.
Juvenile parkinsonism is accompanied by a statokinetic type of tremor – trembling appears with muscle tension, movements. In some cases, statokinetic tremor is combined with rest tremor, typical of late variants of Parkinsonism. In most patients, JP proceeds with muscle rigidity. Patients complain of stiffness in the limbs that makes it difficult to move. Over time, hypertonus causes the flexion of the limbs.
Throughout the day, there is a change in the severity of clinical symptoms – its decrease after sleep, increasing in the evening. Many patients have individual dystonic manifestations (more often dystonia of the feet), sometimes – choreic hyperkinesis. Juvenile parkinsonism proceeds without pronounced cognitive disorders. Often the intellectual development of children corresponds to the age norm.
Complications
In the absence of drug compensation for dopaminergic dysfunction, a gradual progression of hypokinesia occurs. Limitations of the motor sphere make it difficult to move independently, lead to disability. The constant flexor state of the limbs is complicated by the development of joint contractures. Slowing of the gastrointestinal motility causes frequent constipation, due to intestinal paresis, intestinal obstruction may be complicated. Over time, juvenile Parkinsonism leads to characteristic personality changes: isolation, reduced emotionality, the development of depressive, hypochondriac character traits.
Diagnostics
The typical clinical symptoms, the characteristic age of the debut allow the neurologist to assume the diagnosis of JP at the first consultation of the patient. Diagnosis is difficult if parkinsonism debuts at a later age. The following features are taken into account: the symmetry of the onset of symptoms, the presence of statokinetic tremor, dystonic manifestations, fluctuation of symptoms during the day, slow progression of the disease without pronounced cognitive changes. The list of additional surveys includes:
- Neurological examination. There is bradykinesia, tremor, increased muscle tone by plastic type, revival of tendon reflexes. There is postural instability in Romberg’s pose. Pathological pyramidal signs (Babinsky reflex) may be detected.
- Electrophysiological studies. The EEG pattern is nonspecific, characterized by a general decrease in bioelectric activity of the brain. The changes are most pronounced in the akinetic-rigid form of JP. Electromyography in patients with tremor registers volley activity with a frequency of 4-8 peaks per second, with the akinetic-rigid variant — stationary rhythmic asynchronous activity.
- MRI of the brain. In most cases, it does not display pathological changes. It is necessary for the differential diagnosis of JP with other degenerative diseases of the central nervous system. Signs of atrophic changes in basal structures (caudate nucleus, substantia nigra, pale globe) are detected in the later stages of the disease.
- Functional neuroimaging. It is aimed at the study of dopamine metabolism, can be used in the preclinical diagnosis of pathology. PET-CT of the brain with the introduction of fluorodope confirms a reduced accumulation of the drug in the tissues of the substantia nigra, the caudate nucleus.
- Genetic research. Consultation of a geneticist with genealogical analysis allows you to identify the hereditary nature of the pathology, to establish the type of inheritance. DNA diagnostics is carried out comprehensively in several directions, which makes it possible to detect not only various defects, but also point mutations of the 6q25.2-q27 locus. In familial cases, homozygous mutations are detected in 70%, in sporadic cases — in 15% of patients.
Juvenile parkinsonism should be differentiated from Parkinson’s disease with late onset, encephalopathy due to ephedron addiction, secondary parkinsonism of dysmetabolic genesis (in diabetes mellitus, hypothyroidism, hypoparathyroidism), after encephalitis. Magnetic resonance imaging is used to differentiate JP from a number of degenerative lesions of the central nervous system (Gallervorden-Spatz disease, Machado-Joseph syndrome, Wilson’s disease). Secondary parkinsonism is excluded by drug testing, biochemical blood test (glucose, calcium, copper, ceruloplasmin), studies of the concentration of parathyroid hormone, thyroid hormones.
Treatment
Earlier onset of the disease requires careful selection of therapy, taking into account the long-term prospects of treatment. The principle of phasing, individual determination of the pharmacotherapy regimen in accordance with the symptoms is observed. Juvenile parkinsonism has a good response to small doses of dopamine drugs. But, given the need for a gradual increase in dosages during treatment, it is recommended to postpone taking levodopa as much as possible. Therapy is carried out using drugs of the following groups:
- Dopamine receptor agonists (DRA): pramipexole, pergolide. Recommended for the initial therapy of JP. If necessary, they can be combined with monoamine oxidase inhibitors (selegiline, rasagiline), which increase the concentration of dopamine in the central nervous system, and amantadine, which increases the sensitivity of dopamine receptors.
- Levodopa pharmaceuticals. The indication for the appointment is significant hypokinesia, poorly corrected by taking DRA. Treatment is carried out for a long time with small doses of levodopa, with a long history of the disease, a gradual slow increase in the daily dose is required. Levodopa-induced dyskinesia, which occurs after 1-10 years of therapy, is well stopped by adding DRA to the treatment regimen. Moreover, this combination therapy allows you to reduce the dose of levodopa.
- Central cholinolytics. They are used to relieve tremor. In young patients, they should be prescribed in minimal dosages. The recommended maximum duration of continuous therapy is 3-5 years.
- Metabolites. Preparations of vitamins B, coenzyme Q, L-carnitine, magnesium, aminophenyl butyric acid are used. Treatment courses are carried out 2-3 times a year. The purpose of metabolic therapy is to maintain the functioning of the central nervous system and muscle tissue, slow down degenerative processes, normalize mental and cognitive functions.
High-frequency stimulation of the basal ganglia, suppressing excessive activity of the caudate nucleus, is a new promising direction in the therapy of UP. The possibilities of automated delivery of levodopa into the patient’s body using a duodenal pump are considered. This technique is able to smooth out pronounced motor fluctuations that occur in the advanced stage of the disease.
Prognosis and prevention
In comparison with typical Parkinson’s disease, the juvenile variant has a more benign course with slow progression. A good response to therapy, the absence of pronounced atrophic changes, cognitive disorders allow patients to develop normally, maintain mobility for a long time. Severe disability can be observed several decades after the clinical debut. Since the disease has a genetic determinism, specific preventive measures are difficult. The risk of giving birth to a sick child is not so great, therefore, the expediency of refusing childbearing while being in a risk group is questionable.
