Machado-Joseph disease is a genetically determined spinocerebellar ataxia, clinically represented by polymorphic combinations of cerebellar syndrome with manifestations of secondary parkinsonism, hyperkinesis, pyramidal disorders in the form of spastic paralysis and ophthalmoplegia, amyotrophy. It is diagnosed on the basis of a thorough study of clinical manifestations in the patient and his relatives, genealogical analysis, MRI and CT data, detection of an excess number of copies of the CAG triplet during DNA testing. Treatment is symptomatic. The prognosis is unfavorable.
ICD 10
G11.2 Late cerebellar ataxia
General information
Machado-Joseph disease was described in the mid-70s of the 20th century. Presumably, the disease originally originated in the inhabitants of the Azores, and therefore it is sometimes found under the name “Azores disease”. Today, Machado-Joseph disease is spread all over the world. Its cases have been diagnosed in residents of the USA, Brazil, Japan, India, Europe, China, Australia, Canada. It is the most common form of hereditary cerebellar ataxia.
Within the framework of the modern international classification of diseases, this pathology is verified as CCA — spinocerebellar ataxia type III. There is a large variability in the time of debut (from 10 to 70 years) and polymorphism of clinical symptoms due to multisystem damage to cerebral and spinal structures. Depending on the combination of the main clinical syndromes, there are 3 variants of the disease. Polymorphism of manifestations entails certain difficulties in the diagnosis of the disease, which can be properly implemented only with the close cooperation of specialists in the field of neurology and genetics.
Causes
Previously, the etiology was unknown. Thanks to the development of DNA research, it turned out that the main substrate of pathology is a gene mutation that is transmitted to offspring in an autosomal dominant way. The aberration is localized in the 14th chromosome (locus 14q24.3-q32) and consists in the expansion (increase in the number of repeats) of the trinucleotide combination “cytosine-adenine-guanine”. The number of repetitions of the CAG triplet varies significantly and averages 62-84, while normally it does not exceed 37. The greater it is, the earlier the manifestation of the disease occurs.
Morphologically, apoptosis of neurons of the granular layer and Purkinje cells in the cerebellar cortex, degenerative changes in the dentate and red nuclei, the substantia nigra, motor nuclei of cranial nerves and anterior horns of the spinal cord, spinal tracts are observed. Glial growths are detected in the striatum. A distinctive feature is the intact olive of the medulla oblongata.
Symptoms
Machado-Joseph type I disease manifests in the age period of 10-30 years. It is characterized by a combination of pyramidal and extrapyramidal symptoms. Pyramidal syndrome (damage to the corticospinal tracts) usually debuts with spastic paraparesis, followed by weakness in the hands, paresis of the pharyngeal muscles with the development of dysphagia and dysarthria, paresis of the oculomotor nerves with ophthalmoplegia (a symptom of “fixed eyeballs”). There is a clonus of the feet, pathological reflexes. Extrapyramidal syndrome is manifested by symptoms of torsion dystonia, athetosis, secondary parkinsonism. A stiff, slow gait with a wide set of legs is formed. There is unsteadiness when walking, due to muscle spasticity, and not ataxia. Exophthalmos is typical, large fascicular contractions of the tongue, not accompanied by its atrophy. Fasciculations of facial muscles, eyelid myokymia are possible. Vertical and horizontal nystagmus, saccades (unidirectional eye movements) with increased/decreased amplitude are observed.
Machado-Joseph disease type II debuts in the period from 20 to 40 years. It is manifested by symptoms of cerebellar ataxia: abasia, hyper- and dysmetria, imbalance, dysarthria. Typically, a combination of cerebellar symptoms with pyramidal and extrapyramidal manifestations occurring in type I. Ophthalmoplegia and fasciculations are observed much less frequently than in Machado-Joseph type I disease.
Machado-Joseph disease type III is a combination of cerebellar ataxia and amyotrophy. It has the latest onset — after the age of 40. Against the background of cerebellar symptoms, diffuse muscular atrophy is observed, accompanied by hypotension and weakness, loss of tendon reflexes. A distinctive feature is the presence of disorders of all types of sensitivity according to the distal type, indicating polyneuropathy. Exophthalmos and facial fasciculations occur according to various data in 20-50% of patients with this form of the disease. Degeneration of the corticospinal tracts and damage to the extrapyramidal system are not characteristic.
Diagnostics
The large variability in the number of repetitions of the CAG triplet, observed even within the same family, causes a significant polymorphism of the clinical manifestations of Machado-Joseph disease, which entails significant diagnostic difficulties. It is common to have different types of the disease in blood relatives, especially if we are talking about different generations. Casuistic cases are described when Parkinsonism was the leading and only manifestation of the disease. Thus, the key moment in the diagnosis of Machado-Joseph disease is the consultation of a geneticist, a detailed study of the family tree with an examination of as many relatives of the patient as possible, DNA diagnostics.
From the point of view of a neurologist, it is important to identify specific differences in Parkinsonism syndrome, typical of Machado-Joseph disease. There are no postural disorders pathognomonic for Parkinson’s disease and rest tremors, and instability in standing and walking is associated with static-locomotor ataxia. Parkinsonism turns out to be resistant to the action of levodopa drugs, although in the initial stages of the disease there may be an effect in the form of a decrease in muscle rigidity.
Primary neurological diagnostics (Echo-EG) does not give specific signs, its results may be within normal limits. CT and MRI of the brain reveals degeneration of the cerebellar worm and the bridge tire. A typical sign is a pronounced expansion of the IV ventricle against the background of the relative safety of the cerebellar cortex. Differentiate Machado-Joseph disease from other types of spinocerebellar degeneration, Gallervorden-Spatz disease, olivopontocerebellar degeneration, Friedreich’s ataxia, amyotrophic lateral sclerosis, Pierre-Marie ataxia, progressive supranuclear paralysis.
Treatment and prognosis
Effective therapy has not yet been found. Symptomatic treatment is carried out. In Parkinsonism syndrome, dopamine agonists (pramipexole, piribedil) are indicated, amantadine can be used. To relieve spasticity, pharmaceuticals with a muscle relaxant effect (tolperizone, baclofen) are prescribed. In hyperkinesis, valproic acid derivatives or benzodiazepines (clonazepam) are recommended.
Unfortunately, in many cases, symptomatic therapy is not able to stop the progression of Machado-Joseph disease. There is a steady aggravation of symptoms, leading to the death of the patient. The life expectancy after the onset of the disease ranges from 10 to 20 years and depends on the clinical type of pathology. The most transient variant is Machado-Joseph type I disease. Prevention consists in conducting medical and genetic counseling and prenatal diagnostics in burdened families; preventing the birth of a child with a corresponding genetic mutation.
