Spinocerebellar ataxia is a group of genetically heterogeneous hereditary diseases of a neurological nature, which are manifested by various disorders of the cerebellum and sometimes the basal nuclei of the brain. Symptoms of this condition are: the development of ataxia and unstable gait, impaired coordination of movements and other neurological manifestations. The diagnosis of spinocerebellar ataxia is made on the basis of neurological examination data, the study of the patient’s hereditary history, magnetic resonance imaging and molecular genetic studies. There is no specific treatment for this pathology at the moment, methods of supportive and symptomatic therapy are used to preserve the optimal quality of life of the patient.
Spinocerebellar ataxia is a group of hereditary neurological conditions characterized by the development of progressive degeneration of cerebellar cells and sometimes basal nuclei up to their complete atrophy. For the first time, one of the diseases of this group was described back in 1891 by the German neurologist P. Menzel, who revealed the development of ataxia, ophthalmoplegia and other neurological disorders within the same family. Further studies have shown that this condition (now known as spinocerebellar ataxia type 1) is inherited by an autosomal dominant mechanism.
At the moment, the methods of modern genetics have managed to detect more than 20 different genetic variants of this disease, while more than 90% of all cases cause only 6 of them (1, 2, 3, 6, 7 and 8th types). All forms of spinocerebellar ataxia are characterized by autosomal dominant inheritance with the phenomena of anticipation (increased severity of pathology from generation to generation) and “paternal transmission” – a brighter clinical picture of the disease when it is inherited from the father. Therefore, in a number of regions, there is a slight prevalence of male patients in the general structure of pathology. The total occurrence of spinocerebellar ataxia varies widely (1-24:100,000), with type 1 common in most of Europe, type 2 in India, and type 3 in Germany and Japan.
Causes and classification
Despite the significant genetic and partly clinical diversity of spinocerebellar ataxia, the molecular mechanisms of genetic disorders in these diseases are very similar. The main cause of pathology is a change in the number of trinucleotide sequences (CAG) in the coding part of the genes associated with the disease. This leads to an increase in the amount of the amino acid glutamine in the resulting protein, which changes the physicochemical properties of the protein and disrupts its functions. In some cases, the above proteins are directly or indirectly involved in the metabolism of nervous tissue, so a change in their structure leads to spinocerebellar ataxia. Currently, the molecular mechanisms of the 6 main varieties of this disease are best studied – these forms of pathology are most common and together account for more than 90% of cases of spinocerebellar ataxia.
- Type 1 is considered the most common and most studied variant of this pathology. It is caused by mutations in the ATXN1 gene, which is located on the 6th chromosome. Normally, this gene has no more than 36 CAG repeats, an increase in their number leads to the development of the disease. The product of the expression of the ATXN1 gene is a special DNA-binding protein that is actively involved in the metabolism of cerebellar Purkinje cells – in the presence of a mutant variety of the gene, this leads to the appearance of aggregates and gradual degeneration, which causes spinocerebellar ataxia.
- Type 2 is a less common variant of the disease, the etiology is not so thoroughly studied. The cause of the pathology is an increase in the number of CAG repeats in the ATXN2 gene localized on the 12th chromosome. In a healthy variant of the gene, the number of the above sequences ranges from 15 to 36, whereas in spinocerebellar ataxia there may be over 100. The functions of the protein encoded by the ATXN2 gene are currently unknown.
- Type 3 (another name is Machado-Joseph disease in honor of two patients in whom this condition was first described) – the cause of this pathology variant is disorders in the ATXN3 gene located on the 14th chromosome. Normally, the number of CAG repeats in this gene does not exceed 47, with the development of the disease, 53 to 68 repeats are detected. This gene encodes a protein that is presumably involved in the energy exchange of cerebellar neurons and basal nuclei.
- Type 6 is a relatively rare type of disease caused by defects in the CACNA1A gene localized on the 19th chromosome. For the development of pathology, a very slight increase in the number of CAG repeats is sufficient – if 5-20 of them are detected in the normal variant of the gene, then in the presence of ataxia – 21-26. The CACNA1A gene encodes a protein subunit of calcium channels located on cerebellar neurons. In addition to spinocerebellar ataxia, disorders in the CACNA1A gene cause the development of episodic ataxia and some hereditary forms of migraine.
- Type 7 – this type of pathology is caused by violations of the structure of the ATXN7 gene, which is located on the 3rd chromosome. In a healthy person, the number of CAG repeats is no more than 35, whereas with a disease, their number can reach several hundred. The functions of the protein that encodes the ATXN7 gene are currently being studied.
- Type 8 is caused by a genetic defect of the ATXN8 gene located on chromosome 13. As in other cases, the essence of a genetic defect in this condition is a change in the number of trinucleotide sequences of CAG – usually about 15-50, whereas in pathology the number of repeats can be over 1200.
In almost any type of spinocerebellar ataxia, a pathological form of protein excessively rich in glutamine forms deposits in the nuclei or cytoplasm of cerebellar neurons and basal nuclei in the form of dense aggregates. This process goes faster the more the number of CAG repeats in a key gene differs from the norm. This also explains the mechanism of anticipation of the symptoms of spinocerebellar ataxia – during meiosis, during the formation of germ cells, the number of the above trinucleotide sequences may increase, which leads to an increase in symptoms.
Since such a phenomenon occurs more often during the formation of male germ cells, this becomes the cause of the so-called “paternal transmission”, when the anticipation is registered only when the disease is transmitted from the father to the offspring. Many geneticists believe that the main cause of spinocerebellar ataxia lies not in the increase in “histidine” trinucleotides, but in the deletion of the so-called regulatory triplets separating the sites of CAG repeats. For example, in the first type of disease it is CAT, in the second CAA – they regulate the number of CAG repeats and maintain the stability of their number during meiosis.
Despite the significant genetic diversity of spinocerebellar ataxia, the manifestations of different types of this disease are generally similar and differ only in minor details – the age of manifestation, the peculiarities of some symptoms. Almost all forms of pathology are not registered in childhood – only isolated cases of types 1 and 2 have been observed in children younger than 7 years, the average age of their manifestation is 18-30 years. Spinocerebellar ataxia of types 3, 6 and 7 are characterized by even later development – their manifestation almost always occurs in people over 30 years of age. Often, such disorders are detected in the elderly, which makes it difficult to differentiate the diagnosis of this condition with Parkinson’s disease and other neurodegenerative diseases of older age.
Most often, the development of spinocerebellar ataxia begins with the appearance of simple clumsiness in movements, especially when walking, running. In the future, there is a tremor of the hands, gait disorders, paralysis of the oculomotor muscles (ophthalmoplegia), the patient’s handwriting changes (it becomes larger, the lines are uneven). Ultimately, the disease leads to severe cerebellar ataxia, disorders of the pyramidal and extrapyramidal pathways, parkinsonism. Some forms of pathology are characterized by severe visual impairment – the development of optic nerve atrophy, retinal pigment degeneration and other processes.
Spinocerebellar ataxia of the 6th, 7th and 8th types is also manifested by speech disorders (dysarthria) and swallowing, which is the cause of difficult nutrition and exhaustion of patients. It is this circumstance and related disorders (for example, cerebellar atrophy, heart failure) that often cause the death of patients. Depending on the form of the disease, the volume of supportive treatment and the quality of patient care, the life expectancy in spinocerebellar ataxia can range from 10 to 25 years from the moment of the onset of the first symptoms of pathology.
The detection of spinocerebellar ataxia is performed on the basis of neurological examination data, the study of hereditary history, magnetic resonance imaging of the brain and molecular genetic studies. When examining patients at different stages of pathology development, neurological disorders of various severity are determined – tremor of the extremities, ataxia, changes in speech and voice, at the final stages – dysphagia. Some forms of spinocerebellar ataxia are accompanied by a fairly rapid development of visual impairment, leading to complete blindness. Long-term monitoring of such patients confirms the steadily progressive course of the disease. When studying the hereditary history, characteristic signs of spinocerebellar ataxia can be determined – autosomal dominant inheritance, the presence of anticipation in the transmission of the disease from the father.
Brain MRI with spinocerebellar ataxia reveals foci of demyelination and neurodegeneration in the hemispheres, cerebellar worm and basal nuclei. At the terminal stages of the development of the disease, complete atrophy of the cerebellum may occur. Molecular genetic studies in spinocerebellar ataxia are reduced to the search for a pathologically increased number of CAG repeats in the genes associated with this disease. Currently, most laboratories in the world are searching for this defect in the genes that most often lead to the development of pathology – ATXN1, ATXN2, ATXN3, ATXN7, ATXN8 and CACNA1A.
There is no specific treatment of pathology, supportive therapy can somewhat slow down the development of spinocerebellar ataxia, but there is no consensus on its effectiveness at the moment. Vitamin therapy (E, A, group B), nootropic drugs, metabolic stimulants (riboxin) and metabolism in nervous tissue are used. With the development of involuntary movements, it is recommended to use clonazepam and haloperidol. Physical therapy plays an important role in curbing the progression of spinocerebellar ataxia – regular performance of a properly selected set of exercises allows you to strengthen muscles and reduce the severity of balance disorders. For the same purpose, it is recommended to conduct therapeutic massage sessions, electromyostimulation procedures.
Prognosis and prevention
In the long term, the prognosis of any form of spinocerebellar ataxia is unfavorable – this disease is characterized by a pronounced progressive course and eventually leads first to disability, and then to death of the patient. However, in a particular case, the prognosis may be less negative – for example, with the development of pathology in old age and timely maintenance treatment, most severe symptoms simply will not have time to manifest. If spinocerebellar ataxia occurs at a young age or in childhood, the life expectancy of such patients, even with intensive treatment and careful care, will be sharply reduced.
Prevention is carried out by the method of medical and genetic counseling of parents whose hereditary history is burdened by this condition, and genetic prenatal diagnosis. At the same time, it is necessary to take into account the autosomal dominant nature of the inheritance of spinocerebellar ataxia and such features of its transmission as anticipation.