Hereditary diseases of nervous system
Introduction. Hereditary diseases of the nervous system (HDNS) are a large group of nervous diseases with an inborn disorder of the transfer of genetic information and predominantly neurodegenerative damage of the cells of the central nervous system (CNS) and peripheral nervous system (PNS). The HDNS are conditioned by the gene or chromosome mutations and transferred from generation to the next or to the next but one generation. The chromosome mutations can be the disorder of the number of chromosomes (doubled, tripled, absence), or the disordered structure of the chromosome (deletion, inversion, translocation, duplication).
In case of genetic mutations, the changes are observed in the genes at specific chromosome segments. These changes are the cause for monogenic diseases, a rather heterogeneous group of disorders in their clinical manifestations, which constitute the main contingent of this program. The research of HDNS is a complex and sophisticated task not only for contemporary neurogenetics but also for clinical neurology. The pronounced phenotypic polymorphism leads to greatly varied clinical symptoms even within one family. The neurological symptoms can be represented by classical pronounced types, atypical manifestations and inapparent clinical symptoms. The clinical picture of such damages is accompanied by the progressing disorder of the neuromuscular apparatus, speech and sensory activity. During the diagnosis, the specialist considers hereditary anamnesis, patient’s age, localization of pathological process and clinical symptoms. An individual plan of therapy of the hereditary disease of the nervous system is compiled only after detailed instrumental, laboratory, clinical and neurogenetic examination of the patient.
Mostly, the severe monogenic hereditary diseases are transferred in the autosomal recessive fashion, that is, conditioned by the recessive pathological gene, which is a part of the autosome and manifests if a homozygote forms. Such diseases are not associated with gender and an develop in case of phenotypically healthy parents. Some diseases are transferred by dominant type (myotonia, Huntington’s chorea). Such disorders as hemophilia, color-blindness, hereditary atrophy of optic nerves, are transferred in the gender-associated recessive fashion, with mutated X-chromosomes. The mode of inheritance can be specified in the medical-genealogical examination based on the family history. Now, the medical-genealogical consultation and medical genetic tests are the most important, wen the patients with hereditary pathology and their families can get the answer about the opportunity of having a child with hereditary disease. In our hospital the individually tailored program of treatment of the hereditary diseases of the nervous system is developed after detailed the medical-genealogical consultation, medical genetic and proteomic tests and consultation of the neural geneticist and professor of neurology.
General principles of the therapy of hereditary diseases of the nervous system
Up to now, medical community presumes that the hereditary diseases are fatal and they cannot be coped with. Davydenkov SN, a prominent neurologist, the founder of clinical genetics in Russia used to point that poor effectiveness of the therapy of these diseases depends on our poor knowledge about them. It is known that the most effective methods of therapy are those that are able to affect etiological and pathogenetic mechanisms of disease. Etiology of the hereditary conditioned disease is a hereditary factor represented by a mutant gene or chromosome aberration. Hence, it is obvious that the task of the etiologic methods of the therapy must be normalization of the hereditary machine of the injured individual. Obviously, the task is extremely sophisticated, especially that all pathogenetic mechanism from mutation to biochemical features of clinical symptoms is known only in few hereditary diseases. The development of the etiological methods of the treatment of genetically conditioned diseases is in the agenda of medical science and passes experimental stage. This type of research is known as gene engineering, the goal of which is development of the most radical and promising methods to treat hereditary diseases: the method of the introduction of normally functioning genes into the organism and even into genome. The methods of etiological therapy of hereditary disorders pass experimental tests, while the methods of the pathogenetic therapy are already successfully implemented in the clinical practice. To understand pathogenetic therapy the possible mechanisms of the hereditary metabolic defects can be summed up as follows:
- insufficient final product of reaction and more remote products of its transformation;
- deposit of the substrate of the blocked reaction or its precursors;
- change of the main direction of reaction and upregulated formation of the products the amount of which is slight in the norm.
The character of the listed mechanisms of development of the pathological processes conditions the main directions of the pathogenetic therapy of the hereditary diseases of the nervous system (HDNS):
- Replacement therapy – introduction of the lacking substances into the organism. The substances of blood or leukocyte suspension that patient lacks due to the genetic defect are introduced. So, such replacement therapy as introduction of normal plasma is effective for mucopolysaccharidoses; of gamma globulin for agammaglobulinemia, thyroid hormones for familial goiter; dopamine precursors on Parkinson’s disease.
- Dietary therapy implies exclusion of the products that cannot be digested by the organism. In some cases, it is the only and quite efficient method. Phenylketonuria is an example of such a disease that develops due to the hereditary defect of phenylalanine metabolism.
- Combination of the replacement therapy with pathogenetically conditioned dietary measures;
- Elimination of the abnormal metabolism products from the body. The therapy with elimination of the deposited metabolite from the body is used in such cases, as the hepatocerebellar degeneration. Penicillamine, the drug that binds copper, is administered once or twice a day by 250-500 mg.
- The methods of non-specific therapy.The symptomatic, stimulating and general therapy is used in many diseases with unclear pathogenesis. Here, belong various types of progressive muscular dystrophies.
- Surgical methods of therapy.Surgical methods can successfully help cope with hereditary abnormalities that manifest in various defects of development. For example, such effects as fissured palate or congenital dislocation of the hip can be corrected surgically. Good results can be achieved in the surgical correction of the combination of the surgical and hormonal treatment in hereditary hyperplasia of suprarenal cortex, maldevelopment of external sex organs, familial hyperparathyroidism and autoimmune disorders.
The protocols of the therapy of progressing hereditary diseases of nervous system
Diseases. Hereditary systemic degenerations of nervous system, Alzheimer’s disease, systemic cortical atrophies, cerebellum diseases, combined degenerations of cerebellar pathways and peripheral nerves, diseases with the damage of extrapyramidal system: Parkinson’s disease, hepato-cerebral dystrophy, Huntington’s chorea, Minor's disease, generalized tic disorder, deforming muscle dystrophy. The diseases withpyramidal tract dysfunction: Erb-Charcot disease, family amyotrophic lateral sclerosis and others.
To receive the therapy: Hereditary diseases of the nervous system (HDNS) conditioned by gene or chromosome mutations are the diseases that pass from generation to generation or to the next but one. In gene mutations, the changes are observed in the genes at specific sites of the chromosomes. These changes are the cause for monogenic diseases, a rather heterogeneous group of disorders in their clinical manifestations, which constitute the main contingent of this program. The neurological symptoms can be represented by classical pronounced types, atypical manifestations and inapparent clinical symptoms. We have observed that the patients with HDNS are absolutely healthy people till a certain period of time and the disease can debut at different times of their life (in childhood, adolescence or from 35 to 60) due to various etiopathogenetic factors. An individual learns about the disease only when it starts progressing, and this is the key demand for participation in this protocol. Most frequently, the degenerative-atrophic processes in different areas of the CNS grow in an avalanche-like fashion leading to profound dementia in atrophy of brain cortex, severe ataxia in atrophy of the cerebellum cortex, akinetic-rigid disorders and dyskinesias in the degeneration of striatal zone of the brain and muscle atrophy in the damage of motor neurons.
In some cases, the decompensation leads to significant disability due to autoimmune disorders or even to lethal outcomes due to oncological complications. These vital complications are primarily conditioned by the genome-proteome disorders (deletion, inversion, translocation, duplication) in the hematopoietic stem cells (HSCs) as the consequences of the DNA in them. Thus, additional mutations in the genes induces severe disability, dementia or lethal outcome due to the autoimmune inflammation, general of neural tissue or carcinogenic degeneration. The reason for decompensation of the patient with HDNS is the onset of “genome disability” of HSCs and their progeny of immunocompetent cells.
Therapy principle: The problem is crucially important because of the absence of effective methods of treatment of HDNS progress and possible repetition in the next generations. The main hopes in the therapy of HDNS are laid on the technologies of genome editing. But how can we help during the progress of the disease? We do not claim that we can cure the disease, but can we arrest its progress? Yes, we can. This answer has been obtained in our research of the restoration of mortal mutations of the damaged HSCs with our nature-like technology of homologous replacement of the mutant parts of HSCs with two-chain DNA of a healthy donor.
Molecular research in the animal models of the restoration of the damaged HSCs and MSSCs with a large number of DNA mutations and damages conditioned by 3-5 fold lethal dose of ionizing radiation resulted in the development of the novel biotechnology of restoration and replacement of the mutant parts of DNA with analogous parts of healthy DNA during the division of the host’s HSCs. The peripheral blood mononuclear cells (PBMCs) and HSCs of the HDNS patient are isolated by leukapheresis and incubated under specific conditions with the agent Panagen approved for clinical use in Russia. Part of these restored HSCs and PBMCs are used for the reinfusion of the restored cells, while the other part is used for the restoration of the injured neural cells through intrathecal administrations of these cells to the spinal canal.
Result. The technology does not cure genetic diseases of the humans, especially so complicated as the HDNS, but it gives the chance to arrest the progress of the hereditary nervous disease due to a well-known molecular mechanism of a homologous recombination, as well as to compensate the neurological and somatic condition of the HDNS patient. The technology helps prevent the opportunity of the decompensation of various types of the HDNS in healthy compensated members of the family with disease positive family history and high risk of the disease onset and thus to give a sort of bioinsurance from possible progress of the hereditary disease.
