Clinical Features And The Related Genetics Analysis Of Two Asymptomatic Central Nervous System Demyelinating Disease Families

Demyelinating diseases of the central nervous system is a group of diseases that features the demyelination occurring in the brain and spinal cord. This kind of diseases can be classified according to their pathogenesis into two kinds, the hereditary and acquired demyelinating diseases. While it is quite clear that hereditary demyelinating diseases are primarily due to myelination defects, which interrupt the completion of normal development, the aetiology of acquired demyelinating diseases is not yet completely understood., Previous studies have suggested several potential factors, such as viral infections, autoimmune reactions or genetic susceptibility factors regulating imbalances. These factors may interact with each other in causing the disease: triggered by some acquired environment, individuals who carry genes susceptible to immune disorder might have a higher chance to an abnormal autoimmune response to myelin of the central components.Multiple sclerosis is a common acquired demyelinating disease, which has a worldwide distribution, but the distribution has a certain geographical features.Current epidemiological studies suggest that its incidence is closely related to latitude. The farther away from the equator, the higher the risk of MS. Among the high incidence areas, North America, Europe, New Zealand and other areas are on the list, but in the same geographical latitude, Asia has a low morbidity, which may be correlated with lack of a clear understanding of the disease and the low levels of diagnosis.In the study of the pathogenesis, oligodendrocytes disintegrating, inhibiting growth cone collapse causing regeneration after axonal injury is a possible risk factor. The Nogo protein has the ability of inhibiting axonal regeneration in the central nervous system. Nogo gene is located on chromosome 2marking at 2p12-14, which is a family member of reticulon. For Nogo gene, one prominent feature is encoding three protein, Nogo-A, Nogo-B and Nogo-C. Wherein these protein, Nogo-A is mainly expressed in oligodendrocytes in the central nervous system, inhibiting the CNS remyelination by Ng R-mediated.Purpose:We found two pedigrees,the patients’ clinical symptoms are not typical, without any obvious clinical signs, but there is a clear imaging manifestation of demyelination, and through the investigation and improvement of patient examination could we find the incidence of a certain genetic predisposition. Study these two asymptomatic familial pedigrees demyelinating central nervous system. Draw the pedigree charts of the pedigrees, analyze theirs possible mode of inheritance, characteristic signs of progression, symptoms characteristic and imaging features. By extracting the peripheral blood DNA of the members of these two pedigrees, we wish to explore the relationship between Nogo 3’UTR CAA insertion / deletion polymorphism and mutations in the pathogenesis of family members. Moreover, we aim to understand the characteristics of incidence for this group of patients, and the possible genetic characteristics associated with the pathogenesis of genetic mechanisms.Method:1. After the patients and their families signed their informed consents, we completed the investigation of these pedigrees through examining the outpatients and inpatients medical records, surveying questionnaire, taking the relevant history of the disease, improving the related physical and neurology examination. After learning all incidences of family members, age of onset, we drew the family tree of these pedigrees.2. Improved the imaging data of some members of surveyed pedigrees, analyzed features of imaging data.3. Drew the blood specimen of the two family members: 13 cases of illness and 26 non-blood relatives of the pedigrees, using column chromatography adsorption genomic DNA, gene was amplified by polymerase chain reaction(PCR). Agarose gel electrophoresis to determine the target gene, by the dideoxy chain termination method(Sanger method) for the purposes of gene sequencing, the sequencing results were read and analyzed by fragment Applied Biosystems 3730 XL sequencer.Result:1. The patients in Pedigree ⅰ has a disease characteristics of dissemination of lesions in space and in time, but no obvious signs of inconsistent performance with typical MS. Hereditary of them is consistent with autosomal dominant inheritance. Pedigreeⅱis with mild clinical manifestation, and the lesions were found by physical examination, radiologic manifestations consistent with demyelination, but without the typical symptoms, abide by autosomal dominant inheritance.2.Imaging features of Pedigreeⅰ:in members’( Ⅲ2, Ⅲ3, Ⅲ5, Ⅲ8) head MRI, long T1 WI, long T2 WI scattered perpendicular to the ventricle patches in multiple high density can be seen around periventricular and basal ganglia. Imaging features of Pedigreeⅱ: both the memberⅡ1and Ⅱ14 took MRI before and after the onset of the disease in three years, long T1 WI, T2 WI, perpendicular to the ventricle hyperintensity spotty can be seen around the periventricular, and showed no change from the previous special, and no evidence for progress. Foci beside the lateral ventricles, the presence of demyelinating imaging performance(member Ⅰ 1, Ⅱ 3, Ⅱ 5, Ⅱ 8, Ⅱ 10, Ⅱ 12, Ⅱ 16), generally normal imaging findings for the non-kinship family memberⅡ6Ⅱ7,Ⅱ13,Ⅱ15.3. DNA sequencing showed that none Nogo 3’UTR CAA deletionmutation in the two respondents pedigrees.Conclusion:1. The characteristics of the two asymptomatic familial central nervous system demyelinating diseases pedigrees, are about not fully compatible with the current diagnostic criteria for MS. However they have certain genetic characteristics, so the specific pathogenesis needs further study.2. Nogo 3’UTR CAA deletion mutation were missed for the study population, which were reported in previous reports may cause disease. Nogo 3’UTR CAA deletion mutation is not the factors that cause familial disease.3. Nogo3’UTR CAA insertion mutations for the patients, may delay the onset of the process of illness. Self-healing process of myelin proteins may be the protective factors that lead to the group of patients without typical signs.