Neuromuscular DiseasesNeuromuscular DiseasesНервно-мышечные болезни2222-87212413-0443Publishing House ABV Press24010.17650/2222-8721-2017-7-4-50-55CLINICAL CASEКЛИНИЧЕСКИЙ РАЗБОРPresymptomatic genetic counseling in amyotrophic lateral sclerosisДоклиническое медико-генетическое консультирование при боковом амиотрофическом склерозеShpilyukovaYu. A.ШпилюковаЮ. А.
Russian Federation

80 Volokolamskoe Shosse, Моscow 125367, Russia

Россия, 125367 Москва, Волоколамское шоссе, 80

jshpilyukova@gmail.comRosliakovaA. A.РосляковаА. А.
Russian Federation

80 Volokolamskoe Shosse, Моscow 125367, Russia

Россия, 125367 Москва, Волоколамское шоссе, 80

ZakharovaM. N.ЗахароваМ. Н.
Russian Federation

80 Volokolamskoe Shosse, Моscow 125367, Russia

Россия, 125367 Москва, Волоколамское шоссе, 80

IllarioshkinS. N.ИллариошкинС. Н.
Russian Federation

80 Volokolamskoe Shosse, Моscow 125367, Russia

Россия, 125367 Москва, Волоколамское шоссе, 80

Research Center of NeurologyФГБНУ «Научный центр неврологии»110120187450551101201811012018Copyright ©; 2018, Shpilyukova Y.A., Rosliakova A.A., Zakharova M.N., Illarioshkin S.N.Copyright ©; 2018, Шпилюкова Ю.А., Рослякова А.А., Захарова М.Н., Иллариошкин С.Н.2018Shpilyukova Y.A., Rosliakova A.A., Zakharova M.N., Illarioshkin S.N.Шпилюкова Ю.А., Рослякова А.А., Захарова М.Н., Иллариошкин С.Н.https://creativecommons.org/licenses/by/4.0https://nmb.abvpress.ru/jour/article/view/240

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive loss of central and peripheric motor neurons, with genetic factors playing significant role in its  development. In this article, we discuss in detail the difficulties in the analysis of ALS related to incomplete penetrance of mutations,  extreme genetic heterogeneity of this disorder, the lack of clear  genotype-phenotype correlations, etc. Presented is our own  instructive observation in which a clinically unaffected relative of a  patient with the SOD1-associated form of ALS requested presymptomatic ALS genetic  testing and medical-genetic counseling. Key aspects of  recommendations about presymptomatic genetic counseling in persons  from the risk group originating from families with ALS have been presented.

Боковой амиотрофический склероз (БАС) – фатальное нейродегенеративное заболевание, характеризующееся прогрессирующей гибелью центрального и периферического мотонейронов, в развитии которого большую роль играют генетические факторы. В  настоящей статье подробно рассматриваются сложности, возникающие при анализе  генетики БАС, связанные с неполной пенетрантностью мутаций, выраженной генетической гетерогенностью  данного заболевания, отсутствием четких генофено-типических корреляций и др. Представлено собственное наблюдение, в котором у клинически здорового родственника пациента с  SOD1‑ассоциированной формой БАС потребовались доклиническая ДНК-диагностика и медико- генетическое консультирование. Освещены ключевые аспекты рекомендаций по проведению в  семьях, отягощенных БАС, доклинического медико-генетического консультирования у лиц из группы риска.

amyotrophic lateral sclerosisDNA testingSOD1 genepresymptomatic genetic counselinggenetic riskбоковой амиотрофический склерозДНК-диагностикаген SOD1доклиническое медико-генетическое консультированиегенетический риск1. Byrne S., Walsh C., Lynch C. et al. Rate of familial amyotrophic lateral sclerosis: a systematic review and meta-analysis. J Neurol Neurosurg Psychiatry 2011;82(6):623–7. DOI: 10.1136/jnnp.2010.224501. PMID: 21047878.Byrne S., Walsh C., Lynch C. et al. Rate of familial amyotrophic lateral sclerosis: a systematic review and meta-analysis. J Neurol Neurosurg Psychiatry 2011;82(6):623–7. DOI: 10.1136/jnnp.2010.224501. PMID: 21047878.2. Vajda A., McLaughlin R.L., Heverin M. et al. Genetic testing in ALS: a survey of current practices. Neurology 2017;88(10):991–9. DOI: 10.1212/WNL.0000000000003686. PMID: 28159885.Vajda A., McLaughlin R.L., Heverin M. et al. Genetic testing in ALS: a survey of current practices. Neurology 2017;88(10):991–9. DOI: 10.1212/WNL.0000000000003686. PMID: 28159885.3. Roggenbuck J., Quick A., Kolb S.J. Genetic testing and genetic counseling for amyotrophic lateral sclerosis: an update for clinicians. Genet Med 2017;19(3):267–74. DOI: 10.1038/gim.2016.107. PMID: 27537704.Roggenbuck J., Quick A., Kolb S.J. Genetic testing and genetic counseling for amyotrophic lateral sclerosis: an update for clinicians. Genet Med 2017;19(3):267–74. DOI: 10.1038/gim.2016.107. PMID: 27537704.4. Rosen D.R., Siddiquef T., Patterson D. et al. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic. Nature 1993;364(6435):362. DOI: 10.1038/364362c0. PMID: 8332197.Rosen D.R., Siddiquef T., Patterson D. et al. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic. Nature 1993;364(6435):362. DOI: 10.1038/364362c0. PMID: 8332197.5. Veldink J.H. ALS genetic epidemiology ‘How simplex is the genetic epidemiology of ALS?’ J Neurol Neurosurg Psychiatry 2017;88(7):537. DOI: 10.1136/jnnp-2016-315469. PMID: 28209650.Veldink J.H. ALS genetic epidemiology ‘How simplex is the genetic epidemiology of ALS?’ J Neurol Neurosurg Psychiatry 2017;88(7):537. DOI: 10.1136/jnnp-2016-315469. PMID: 28209650.6. Абрамычева Н.Ю., Лысогорская Е.В., Шпилюкова Ю.А. и др. Молекулярная структура бокового амиотрофического склероза в российской популяции. Нервно-мышечные болезни 2016;6(4):21–7. [Abramycheva N.Yu., Lysogorskaya E.V., Shpilyukova Yu.S. et al. Molecular structure of amyotrophic lateral sclerosis in Russian population. Nervno- myshechnye bolezni = Neuromuscular Diseases 2016;6(4):21–7. (In Russ.)]. DOI: 10.17650/2222-8721-2016-6-4-21-27.Абрамычева Н.Ю., Лысогорская Е.В., Шпилюкова Ю.А. и др. Молекулярная структура бокового амиотрофического склероза в российской популяции. Нервно-мышечные болезни 2016;6(4):21–7. [Abramycheva N.Yu., Lysogorskaya E.V., Shpilyukova Yu.S. et al. Molecular structure of amyotrophic lateral sclerosis in Russian population. Nervno- myshechnye bolezni = Neuromuscular Diseases 2016;6(4):21–7. (In Russ.)]. DOI: 10.17650/2222-8721-2016-6-4-21-27.7. Abramycheva N.Y., Lysogorskaia E.V., Stepanova M.S. et al. C9ORF72 hexanucleotide repeat expansion in ALS patients from the Central European Russia population. Neurobiol Aging 2015;36(10):2908. e5–9. DOI: 10.1016/j.neurobiolaging.2015.07.004. PMID: 26254955.Abramycheva N.Y., Lysogorskaia E.V., Stepanova M.S. et al. C9ORF72 hexanucleotide repeat expansion in ALS patients from the Central European Russia population. Neurobiol Aging 2015;36(10):2908. e5–9. DOI: 10.1016/j.neurobiolaging.2015.07.004. PMID: 26254955.8. Lysogorskaia E.V., Abramycheva N.Y., Zaharova M.N. Genetic studies of Russian patients with amyotrophic lateral sclerosis. Amyotroph Lateral Scler Frontotemporal Degener 2015;17(1–2):135–41. DOI: 10.3109/21678421.2015.1107100. PMID: 26551617.Lysogorskaia E.V., Abramycheva N.Y., Zaharova M.N. Genetic studies of Russian patients with amyotrophic lateral sclerosis. Amyotroph Lateral Scler Frontotemporal Degener 2015;17(1–2):135–41. DOI: 10.3109/21678421.2015.1107100. PMID: 26551617.9. Boeve B.F., Boylan K.B., Graff-Radford N.R. et al. Characterization of frontotemporal dementia and/or amyotrophic lateral sclerosis associated with the GGGGCC repeat expansion in C9ORF72. Brain 2012;135(3):765–83. DOI: 10.1093/brain/aws004. PMID: 22366793.Boeve B.F., Boylan K.B., Graff-Radford N.R. et al. Characterization of frontotemporal dementia and/or amyotrophic lateral sclerosis associated with the GGGGCC repeat expansion in C9ORF72. Brain 2012;135(3):765–83. DOI: 10.1093/brain/aws004. PMID: 22366793.10. Andersen P.M., Nilsson P., Keränen M.L. et al. Phenotypic heterogeneity in motor neuron disease patients with CuZn-superoxide dismutase mutations in Scandinavia. Brain 1997;120(10):1723–37. PMID: 9365366.Andersen P.M., Nilsson P., Keränen M.L. et al. Phenotypic heterogeneity in motor neuron disease patients with CuZn-superoxide dismutase mutations in Scandinavia. Brain 1997;120(10):1723–37. PMID: 9365366.11. Felbecker A., Camu W., Valdmanis P.N. et al. Four familial ALS pedigrees discordant for two SOD1 mutations: are all SOD1 mutations pathogenic? J Neurol Neurosurg Psychiatry 2010;81(5):572–7. DOI: 10.1136/jnnp.2009.192310. PMID: 20460594.Felbecker A., Camu W., Valdmanis P.N. et al. Four familial ALS pedigrees discordant for two SOD1 mutations: are all SOD1 mutations pathogenic? J Neurol Neurosurg Psychiatry 2010;81(5):572–7. DOI: 10.1136/jnnp.2009.192310. PMID: 20460594.12. Mandich P., Mantero V., Verdiani S. et al. Complexities of genetic counseling for ALS: a case of two siblings with discordant genetic test results. J Genet Couns 2015;24(4):553–7. DOI: 10.1007/s10897-015-9831-y. PMID: 25843563.Mandich P., Mantero V., Verdiani S. et al. Complexities of genetic counseling for ALS: a case of two siblings with discordant genetic test results. J Genet Couns 2015;24(4):553–7. DOI: 10.1007/s10897-015-9831-y. PMID: 25843563.13. Weishaupt J.H., Waibel S., Birve A. et al. A novel optineurin truncating mutation and three glaucoma-associated missense variants in patients with familial amyotrophic lateral sclerosis in Germany. Neurobiol Aging 2013;34(5):1516.e9–15. DOI: 10.1016/j.neurobiolaging.2012.09.007. PMID: 23062601.Weishaupt J.H., Waibel S., Birve A. et al. A novel optineurin truncating mutation and three glaucoma-associated missense variants in patients with familial amyotrophic lateral sclerosis in Germany. Neurobiol Aging 2013;34(5):1516.e9–15. DOI: 10.1016/j.neurobiolaging.2012.09.007. PMID: 23062601.14. Blitterswijk M., Vlam L., Es M.A. et al. Genetic overlap between apparently sporadic motor neuron diseases. PLoS One 2012;7(11):e48983. DOI: 10.1371/journal.pone.0048983. PMID: 23155438.Blitterswijk M., Vlam L., Es M.A. et al. Genetic overlap between apparently sporadic motor neuron diseases. PLoS One 2012;7(11):e48983. DOI: 10.1371/journal.pone.0048983. PMID: 23155438.15. Siddique T., Deng H., Hentati A. Identification of new mutations in familial amyotrophic lateral sclerosis. Am J Hum Genet 1994;55(Suppl 3):A1419.Siddique T., Deng H., Hentati A. Identification of new mutations in familial amyotrophic lateral sclerosis. Am J Hum Genet 1994;55(Suppl 3):A1419.16. Aoki M., Abe K., Houi K. et al. Variance of age at onset in a Japanese family with amyotrophic lateral sclerosis associated with a novel Cu/Zn superoxide dismutase mutation. Ann Neurol 1995;37(5):676–9. DOI: 10.1002/ana.410370518. PMID: 7755363.Aoki M., Abe K., Houi K. et al. Variance of age at onset in a Japanese family with amyotrophic lateral sclerosis associated with a novel Cu/Zn superoxide dismutase mutation. Ann Neurol 1995;37(5):676–9. DOI: 10.1002/ana.410370518. PMID: 7755363.17. Iwai K., Yamamoto M., Yoshihara T. et al. Anticipation in familial amyotrophic lateral sclerosis with SOD1-G93S mutation. J Neurol Neurosurg Psychiatry 2002;73(6):819–22. DOI: 10.1136/jnnp.72.6.819. PMID: 12023436.Iwai K., Yamamoto M., Yoshihara T. et al. Anticipation in familial amyotrophic lateral sclerosis with SOD1-G93S mutation. J Neurol Neurosurg Psychiatry 2002;73(6):819–22. DOI: 10.1136/jnnp.72.6.819. PMID: 12023436.18. Stewart H.G., Аndersen P.M. Neurophysiology of hereditary amyotrophic lateral sclerosis. In: Clinical Neurophysiology of Motor Neuron Diseases. Ed. A. Eisen. Elsevier, Amsterdam, The Netherlands, 2004. Pp. 543–562.Stewart H.G., Аndersen P.M. Neurophysiology of hereditary amyotrophic lateral sclerosis. In: Clinical Neurophysiology of Motor Neuron Diseases. Ed. A. Eisen. Elsevier, Amsterdam, The Netherlands, 2004. Pp. 543–562.19. Benatar M., Stanislaw C., Reyes E. et al. Presymptomatic ALS genetic counseling and testing: experience and recommendations. Neurology 2016;86(24):2295–302. DOI: 10.1212/WNL.0000000000002773. PMID: 27194384.Benatar M., Stanislaw C., Reyes E. et al. Presymptomatic ALS genetic counseling and testing: experience and recommendations. Neurology 2016;86(24):2295–302. DOI: 10.1212/WNL.0000000000002773. PMID: 27194384.20. Lerman C., Croyle R.T., Tercyak K.P., Hamann H. Genetic testing: psychological aspects and implications. J Neurol Neurosurg Psychiatry 2002;72(6):819–20. DOI: 10.1136/jnnp.72.6.819. PMID: 12023436.Lerman C., Croyle R.T., Tercyak K.P., Hamann H. Genetic testing: psychological aspects and implications. J Neurol Neurosurg Psychiatry 2002;72(6):819–20. DOI: 10.1136/jnnp.72.6.819. PMID: 12023436.21. Boulis N., O'Connor D., Donsante A. Molecular and cellular therapies for motor neuron diseases. Elseiver, Amsterdam, The Netherlands, 2017. Р. 321.Boulis N., O'Connor D., Donsante A. Molecular and cellular therapies for motor neuron diseases. Elseiver, Amsterdam, The Netherlands, 2017. Р. 321.