Genetic identification, clinical features and prevalence of Spinocerebellar ataxia type 1 in Sakha Republic (Yakutia)
Goldfarb L.G., Platonov F.A. PDF
Annotation. Over the past several decades, more than 500 cases of Autosomal dominant spinocerebellar ataxia type 1 (SCA1) have been identified in the Republic of Sakha (Yakutia) of North-Eastern Siberia. The disease leads to long-term disability and death, making it a serious public health burden. The prevalence of SCA1 in the indigenous Sakha population has been steadily increasing since the 1970s. It has recently stabilized at a level of 45-53 per 100,000 due to efforts undertaken to limit its further spread. We describe results of a multi-year study of SCA1 in the Sakha population, including molecular genetics, distribution, clinical, electrophysiological and histopathological characteristics. Each studied patient had a mutation in the coding region of the ATXN1 gene on chromosome 6p22.3. The mutation presents as an uncontrolled increase in the number of trinucleotide CAG repeats from normal 25-32 to 39-72 with a loss of a CAT bridge in the middle of the CAG stretch. The number of continuous CAG triplets in the mutant ATXN1 gene correlates with the age of onset and the severity of the disease. The instability of this genomic segment is manifested in meiosis: the number of CAG repeats in a mutant gene increases in transmission from the father by an average of +3.04 repetitions and from the mother by +0.182 repetitions. The total number of repeats transmitted from one generation to another in the Sakha population is on average +1.614, which explains the increase in SCA1 prevalence. Patients from three spatially separate geographic regions of the Republic have the same haplotype, which confirms the origin of the mutation from a common ancestor about 37 generations ago. SCA1 patients in Mongolia, China and the U.S. show a different haplotype. To determine the potential of SCA1 for further spread, the fertility rates of the ATXN1 mutation carriers were evaluated and the Crow selection index calculated. The resulting score of 0.19 indicates that the mutation has little chance of being eliminated from the population without targeted preventive measures.
Key words: Republic of Sakha (Yakutia), Autosomal dominant spinocerebellar ataxia type 1 (SCA1), ATXN1 gene, trinucleotide repeat expansion.
For citation: Goldfarb L.G., Platonov F.A. Genetic identification, clinical features and prevalence of Spinocerebellar ataxia type 1 in Sakha Republic (Yakutia) // Siberian Research. 2019. 2 (2). P. 62 – 73. http://doi.org/10.33384/26587270.2019.02.008e
Received July 12, 2019; accepted October 31, 2019; published December 1, 2019
Goldfarb Lev G., MD, PhD, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20852, USA, https://orcid.org/0000-0002-5822-4272, e-mail: email@example.com.
Platonov Fyodor A., MD, PhD, Institute of Health, M.K. Ammosov North-Eastern Federal University, Yakutsk 677010, The Russian Federation, email: firstname.lastname@example.org
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A note added after this review has been accepted for publication:
The authors became aware of a recent publication by Varlamova et al. (2018) on the discovery of Dentatorubral-pallidoluyisian atrophy (DRPLA) in five members of a Sakha family. This disease similarly to SCA1 is associated with an expansion of an uninterrupted CAG repeat in the ATN1 gene. And similarly, ataxia is the dominant clinical feature of DRPLA.
Varlamova MA, Nazarova PS, Ilyinova EA, Pavlova NI, Sidorova OG, Kononova SK, Solovyova NA, Dyakonova AT, Kurtanov XA. Clinical-genealogical and molecular-genetic features of patients with spinocerebellar ataxia type 1 and dentatorubropallidoluyuisian atrophy in Yakutia. Current Problems of Science and Education. 2018; 6.