Sensory ataxic neuropathy, dysarthria and ophthalmoparesis (SANDO syndrome): characteristics of a series of clinical observations in Russia
- Authors: Nuzhniy Y.P.1, Klyushnikov S.A.1, Seliverstov Y.A.1, Krylova T.D.2, Tsygankova P.G.2, Zakharova Y.Y.2, Kasatkin D.S.3, Spirin N.N.3, Abramycheva N.Y.1, Illarioshkin S.N.1
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Affiliations:
- Research Center of Neurology
- Research Center for Medical Genetics
- Yaroslavl State Medical University
- Issue: Vol 13, No 2 (2019)
- Pages: 5-13
- Section: Original articles
- Submitted: 25.06.2019
- Published: 25.06.2019
- URL: https://annaly-nevrologii.com/journal/pathID/article/view/586
- DOI: https://doi.org/10.25692/ACEN.2019.2.1
- ID: 586
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Full Text
Abstract
Introduction. Mitochondrial ataxias are an extremely heterogeneous group of diseases, which include the SANDO (an acronym stands for sensory ataxic neuropathy, dysarthria and ophthalmoparesis) syndrome. SANDO syndrome is one of the characteristic phenotypes associated with mutations in the POLG gene.
Study objective. To analyse the clinical picture and the results of clinical and laboratory tests in a Russian case series of genetically confirmed SANDO syndrome.
Materials and methods. Nine patients (4 men and 5 women aged 33.4±11.3 years) with SANDO syndrome and identified mutations in the POLG gene were examined. A clinical evaluation using the SARA and ICARS (for ataxia) and MoCA (cognitive function) scales, laboratory study of liver function, electrocardiography, stimulation electromyography and brain MRI were performed; 6 patients underwent electroencephalography. MLPA analysis and the original multigene NGS panel were used for genetic screening.
Results. The average age of disease onset was 27.7±8.2 years, with significant variability (from 14 to 49 years). The disease was characterized by a rather typical clinical picture, which included sensory ataxia, polyneuropathy, dysarthria and external ophthalmoparesis in all patients; the median score was 13.5/40 [11; 25] points on the SARA scale, 39.5/100 [33; 63] points on the ICARS scale, and 22 [20; 25] points on the MoCA scale. Two patients showed signs of frontal lobe dysfunction. In most patients, MRI revealed changes in the white matter of the cerebellar hemispheres, brainstem, thalamus and semioval centres, but no pathology was detected on MRI in 3 patients. The p.W748S mutation in the POLG gene made up 83% of the mutant alleles, while the p.L931R and p.L311P pathogenic mutations found in 2 patients are new variants and have not been described in international databases.
Conclusion. Our findings suggest that the true frequency of SANDO syndrome in the population may be higher than previously thought. Therefore, a suspicion of this disease should be maintained even in the absence of characteristic changes on neuroimaging. For the timely detection of SANDO syndrome, we propose an appropriate diagnostic algorithm, which should be followed when examining patients with ataxia.
About the authors
Yevgeny P. Nuzhniy
Research Center of Neurology
Author for correspondence.
Email: enuzhny@mail.ru
Russian Federation, Moscow
Sergey A. Klyushnikov
Research Center of Neurology
Email: enuzhny@mail.ru
Russian Federation, Moscow
Yury A. Seliverstov
Research Center of Neurology
Email: enuzhny@mail.ru
ORCID iD: 0000-0002-6400-6378
Cand. Sci. (Med.), senior researcher, Scientific advisory department
Russian Federation, MoscowTatiana D. Krylova
Research Center for Medical Genetics
Email: enuzhny@mail.ru
Russian Federation, Moscow
Polina G. Tsygankova
Research Center for Medical Genetics
Email: enuzhny@mail.ru
Russian Federation, Moscow
Yekaterina Yu. Zakharova
Research Center for Medical Genetics
Email: enuzhny@mail.ru
Russian Federation, Moscow
Dmitriy S. Kasatkin
Yaroslavl State Medical University
Email: enuzhny@mail.ru
Russian Federation, Yaroslavl
Nikolai N. Spirin
Yaroslavl State Medical University
Email: enuzhny@mail.ru
Russian Federation, Yaroslavl
Natalia Yu. Abramycheva
Research Center of Neurology
Email: enuzhny@mail.ru
Russian Federation, Moscow
Sergey N. Illarioshkin
Research Center of Neurology
Email: enuzhny@mail.ru
Russian Federation, Moscow
References
- Wallace D.C., Singh G., Lott M.T. et al. Mitochondrial DNA mutation associated with Leber's hereditary optic neuropathy. Science 1988; 242: 1427–1430. PMID: 3201231.
- Van Goethem G., Dermaut B., Löfgren A. et al. Mutation of POLG is associated with progressive external ophthalmoplegia characterized by mtDNA deletions. Nat Genet 2001; 28: 211–212. doi: 10.1038/90034. PMID: 11431686.
- Human DNA Polymerase Gamma Mutation Database. URL: https://tools.niehs.nih.gov//polg.
- Young M.J., Copeland W.C. Human mitochondrial DNA replication machinery and disease. Curr Opin Genet Dev 2016; 38: 52–62. doi: 10.1016/j.gde.2016.03.005. PMID: 27065468.
- Stumpf J.D., Saneto R.P., Copeland W.C. Clinical and molecular features of POLG-related mitochondrial disease. Cold Spring Harb Perspect Biol 2013; 5: a011395. doi: 10.1101/cshperspect.a011395. PMID: 23545419.
- Rudenskaya G.E., Zakharova E.Yu. [Hereditary neurometabolic diseases of adolescence and adulthood]. Moscow, 2018. 392 p. (In Russ.)
- Abramycheva N.Yu., Fedotova E.Yu., Klyushnikov S.A. et al. [An original target genetic panel to diagnose neurodegenerative diseases on the basis of next-generation sequencing: first experience]. Sovremennye tehnologii v medicine 2016; 8(4): 185–190. DOI: 0.17691/stm2016.8.4.23. (In Russ.)
- Lasota J. Mitochondrial POLG mutation, mtDNA depletion, and cardiomyopathy. Lab Invest 2007; 87: 316. PMID: 17486695.
- Fadic R., Russell J.A., Vedanarayanan V.V. et al. Sensory ataxic neuropathy as the presenting feature of a novel mitochondrial disease. Neurology 1997; 49: 239–245. PMID: 9222196.
- Klyushnikov S.A., Krylova T.D., Tsygankova P.G. et al. [SANDO syndrome is a novel form of autosomal-recessive ataxia]. In: [Proceedings of the III National Congress against Parkinson’s Diseases and Movement Disorders]. Moscow; 2014: 330–331. (In Russ.)
- Mikhaylova S.V., Zakharova E.Yu., Tsygankova P.G., Abrukova A.V. [Clinical polymorphism of mitochondrial encephalomyopathies caused by mutations in gamma polymerase gene]. Rossiyskiy vestnik pediatrii i perinatologii 2012; 4: 54–61. (In Russ.)
- Tranchant С., Anheim M. Movement disorders in mitochondrial diseases. Rev Neurol (Paris) 2016; 172: 524–529. doi: 10.1016/j.neurol.2016.07.003. PMID: 27476418.
- Schulte C., Synofzik M., Gasser T. et al. Ataxia with ophthalmoplegia or sensory neuropathy is frequently caused by POLG mutations. Neurology 2009; 73: 898–900. doi: 10.1212/WNL.0b013e3181b78488. PMID: 19752458.
- Hanisch F., Kornhuber M., Alston C.L. et al. SANDO syndrome in a cohort of 107 patients with CPEO and mitochondrial DNA deletions. J Neurol Neurosurg Psychiatry 2015; 86: 630–634. doi: 10.1136/jnnp-2013-306748. PMID: 25143630.
- Janssen W., Quaegebeur A., Van Goethem G. et al. The spectrum of epilepsy caused by POLG mutations. Acta Neurol Belg 2016; 116: 17–25. doi: 10.1007/s13760-015-0499-8. PMID: 26104464.
- Hikmat O., Eichele T., Tzoulis C., Bindoff L.A. Understanding the epilepsy in POLG related disease. Int J Mol Sci 2017; 18: E1845. doi: 10.3390/ijms18091845. PMID: 28837072.
- Henao A.I., Pira S., Herrera D.A. et al. Characteristic brain MRI findings in ataxia-neuropathy spectrum related to POLG mutation. Neuroradiol J 2016; 29: 46–48. doi: 10.1177/1971400915621324. PMID: 26755490.
- Hakonen A.H., Heiskanen S., Juvonen V. et al. Mitochondrial DNA polymerase W748S mutation: a common cause of autosomal recessive ataxia with ancient European origin. Am J Hum Genet 2005; 77: 430–41. doi: 10.1086/444548. PMID: 16080118.
- Tsygankova P.G. [Molecular and genetic characteristics of mitochondrial respiratory chain diseases in children: biol. sci. diss.]. Moscow, 2012. 161 p. (In Russ.)