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Tsygankova MiP2010

From Bioblast
Tsygankova PG, Zakharova EY, Itkis YS, Mikhailova SV, Rudenskaya GE, Dadali EL, Nikolaeva EA (2010) Developing the algorithm for molecular diagnostics of infantile mitochondrial encephalomyopathies. MiP2010.

Link: Abstracts Session 3

Tsygankova PG, Zakharova EY, Itkis YS, Mikhailova SV, Rudenskaya GE, Dadali EL, Nikolaeva EA (2010)

Event: MiP2010

Inherited mitochondrial disorders affect both children and adults and may present with wide spectrum of clinical phenotypes. By the literature data the majority of adult forms are caused by mutations in mtDNA whereas infantile and children cases of mito disease are due to nuclear genes mutations [1]. Among the infantile forms the most frequent is Leigh syndrome (LS). LS and Leigh-like syndrome are mitochondrial disorders with the largest genetic heterogeneity [2]. Pathological mutations have been found either in the mitochondrial or in the nuclear genome. Prognosis of LS is poor. The identification of molecular defect contributes to management and genetic counselling in burdened families. Among other forms of infantile mitochondrial encephalomyopathies are Pearson syndrome, Alpers syndrome, mtDNA depletion syndromes [3], etc. The aim of our study was to determine the most frequent molecular defect in Leigh syndrome patients and to reveal mutations in patients with another form of infantile mitochondrial encephalomyopathies that had not been diagnosed in our country earlier.


โ€ข O2k-Network Lab: RU Moscow Itkis YS


Labels: MiParea: mt-Medicine, Patients  Pathology: Neurodegenerative 

Organism: Human 






Full text

Inherited mitochondrial disorders affect both children and adults and may present with wide spectrum of clinical phenotypes. By the literature data the majority of adult forms are caused by mutations in mtDNA whereas infantile and children cases of mito disease are due to nuclear genes mutations [1]. Among the infantile forms the most frequent is Leigh syndrome (LS). LS and Leigh-like syndrome are mitochondrial disorders with the largest genetic heterogeneity [2]. Pathological mutations have been found either in the mitochondrial or in the nuclear genome. Prognosis of LS is poor. The identification of molecular defect contributes to management and genetic counselling in burdened families. Among other forms of infantile mitochondrial encephalomyopathies are Pearson syndrome, Alpers syndrome, mtDNA depletion syndromes [3], etc. The aim of our study was to determine the most frequent molecular defect in Leigh syndrome patients and to reveal mutations in patients with another form of infantile mitochondrial encephalomyopathies that had not been diagnosed in our country earlier.

Our series includes 65 patients: 53 with LS, 6 with Alpers syndrome, 3 with mtDNA depletion syndrome and 3 with Pearson syndrome. We used PCR-RLFP, SSCP and direct sequencing for detecting the mutations. We analyzed 10 nuclear genes and mtND3-6, ATP6.

We conducted molecular genetic research in a series of 53 patients with Leigh and Leigh-like phenotypes. Initially we performed sequence analysis of nuclear genes, encoding subunits of Complex I (CI) and CIV assembly factor SURF1. Later we added sequence of MTND3-ND6, MTATP6 regions of mtDNA. We revealed mutations in SURF1 gene to be the major cause of Leigh syndrome in our patients (62% of cases). The most frequent mutation is c.845delCT, known to be common among Polish and Czech patients. Mutations in mtDNA were found in 8 patients. Three patients have the 8993T>G mutation in ATP6. One patient has 8839G>C transition which wasnโ€™t described earlier. Four other patients have mutations in ND5 and ND6 regions (13094T>C, 13513G>A, 14441T>C). To confirm the pathogenic nature of new mutations family segregation analysis, protein region conservation analysis and 200 control group screening were performed. We managed to reveal molecular defect in 86% of Leigh syndrome cases.

We analyzed clinical, biochemical and genetic features of LS and made the algorithm for molecular diagnostic of LS that could be used in the genetics laboratories, especially in Eastern Europe countries. The algorithm include SURF1 gene screening for frequent mutations, 8993T>G, 13513G>A screening test, SURF1 whole gene sequencing, ND3-ND6 sequencing. In patients with Alpers syndrome we revealed mutations in POLG genes (G848S, W748S, A467T, T855S, G268A, L311P), all in heterozygous state. In two patients with MDS we revealed mutations in the DGUOK gene (R105X, c.509insG) in homozygous state. And in another one patient with MDS we detected two novel mutations in the MPV17 gene (c.121C>T, c.185delT).

1. Schaefer AM, McFarland R, Blakely EL, He L, Whittaker RG, Taylor RW, Chinnery PF, Turnbull DM (2008) Prevalence of mitochondrial DNA disease in adults. Ann. Neurol. 63: 35-39.

2. Finsterer J (2008) Leigh and Leigh-like syndrome in children and adults. Pediatr. Neurol. 39: 223-235.

3. Spinazzola A, Invernizzi F, Carrara F, Lamantea E, Donati A, Dirocco M, Giordano I, Meznaric-Petrusa M, Baruffini E, Ferrero I, Zeviani M (2009) Clinical and molecular features of mitochondrial DNA depletion syndromes. J. Inherit. Metab. Dis. 32: 143-158.