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Tuberous sclerosis (TS) is a rare autosomal-dominant genetic disease. TS is manifested by the development of multiple hamartomas, which affect brain, kidneys, retina, skin and other organs. This study aimed to reveal specific features of molecular epidemiology of TS in Russia. Blood DNA samples from 61 patients with definite (n = 53) or probable (n = 8) clinical diagnosis of TS were tested for mutations in TSC1 and TSC2 genes using Sanger sequencing and MLPA analysis. Five TSC1/2 mutation-negative patients were further analyzed by exome sequencing. TSC1/2 mutations were detected in 53/61 patients (87%): 39 (74%) carried mutations in the TSC2 and 14 (26%) in the TSC1. Large rearrangements (exon deletions/duplications) affected exclusively TSC2, accounting for 15% of lesions of this gene. 6/8 (75%) patients with incomplete clinical manifestation of TS carried TSC1/2 gene lesion. Overall, 96% of detected germline TSC1/2 mutations occurred de novo. Patients with no mutation identified (NMI) differed from TSC1/2 mutation carriers, being lacking cortical tubers and subependymal nodules but having higher frequencies of renal angiomyolipomas, rhabdomyomas, and lymphangioleiomyomatosis. Exome sequencing failed to identify overt disease-causing mutation candidates among NMI patients. Russian patients with TS have increased frequency of TSC2 large gene rearrangements and TSC1/2 mutations occurring de novo as compared to other studies. Patients with suspected TS diagnosis but NMI status may represent a distinct disease entity.

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The authors present a case-report of 13 year-old girl with L-2-hydroxyglutaric aciduria [MIM#236792], a rare autosomal/recessive metabolic disorder caused by mutations in the L-encoding 2-hydroxyglutarate dehydrogenase (L2HGDH, 14q21.3). Clinical signs of the disease are presented by predominantly neurological symptoms (epilepsy, cerebellar ataxia, cognitive impairment). The distinctive feature is the specific multifocal lesion of the white matter detected on MRI. The characteristic neuroimaging picture and positive results of biochemical and molecular genetic diagnosis were identified.

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