Background: In this retrospective study, we analysed clinical, biochemical and molecular genetic data of 47 Czech patients with Single, Large-Scale Mitochondrial DNA Deletions (SLSMD). Methods: The diagnosis was based on the long-range PCR (LX-PCR) screening of mtDNA isolated from muscle biopsy in 15 patients, and from the buccal swab, urinary epithelial cells and blood in 32 patients. Results: A total of 57% patients manifested before the age of 16. We did not find any significant difference between paediatric and adult manifestation in either the proportion of patients that would develop extraocular symptoms, or the timespan of its progression. The survival rate in patients with Pearson Syndrome reached 60%. Altogether, five patients manifested with atypical phenotype not fulfilling the latest criteria for SLSMD. No correlation was found between the disease severity and all heteroplasmy levels, lengths of the deletion and respiratory chain activities in muscle. Conclusions: Paediatric manifestation of Progressive External Ophthalmoplegia (PEO) is not associated with a higher risk of multisystemic involvement. Contrary to PEO and Kearns-Sayre Syndrome Spectrum, Pearson Syndrome still contributes to a significant childhood mortality. SLSMD should be considered even in cases with atypical presentation. To successfully identify carriers of SLSMD, a repeated combined analysis of buccal swab and urinary epithelial cells is needed.
Leber hereditary optic neuropathy (LHON) and dominant optic atrophy (DOA) are the major prototypes of mitochondrial optic neuropathies (MON). Both disorders are a result of a dysfunction of mitochondrial energetic competence. LHON occurs as a result of three primary pathogenic homoplasmic point mutations of mitochondrial DNA at positions 11778/MT-ND4, 3460/MT-ND1 and 14484/MT-ND6 in Complex I, and DOA, in 90% of cases, is caused by heterozygous mutations in the nuclear-encoded OPA1 gene. Despite their contrasting genetic bases, both LHON and DOA share remarkable pathological similarities, marked by selective degeneration of retinal ganglion cells (RGC), which leads to subacute or chronic visual impairment. A subtype of RGC, expressing the photopigment melanopsin (mRGC), is responsible for light-dependent physiological processes (Chen, Badea, & Hattar, 2011). The pupillary reflex and the light-induced suppression of nocturnal melatonin secretion seem to be spared in patients with MON (La Morgia et al., 2010), which suggests that the integrity of the retinohypothalamic tract is intact. However, none of the studies concerned possible alterations in
Leber hereditary optic neuropathy is a primary mitochondrial disease characterized by acute visual loss due to the degeneration of retinal ganglion cells. In this study, we describe a patient carrying a rare missense heteroplasmic variant in MT-ND1, NC_012920.1:m.4135T>C (p.Tyr277His) manifesting with a typical bilateral painless decrease of the visual function, triggered by physical exercise or higher ambient temperature. Functional studies in muscle and fibroblasts show that amino acid substitution Tyr277 with His leads to only a negligibly decreased level of respiratory chain complex I (CI), but the formation of supercomplexes and the activity of the enzyme are disturbed noticeably. Our data indicate that although CI is successfully assembled in the patient’s mitochondria, its function is hampered by the m.4135T>C variant, probably by stabilizing CI in its inactive form. We conclude that the m.4135T>C variant together with a combination of external factors is necessary to manifest the phenotype.
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