MITOCHONDRIAL DISEASES (LHON, MELAS, MERRF)

Mitochondrial diseases are caused by disorders of the mitochondrial respiratory chain and thus of oxidative phosphorylation and, in addition, by disorders of other biochemical mechanisms, such as ß-oxidation, mitochondrial fusion and division, and many others. They arise from pathogenic variants of both mitochondrial (mt) and nuclear-encoded (over 1,000) genes. Symptoms affecting almost all organs have been described. Variants of mtDNA can occur in homo- or heteroplasmic form, whereby the extent of heteroplasmy can only be of pathological significance above a certain threshold value.

Mitochondrial diseases caused by pathogenic variants in mitochondrial-encoded genes are always maternally inherited.

The diseases examined here in which mtDNA variants play a role include:

Leber's hereditary optic neuropathy (LHON), characterized by bilateral, painless, subacute vision loss during adulthood due to selective degeneration of the retinal ganglion cell layer and the optic nerve. In approximately 90% of patients, one of three pathogenic mtDNA variants can be detected: m.3460G>A, m.11778G>A, or m.14484T>C.

MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes), a multisystem disorder with onset in childhood. The most common pathogenic variant affects m.3243A>G of the MT-TL1 gene, but variants in other mtDNA genes have also been described.

MERRF (myoclonic epilepsy with ragged red fibers), a multisystem disease with primarily myoclonic, later generalized epilepsy, ataxia, weakness, and dementia. The most common pathogenic variant m.8344A>G affects the MT-TK gene, but other mtDNA changes are also known.

The advantage of the NGS method is that it simultaneously determines the degree of heteroplasmy.

References

Klopstock T et al. 2021. Dtsch Arztebl Int. 118(44):741 / Cornelia Kornblum et al. AWMF-Leitlinie „Mitochondriale Erkankungen“ / Di Stadio et al. 2018, Orph J of Rare Dis 13:35 / Theodorou-Kanakari et al. 2018, Adv Ther 35:1510 / Finsterer et al. 2018, Ped Neurol 80:8 / Jurkute et al. 2017, Curr Opin Ophthalmol 28:403 / Wang & Lee 2015, Chin Med J 128:1820 / Farrar et al. 2013, Trends Genet 29:488