Mitochondrial genome variation in male LHON patients with the m.11778G > A mutation

Abstract

Leber hereditary optic neuropathy (LHON) is a mitochondrial disorder with symptoms limited to a single tissue, optic nerve, resulting in vision loss. In the majority of cases it is caused by one of three point mutations in mitochondrial DNA (mtDNA) but their presence is not sufficient for disease development, since ~50% of men and ~10% women who carry them are affected. Thus additional modifying factors must exist. In this study, we use next generation sequencing to investigate the role of whole mtDNA variation in male Polish patients with LHON and m.11778G > A, the most frequent LHON mutation. We present a possible association between mtDNA haplogroup K and variants in its background, a combination of m.3480A > G, m.9055G > A, m.11299 T > C and m.14167C > T, and LHON mutation. These variants may have a negative effect on m.11778G > A increasing its penetrance and the risk of LHON in the Polish population. Surprisingly, we did not observe associations previously reported for m.11778G > A and LHON in European populations, particularly for haplogroup J as a risk factor, implying that mtDNA variation is much more complex. Our results indicate possible contribution of novel combination of mtDNA genetic factors to the LHON phenotype.

Optic Nerve Structural and Functional Changes in LHON-Affected and Asymptomatic Maternal Relatives: Association with H and HV Mitochondrial Haplogroups

“…Increased penetrance of vision loss of LHON in 11778G>A in M7b and B5 haplogroup has been suggested in Chinese studies, whereas Haplogroup F was protective [ 22 , 23 ]. Penetrance of vision loss and LHON expression in 11778G>A has also been described with the J haplogroup in Italy [ 18 ] and the K haplogroup in a study in Poland [ 24 ]. In these different populations different patterns of penetrance associated with mitochondrial haplogroups are observed.…”

Leber Mitochondrial Optic Neuropathy in Pediatric Females With Focus on Very Early Onset Cases

“…[61][62][63][64][65][66][67][68] Among articles describing cases (n = 96), those regarding only male children (for a total of 8 males) were excluded. [69][70][71][72][73][74] We also excluded articles including large series of patients not reporting the difference between males and females, [75][76][77][78][79][80] cases with only adult onset, [81][82][83][84][85][86][87][88][89][90][91][92][93][94] and those with lack of information about age at onset. [95][96][97][98][99][100][101][102] For every report included, we retrieved the type of study, number of pediatric cases, and number of female cases; for female children, we extracted age of onset, type of onset, neuro-ophthalmologic data (visual acuity, fundus oculi, visual field tests, color vision, optical coherence tomography, and visual evoked potentials) and information about recovery.…”

Idebenone – a new drug for patients with Leber's hereditary optic neuropathy

“…Pathological changes in the mitochondria are not sufficient for disease development; mutations in the cell nucleus are probably also required. The variability of symptoms in individuals suggests the influence of still other, extrinsic factors, such as alcoholism, nicotinism, B vitamin deficiency, and a morphologically small nerve II disc [5,6]. It should be noted that vision loss occurs in 50% of male carriers of the defective gene, and only in 10% of females, which is explained by the protective effect of female sex hormones [4][5][6].…”

“…The variability of symptoms in individuals suggests the influence of still other, extrinsic factors, such as alcoholism, nicotinism, B vitamin deficiency, and a morphologically small nerve II disc [5,6]. It should be noted that vision loss occurs in 50% of male carriers of the defective gene, and only in 10% of females, which is explained by the protective effect of female sex hormones [4][5][6]. Ophthalmoscopic examination in the early stages of the disease may not reveal pathology -the fundus of the eyes may be normal, which applies to 20-40% of cases.…”

“…Electrophysiologic studies (pattern electroretinogram [PERG], multifocal electroretinogram [mfERG], and visual evoked potentials [VEP]) may be helpful in unclear cases. Genetic testing is the conclusive test [5][6][7]. Sometimes, ophthalmic symptoms are accompanied by osteoarticular, cardiac (arrhythmia), or neurological pathologies such as neuropathy, dystonia, dysarthria, or myopathy.…”