A family with 3460G>A and 11778G>A mutations and haplogroup analysis of Polish Leber hereditary optic neuropathy patients
Introduction
Leber hereditary optic neuropathy (LHON [MIM 535000]) is a maternally inherited acute or subacute vision loss due to optic nerve atrophy. It occurs typically in young adults, mostly men, and is the most frequent disease caused by mutations in mitochondrial DNA. Three of them: 3460G>A, 14484T>C and 11778G>A are responsible for more than 90% of LHON cases. Generally, LHON mutations map in genes encoding complex I subunits, mostly ND4 (seven known mutations) and ND6 (nine mutations) (Chinnery et al., 2001, Yen et al., 2006). The existence of two pathogenic mutations in one individual is very rare. Only four such families have been described, all carrying the combination of 11778G>A and 14484T>C at different levels of heteroplasmy (Riordan-Eva et al., 1995, Brown et al., 2001, Howell et al., 2002).
A mitochondrial mutation is a necessary, but frequently not sufficient condition for the disease which is indicated by low penetrance (about 50% in men and only 10% in women) and higher incidence in men (Harding et al., 1995). Although the complete set of factors contributing to the origin of the disease is still unknown, it is generally accepted that environmental factors and different genetic variants (mitochondrial and nuclear) may be engaged in that process. Among environmental factors, cigarette smoking and alcohol consumption have been postulated, but detailed case-control studies have excluded that possibility. Among possible genetic factors, the most important seems to be the X-linked locus interacting with specific LHON mutations, which would explain the observed sex bias (Hudson et al., 2005).
In the studies of mitochondrial DNA background of LHON mutations, there is a long history of so-called secondary mutations: mitochondrial DNA variants frequently found in patients with one of the three common mutations, like the 15257G>A change. They were postulated to intensify the symptoms and increase the probability of manifestation of the disease in mutation carriers. Most of them are now recognised as polymorphisms, being only the evidence of a common evolutionary past. This does not mean that the mitochondrial background is not important. An increased frequency of haplogroup J, one of the European haplogroups (Torroni et al., 1996, Piechota et al., 2004), in comparison to the general population, was observed in patients with 14484T>C and 11778G>A mutations in numerous populations (Torroni et al., 1997, Carelli et al., 2006). There are two possible explanations of this phenomenon: polymorphisms contributing to the haplogroup are not completely neutral and they influence the phenotype, or it is only the result of a common past – the founder effect. Both theories can be true; a founder effect was proven for the 14484T>C mutation for French–Canadian and Dutch patient populations sharing a common ancestor before the year 1600 (Howell et al., 2003). For the 11778G>A mutation, where the incidence of J haplogroup is not as high as for 14484T>C, but still significant for some populations, there are no data supporting the founder effect theory. Recently published haplogroup analysis for more than 3500 LHON mutation carriers revealed that for the 11778G>A mutation, the risk of visual failure is higher when the subject belongs to haplogroup J, but is lower for the H haplogroup. The haplogroup K increases penetrance for 3460G>A mutation holders (Hudson et al., 2007).
The mechanism of vision loss in LHON is controversial. Mitochondrial DNA codes for 13 proteins of four subunits of the respiratory chain. Most known pathogenic mutations disturb its function, leading to respiratory failure, and frequently, multiorgan disease. LHON mutations behave differently. First – they affect only the optic nerve. Typically, no other neurological symptoms are present. Second – the results of studies of their influence on the activity of complex I and respiratory chain observed in culture of cells harbouring one of the LHON mutations are contradictory. Respiration is lower than in wild type cells, but the differences are too small to explain all the pathological findings. At the same time, higher sensitivity to Fas induced apoptosis was observed in 11778G>A fibroblasts (Danielson et al., 2002). Currently, the most appealing theory is based on physiology of the optic nerve. Retinal ganglion cells show a characteristic gradient of mitochondria; the organelles are grouped in synapses – the most energy-consuming part of the cell. Even a small decrease in ATP production, due to the mitochondrial mutation, may influence the motility of mitochondria leading to their incorrect distribution, and a further decrease in ATP production, resulting in higher ROS generation and finally apoptosis (Yu Wai Man et al., 2005). Disturbances in mitochondrial motility leading to apoptosis seem to be a common mechanism of optic neuropathies caused by genetic and environmental factors (Carelli et al., 2004, Carelli et al., 2007).
Molecular diagnosis of LHON in Poland has been performed since 2000 (Mroczek-Tonska et al., 2002, Jamrozik et al., 2003).
Section snippets
Patients and DNA samples
Patients were referred for molecular diagnosis by ophthalmologists from different ophthalmologic hospitals and departments in Poland. Informed consent was obtained in the referring centers.
Using standard methods, total DNA was isolated from peripheral blood in the directing institutions or in the Department of Medical Genetics of the Institute of Mother and Child.
For haplogroup analysis DNA of 28 probands with Leber mutations (11778G>A – 22 samples, 3460G>A – 3, 14484T>C – 4; one proband with
Results
In 2005 three young men from the same family (family designated p24, Fig. 1) were referred to the Department of Ophthalmology, Medical University of Warsaw, with the suspicion of LHON. Patient 9, born in 1978, had observed vision loss first in the LE/left eye/and then in the RE/right eye/in 2000 (age 22 years). Ophthalmologic examination showed in LE BCVA (best corrected visual acuity) 2.5/50, Sn (Snellen’s) 5.0, T = 15 mm Hg; in RE BCVA 0.5/50, Sn not reading, IOP (intraocular pressure) = 16 mm Hg.
Discussion
The family with two primary LHON mutations is the first described family bearing the combination of 3460G>A and 11778G>A mutations. The existence of two mutations does not seem to influence the clinical picture of the disease – affected individuals show only the typical LHON symptoms, without any additional neurological signs. The onset of the disease is also characteristic for LHON. That can be explained by the fairly low level of 3460G>A mutation in blood and/or hair of some family members,
Acknowledgements
We thank Maria M. Stewart for careful reading of the manuscript.
This work was supported by Polish Ministry of Science and Higher Education grant N N401 226334.
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Cited by (16)
Long-term screening for primary mitochondrial DNA variants associated with Leber hereditary optic neuropathy: incidence, penetrance and clinical features
2020, MitochondrionCitation Excerpt :In a German pedigree, harbouring both homoplasmic MT-ND4 m.11778G>A and heteroplasmic MT-ND6 m.14484T>C, more females were affected with marked phenotypic heterogeneity (Catarino et al., 2017). In contrast however, a Polish pedigree harbouring both the heteroplasmic MT-ND1 m.3460G>A and homoplasmic MT-ND4 m.11778G>A variants displayed the typical higher penetrance of optic failure in males and there were no other neurological features (Tonska et al., 2008) suggesting disease co-incidence or that non-mtDNA disease modifying factors are likely and remain to be delineated. A total of 734 patients were systematically screened by our diagnostic laboratory for the three primary pathogenic LHON variants over the course of 20 years.
Characterization of a Leber's hereditary optic neuropathy (LHON) family harboring two primary LHON mutations m.11778G > A and m.14484T > C of the mitochondrial DNA
2017, MitochondrionCitation Excerpt :We report a comprehensive clinical, genetic, and functional study of a LHON family of German descent, the first family described with multiple LHON patients harboring the two primary mutations of the mtDNA m.11778G > A homoplasmic and m.14484T > C heteroplasmic. The previous reports in the literature of patients with LHON with two primary LHON mutations of the mtDNA are summarized in Table 2, including one family with multiple affected patients with LHON due to m.11778G > A heteroplasmic and m.14484T > C homoplasmic (Howell et al., 2002), and one with m.11778G > A homoplasmic and m.3460G > A heteroplasmic (Tonska et al., 2008), and a total of four singleton patients with both m.11778G > A and m.14484T > C mutations. We observed in our family a remarkably low (1:3) male-to-female ratio of affected patients.
Leber hereditary optic neuropathy - Historical report in comparison with the current knowledge
2015, GeneCitation Excerpt :The existence of two pathogenic mutations in one individual is very rare. There are few reports on such LHON families — the combination of 11778G>A and 14484T>C mutations at different levels of heteroplasmy is the most frequent (Tońska et al., 2008). Although it seems that such a genotype does not influence the clinical presentation or severity of the disease, this degree of penetrance (in men) is striking, as all the male family members were affected, which is unusual in most LHON families with a single mutation.
Genotype-phenotype correlations in Leber hereditary optic neuropathy
2010, Biochimica et Biophysica Acta - BioenergeticsCitation Excerpt :Although the presence of two mutations would have been expected to result in a more severe phenotype it only seemed to positively influence penetrance and the LHON plus phenotype was observed only in one family with the 11778G>A and 14484T>C mutations. This lack of aggravation of the phenotype by two mutations in subunits of the same mitochondrial complex may indicate that even though the mutations differ in severity, they affect exactly the same process in mitochondria [50–53]. Even the family bearing the two severe mutations 3460G>A and 11778G>A did not have any additional symptoms other than LHON [53].
Leber Mitochondrial Optic Neuropathy in Pediatric Females With Focus on Very Early Onset Cases
2023, Journal of Child NeurologyLeber hereditary optic neuropathy—new insights and old challenges
2021, Graefe's Archive for Clinical and Experimental Ophthalmology