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Previous studies suggest that Leber's hereditary optic neuropathy (LHON) may be a systemic disorder with manifestations in organs other than the optic nerves. To evaluate nervous system involvement 38 men and eight women with LHON were re-examined. The patients were divided into three groups according to mtDNA analysis--namely, patients with the 11...
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LHON is characterized by bilateral asynchronous visual loss in young adults. This type of neuropathy is related to mitochondrial DNA mutation and therefore is maternally inherited. Males are predominantly affected but they do not transmit the disease to their offspring. Clinical picture - although characteristic - is not impressive. At the beginnin...
Background:
Leber hereditary optic neuropathy (LHON) is the most common mitochondrial disorder, frequently resulting in acute or subacute severe bilateral central vision loss. Vitamin B12 deficiency is also a known cause of optic neuropathy through mitochondrial dysfunction. Here we evaluated the prevalence and clinical significance of vitamin B12...
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Background
Investigation of the OPA1 mutation spectrum in autosomal dominant optic atrophy (ADOA) in Denmark.
Methods
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Citations
... These mutations primarily affect respiratory chain complex I genes, including mitochondrial genes ND1, ND4, and ND6, among others [2]. It is less frequently associated with systemic pathology, including cardiac conduction defects or neurological conditions, manifesting as myelopathy, seizures, and movement disorders like dystonia, tremors, and psychiatric illness [3]. In those cases, the condition is termed LHON-plus syndrome [3]. ...
... It is less frequently associated with systemic pathology, including cardiac conduction defects or neurological conditions, manifesting as myelopathy, seizures, and movement disorders like dystonia, tremors, and psychiatric illness [3]. In those cases, the condition is termed LHON-plus syndrome [3]. Visual loss and other sequelae are usually permanent, although there have been cases of spontaneous remission and reports of success with the administration of Idebenone [4]. ...
... The majority of LHON cases occur in young adult males, typically between 15 and 35 years of age, with a mean onset age of 27 years [5]. LHON-plus is associated with a wide variety of phenotypes involving the nervous system, including peripheral neuropathy, myelopathy, motor disorders, such as dystonia [6], spasticity, cerebellar ataxia, multiple sclerosis-like features, refractory epilepsy, psychiatric disturbances, and rarely, even severe neurodegenerative diseases [3,7]. It has also been documented to involve the cardiovascular system, causing arrhythmias and conduction defects such as preexcitation syndrome and cardiomyopathy [8][9][10]. ...
... Twenty-four percent of patients may occasionally be accompanied by headache or eye discomfort, which is similar to the general symptoms of multiple sclerosis, such as UHthoff phenomenon (transient blurred vision after exercise or hot bath) [17]. About 9% patients have cardiac preexcitation syndrome. ...
Leber’s hereditary optic neuropathy (LHON) is a mitochondrial genetic disease with central vision loss as the main symptom. It is one of the diseases that cause vision loss and optic atrophy in young and middle-aged people. The mutations of these three primary mitochondrial mutations, m.11778G>A, m.14484T>C, and m.3460G>A, are the main molecular basis, but their pathogenesis is also affected by nuclear genes, mitochondrial genetic background, and environmental factors. This article summarizes the research progress on molecular pathogenesis, clinical symptoms, and treatment of LHON in recent years, aiming to summarize the genetic pathogenesis and clinical treatment points of LHON.
... LHON-Plus is a well-described entity wherein up to 59% of patients with LHON have been noted to develop additional neurological symptoms. [3,4] These patients are known to begin with optic nerve involvement and later can develop progressive neurological syndromes over time with postural and action tremors being the most common one. [3] A subset of these patients may even develop a multiple-sclerosis-like illness known as "Harding's disease," whose exact pathophysiology is not clear. ...
... [3,4] These patients are known to begin with optic nerve involvement and later can develop progressive neurological syndromes over time with postural and action tremors being the most common one. [3] A subset of these patients may even develop a multiple-sclerosis-like illness known as "Harding's disease," whose exact pathophysiology is not clear. Our cohort, however, included patients with only ocular manifestations. ...
... The disease onset is typically in adult age, with both eyes affected simultaneously or in few months' succession [2]. Moreover, extra-ocular manifestations such as cardiac conduction abnormalities [3] and neurological manifestations such as dystonia, tremor, and parkinsonism [4] are encountered in some patients. Association of LHON with multiple sclerosis (MS) has also been reported and multiple sclerosis -like disease has been described with multiple episodes of visual impairment, predominance for women, and an average interval of 1.66 years in the impairment of the eyes [5,6]. ...
Background
Leber’s hereditary optic neuropathy (LHON) is a common form of mitochondrial disease. The typical clinical presentation of LHON is subacute, painless loss of vision resulting from bilateral optic nerve atrophy. Moreover, extra-ocular manifestations such as cardiac conduction abnormalities and neurological manifestations such as multiple sclerosis (MS) like disease or parkinsonism are encountered in some patients. Abnormal findings in spinal cord MR imaging or in the cerebrospinal fluid (CSF) have been observed in previous cases of LHON-associated myelopathy.
Case presentation
We report a male patient with LHON who developed symptoms of myelopathy including gait unsteadiness, enhanced deep tendon reflexes and sensory loss of the lower extremities. Imaging of the brain and spinal cord, CSF analysis, as well as neurography and electromyography did not disclose any abnormalities. The somatosensory evoked potential (SEP) findings were suggestive of dorsal column dysfunction.
Conclusions
The patient case demonstrates that myelopathy associated with LHON can present without abnormal findings in central nervous system MR imaging or in the CSF, and without evidence suggestive of multiple sclerosis or MS-like disease. The dorsal column seems to be particularly vulnerable to myelopathy changes in LHON. Evoked potential investigations may assist in confirming the diagnosis, when clinical features are in line with myelopathy but findings in CSF analysis and central nervous system imaging are normal.
... [84,89] LHON can also manifest systemic symptoms, classified as "Leber's plus", with decreased ability to control muscle movements, tremors, and cardiac arrhythmia; this has been compared to multiple sclerosis (MS) due to its mitochondrial inheritance as well as similar white matter brain lesions seen on MRI. [90,91] Auditory dysfunction has been noted in case studies that found patients, particularly those containing the mt11778 mutation, showing impaired detection of auditory cues and abnormal speech understanding. [82] . ...
... Adulthood Males · Decreased muscle control [90,91] · Tremors [90,91] · Cardiac arrhythmia [90,91] · Optic Atrophy [88] · Progressive bilateral vision loss [86] · Loss of color vision (red-green spectrum) [84,89] · SNHL [71,73,82] Marfan Syndrome Infancy, Neonatal ...
... Adulthood Males · Decreased muscle control [90,91] · Tremors [90,91] · Cardiac arrhythmia [90,91] · Optic Atrophy [88] · Progressive bilateral vision loss [86] · Loss of color vision (red-green spectrum) [84,89] · SNHL [71,73,82] Marfan Syndrome Infancy, Neonatal ...
(SNHL) can have a large impact on the outcome and treatment of pediatric patients. Due to the common co-incidence of ocular manifestations and SNHL in children, both ophthalmologic and hearing loss screening and routine examinations must be conducted to minimize adverse outcomes and worsening of pathology. Early evaluation and diagnosis is imperative for intervention and further development of the patient. Coincidence requires a thorough evaluation that includes a comprehensive history, examination, and diagnostic testing. In this article, a literature review was conducted to analyze the presentations of various diseases and syndromes, such as Alport Syndrome, Waardenburg Syndrome, Norrie Disease, Usher Disease, Stickler Syndrome, Marfan Syndrome, Congenital Rubella, and Hereditary Optic Neuropathies. We divided the various ocular pathologies into anterior and posterior segment presentations and associated systemic findings for better understanding. Additionally, this review aims to include an update on the management of patients with both ocular and hearing loss manifestations.
... Retinal ganglion cells (RGCs) are preferentially affected, leading to optic nerve degeneration, but additional extraocular abnormalities have been described in LHON pedigrees. Previous studies suggest that LHON may be a systemic disorder with manifestations in organs other than the optic nerves (Nikoskelainen et al., 1995). These include nonneurological as well as neurological abnormalities. ...
... original description by Harding et al. (1992) (Figure 5; Bower et al., 1992;Harding et al., 1992;Nikoskelainen et al., 1995;Ceranić and Luxon, 2004;McFarland et al., 2007;La Morgia et al., 2008;Shiraishi et al., 2014;Shimada and Horiguchi, 2016;Bittner et al., 2019); the most common disease was LHON-MS (Harding disease) (Harding et al., 1992;Kellar-Wood et al., 1994;Bhatti and Newman, 1999). The last decade witnessed important discoveries in immune-mediated diseases of the optic nerve; the recognition of LHON plus is increasingly clear. ...
Objective
To elucidate the clinical, radiologic characteristics of Leber’s hereditary optic neuropathy (LHON) associated with the other diseases.
Materials and methods
Clinical data were retrospectively collected from hospitalized patients with LHON associated with the other diseases at the Neuro-Ophthalmology Department at the Chinese People’s Liberation Army General Hospital (PLAGH) from December 2014 to October 2018.
Results
A total of 13 patients, 24 eyes (10 men and 3 women; mean age, 30.69 ± 12.76 years) with LHON mitochondrial DNA (mtDNA) mutations, were included in the cohort. 14502(5)11778(4)11778 &11696(1)12811(1)11696(1)3460(1). One patient was positive for aquaporin-4 antibody (AQP4-Ab), and two were positive for myelin oligodendrocyte glycoprotein antibody (MOG-Ab). Three patients were associated with idiopathic optic neuritis (ON). Two patients were with compression optic neuropathy. Three patients were with the central nervous system (CNS) diseases. One patient was with proliferative diabetic retinopathy (PDR) and one with idiopathic orbital inflammatory syndrome (IOIS). At the onset, visual acuity (VA) in eighteen eyes was below 0.1, one eye was 0.5, five eyes were above 0.5, while VA in sixteen eyes was below a 0.1 outcome, three eyes experienced moderate vision loss. MRI images showed T2 lesions and enhancement in nine patients who received corticosteroids treatment; additional immune modulators treatment was performed on two patients. None of the patients had relapse during the follow-up time.
Conclusion
Leber’s hereditary optic neuropathy can be accompanied with multiple-related diseases, especially different subtypes of ON, which were also exhibited with IOIS and compression optic neuropathy for the first time in this cohort. This condition may be a distinct entity with an unusual clinical and therapeutic profile.
... Although not formally diagnosed in this patient, this could be compatible with the entity described as "LHON-plus" in which LHON patients have systemic neurological involvement. 26 Patient 12 had viral meningitis as an infant with secondary hemiplegia, as well as a fibrosarcoma removed at a young age. Patient 13 had coexistent diagnoses of lupus, rheumatoid arthritis, and polycystic ovarian syndrome. ...
Background
Leber hereditary optic neuropathy (LHON) is a rare but bilaterally blinding disease. Three characteristic disease-causing point mutations, and other less common mutations, are most often found on the mitochondrially encoded genes of NADH-ubiquinone oxidoreductase core subunits (MT-ND). The purpose of this study is to provide an overview of LHON mutations in Southwestern Ontario and to describe the associated demographic and clinical characteristics.
Methods
A retrospective genetic and clinical chart review was performed from January 2015 to 2020. Patients were identified within a mitochondrial mutation database and included if a mutation was detected on the MT-ND1, -ND4, or -ND6 genes. A clinical chart review was done on all available patients.
Results
Forty-five of 63 patients identified had classic disease-causing mutations (6.7% m.3460G>A, 44.4% m.11778G>A, and 48.9% m.14484T>C). Several of the remaining 18 patients had rare mutations previously documented in association with LHON. Of the 14 patients with clinical charts accessible for review, 12 had symptomatic disease, and all but one had bilateral optic neuropathies. Nine patients had classic LHON mutations and 3 had possible novel mutations; 7 were males; 9 had final visual acuity ≤ 20/200 in at least one eye; and 6 of those had ≤20/400 in both eyes.
Conclusions
This study adds to the literature on LHON in Canada, and specifically Southwestern Ontario. The demographic and clinical data regarding LHON in this geographic location, as well as possible novel disease-causing mutations, provide important information to aid clinicians in recognizing cases of LHON that may otherwise be disregarded.
... Although visual dysfunction is the most common symptom of LHON, other systemic abnormalities can also occur. These include dystonia, Parkinsonism, extra-pyramidal motor symptoms, peripheral neuropathy, cardiac conduction abnormalities, spinal cord disease, and skeletal muscle abnormalities (6)(7)(8)(9)(10)(11)(12)(13). The maternal transmission indicates that mutations in the mitochondrial DNA (mtDNA) play key roles in the development of LHON. ...
The T12811C mitochondrial DNA (mtDNA) mutation has been reported in Leber hereditary optic neuropathy (LHON) previously, with vision loss as the main manifestation. The involvement of other organ systems, including the central and peripheral nervous system, heart, and extraocular muscles, has not been well described. This case series report investigated four patients with T12811C mtDNA mutation, verified through a next generation sequencing. Two male patients presented with bilateral subacute visual decrease combined with involvement of multiple organ systems: leukoencephalopathy, hypertrophic cardiomyopathy, neurosensory deafness, spinal cord lesion and peripheral neuropathies. Two female patients presented with progressive ptosis and ophthalmoplegia, one of whom also manifested optic atrophy. This study found out that patients harboring T12811C mtDNA mutation manifested not only as vision loss, but also as a multi-system disorder affecting the nervous system, heart, and extraocular muscles.
... In an early study to explore a possible connection between MS and LHON, Harding et al. 17 described the primary mutation m.11778G>A in eight LHON women who developed neurological features compatible with a diagnosis of MS. This was followed by many other reports which verified the presence of primary LHON mutations in a sub-group of MS patients or patients with MS-like syndrome in the European and North American populations [25][26][27][28] . While a study by Vanopdenbosch et al. 29 showed that the association of LHON primary mutations with MS is more than a coincidence and that carrying a primary mutation is a risk factor for developing MS, at least in Caucasian populations. ...
... MS has long been known to be associated with LHON, a mitochondrial inherited form of vision loss caused by point mutations in mtDNA genes. Both primary and secondary LHON variants have been reported in MS 17,[25][26][27][28][29][30] . However, the presence and relative frequencies of LHON variants in MS patients vary between populations, possibly due to genetic, racial and other factors, which differ in different ethnicities [25][26][27][28][29][30][31][32][33] . ...
... Both primary and secondary LHON variants have been reported in MS 17,[25][26][27][28][29][30] . However, the presence and relative frequencies of LHON variants in MS patients vary between populations, possibly due to genetic, racial and other factors, which differ in different ethnicities [25][26][27][28][29][30][31][32][33] . In the current study, we analyzed our recently generated large-scale genomic sequence data of the entire mtDNA from 47 unrelated Saudi Arab individuals, 23 patients diagnosed with RRMS and 24 healthy control subjects to investigate the presence of mutations/variants involved in or associated with LHON in those subjects. ...
Several mitochondrial DNA (mtDNA) mutations of Leber's hereditary optic neuropathy (LHON) have been reported in patients with multiple sclerosis (MS) from different ethnicities. To further study the involvement of LHON mtDNA mutations in MS in the Arab population, we analyzed sequencing data of the entire mitochondrial genome from 47 unrelated Saudi individuals, 23 patients with relapse-remitting MS (RRMS) and 24 healthy controls. Ten LHON mutations/variants were detected in the patients but were absent in the controls. Of them, the common primary pathogenic mutation m.14484T>C and the rare mutation m.10237T>C were found in one patient, whereas the rare mutation m.9101T>C was found in another patient. The remaining were secondary single nucleotide variants (SNVs) found either in synergy with the primary/rare mutations or individually in other patients. Patients carrying LHON variants also exhibited distinct mtDNA variants throughout the mitochondrial genome, eight were previously reported in patients with LHON. Moreover, five other LHON-related SNVs differed significantly in their prevalence among patients and controls (P < 0.05). This study, the first to investigate LHON mtDNA mutations/variants in a Saudi cohort may suggest a role of these mutations/variants in the pathogenesis or genetic predisposition to MS, a possibility which needs to be explored further in a large-scale.
... LHON was the first disease to be associated with mtDNA point mutations, the most frequent PMD and the first for which a treatment has been approved [69]. Neurological supplementary features, including cerebellar ataxia, have been reported in a minority of LHON cases, configuring a phenotype known as 'LHON-plus' [70][71][72][73]. The most common cause of LHON, accounting for about 90% of cases, are mtDNA amino acid substitutions (11778A > G, m.14484T > C, m.3460G > A), usually homoplasmic, in MT-ND4, MT-ND6, MT-ND1 genes, respectively. ...
... Cerebellar atrophy Not specific [22,48,59,65,69,72,81,91,97] T2/FLAIR hyperintense white matter KSS, POLG1-related, MERRF, MELAS, IOSCA, ADOA plus [22,23,48,65,69,91] Dentate nuclei signal changes KSS [22] Brainstem signal changes/atrophy KSS, IOSCA [22,23] Inferior olivary nuclei lesions POLG1-related [91] Basal ganglia lesions KSS, POLG1-related, MERRF, NARP [22,48,59,91] Spinal cord signal changes KSS [101] Cortical atrophy IOSCA [23] Brainstem and basal ganglia bilateral symmetrical lesions LS [60,61] Stroke like lesions MELAS [64,65] Cerebral white matter + dorsal column/lateral corticospinal tracts + pyramids LBSL [95] In italics: peculiar MRI patterns of LS, MELAS and LBSL. ...
Ataxia is increasingly being recognized as a cardinal manifestation in primary mitochondrial diseases (PMDs) in both paediatric and adult patients. It can be caused by disruption of cerebellar nuclei or fibres, its connection with the brainstem, or spinal and peripheral lesions leading to proprioceptive loss. Despite mitochondrial ataxias having no specific defining features, they should be included in hereditary ataxias differential diagnosis, given the high prevalence of PMDs. This review focuses on the clinical and neuropathological features and genetic background of PMDs in which ataxia is a prominent manifestation.
