Leber hereditary optic neuropathy, progressive visual loss, and multiple-sclerosis-like symptoms

doi:10.1016/S0002-9394(01)01045-5

American Journal of Ophthalmology

Volume 132, Issue 4, October 2001, Pages 591-593

https://doi.org/10.1016/S0002-9394(01)01045-5 Get rights and content

Abstract

PURPOSE: To report a case of Leber hereditary optic neuropathy with multiple-sclerosis-like symptoms.

METHODS: Observational case report. A 34-year-old man was found to have Leber hereditary optic neuropathy and a mutation at position 11778 of the mitochondrial genome. The progression of vision loss and onset of weakness in the right leg warranted neuroimaging.

RESULTS: Magnetic resonance imaging documented multiple lesions in the brain and spinal cord.

CONCLUSION: Although rarely reported, progression of optic neuropathy over months has been previously documented in Leber hereditary optic neuropathy. The emergence of multiple sclerosis-like symptoms and signs in our patient may be part of the spectrum of Leber hereditary optic neuropathy or a coincidental occurrence.

Section snippets

Case

: A 34-year-old man had loss of visual acuity in his right eye to counting fingers in December 1989. Deterioration continued, and 6 months later, visual acuity in his left eye declined rapidly to counting fingers. Neuroimaging did not suggest multiple sclerosis. The onset of symptoms was not associated with excessive alcohol intake or smoking. He was found to have Leber hereditary optic neuropathy and was subsequently treated with vitamin B12 injections. Visual field testing done in consecutive

Acknowledgements

We would like to thank D. C. Wallace, PhD, Center for Molecular Medicine, Emory University School of Medicine, for performing the mutational analysis, confirming the 11778 mutation in the male Leber hereditary optic neuropathy patient. Accession numbers and URLs for data in this article are as follows: Online Mendelian Inheritance in Man (OMIM), http://www.ncbi.nlm.nih.gov/Omim (for Leber optic atrophy [MIM 535000]).

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Severe manifestation of Leber's hereditary optic neuropathy due to 11778G>A mtDNA mutation in a female with hypoestrogenism due to Perrault syndrome
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Citation Excerpt :
Hearing loss with onset at 63 years of age, has been found in one male patient with a 11778A>G mutation (Zoccolella et al., 2010) while other authors reported no evidence whatsoever of auditory dysfunctions in a case-series of LHON patients (Yu-Wai-Man et al., 2008). Patients reported with LHON manifested numerous neurological abnormalities, such as multiple sclerosis-like symptoms and widespread white matter changes, suggesting demyelination, postural tremor and Parkinsonism with dystonia, but also cerebellar ataxia, epilepsy and spasticity, that have been observed in our patient (Harding et al., 1992; Murakami et al., 1996; Palace, 2009; Tran et al., 2001). In LHON, female carriers of the 11778A>G mutation present symptoms of optic neuropathy in 8–17% of cases.
Perrault syndrome (PS) is a rare autosomal recessive condition with ovarian dysgenesis, hearing deficit and neurological abnormalities in female patients. The molecular basis of the syndrome is heterogeneous, mutations in the HSD17B4 gene have been identified in one family and mutations in the HARS2 gene have been found in another one.
We have excluded pathogenic changes in the HSD17B4 gene and in the HARS2 gene by a direct sequencing of all coding exons in a female with clinical hallmarks of PS, ataxia and mild mental retardation.
In addition, the patient suffers from severe Leber's hereditary optic neuropathy (LHON) due to 11778G>A mtDNA mutation.
This case is the first reported patient with PS and LHON. Possible influence of hypoestrogenism on the manifestation of optic neuropathy in this patient is discussed in the context of recent findings concerning the crucial role of estrogens in supporting the vision capacity in LHON-related mtDNA mutation carriers.
Multiple sclerosis and mitochondrial gene variations: A review
2013, Journal of the Neurological Sciences
Citation Excerpt :
However, investigation for LHON mtDNA mutations in both females and males with MS or MS-like disease and predominant optic nerve involvement was suggested. Tran et al. reported a 34-year-old man suffering from LHON with an mtDNA mutation at np 11,778 with MS-like symptoms (the progression of vision loss and onset of weakness in the right leg) [67]. Multiple lesions in the brain and spinal cord were diagnosed by MRI (magnetic resonance imaging).
Multiple sclerosis (MS) is a debilitating disease of the central nervous system. Its etiology is still an unanswered enigma; its symptoms are varied and unpredictable; and there is no cure for it. Genetics has been introduced as a contributing factor to MS. Not only may MS stem from nuclear gene variations/mutations, but also it may arise from mitochondrial gene variations/mutations. The association of mitochondrial DNA variations/mutations with the pathogenesis of MS has, so far, been analyzed by several studies. This paper reviews the literature with regard to MS and corresponding mitochondrial DNA variations.
Mitochondrial changes associated with demyelination: Consequences for axonal integrity
2012, Mitochondrion
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Widespread necrotic white matter lesions characteristic of MS are observed (Kovacs et al., 2005). Patients in this original description showed ocular findings similar to acute optic neuropathy yet these patients did not improve and showed severe progressive visual loss (Tran et al., 2001), unlike general LHON characteristics. MS is the most common demyelinating disease of the central nervous system and, as such, much can be learnt from studies of the demyelinated axons (Compston and Coles, 2008).
The loss of myelin sheath (demyelination) renders axons vulnerable to a variety of insults. Axonal degeneration is well recognised in inflammatory demyelinating disorders of the central nervous system (CNS) such as multiple sclerosis (MS) and also certain neurodegenerative diseases. Energy required for nerve impulse conduction and maintenance of structural integrity of axons is met by mitochondria. Based on the distribution of ion channels and the Na⁺/K⁺ ATPase, the energy requirements of demyelinated and dysmyelinated axons are likely to differ from myelinated axons. In this review we discuss the changes in mitochondrial presence within axons in relation to presence or absence of healthy myelin sheaths and propose the increase in mitochondrial presence following demyelination as an adaptive process. An energy deficit within demyelinated axons is likely to be more detrimental compared to myelinated axons, judging by the neuropathological findings in primary mitochondrial disorders due to mitochondrial and nuclear DNA mutations and the mitochondrial changes that follow demyelination. Agents that enhance and protect mitochondria, as potential therapy, need to be considered and investigated in earnest for demyelinating disorders of the CNS such as MS.
A novel mitochondrial DNA deletion producing progressive external ophthalmoplegia associated with multiple sclerosis
2011, Journal of Clinical Neuroscience
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Detailed study of individuals with overlap syndromes may illuminate disease mechanisms in both disorders. It is plausible that mtDNA variation is a susceptibility factor in classical multiple sclerosis (MS) given: (i) the observed increase in maternal transmission of MS;2,3 (ii) the role that mtDNA variations have in neurodegenerative diseases;4,5 and (iii) reports of MS-like illnesses in patients with genetically characterised mitochondrial disease.6–17 Inflammatory demyelinating central nervous system (CNS) disease and mitochondrial DNA disease coexist at a frequency much greater than chance alone would suggest.16
We report a previously undescribed 7676 base pair mitochondrial (mt)DNA deletion involving genes of complex I, complex IV subunits 2 and 3 (cytochrome oxidase [Cox] II, III), adenosine triphosphatase 8 and 6, cytochrome b and 8 transfer (t)RNA genes producing myopathy and progressive external ophthalmoplegia (PEO) in a 44-year-old right-handed Caucasian man with features of multiple sclerosis (MS). We performed complete mtDNA sequencing and deletion analysis, spectrophotometric analysis of muscle and platelet respiratory chain activity, measurement of platelet mitochondrial membrane potential with the potentiometric dye JC-1 and magnetic resonance spectroscopy (MRS) and MRI studies of normal-appearing and lesional cerebral tissue. The deletion resulted in significant respiratory chain deficiency in muscle and blood and abnormalities of the platelet mitochondrial membrane potential. However, cerebrospinal fluid analysis, magnetic resonance spectroscopy and MRI features suggested inflammatory central nervous system demyelination rather than a primary respiratory chain disorder. We conclude that this novel mtDNA deletion causing myopathy and PEO is associated with severe muscle and platelet cellular energetic abnormalities. Furthermore, clinical and paraclinical features of multiple sclerosis were found. The potential pathomechanistic interaction between mtDNA variation and multiple sclerosis is reviewed.
Leber's optic neuropathy associated with disseminated white matter disease: A case report and review
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Leber’s hereditary optic neuropathy (LHON), a mitochondrial disease, is clinically characterized by a bilateral subacute loss of central vision consecutive to optic nerve involvement. In some cases of LHON, neurological features are reported including multiple sclerosis-like (MSL) phenotype. We report one additional male patient displaying LHON-MSL associated with the prevalent G11778A mutation and review the cases with expendable data published so far in the literature. We discuss the respective roles of inflammation and energetic metabolism dysregulation in the development of brain lesions. We propose to treat these patients early with both antioxidative and immunosuppressive drugs in order to avoid further handicap.
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Brief reportLeber hereditary optic neuropathy, progressive visual loss, and multiple-sclerosis-like symptoms

Abstract

Section snippets

Case

Acknowledgements

Am J Ophthalmol

Mitochondrial DNA mutation associated with Leber’s hereditary optic neuropathy

Science

Brief report
Leber hereditary optic neuropathy, progressive visual loss, and multiple-sclerosis-like symptoms