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Leber's Hereditary Optic Neuropathy

LHON

Leber's hereditary optic atrophy is an inherited neuropathy associated with bilateral central and centrocecal vision loss. Most patients don't experience additional symptoms. Treatment is mainly supportive and to date, the disease is considered incurable.

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Presentation

Symptom onset typically occurs in adolescents or young adults. In most affected individuals, the disease manifests in form of progressive, unilateral visual impairment. Few weeks or months later, enlarging scotomas start to reduce the visual field of the other eye, too. About a fourth of patients claims bilateral vision loss from the beginning. LHON patients don't report any pain, but dyschromatopsia is common and may precede severe vision loss in central areas of the visual field. Few patients present with only mild optic nerve function impairment, claim color blindness, particularly with regards to red and green shades, and describe reduced contrast sensitivity. Physicians don't usually relate these symptoms with LHON, but the description of such anomalies by family members of LHON patients may prompt a suspicion of a hereditary disorder. The active phase of the disease extends over several months [7]. Afterwards, visual acuity is generally stable.

LHON may also follow multiple sclerosis (MS)-like courses marked by recurrent episodes of vision loss and ocular pain. After each episode, vision is partially recovered, but patients do eventually go blind. This variant of the disease is mostly observed in women, is associated with a generalized demyelinating disorder, and is thus considered an own entity (Harding disease) [13].

Central Scotoma
  • The left eye had a central scotoma and a relative afferent pupillary defect. Ophthalmoscopy revealed a hyperaemic optic disc with indistinct margins in the left eye.[ncbi.nlm.nih.gov]
  • Swelling of the optic nerve head, vascular tortuosity, peripapillary telangiectasia, microangiopathy and central scotomas on visual field testing are all signs of LHON.[orpha.net]
  • These patients' pattern of visual recovery by developing small islands of normal vision within a central scotoma is characteristic in such rare cases of LHON.[ncbi.nlm.nih.gov]
  • scotoma and spotted partial defects of the remaining visual field.[ncbi.nlm.nih.gov]
  • Goldmann perimetry revealed bilateral central scotomas.[ncbi.nlm.nih.gov]
Visual Impairment
  • The findings of the present study suggested that the m.5587T C mutation may be involved in the pathogenesis of visual impairment.[ncbi.nlm.nih.gov]
  • There are also links to Leber's-related sites and scientific papers, and useful information for visually impaired people living in the United Kingdom. Leber's Hereditary Optic Neuropathy is a rare condition which can cause loss of central vision.[web.archive.org]
  • Therefore, idebenone is a valuable agent to treat visual impairment in adolescents and adults with LHON.[ncbi.nlm.nih.gov]
  • Diseases like MELAS syndrome may be related to visual impairment, yet most patients don't experience such symptoms.[symptoma.com]
  • We hypothesize that the two diseases may have a cumulative effect on oxidative stress and retinal ganglion cell death with the consequent rapid progression of visual impairment.[ncbi.nlm.nih.gov]
Visual Acuity Decreased
  • Meantime, the visual acuity decreased to CF in both eyes. We initiated treatment with idebenone (300 mg T.I.D.).[ncbi.nlm.nih.gov]
Eye Pain
  • Loss of vision due to LHON does not cause any eye pain, but it is quite an alarming experience as the loss of central vision presents suddenly and can progress quite quickly, leaving only peripheral vision.[fightingblindness.ie]
Headache
  • A history of worsening headaches, trauma, nutritional deficits (alcohol abuse), previous demyelinating disease, cancer, infiltrative orbital or lung disease, sexually transmitted disease, recent travel or disease exposure may identify other causes of[eyewiki.aao.org]
  • Vision loss is, typically painless but may be associated with headache, Uhthoff's symptom (transient worsening with warmth or exercise), eye discomfort, photopsias, limb parasthesias, and dizziness [Newman et al 1991] [Riordan-Eva et al 1995] .[ifond.org]
Tic Disorder
  • Movement disorders were the most common finding; nine patients had constant postural tremor, one chronic motor tic disorder, and one parkinsonism with dystonia. Four patients had peripheral neuropathy with no other evident cause.[ncbi.nlm.nih.gov]

Workup

Reliable anamnestic data support a tentative diagnosis of LHON, but it is important to remember that only 50% and 10% of men and women carrying LHON-associated gene defects, respectively, develop symptomatic optic neuropathy [5]. Thus, many cases may seem to have arisen de novo, without a family history of vision loss being known. Moreover, LHON patients typically have a non-remarkable medical history.

The following triad of signs has long since been considered pathognomonic for LHON [14]:

These signs may be observed in LHON patients during the active phase of the disease as well as in unaffected carriers and patients prior to symptom onset. According to more recent studies, observation of those alterations is highly suggestive of LHON, but the approach lacks sensitivity. Telangiectatic lesions and pseudo edema of the optic disc may disappear as early as during the active phase of the disease. Accordingly, the absence of either of the aforementioned signs does not rule out LHON.

Modern techniques like optical coherence tomography may be utilized to assess the condition of the retinal nerve fiber layer. During early stages of the disease, it is usually thickened. Upon atrophy of the retinal nerve fiber layer, its thickness is gradually reduced [15]. Visual evoked potentials and electroretinograms often reflect the loss of retinal ganglion cells and optic nerve fiber degeneration, while images obtained by computed tomography or magnetic resonance imaging are usually inconspicuous [8].

Finally, genetic analyses may be conducted to directly prove the presence of mtDNA mutations.

Right Bundle Branch Block
  • His cardiological history was positive for arterial hypertension, noncompaction, myocardial thickening, intermittent right bundle-branch-block (RBBB) and Wolff-Parkinson-White (WPW) syndrome.[ncbi.nlm.nih.gov]
Central Scotoma
  • The left eye had a central scotoma and a relative afferent pupillary defect. Ophthalmoscopy revealed a hyperaemic optic disc with indistinct margins in the left eye.[ncbi.nlm.nih.gov]
  • Swelling of the optic nerve head, vascular tortuosity, peripapillary telangiectasia, microangiopathy and central scotomas on visual field testing are all signs of LHON.[orpha.net]
  • These patients' pattern of visual recovery by developing small islands of normal vision within a central scotoma is characteristic in such rare cases of LHON.[ncbi.nlm.nih.gov]
  • scotoma and spotted partial defects of the remaining visual field.[ncbi.nlm.nih.gov]
  • Goldmann perimetry revealed bilateral central scotomas.[ncbi.nlm.nih.gov]

Treatment

Treatment is mainly supportive. Provision of visual aids may significantly increase LHON patients' life quality. Additionally, the following approaches to LHON therapy have been suggested [16]:

  • Administration of antioxidants to reduce the damage of retinal ganglion cells and the retinal nerve fiber layer. To this end, patients have been prescribed idebenone and α-tocotrienol-quinone (EPI-743). Idebenone is furthermore assumed to compensate for complex I deficiencies by mediating electron transfer to complex III [17].
  • Allotopic gene expression. The respective genes may be induced into the nuclear genome of retinal ganglion cells. They are transported here by adeno-associated virus vectors and a mitochondrial targeting sequence assures their transport into mitochondria [18] [19].
  • The introduction of genes into mtDNA.
  • Transplantation of retinal ganglion cells obtained from stem cells.

No recommendations can be given regarding dosage and duration of therapy and more extensive clinical trials are required to demonstrate the efficacy of the afore-described therapeutic measures.

Prognosis

With regards to the maintenance of vision, LHON patients have a poor prognosis. Bilateral vision loss is permanent in the vast majority of cases. Dense scotoma in the central and centrocecal areas of the visual field often cause visual acuity to drop below 20/200 and affected individuals go legally blind. An exacerbation of visual impairment after the active phase of the disease is unlikely, though [5]. Of note, spontaneous remission has occasionally been reported [9] [10]. In this context, mutation mt.14484, young age at symptom onset, subacute vision loss, and a larger optic disc have been identified as favorable prognostic factors [11] [12].

Etiology

As its name implies, LHON is a hereditary disorder. It is caused by mutations affecting the mtDNA, most commonly by the replacement of guanine with adenine at position mt.3460 or mt.11778, or by an exchange of thymine for cytosine at position mt.14484. In fact, these mutations have been shown to account for more than 90% of LHON cases in Caucasians [1]. They affect genes MT-ND1, MT-ND4, and MT-ND6, respectively, which encode for NADH:ubiquinone oxidoreductase core subunits 1, 4, and 6. These and other subunits constitute an enzyme required for complex I of the electron transport chain and the synthesis of those subunits may occasionally be disturbed by other mutations of the mtDNA. Of note, in a minor share of LHON patients, no causative mtDNA mutations can be found [2].

The observation of reduced penetrance, marked sex bias, and variable age at symptom onset support the hypothesis of LHON being a multifactorial disease [3]. The contribution of other genes and environmental factors to LHON etiology has repeatedly been suggested and it has been speculated that specific mtDNA haplogroups may predispose for the disease [4]. Moreover, up to 15% of LHON are thought to be heteroplasmic and this condition may lower a patient's risk of sustaining severe visual impairment [5]. Compelling evidence is scarce, though.

Epidemiology

For the northeast of England, the prevalence of LHON-associated vision loss has been estimated to 1 in 31,000 people, while the prevalence of mtDNA mutations related to the disease amounts to 1 in 8,000 inhabitants [6]. The pronounced difference between both values illustrates the effect of gene penetrance. In Denmark, the prevalence of LHON has recently been calculated to be 1 in 54,000 inhabitants [2]. According to that same study, gender-specific prevalence rates are 1 in 34,000 males and 1 in 123,000 females. Even though these values may not precisely represent the situation in other geographical regions, they do demonstrate a strong preponderance of male patients, with a male-to-female ratio of approximately 4:1. Considering the fact that sons and daughters are equally likely to inherit defective mtDNA, gender-dependent differences in disease incidence and prevalence must result from the influence of regulatory genes differently expressed in men and women or from distinct exposure to environmental factors. The average age at symptom onset has been stated to be 25 years in men and 33 years in women, but vision loss may essentially be experienced at any age.

Sex distribution
Age distribution

Pathophysiology

Gene defects related with LHON result in a reduced activity of mitochondrial NADH:ubiquinone oxidoreductase, disturbances of complex I of the electron transport chain, and mitochondrial dysfunction. Retinal ganglion cells and their axons are particularly sensitive to disturbances in mitochondrial function and energy supply [7]: Histopathological studies confirmed a drastic loss of retinal ganglion cells and the retinal nerve fiber layer as major findings in LHON patients. Mitochondrial dysfunction may not only trigger retinal ganglion cell death, but also microangiopathic lesions like dilation of retinal artery branches increased arteriovenous shunting and telangiectasis that provokes hyperemia of the optic disc and functional impairment of ganglion cell axons. Additionally, a marked reduction of myelinated axons has been observed in sections of the optic nerve. Here, myelinated axon loss was most pronounced in the center of the optic nerve while varying degrees of axonal sparing were noted in peripheral regions. Although these studies were carried out decades after the onset of symptoms, further findings implied an ongoing process of demyelination and remyelination, namely the presence of nerve fibers sheathed by myelin layers of different thickness, mitochondrial accumulation within demyelinated fibers, lipofuscin-filled phagocytes, and activated astrocytes.

Further research efforts have to be undertaken to resolve open issues, e.g., if photoreceptors are more susceptible to shortages in energy supply than retinal ganglion cells, then way is LHON not associated with loss of photoreceptors? Why don't other genetic disorders of the mitochondrial DNA cause optic nerve atrophy? Diseases like MELAS syndrome may be related to visual impairment, yet most patients don't experience such symptoms. While the afore-described pathophysiological mechanisms surely contribute to vision loss in LHON patients, they may only constitute the tip of the iceberg.

Prevention

It has been speculated that tobacco consumption, alcohol intake - both habits are associated with increased oxidative stress -, as well as head trauma, uncontrolled diabetes, anti-retroviral therapy and use of drugs that interfere with the mitochondrial function may contribute to symptom onset in carriers [7]. Although evidence supporting these claims is still scarce, members of affected families should be advised to take the appropriate preventive measures. This also applies to patients who've already passed the active phase of the disease, since risk factors for disease onset may impair recovery.

Summary

Leber's hereditary optic atrophy, often also referred to as Leber's hereditary optic neuropathy (LHON), is an inherited neuropathy that usually manifests around the third decade of a patient's life. Symptom onset is generally subacute, and most affected individuals initially, claim unilateral central vision loss, but several weeks later, scotomas also reduce the contralateral field of vision. In most cases, vision loss is severe and permanent; the disease is currently considered incurable.

LHON may be caused by distinct mutations in the mitochondrial DNA (mtDNA), and as such, it is inherited maternally. A mother carrying the respective gene defects will pass them to all her children, while only her daughters will transmit them to the next generation. All mutations known to be associated with LHON show reduced penetrance and thus, it may be necessary to obtain an extensive family history to support a tentative diagnosis of LHON. The diagnosis of LHON is based on ophthalmological findings.

Patient Information

Leber's hereditary optic atrophy, often also referred to as Leber's hereditary optic neuropathy (LHON), is a rare disorder characterized by subacute vision loss. Symptom onset typically occurs around the third decade of life and may consist in either unilateral or bilateral visual impairment. Affected individuals typically describe enlarging central visual field defects, possibly associated with color blindness and a loss of contrast sensitivity. In most patients, these symptoms initially affect one eye, while involvement of the other eye is not noted until few weeks or months later. The process is not painful and additional symptoms are not usually experienced. Within a few months, visual acuity drops to very low levels and most LHON patients go legally blind.

LHON is caused by mutations in the mitochondrial DNA and as such, it is inherited maternally. A mother carrying the respective gene defects will pass them to all her children, while only her daughters will transmit them to the next generation. However, LHON-associated gene defects show reduced penetrance, i.e., not all carriers develop symptoms. In fact, it has been estimated that only 50% of men and 10% of women who inherited such genes develop severe visual impairment.

Unfortunately, there is no cure for this disease. Antioxidants may be administered to protect retinal cells, but the efficacy of this measure has not been proven. Current research efforts are focused on gene therapy: The aim at developing a technique that allows for the integration of normal genes into the DNA of retinal cells. Patients are strongly advised to refrain from smoking and excess alcohol intake since these habits are related to increased oxidative stress that may favor the degeneration of retinal cells and the optic nerve.

References

Article

  1. Mackey DA, Oostra RJ, Rosenberg T, et al. Primary pathogenic mtDNA mutations in multigeneration pedigrees with Leber hereditary optic neuropathy. Am J Hum Genet. 1996; 59(2):481-485.
  2. Rosenberg T, Norby S, Schwartz M, et al. Prevalence and Genetics of Leber Hereditary Optic Neuropathy in the Danish Population. Invest Ophthalmol Vis Sci. 2016; 57(3):1370-1375.
  3. Khan NA, Govindaraj P, Jyothi V, Meena AK, Thangaraj K. Co-occurrence of m.1555A>G and m.11778G>A mitochondrial DNA mutations in two Indian families with strikingly different clinical penetrance of Leber hereditary optic neuropathy. Mol Vis. 2013; 19:1282-1289.
  4. Hudson G, Carelli V, Spruijt L, et al. Clinical expression of Leber hereditary optic neuropathy is affected by the mitochondrial DNA-haplogroup background. Am J Hum Genet. 2007; 81(2):228-233.
  5. Man PYW, Turnbull DM, Chinnery PF. Leber hereditary optic neuropathy. J Med Genet. 2002; 39(3):162-169.
  6. Man PYW, Griffiths PG, Brown DT, Howell N, Turnbull DM, Chinnery PF. The epidemiology of Leber hereditary optic neuropathy in the North East of England. Am J Hum Genet. 2003; 72(2):333-339.
  7. Carelli V, Ross-Cisneros FN, Sadun AA. Mitochondrial dysfunction as a cause of optic neuropathies. Prog Retin Eye Res. 2004; 23(1):53-89.
  8. Meyerson C, Van Stavern G, McClelland C. Leber hereditary optic neuropathy: current perspectives. Clin Ophthalmol. 2015; 9:1165-1176.
  9. Stone EM, Newman NJ, Miller NR, Johns DR, Lott MT, Wallace DC. Visual recovery in patients with Leber's hereditary optic neuropathy and the 11778 mutation. J Clin Neuroophthalmol. 1992; 12(1):10-14.
  10. Acaroglu G, Kansu T, Dogulu CF. Visual recovery patterns in children with Leber's hereditary optic neuropathy. Int Ophthalmol. 2001; 24(6):349-355.
  11. Barboni P, Savini G, Valentino ML, et al. Leber's hereditary optic neuropathy with childhood onset. Invest Ophthalmol Vis Sci. 2006; 47(12):5303-5309.
  12. Ramos Cdo V, Bellusci C, Savini G, et al. Association of optic disc size with development and prognosis of Leber's hereditary optic neuropathy. Invest Ophthalmol Vis Sci. 2009; 50(4):1666-1674.
  13. Pfeffer G, Burke A, Yu-Wai-Man P, Compston DA, Chinnery PF. Clinical features of MS associated with Leber hereditary optic neuropathy mtDNA mutations. Neurology. 2013; 81(24):2073-2081.
  14. Smith JL, Hoyt WF, Susac JO. Ocular fundus in acute Leber optic neuropathy. Arch Ophthalmol. 1973; 90(5):349-354.
  15. Barboni P, Savini G, Valentino ML, et al. Retinal nerve fiber layer evaluation by optical coherence tomography in Leber's hereditary optic neuropathy. Ophthalmology. 2005; 112(1):120-126.
  16. Gueven N, Faldu D. Therapeutic strategies for Leber's hereditary optic neuropathy: A current update. Intractable Rare Dis Res. 2013; 2(4):130-135.
  17. Giorgio V, Petronilli V, Ghelli A, et al. The effects of idebenone on mitochondrial bioenergetics. Biochim Biophys Acta. 2012; 1817(2):363-369.
  18. Guy J, Qi X, Koilkonda RD, et al. Efficiency and safety of AAV-mediated gene delivery of the human ND4 complex I subunit in the mouse visual system. Invest Ophthalmol Vis Sci. 2009; 50(9):4205-4214.
  19. Chadderton N, Palfi A, Millington-Ward S, et al. Intravitreal delivery of AAV-NDI1 provides functional benefit in a murine model of Leber hereditary optic neuropathy. Eur J Hum Genet. 2013; 21(1):62-68.

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Last updated: 2019-07-11 20:02