Ophthalmologic Manifestations in MELAS

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Article initiated by:

Amir Ali, BSA, Andrew Go Lee, MD, Peter W. Mortensen, MD, Subahari Raviskanthan, MBBS

All contributors:

Nagham Al-Zubidi, MD, Subahari Raviskanthan, MBBS, Danah Albreiki, MBBS FRCSC

Assigned editor:

Danah Albreiki, MBBS FRCSC

Review:

Assigned status Update Pending

 by Danah Albreiki, MBBS FRCSC on October 10, 2023.

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Topic

Ophthalmologic Manifestations in MELAS

Disease

Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like episodes (MELAS) is a mitochondrial genetic syndrome characterized by the features of its acronym. MELAS was first noted by Pavlakis in 1984 and described as having three typical features: 1) encephalopathy with seizures, dementia or both 2) lactic acidosis, ragged red fibers on muscle biopsy, or both; and 3) stroke-like episodes before the age of 40. Patients do not necessarily present with all or only these three classical presentations. Other leading clinical manifestations are headaches/vomiting, limb/muscle weakness, mental retardation, short stature, hearing loss, coma, myoclonus, cerebellar signs, diabetes mellitus, and cardiomyopathy/heart failure. This review will focus on ophthalmic features found in more than 50% of patients diagnosed with MELAS.

Epidemiology

MELAS is one of the most prevalent mitochondrial disorders and affects 11.5/100,000 people. The prevalence of MELAS in Japan is 0.2:100,000. The prevalence of the specific m.3243 A>G mutation is 16-18:100000 and 236:100,000 in Finland and Australia, respectively.

Etiology

Several mitochondrial genes have been identified which, if mutated, can lead to MELAS. The mutations are transferred by maternal inheritance and can occur in both males and females, equally. Having the mtDNA pathogenic variant does not imply an individual will be symptomatic however and heteroplasmy (tissue distribution of mutated mtDNA) and threshold effects in each tissue determine phenotypic expression. The most common mutation in MELAS is the TL1 gene coding for mitochondrial transfer RNA leucine 1, part of the transcription machinery. Multiple nucleotide locations can be affected in the TL1 gene, but the single m.3243 A>G point mutation accounts for nearly 80% of all cases. Other mutations in this TL1 gene and in other genes have been discovered.

Pathophysiology

Due to mitochondrial nucleotide mutations there is decreased protein translation causing malfunction of the electron transport chain, an important process of oxidative phosphorylation ATP production. This malfunction leads to an energy deficit in highly active tissues, including brain and muscles, causing ischemia, manifest as stroke like episodes in the brain, and lactic acidosis in other tissues. The relative deficiency of nitric oxide (NO) in MELAS, leads to decreased vasodilation, a normal homeostatic response to increasing oxygen demand. NO deficiency is multifactorial and results from decreased precursors, diminished production in vascular endothelial cells, sequestration by cyclo-oxygenase (COX), and shunting to reactive nitrogen species. Other mechanisms including mitochondrial angiopathy from mitochondrial dysfunction of smooth muscle cells, and mitochondrial cytopathy triggering energy failure in brain tissue, are also purported. Arginine and citrulline can be given as supplements to patients with MELAS, to increase the availability of NO precursors. Other mechanisms of MELAS are still under investigation.

Symptoms

The majority of symptoms of MELAS involve the brain and muscles. More than 50% of patients have reported visual disturbances. The stroke-like episodes in MELAS contributes to the retrochiasmal visual loss, which can manifest as hemianopia, or cortical vision loss.

Signs

MELAS has ocular manifestations in the iris, lens, retina, choroid, optic nerve, motility, and extraocular muscles. These manifestations may result in signs such as optic neuropathy, cataract, refractive error, pigmentary retinopathy, macular degeneration, retinal dystrophy, nystagmus, progressive external ophthalmoplegia, ptosis, as well as hemianopia and cortical blindness from stroke like episodes. Optic atrophy, pigmentary retinopathy, and progressive external ophthalmoplegia have a documented frequency of around 20%, 15-20%, and 10-15%, respectively. With increasing research, new ocular associations are being made in MELAS patients.

Diagnosis

Clinical history including family hx, examination, muscle histology, and/or biochemistry (lactate level) together may lead the physician to suspect MELAS, however, the diagnosis is confirmed by genetic testing. Multiple mtDNA point mutations with known MELAS associations are tested, although the most common variant is A-G nucleotide m.3243 found to be the culprit of nearly 80% of MELAS cases.

Prior to genetic testing, Hirano proposed diagnostic criterion in 1992, requiring all of the following to make a diagnosis of MELAS:

• Encephalopathy (dementia and / or seizures)
• Stroke like episodes in young age
• Evidence of mitochondrial dysfunction (lactic acidosis or ragged red fibers in muscle biopsy)

It is important to note that not all patients with the mtDNA mutation present with the full syndrome, and as in other syndromes, patients can present in a spectrum of the disease. MELAS should also be considered in those who have a diagnosis of vasculitis with seizures or seizure-like episodes, and where the imaging abnormalities cross multiple vascular territories. Cerebrospinal fluid, angiographic, and biopsy studies may still be performed to exclude vasculitides.

Management

In general, MELAS is treated symptomatically, with anti-convulsants for seizures and cochlear implants for hearing impairment. Overall disease process agents have been proposed that affect oxidative phosphorylation, such as coenzyme Q10, L-carnitine, creatinine which may benefit some individuals. Once the individual has the first stroke-like episode, arginine should be given prophylactically to reduce the stroke-like episodes, initially intravenously during the acute phase. Any other stresses on the body, such as febrile illness may trigger acute exacerbations, so individuals should receive all vaccines and follow precautionary measures. Mitochondrial toxins (including aminoglycosides antibiotics, linezolid, cigarettes, and alcohol), valproic acid, metformin, and dichloroacetate should be avoided. Annual evaluations with audiology, neurology, cardiology should be considered. Routine urinalysis, electrocardiography, and fasting blood glucose could also be performed. Pregnant women should be monitored for diabetes mellitus and respiratory insufficiency. Prenatal screening and preimplantation genetic diagnosis is not 100% sensitive, and genetic counseling is recommended.

Annual surveillance with ophthalmology should be considered. Treatments should be specific to the ocular complaint and are not necessarily MELAS specific. However, in addition to standard therapy for ptosis, eyelid “crutches,” blepharoplasty, and frontalis muscle-eyelid implantation can be considered.

Prognosis

Compared to other mitochondrial disorders, MELAS has a generally worse prognosis, although this can be quite variable. The progression over the years relates to frequency of stroke-like events. When compared to carrier relatives, the death rate is 17-fold higher in fully symptomatic individuals. In symptomatic individuals the overall median survival time was 16.9 years from onset of focal neurologic disease. The mean age of death was 34.5 ± 19 years (range 10.2-81.8 years) and 22% of deaths occurred in those younger than 18 years.