Continuing Education Activity

Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) is a mitochondrial disease primarily affecting the nervous system and muscles. MELAS presents in children or young adults as recurrent episodes of encephalopathy, myopathy, headache, and focal neurological deficits. The condition is relentlessly progressive, resulting in neurological impairment by adolescence or early adulthood. This activity describes the pathophysiology and presentation of MELAS syndrome and highlights the role of the interprofessional team in its management.

Objectives:

• Review the cause of MELAS syndrome.
• Describe the presentation of MELAS syndrome.
• Summarize the differential diagnosis of MELAS syndrome.
• Outline the importance of improving care coordination among interprofessional team members to improve outcomes for patients affected by MELAS syndrome.

Introduction

Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) is a mitochondrial disease primarily affecting the nervous system and muscles. MELAS presents in children or young adults as recurrent episodes of encephalopathy, myopathy, headache, and focal neurological deficits. The condition is relentlessly progressive, resulting in neurological impairment by adolescence or early adulthood.

Etiology

MELAS is a mitochondrial inherited genetic disorder. Paternal mitochondria are present only in the tailpiece of the sperms. As a result, they are lost during fertilization and mitochondrial disorders including MELAS are maternally inherited. In rare instances, MELAS may result from a sporadic mutation with no family history. Mitochondrial genetic disorders are the result of mutations causing impaired mitochondrial function, including oxidative phosphorylation and energy production. In MELAS, mutations in tRNA are believed to cause impairment of protein assembly into respiratory chain complexes, though the exact mechanisms have yet to be elucidated. Mitochondria are the powerhouse of cells. Any mitochondrial disorder will affect the most metabolically active organs of the body especially the brain and muscles.

Many different transfer RNA (tRNA) mutations can cause MELAS. The most common mutation is in the MTTL1 mitochondrial gene. A single base pair mutation, m.3243A>G, is found in 80% patients, and a second common mutation, m.3271T>C, is found in 10%.[1][2] However, many other genes are being identified with similar phenotypic syndromes such as POLG and BCS1L.

The neurological symptoms of MELAS are believed to result from a combination of impaired mitochondrial energy production, microvascular angiopathy, and nitric oxide deficiency, which may cause impaired cerebral vasodilation.[3]

Epidemiology

MELAS is one of the most common mitochondrial diseases, with an estimated incidence of 1 in 4000.

Both genders are equally affected, but only women can pass the condition on as mitochondria are carried in the tails of sperm cells and therefore shed outside the zygote during fertilization.

Pathophysiology

Each somatic cell possesses multiple and variable copies of the same mitochondrial DNA or genome. This mitochondrial DNA is also damaged to different degrees with the aging of cells. Like any mitochondrial disorder, MELAS exhibits heteroplasmy or a variation in the types of mitochondrial DNA found in different tissues in the same person. It is common for genetic mutations only to affect some mitochondria, which leads to a variable appearance of diseased mitochondria in different tissues in the same person. This phenomenon explains the wide variability in the presentation of different tissues within an individual and also presentation among different patients with the same diagnosis. This also has implications for diagnosis, as occasionally serum and urine studies may be negative if those cell lines are unaffected, making it necessary to perform muscle biopsy to examine affected tissue.

Mitochondrial disorders including MELAS affect mainly tissues with the highest metabolic activities. These include skeletal and heart muscles, brain, eye, and the inner ear. Due to the impaired mitochondrial respiratory chain function and oxidative phosphorylation, the increased anaerobic glycolytic activities will lead to increased lactic acid during acute attacks.

Histopathology

The hallmark of mitochondrial disease is an accumulation of mitochondria in muscle fibers visualized on Gomori trichrome stain. The diseased mitochondria proliferate in an attempt to compensate for poor energy production and appear bright red compared to the blue myofibers, therefore called "ragged red fibers." MELAS also shows strongly succinate dehydrogenase (SDH)-reactive blood vessels due to mitochondrial proliferation in perivascular smooth muscle and endothelial cells.

History and Physical

Children with MELAS often have normal early psychomotor development until the onset of symptoms between 2 and 10 years old. Though less common, infantile onset may occur and may present as failure to thrive, growth retardation and progressive deafness. Onset in older children typically presents as recurrent attacks of a migraine-like headache, anorexia, vomiting, and seizures. Children with MELAS are also frequently found to have short stature.

Myopathy in MELAS initially presents as exercise intolerance or proximal muscle weakness. Due to the severity of the other neurological features, the myopathy is often under-recognized. The myopathy in MELAS often does not cause a significant functional disturbance.

Seizures in MELAS may be focal or generalized and have no recognized syndrome-specific semiology or EEG findings. Children with younger age of onset tend to have higher rates of drug-resistance epilepsy and therefore more severe clinical dysfunction.

Seizures are often accompanied by sudden focal neurological deficits which are termed "stroke-like episodes." These episodes differ from a typical stroke in that they do not conform to any vascular territory, the MRI findings may fluctuate or resolve more quickly than typical stroke, and the apparent diffusion coefficient on MRI is not always decreased like typical infarct, and may instead be increased or mixed. Typical focal neurologic deficits include hemiparesis, hemianopia, or aphasia. Residual deficits from stroke-like episodes gradually impair neurologic function. By adolescence or young adulthood, patients often have impaired motor function, vision, mentation, and sensorineural hearing loss.

Encephalopathy is another key feature. Altered level of consciousness is often associated with the stroke-like episodes. Mental deterioration begins during childhood and is slowly progressive.

Other organ systems may also be involved in MELAS. Patients are reported to have cardiac conduction disorders, diabetes, and chronic fatigue.

Evaluation

MRI: Multifocal infarct-like cortical areas in different stages of ischemic evolution, areas that do not conform to any known vascular territory. Initial lesions often occur in the occipital or parietal lobes with eventual involvement of the cerebellum, cerebral cortex, basal ganglia, and thalamus.

Lactate is often elevated in serum and cerebrospinal fluid (CSF). MR spectroscopy may show an elevated lactate peak in affected and even unaffected brain areas.

Muscle biopsy shows ragged red fibers. However, genetic evaluation should be done first, which eliminates the need for muscle biopsy in most cases.

Diagnosis may be molecular or clinical:

1. Stroke-like episodes before 40 years old
2. Encephalopathy with seizures or dementia
3. Blood lactic acidosis* or ragged red fibers on muscle biopsy

*Due to mitochondrial heteroplasmy, urine and blood testing is preferable to blood alone

Treatment / Management

There is no treatment to stop disease progression.

Symptomatic treatment of seizures with anti-epileptic medications. There are several case reports of aggravation of MELAS epilepsy with use of Valproate, though the mechanisms behind this interaction are still being investigated.

Vitamins such as coenzyme Q10 or L-carnitine are thought to help increase energy production by mitochondria and may slow the effects of the disease. There are ongoing MELAS phase I and II trials of Idebenone, a synthetic coenzyme Q10, which has been shown to improve neurological function in other mitochondrial disorders (Scaglia, ClinicalTrials.gov Identifier: NCT00887562)

L-arginine has been shown to attenuate the severity of symptoms when used in acute attacks and decrease the frequency of episodes[4][3]. L-citrulline is also believed to be beneficial in recovery reduction of stroke risk. This relationship is theorized to be due to correction of nitric oxide deficiency in MELAS patients, as arginine and citrulline are precursors to nitric oxide production.

Differential Diagnosis

Other mitochondrial disorders should be considered in patients presenting with a family history concerning for maternal mitochondrial inheritance.

Kearns-Sayre is a rare neuromuscular disorder which also may present as visual disturbance, short stature, hearing loss, and ataxia. However, Kearns-Sayre is distinguished by its characteristic visual findings:

• Chronic progressive external ophthalmoplegia
• Atypical retinitis pigmentosa
• Pigmentary degeneration of the retina

In addition to these visual findings, Kearns-Sayre patients often have cardiac manifestations which help distinguish these patients from MELAS patients.

Myoclonus epilepsy associated with ragged red fibers (MERRF) may be confused with MELAS as they both involve seizures, mental deterioration, and myopathy with ragged red fibers on biopsy. MERRF patients may also have hearing loss, visual disturbance secondary to optic atrophy, and short stature. The characteristic myoclonic seizure in MERRF may help to narrow diagnosis, but genetic testing should be considered to distinguish the 2 conditions.

Leigh syndrome may also present with progressive neurological deterioration, seizures, and vomiting mainly in young children.

Enhancing Healthcare Team Outcomes

Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) is a mitochondrial disease primarily affecting the nervous system and muscles. MELAS presents in children or young adults as recurrent episodes of encephalopathy, myopathy, headache, and focal neurological deficits. Because the condition is relentlessly progressive, resulting in neurological impairment by adolescence or early adulthood, it is best managed by an interprofessional team. In most patients the treatment is supportive but the overall prognosis is poor. It is important to get a social worker and physical therapy involved early in the course of the disease because these professionals can help improve the quality of life.[5][3][6][7][8]