Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes

WikiDoc Resources for Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes
Articles
Most recent articles on Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes Most cited articles on Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes Review articles on Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes Articles on Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes in N Eng J Med, Lancet, BMJ
Media
Powerpoint slides on Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes Images of Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes Photos of Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes Podcasts & MP3s on Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes Videos on Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes
Evidence Based Medicine
Cochrane Collaboration on Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes Bandolier on Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes TRIP on Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes
Clinical Trials
Ongoing Trials on Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes at Clinical Trials.gov Trial results on Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes Clinical Trials on Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes at Google
Guidelines / Policies / Govt
US National Guidelines Clearinghouse on Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes NICE Guidance on Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes NHS PRODIGY Guidance FDA on Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes CDC on Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes
Books
Books on Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes
News
Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes in the news Be alerted to news on Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes News trends on Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes
Commentary
Blogs on Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes
Definitions
Definitions of Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes
Patient Resources / Community
Patient resources on Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes Discussion groups on Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes Patient Handouts on Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes Directions to Hospitals Treating Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes Risk calculators and risk factors for Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes
Healthcare Provider Resources
Symptoms of Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes Causes & Risk Factors for Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes Diagnostic studies for Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes Treatment of Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes
Continuing Medical Education (CME)
CME Programs on Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes
International
Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes en Espanol Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes en Francais
Business
Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes in the Marketplace Patents on Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes
Experimental / Informatics
List of terms related to Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Imam Ali Shah, MBBS [2]

Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes
OMIM	540000
DiseasesDB	8254
MeSH	D017241

Overview

Mitochondrial myopathy, encephalopathy, lactic acidosis, stroke-like episodes, abbreviated to MELAS is one of the family of mitochondrial cytopathies, which also include MERRF, and Leber's Hereditary Optic Atrophy. A feature of these diseases is that they are caused by defects in the mitochondrial genome which is inherited purely from the female parent. The disease can manifest in both sexes.

Pathophysiology

The genetic hallmark of MELAS is heteroplasmy, a state in which each somatic cell contains a heterogeneous population of mitochondrial DNA (mtDNA) genomes. Over an individual's lifespan, the accumulation of damage can alter this mitochondrial genome. Consequently, a mixture of normal (wild-type) and mutated mtDNA coexists within cells. The proportion of mutated to normal mtDNA, often termed the "mutational load," varies significantly across different tissues of a single individual.

This tissue-specific mosaicism underpins the profound clinical heterogeneity observed both among different patients with MELAS and within the various organ systems of an affected person. The clinical expression of the disease in a particular tissue is contingent upon its mutational load, creating a complex and variable presentation. This phenomenon poses significant diagnostic challenges. For instance, analyses of readily accessible samples like blood or urine may yield false-negative results if the mutational load in these cell lines is below the pathogenic threshold. In such diagnostically ambiguous cases, a muscle biopsy is often required, as skeletal muscle's high energy requirements typically ensure a higher, more detectable concentration of the mutated mitochondria.

Two primary, potentially complementary, hypotheses have been proposed to explain the pathophysiology of MELAS syndrome:

1. The Cytopathic Hypothesis: This theory posits that the fundamental defect lies within the energy-producing cells themselves. The mitochondrial mutations lead to defective oxidative phosphorylation (OXPHOS), resulting in a critical energy deficit. During periods of elevated metabolic demand, this bioenergetic failure precipitates neuronal dysfunction and, ultimately, cell death. This model effectively explains the selective vulnerability of high-energy brain regions, such as the visual cortex, which are often affected early and severely.

2. The Angiopathic Hypothesis: This model proposes that the primary pathology is rooted in the vascular system. According to this theory, the mitochondrial defect within the endothelial cells lining small blood vessels causes significant dysfunction. This leads to impaired vascular autoregulation and a failure to adequately control regional blood flow, resulting in neuronal ischemia. Tissues with the highest metabolic activity, including the brain, skeletal muscle, heart, eyes, and inner ear, are most susceptible to this vascular insufficiency.

The neurological manifestations in MELAS are likely a consequence of a confluence of these parenchymal and vascular defects. Impaired OXPHOS not only starves cells of energy but also increases the production of damaging free radicals (reactive oxygen species). These molecules can induce vasoconstriction, counteracting the effects of crucial vasodilators like nitric oxide. Furthermore, MELAS is specifically associated with a state of nitric oxide deficiency, which arises from both impaired production and enhanced postproduction sequestration. This lack of nitric oxide, combined with microvascular angiopathy and the underlying cellular energy crisis, severely compromises cerebral vasodilation, preventing an adequate increase in blood flow to meet metabolic demands and exacerbating ischemic damage. A systemic consequence of this impaired aerobic metabolism is a compensatory increase in anaerobic glycolysis, which leads to the characteristic elevation of lactic acid, especially during acute metabolic crises.

Genetics

Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes is a condition related to changes in mitochondrial DNA. Mutations in the MT-ND1, MT-ND5, MT-TH, MT-TL1, and MT-TV genes cause mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes. The genes associated with MELAS are contained in mitochondrial DNA. Some of the genes related to MELAS provide instructions for making proteins involved in normal mitochondrial function. These proteins are part of a large enzyme complex in mitochondria that helps convert oxygen and simple sugars to energy. Other genes associated with this disorder provide instructions for making molecules called transfer RNAs (tRNAs), which are chemical cousins of DNA. These molecules help assemble protein building blocks called amino acids into full-length, functioning proteins within mitochondria.

Mutations in a particular transfer RNA gene, MT-TL1, cause more than 80 percent of all cases of MELAS. These mutations impair the ability of mitochondria to make proteins, use oxygen, and produce energy. Researchers have not determined how changes in mitochondrial DNA lead to the specific signs and symptoms of MELAS. They continue to investigate the effects of mitochondrial gene mutations in different tissues, particularly in the brain.

This condition is inherited in a mitochondrial pattern, which is also known as maternal inheritance. This pattern of inheritance applies to genes contained in mitochondrial DNA. Because egg cells, but not sperm cells, contribute mitochondria to the developing embryo, only females pass mitochondrial conditions to their children. Mitochondrial disorders can appear in every generation of a family and can affect both males and females, but fathers do not pass mitochondrial traits to their children. In most cases, people with MELAS inherit an altered mitochondrial gene from their mother. Less commonly, the disorder results from a new mutation in a mitochondrial gene and occurs in people with no family history of MELAS.

Epidemiology and Demographics

MELAS is recognized as one of the most common mitochondrial disorders, affecting approximately 1 in every 4000 individuals. While both sexes are equally susceptible to developing the condition, only females can transmit MELAS due to the unique nature of mitochondrial inheritance. Mitochondria are carried within the tails of sperm cells, which are shed outside the zygote during fertilization and are therefore not transmitted, resulting in this gender-specific inheritance pattern. Notably, there is no discernible racial preference associated with MELAS.

Natural History, Complications and Prognosis

Prognosis

There is no known treatment for the underlying disease, which is progressive and fatal. Patients are managed according to what areas of the body are affected at a particular time. Antioxidants and vitamins have been used, but there have been no consistent successes reported.

Diagnosis

Diagnosing MELAS is a multifaceted process that integrates clinical presentation, biochemical markers, neuroimaging, histopathology, and molecular genetic analysis. Due to the significant clinical heterogeneity and multisystemic nature of the disorder, a definitive diagnosis relies on a constellation of findings rather than a single pathognomonic feature.

Clinical and Biochemical Evaluation

The first step in diagnosis is a comprehensive clinical evaluation, including a detailed patient history and neurological examination. This focuses on key symptoms such as recurrent headaches, seizures, myopathy, sensorineural hearing loss, and cognitive decline. The hallmark feature is the occurrence of stroke-like episodes in individuals under 40 years of age, which may present with transient hemiparesis, cortical blindness, or aphasia.

A cardinal feature is the presence of elevated lactate levels in both the blood and cerebrospinal fluid (CSF), particularly during acute metabolic stress or following a stroke-like event. An elevated lactate-to-pyruvate ratio also suggests a respiratory chain defect.

Neuroimaging and Histopathology

Magnetic Resonance Imaging (MRI) of the brain is the preferred modality. It typically reveals multifocal, cortical, or subcortical T2-hyperintense lesions that are incongruent with the distribution of major vascular territories. These stroke-like lesions demonstrate a predilection for the posterior cerebral regions (including the occipital, parietal, and temporal lobes) and may exhibit transient and migratory behavior on serial imaging. During the acute phase, Diffusion-Weighted Imaging (DWI) can show restricted diffusion. Furthermore, Magnetic Resonance Spectroscopy (MRS) can detect an elevated lactate peak within the affected brain parenchyma, providing in vivo evidence of impaired oxidative metabolism.

A muscle biopsy is a key diagnostic procedure, especially when genetic testing from blood is inconclusive. The biopsy classically shows ragged-red fibers (RRF), which are myocytes with subsarcolemmal accumulations of abnormal mitochondria. While RRF indicate mitochondrial dysfunction, they are not specific to MELAS. A more specific finding is the presence of strongly succinate dehydrogenase-reactive blood vessels (SSVs), which reflects mitochondrial proliferation in the smooth muscle and endothelial cells of intramuscular arterioles and capillaries.

Molecular Genetic Testing

Molecular genetic testing to identify a pathogenic mutation in mitochondrial DNA (mtDNA) is the confirmatory diagnostic test. The most prevalent mutation, found in approximately 80% of affected patients, is an A-to-G transition at nucleotide position 3243 (m.3243A>G) in the mitochondrial tRNA^(Leu(UUR)) gene (MT-TL1). Other less common point mutations in MT-TL1 (e.g., m.3271T>C) and other mtDNA genes have also been implicated.

Due to heteroplasmy, a blood sample may have a low or undetectable level of the mutation, leading to a false-negative result. If clinical suspicion remains high, genetic analysis should be performed on other tissues (such as urine sediment, skin fibroblasts, or, most reliably, skeletal muscle) which typically harbor a higher mutational load.

Formal Diagnostic Criteria

To standardize the diagnosis, formal clinical criteria were established by Hirano et al. (1992).

A diagnosis of MELAS requires the presence of all three of the following definitive criteria:

1. Stroke-like episodes before the age of 40.
2. Encephalopathy characterized by seizures and/or dementia.
3. Evidence of mitochondrial dysfunction, confirmed by either:
   • Lactic acidosis, or
   • Ragged-red fibers (RRF) on muscle biopsy.

The diagnosis is considered secure if a patient meets the three definitive criteria and also exhibits at least two of the following supportive findings:

1. Normal early psychomotor development.
2. Recurrent headaches.
3. Recurrent vomiting episodes.

In contemporary practice, these clinical criteria serve as a robust framework to guide the diagnostic process, which is ultimately confirmed by identifying a causative mtDNA mutation.

History and Symptoms

MELAS is a condition that affects many of the body's systems, particularly the brain and nervous system (encephalo-) and muscles (myopathy). In most cases, the signs and symptoms of this disorder appear in childhood following a period of normal development. Early symptoms may include

• Muscle weakness
• Muscle pain
• Recurrent headaches
• Loss of appetite
• Vomiting
• Seizures
• Abdominal pain
• Extreme tiredness (fatigue)
• Difficulty breathing

Physical Examination

Eye

• Vision abnormalities

Ear

• Hearing loss

Extremeties

• Myoclonus

Neurologic

• Stroke-like episodes beginning before age 40
• Temporary muscle weakness on one side of the body (hemiparesis)
• Altered consciousness
• Ataxia
• Seizures
• Dementia

Laboratory Findings

Laboratory workup involves assessing serum pyruvic acid, serum lactic acid, cerebrospinal fluid (CSF) pyruvic acid, and CSF lactic acid. An elevation in lactic acid levels, especially during an acute stroke-like episode, is a frequent initial finding. However, lactic acids may be normal in some people and an increased CSF lactic acid level has been shown to be a more reliable indicator of disease. However, systemic metabolic acidosis does not occur.