MELAS syndrome, an acronym for Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes, is a rare genetic disorder caused by malfunctioning mitochondria, the energy-producing structures in cells. This condition primarily impacts the nervous system and muscles. Although individuals are born with MELAS, its symptoms manifest in childhood or early adulthood, before the age of 20.
Genetic Origins of MELAS
The genetic basis of MELAS lies not in nuclear DNA, but within the DNA located in the mitochondria (mtDNA). A defining characteristic of mitochondrial diseases is their maternal inheritance pattern; the genetic mutations are passed down exclusively from the mother because mitochondria and their DNA are inherited from the egg cell.
Approximately 80% of MELAS cases are caused by a specific point mutation, m.3243A>G, in the mitochondrial gene MT-TL1. This gene is involved in building proteins within the mitochondria. While this mutation is the most common, other mutations in different mitochondrial genes can also lead to the disorder.
Heteroplasmy is a concept that explains the variability of MELAS. This term describes having a mixture of mutated and normal mtDNA within a person, and even within a single cell. The ratio of mutated to healthy mtDNA differs between tissues, which determines which organs are affected and the severity of symptoms.
Clinical Manifestations and Symptoms
The symptoms of MELAS are wide-ranging because mitochondria are present in nearly every cell. The name itself outlines the three most prominent features of the disorder.
Mitochondrial Encephalomyopathy refers to the combination of brain disease (encephalopathy) and muscle disease (myopathy). Encephalopathy can manifest as seizures, developmental delays, learning disabilities, and a progressive loss of intellectual function, or dementia. Myopathy contributes to muscle weakness, pain, and exercise intolerance, where even mild physical activity can cause profound fatigue.
Lactic Acidosis is a buildup of lactic acid in the bloodstream. When mitochondria fail to produce energy effectively, the body relies on less efficient metabolic pathways that generate lactic acid as a byproduct. This accumulation can lead to symptoms such as recurrent nausea, vomiting, abdominal pain, fatigue, and rapid breathing.
Stroke-like episodes are a hallmark of MELAS and begin before the age of 40. These are not conventional strokes caused by blood clots but are distinct episodes of brain injury that can result in temporary muscle weakness on one side of the body (hemiparesis), vision loss, altered consciousness, and severe, migraine-like headaches. These episodes can recur and progressively damage the brain.
Beyond these defining characteristics, individuals with MELAS may experience other symptoms. Hearing loss and diabetes are common, appearing before the more severe neurological issues. Other manifestations include short stature, heart muscle disease (cardiomyopathy), kidney problems, and involuntary muscle spasms (myoclonus).
The Diagnostic Process
Diagnosing MELAS combines clinical observations with specialized tests. The process begins when a patient presents with suggestive symptoms, such as stroke-like episodes in a young person, muscle weakness, and developmental delays. A review of the patient’s symptoms and family history are the first steps.
Physicians order specific tests, analyzing blood and cerebrospinal fluid (CSF) for elevated levels of lactate and pyruvate, which indicate mitochondrial dysfunction. High lactic acid levels in the blood are an initial clue pointing toward MELAS.
Brain imaging is part of the diagnostic workup. Magnetic resonance imaging (MRI) is used to find characteristic stroke-like lesions. A feature of these lesions is that they appear in brain regions that do not conform to the patterns of common strokes. Magnetic resonance spectroscopy (MRS) can also detect elevated lactate levels directly within brain tissue.
A muscle biopsy may be performed, where a small sample of tissue is examined under a microscope to reveal “ragged-red fibers,” which are cells crowded with abnormal mitochondria. While these tests provide strong evidence, a definitive diagnosis requires molecular genetic testing to identify a mutation in the mtDNA. Testing urine or skin cells can be more informative than blood tests, as the proportion of mutated mtDNA varies between tissues.
Symptom Management and Therapeutic Approaches
There is no cure for MELAS, so treatment focuses on managing symptoms and improving quality of life. This supportive approach requires a multidisciplinary team of specialists to address the various complications of the disease.
A primary focus of therapy is managing stroke-like episodes. Intravenous administration of the amino acid L-arginine during an acute episode can improve symptoms. Regular oral supplementation with L-arginine or its precursor, L-citrulline, may also reduce the frequency and severity of these events by improving blood flow in the brain.
Many patients are treated with a “mitochondrial cocktail,” a combination of vitamins and supplements intended to support mitochondrial function, though their efficacy varies. This cocktail frequently includes Coenzyme Q10 and L-carnitine to help with energy production. Other supplements like riboflavin (vitamin B2) and thiamine may also be part of the regimen.
Seizures are managed with anti-epileptic drugs, though certain medications like valproate are avoided. Hearing loss may be addressed with hearing aids or cochlear implants. Diabetes and cardiomyopathy are treated with standard medical approaches. Physical and occupational therapy help maintain muscle strength and functional abilities.
Disease Progression and Outlook
MELAS is a progressive disorder, and its course is highly variable from person to person. This variability is influenced by genetic factors, like the specific mtDNA mutation and the level of heteroplasmy (the proportion of mutated mtDNA in different tissues).
Progression is marked by cumulative damage from repeated stroke-like episodes. These events lead to a decline in neurological function, causing cognitive impairment, dementia, and movement problems. The strain on the body’s energy production can also lead to the deterioration of other organs, including the heart, kidneys, and pancreas.
Predicting a specific life expectancy is difficult due to this variability. The outlook depends on the severity of symptoms, the impact of stroke-like episodes, and the degree of multi-organ involvement. Proactive and continuous medical care is necessary to manage complications and address the evolving challenges of the disease.