Mitochondrial encephalomyopathy lactic acidosis and stroke-like episodes

Other Names: MELAS; MELAS syndrome

Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) is a condition that affects many of the body's systems, particularly the brain and nervous system (encephalo-) and muscles (myopathy).

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Epidemiology

The exact incidence of MELAS is unknown. It is one of the more common conditions in a group known as mitochondrial diseases. Together, mitochondrial diseases occur in about 1 in 4,000 people.

Cause

MELAS can result from mutations in one of several genes, including MT-ND1, MT-ND5, MT-TH, MT-TL1, and MT-TV. These genes are found in the DNA of cellular structures called mitochondria, which convert the energy from food into a form that cells can use. Although most DNA is packaged in chromosomes within the nucleus, mitochondria also have a small amount of their own DNA, known as mitochondrial DNA or mtDNA.

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, fats, 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 mtDNA 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.

Inheritance

This condition is inherited in a mitochondrial pattern, which is also known as maternal inheritance. This pattern of inheritance applies to genes contained in mtDNA. Because egg cells, but not sperm cells, contribute mitochondria to the developing embryo, children can only inherit disorders resulting from mtDNA mutations from their mother. These disorders can appear in every generation of a family and can affect both males and females, but fathers do not pass traits associated with changes in mtDNA 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.

Signs and symptoms

The signs and symptoms of MELAS often appear in childhood following a period of normal development. Early symptoms may include muscle weakness and pain, recurrent headaches, loss of appetite, vomiting, and seizures. Most affected individuals experience stroke-like episodes beginning before age 40. These episodes may involve temporary muscle weakness on one side of the body, altered consciousness, vision abnormalities, seizures, and severe headaches resembling migraines. Repeated stroke-like episodes can progressively damage the brain, leading to vision loss, problems with movement, and a loss of intellectual function. Many people with MELAS have a buildup of lactic acid in their bodies (lactic acidosis). This can lead to vomiting, abdominal pain, extreme fatigue, muscle weakness, and difficulty breathing. Involuntary muscle spasms, impaired muscle coordination, hearing loss, heart and kidney problems, diabetes, and hormonal imbalances may also occur.

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. 80%-99% of people have these symptoms

• Abnormal mitochondria in muscle tissue
• Aphasia(Difficulty finding words)
• Aplasia/Hypoplasia of the cerebral white matter(Absent/small cerebral white matter)
• Dementia(Dementia, progressive)
• EEG abnormality
• Increased serum lactate
• Lactic acidosis(Increased lactate in body)
• Migraine(Intermittent migraine headaches)
• Muscle weakness(Muscular weakness)
• Ragged-red muscle fibers
• Stroke-like episode

Widened cerebral subarachnoid space

30%-79% of people have these symptoms

• Anxiety(Excessive, persistent worry and fear)
• Ataxia
• Basal ganglia calcification
• Bilateral tonic-clonic seizure(Grand mal seizures)
• Depressivity(Depression)
• Encephalopathy
• Fluctuations in consciousness
• Focal-onset seizure(Seizure affecting one half of brain)
• Gait disturbance(Abnormal gait)
• Hemiparesis(Weakness of one side of body)
• Impaired visuospatial constructive cognition
• Increased CSF lactate
• Increased CSF protein
• Memory impairment(Forgetfulness)
• Myoclonus
• Myopathy(Muscle tissue disease)
• Recurrent paroxysmal headache
• Sensorineural hearing impairment
• Short attention span(Poor attention span)
• Short stature(Decreased body height)
• Visual loss(Loss of vision)
• Vomiting(Throwing up)

Diagnosis

Measurement of plasma lactate concentration is indicated in individuals with features of a myopathy or CNS disease. Fasting blood lactate concentrations above 3 mm/L support a diagnosis of mitochondrial disease. Measurement of CSF lactate concentration is indicated in individuals with suspected CNS disease. Fasting CSF lactate concentrations above 1.5 mm/L support a diagnosis of mitochondrial disease.

Magnetic resonance spectroscopy and exercise testing may also be of use to detect an elevated lactate level in brain or muscle at rest, or a delay in the recovery of the ATP peak in muscle after exercise.

Neuroimaging is indicated in individuals with suspected CNS disease. CT may show basal ganglia calcification and/or diffuse atrophy. MRI may show focal atrophy of the cortex or cerebellum, or high signal change on T2-weighted images, particularly in the occipital cortex . There may also be evidence of a generalized leukoencephalopathy . Cerebellar atrophy is a prominent feature in children .

Electroencephalography (EEG) is indicated in individuals with suspected encephalopathy or seizures.

Encephalopathy may be associated with generalized slow wave activity on the EEG. Generalized or focal spike and wave discharges may be seen in individuals with seizures.

Peripheral neurophysiologic studies are indicated in individuals with limb weakness, sensory symptoms, or areflexia. Electromyography (EMG) is often normal but may show myopathic features. Nerve conduction velocity (NCV) may be normal or may show a predominantly axonal sensorimotor polyneuropathy.

Magnetic resonance spectroscopy (MRS) and exercise testing (with measurement of blood concentration of lactate) may be used to detect evidence of abnormal mitochondrial function non-invasively. Cardiac. Both electrocardiography and echocardiography may indicate cardiac involvement (cardiomyopathy or atrioventricular conduction defects).

Treatment

There is no curative treatment. The disease remains progressive and fatal. Patients are managed according to what areas of the body are affected at a particular time. Enzymes, amino acids, antioxidants and vitamins have been used.

Also the following supplements may help:

• CoQ10 has been helpful for some MELAS patients. Nicotinamide has been used because complex l accepts electrons from NADH and ultimately transfers electrons to CoQ10.
• Riboflavin has been reported to improve the function of a patient with complex l deficiency and the 3250T-C mutation.
• The administration of L-arginine during the acute and interictal periods may represent a potential new therapy for this syndrome to reduce brain damage due to impairment of vasodilation in intracerebral arteries due to nitric oxide depletion.

NIH genetic and rare disease info

• NIH info on Mitochondrial encephalomyopathy lactic acidosis and stroke-like episodes

Mitochondrial encephalomyopathy lactic acidosis and stroke-like episodes is a rare disease.

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