NORD gratefully acknowledges Fernando Scaglia, MD, FACMG, Associate Professor, Department of Molecular and Human Genetics, Baylor College of Medicine, for assistance in the preparation of this report.
MELAS (Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like episodes) syndrome is a rare disorder that begins in childhood, usually between two and fifteen years of age, and mostly affects the nervous system and muscles. The most common early symptoms are seizures, recurrent headaches, loss of appetite and recurrent vomiting. Stroke-like episodes with temporary muscle weakness on one side of the body (hemiparesis) may also occur and this can lead to altered consciousness, vision and hearing loss, loss of motor skills and intellectual disability. MELAS is caused by mutations in mitochondrial DNA and in one patient, this syndrome has been associated with mutations in a nuclear gene, POLG1.
Symptoms of MELAS syndrome usually begin between the ages of two and fifteen years, but delayed onset cases have also been reported between fifteen and forty years and late onset cases after forty years. In approximately 75 percent of cases, onset of the disorder is before the age of 20 years. Symptoms and physical findings associated with MELAS syndrome vary greatly between affected individuals in the same family and between different families. The distinguishing feature in MELAS syndrome is the recurrence of stroke-like episodes. It is currently thought that the deficiency of a compound called nitric oxide in the small blood vessels of the brain may be responsible for the stroke-like episodes. Short stature and hearing loss may be present and fatigue and difficulty tolerating exercise may be early symptoms.
People with MELAS syndrome have an accumulation of lactic acid in the blood (lactic acidosis), that can lead to vomiting, abdominal pain, fatigue, muscle weakness and difficulty breathing. This accumulation of lactic acid has also been noted in the spinal fluid and in the brain. In some cases, affected individuals will experience a slow deterioration of intellectual function (dementia), and/or a diminished ability to communicate by speech, writing, and/or signs (aphasia). Individuals with MELAS syndrome may also have episodes of confusion and hallucinations often due to a preceding fever (febrile illness) and/or headache. Less common symptoms include involuntary muscle spasms (myoclonus), impaired muscle coordination (ataxia), cardiomyopathy, diabetes mellitus, depression, bipolar disorder, gastrointestinal problems and kidney problems.
MELAS is caused by mutations in mitochondrial DNA (mtDNA). Mutations affecting the genes for mtDNA are inherited from the mother. MtDNA that is found in sperm cells is typically lost during fertilization and as a result, all human mtDNA comes from the mother. An affected mother will pass on the mutation to all her children, but only her daughters will pass on the mutation to their children. Mitochondria, which are found by the hundreds or thousands in the cells of the body, particularly in muscle and nerve tissue, carry the blueprints for regulating energy production.
Both normal and mutated mtDNA can exist in the same cell, a situation known as heteroplasmy. The number of defective mitochondria may be out-numbered by the number of normal mitochondria. Symptoms may not appear in any given generation until the mutation affects a significant proportion of mtDNA. The uneven distribution of normal and mutant mtDNA in different tissues can affect different organs in members of the same family. This can result in a variety of symptoms in affected family members.
Mutations in the mtDNA gene MT-TL1 are associated with MELAS in approximately 80% of cases. Mutations in MT-TQ, MT-TH, MT-TK, MT-TS1, MT-ND1, MT-ND5, MT-ND6, and MT-TS2 have also been associated with MELAS syndrome.
Some cases of MELAS syndrome appear to occur as the result of a new spontaneous mutation in a mitochondrial gene and are not inherited.
In addition, mutations in a nuclear gene (POLG1) have been associated with MELAS syndrome in one case.
MELAS syndrome is a rare disorder that affects males and females in equal numbers. Although rare, MELAS syndrome is probably the most common type of mitochondrial myopathy caused by mutations in mtDNA. Some researchers believe that mitochondrial myopathies may go unrecognized and underdiagnosed in the general population, making it difficult to determine the true frequency of disorders like MELAS syndrome.
MELAS is diagnosed based on clinical findings and molecular genetic testing.
Clinical testing may include measurement of lactate and pyruvate concentrations and CSF protein which are elevated in MELAS syndrome. Brain imaging techniques such as magnetic resonance imaging (MRI) may be used to look for stroke-like lesions and magnetic resonance spectroscopy (MRS) may be used to look for a lactate peak in the brain. Electrocardiogram may be used to diagnose heart rhythm abnormalities and echocardiogram may be used to diagnose cardiomyopathy. Muscle biopsy will usually show ragged red fibers.
The mtDNA mutations associated with MELAS can usually be detected in white blood cells, but due to heteroplasmy (see Causes), other tissue samples may be necessary such as skin, hair follicles, urinary sediment and skeletal muscle. Urinary sediment has the best yield for detecting the mutation when compared to blood, skin, and hair follicles.
No specific treatment is available for MELAS syndrome. Anti-convulsant drugs are used to help prevent and control seizures associated with MELAS syndrome. Valproic acid should not be used as an anticonvulsant. Cochlear implants have been used to treat sensorineural deafness. Therapies are sometimes used to increase energy production by the mitochondria and slow the effects of the condition. Coenzyme q10 and L-carnitine have been beneficial in some patients. In patients with mitochondrial myopathies in general, moderate treadmill training may result in improvement of aerobic capacity and drop in resting lactate levels. The use of intravenous L-arginine has been reported to improve the symptoms of disease during the acute stroke-like episodes. The use of oral arginine has been reported to decrease the recurrence of stroke-like episodes when used during the asymptomatic period.
Genetic counseling is recommended for affected individuals and their families.
Medications including carnitine, coenzyme Q10, menadione, ascorbic acid, riboflavin, thamine, nicotinamide, creatine monohydrate, idebenone, succinate and dichloroacetate have been helpful in individual patients but further studies are needed to prove their efficacy. Arginine and citrulline are being investigated as potential therapies to reduce brain damage from stroke-like episodes.
Columbia University in New York City is seeking study participants for a double-blind, placebo controlled clinical trial of idebenone in MELAS (Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like Episodes). The Phase IIa study will compare two different doses of an experimental medication, idebenone, administered over a one month period to determine the efficacy of the drug. People with MELAS and the 3243 mutation, aged 8-65 years, may be eligible. The main goal of the clinical trial is to determine if idebenone has an effect on brain lactate as measured by magnetic resonance spectroscopy (MRS). MRS is done in an MRI scanner, and is safe and typically well tolerated. An additional goal is to study the safety and tolerability of idebenone in people with MELAS. The principal investigator is Dr. Michio Hirano. If you or a family member would like more information regarding this study please see our website or contact the Research Coordinator, Kris Engelstad, at the number listed below.
Contact: Kris Engelstad, Research Coordinator
Baylor College of Medicine and Texas Children’s Hospital are recruiting individuals with MELAS syndrome for two clinical studies. The first study aims to measure nitric oxide in affected individuals and to see if giving arginine or citrulline will increase the formation of nitric oxide. Nitric oxide is thought to be helpful in improving and preventing strokes, therefore, if arginine and/or citrulline are shown to increase the formation of nitric oxide, they could be used to prevent and improve the strokes in patients with MELAS syndrome. Diabetes is common in MELAS syndrome and the purpose of the second study is to assess how the affected individuals breakdown and build sugar in their bodies. This may result in better understanding of the causes of diabetes in MELAS which can influence the prognosis and treatment of diabetes in subjects with MEAS. Adults and children affected with MELAS syndrome and carrying the m.3243 A>G mutation can participate. Study participants will be admitted to the General Clinical Research Center (GCRC) at Texas Children’s Hospital where nitric oxide and glucose production will be measured by stable isotopes infusion which is a safe procedure. The principal investigator is Dr. Fernando Scaglia. For more information, contact:
Dr. Ayman El-Hattab
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
For information about clinical trials sponsored by private sources, contact:
Contact for additional information about MELAS syndrome:
Fernando Scaglia, MD, FACMG
Department of Molecular and Human Genetics
Baylor College of Medicine
email address: email@example.com
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