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The Wide Phenotypic Spectrum of the Common MELAS-Causing Mutation


  • ✓ Findings from a new study suggest that neurologists and other physicians should be thinking about a mitochondrial etiology — in particular for MELAS — when confronted with a multisystem disorder.

WASHINGTON—MELAS is a progressive neurodegenerative disorder characterized by mitochondrial encephalopathy with myopathy, lactic acidosis, and stroke-like episodes. The mitochondrial A3243 mutation, the most common cause of MELAS, is also responsible for a wide array of symptoms in people without the full-blown MELAS syndrome.

This and other findings from the first large, prospective cohort study were described here in October at the annual meeting of the American Neurological Association.


Dr. Petra Kaufmann: “This study shows that carriers [of the MELAS mutation] have a high burden of disease. Some of these problems are treatable, so early detection and proactive management may reduce this burden.”

The findings suggest that neurologists and other physicians should be thinking about a mitochondrial etiology when confronted with a multisystem disorder, said Petra Kaufmann, MD, assistant professor of neurology at Columbia University, who led the study.

“The wide spectrum of symptoms is one of the challenges” the mutation presents, she said. “This makes diagnosis and management of these patients complex.”

Among features that make up MELAS — in addition to those suggested by the disorder's name — are seizures, diabetes mellitus, hearing loss, short stature, lipomas, and exercise intolerance.


Dr. Fernando Scaglia: “It is important to recognize that individuals who carry this mutation may have symptoms beyond those of the traditional MELAS syndrome.”


Dr. Kaufman said the clinical features of mutation carriers are probably under-recognized. She noted that a recent population-based study suggested that the mutation may be as high as 236 per 100,000 people (Mitochondrion 2007;7(3):230–233). The point mutation can be identified by a blood test.

To assess the full range of symptoms in carriers, Dr. Kaufmann and colleagues studied 123 people who had the mutation — 45 were diagnosed with MELAS — from 45 families with the mutation, along with 30 controls (from the same families who did not have the mutation). In this context, Dr. Kaufmann explained, a carrier is a person with the mutation who does not have the full set of MELAS symptoms.


The average proportion of mutant mitochondria in blood was 27 percent in MELAS patients, and 11 percent in carrier relatives. Dr. Kaufmann noted that these average figures hide the extensive variability within families, and even from tissue to tissue within a single individual.

“Often there is quite a range, but if someone has 30- to 40-percent in one tissue, they are quite likely to have medical problems,” she said. This variability traces back to the random distribution of mutant mitochondria into different eggs during oocyte formation and in different embryonic tissues during development.

“Within an individual, a large proportion of mutations could end up in the brain, for instance, but in another person they might be concentrated in peripheral organs,” Dr. Kaufmann explained. As a consequence, the range and severity of symptoms varies considerably from parent to child, and among siblings. “It is difficult to predict [how any one person will be affected],” she said, “and we cannot provide accurate genetic counseling.”


On almost all clinical features the researchers examined, carriers scored somewhere between controls and those with MELAS. More than one-third of carriers had exercise intolerance and hearing loss, about 40 percent had gastrointestinal disturbance, and ten to twenty percent had short stature, ptosis, diabetes, or night blindness. Memory problems were much more common in MELAS patients (70 percent) than in carriers (15 percent) or controls (18 percent).

Neuropsychiatric symptoms were also common, with a low frustration threshold or depression in about one-third of patients with the mutation but not the MELAS diagnosis. Medical records showed that significantly more often than controls, carriers had delayed motor or speech development and reading or learning problems.

One in six carriers required special education classes, versus one in two for MELAS patients, and one in 25 for controls. Migraine, myoclonus, clumsiness, and paresthesias were common in 15- to 30-percent of carriers.

Like MELAS patients, carriers were likely to be underweight, of short stature, and to have a small head circumference. Laboratory findings typical of MELAS, including elevated lactate, triglycerides, and urine creatinine, were also seen in carriers.

“Patients and carriers in families affected by this disease are interested in knowing what will happen to them, and what the typical picture is for the disorder,” Dr. Kaufmann said. “This study shows that carriers have a high burden of disease. Some of these problems are treatable, so early detection and proactive management may reduce this burden.” Potentially treatable aspects of the disorder include glucose intolerance, cardiomyopathy, and psychiatric symptoms.

“Neurologists should consider mitochondrial disease with patients with some unexplained cognitive or neuropsychological problems, and perhaps migraine, associated with other findings,” she said.

“If there are other signs that suggest mitochondrial disease, such as glucose intolerance, diabetes, or hearing loss, then a careful family history, looking for maternal inheritance, is warranted. If they consider that, it might avoid some diagnostic tests that would otherwise be necessary.” Non-neurologists as well should consider the diagnosis, she said, given the wide range of non-neurologic symptoms.


These messages were echoed by Fernando Scaglia, MD, assistant professor of genetics in the department of molecular and human genetics at Baylor College of Medicine and Texas Children's Hospital, where he conducts research on mitochondrial disorders. Dr. Scaglia was not involved in the current study.

“It is important to recognize that individuals who carry this mutation may have symptoms beyond those of the traditional MELAS syndrome,” Dr. Scaglia said in a telephone interview with Neurology Today.

“These other symptoms may occur before patients have the full-blown syndrome. Increasing awareness of these problems is important for improving care of these individuals.” Earlier symptomatic treatment may lead to better outcomes not just for those with a MELAS diagnosis, but for other carriers of the mutation, he said.


• Manwaring N, Jones MM, Sue CM, et al. Population prevalence of the MELAS A3243G mutation. Mitochondrion 2007;7(3):230–233.

    More About MELAS

    Egg cells, but not sperm cells, contribute mitochondria to the developing embryo, so only women pass mitochondrial conditions to their children. In most cases, the signs and symptoms of MELAS appear in childhood between the ages of two and ten years, following a period of normal development.

    Early symptoms may include muscle weakness and pain, recurrent headaches, loss of appetite, vomiting, and seizures. Seizures are often associated with stroke-like episodes of transient hemiparesis or cortical blindness, as well as altered consciousness. These stroke-like episodes gradually cause impaired motor abilities, vision, and mentation, often by adolescence or young adulthood.

    The lesions are stroke-like but not strokes because they do not conform to the distribution of particular blood vessels and are thought to be a mismatch between metabolic demands of the brain and inadequate delivery of blood.

    Most people with MELAS have a buildup of lactic acid or lactic acidosis. Increased acidity in the blood can lead to vomiting, abdominal pain, fatigue, muscle weakness, and difficulty breathing.