by Sharon Hesterlee

This is the first of a two-part Quest series about mitochondrial myopathy. This article covers the basic biology of mitochondria and explains inheritance patterns and determinants of severity in mitochondrial diseases. Part 2 will discuss diagnosis and treatment, including a look at new information about mitochondrial diseases in the research pipeline.

We all know what it's like to drive or ride in a car that isn't performing at its peak; we know from experience that trouble-shooting the problem can be a difficult, costly proposition.

In some ways, the cells in our bodies are like little mechanical devices that occasionally break down. They have a lot of parts, some moving and some not, each with a specific role to perform in the cell. An endless variety of things can go wrong in the cell, affecting the entire body's ability to perform.

We can compare a cell with muscular dystrophy to a car with cracks in the frame. The cracks become slightly wider whenever the car is driven. In the same vein, a cell with mitochondrial disease might be compared to a car that's only running on three cylinders. No matter how much gas you put into the car, without a fully operating engine it's not going to go over 25 miles per hour.

In each of our cells, the mitochondria (singular: mitochondrion) make up the equivalent of a car's engine. These tiny biological machines combine the food we eat with oxygen to produce energy to keep our bodies going. The energy produced by the mitochondria is stored in the form of a chemical called adenosine triphosphate, or ATP.

In addition to making energy, mitochondria are also deeply involved in a variety of other activities, such as making steroid hormones and manufacturing the building blocks of DNA. Each cell in our body contains, on average, between 500 and 2,000 of these hard-working machines. When the mitochondria aren't functioning properly, an "energy crisis" can develop in tissues such as muscle, brain and heart, which normally are heavy energy consumers.

Just as engine problems can slow or stop a car, problems with mitochondria can bring the body to a halt.

William Duff of Orchard Run, W.Va., who was once an avid hiker, suspected he might have a problem when he started getting tired on the trail and having to take frequent breaks. Then the muscles in his legs began to contract spontaneously all of the time. A mitochondrial disease called MELAS was diagnosed two years ago.

Duff suggests that having MELAS is like experiencing old age at 37.

"Any kind of exertion brings on fatigue. Sometimes I get up in the morning and I just have no energy at all," he says. "It's hard to explain. Just simple daily functions are very tiring."

{Photo of Downs family}
The Downs Family
Duff's spontaneous muscle contractions have spread throughout his extremities, trunk and face. Now he's also having trouble with drooping eyelids, memory deficits, stomach reflux, and difficulty absorbing nutrients.

For Lori and Jeff Downs of North Reading, Mass., their daughter Alycia's mitochondrial disease has meant an uphill battle to cope with her severe gastrointestinal problems.

"Alycia was a normal-term baby and her birth was fairly normal," says Lori Downs. "The first problem that we had was with her feeding -- it was just a struggle. It would take her an hour to take that half an ounce and she would sweat and struggle, and she wasn't gaining weight."

The Downses eventually worked out a feeding solution for Alycia by boosting her calorie intake and making the nipple easier to use. Now almost 4 years old, Alycia still struggles with gaining weight, and has some muscle weakness, drooping eyelids, difficulty maintaining her balance and focused cognitive deficits.

The experiences of Duff and the Downs family illustrate just a few of the different manifestations of mitochondrial disease. In the same way that a car can show many different signs of engine problems, mitochondrial diseases -- of which hundreds of varieties have been identified -- can cause a complex variety of symptoms.

These include muscle weakness, muscle cramps, seizures, food reflux, learning disabilities, deafness, short stature, paralysis of eye muscles, diabetes, cardiac problems and strokelike episodes, to name a few. The symptoms can range in severity from life-threatening to almost unnoticeable, sometimes taking both extremes in members of the same family.

Because some people have specific subsets of these symptoms, clinical researchers have grouped those that occur together into "syndromes," producing a bewildering array of descriptive acronyms such as MELAS (mitochondrial encephalomyopathy with lactic acidosis and strokelike episodes) or MERFF (myoclonus epilepsy with ragged red fibers).

You may also hear the terms "mitochondrial myopathy" (indicating muscle involvement) or "mitochondrial encephalomyopathy" (indicating brain and muscle involvement). MDA covers diseases in both of these categories, which include many different syndromes (see mitochondrial encephalomyopathies chart, below).

The mitochondrial encephalomyopathies and myopathies are typically caused by defects in a part of the mitochondrion known as the respiratory chain or the electron transport chain. To see exactly how these diseases occur, see "What Mitochondria Do and What Can Go Wrong."


The terminology used in describing mitochondrial disorders can be confusing. A single syndrome (combination of symptoms) may have many different causes, while more than one syndrome may have the same cause.

In most cases, the underlying causes of these syndromes are deficiencies in the respiratory chain of the mitochondria (see "What Mitochondria Do"). You may be given a diagnosis named for the cause, such as COX deficiency or complex I and IV deficiency. The following have names based on the symptoms of the disease, but are caused by respiratory chain deficiencies.

(mendelian) Mendelian Inheritance
(maternal) Maternal Inheritance
(sporadic) Sporadic

KSS: Kearns-Sayre syndrome (sporadic)
Onset: Before age 20
Disease characteristics: May cause blindness, eye muscle paralysis, severe heart problems, coordination problems, mental retardation and coma.

Leigh's syndrome: Subacute necrotizing encephalomyopathy (mendelian)
Onset: Infancy; progression can be fast or slow.
Disease characteristics: May cause brain abnormalities, vomiting, seizures, feeding difficulties, heart problems, epilepsy, speech difficulties and muscle weakness.

MELAS: Mitochondrial encephalomyopathy, lactic acidosis and strokelike episodes. This is the most common type of mitochondrial encephalomyopathy. (maternal)
Onset: Before age 20
Disease characteristics: May cause exercise intolerance, seizures, dementia, muscle weakness, heart problems.

MERFF: Myoclonus epilepsy with ragged-red fibers (maternal) (sporadic)
Onset: Usually before adolescence; variable progression.
Disease characteristics: May cause epilepsy, coordination loss, dementia and muscle weakness.

MILS: Maternally inherited Leigh's syndrome (maternal)
Disease characteristics: Same as Leigh's syndrome

MNGIE: Myogastrointestinal encephalomyopathy (mendelian)
Onset: Before age 20
Disease characteristics: May cause eye muscle paralysis, muscle weakness, digestive tract disorders, loss of coordination and brain abnormalities.

NARP: Neuropathy, ataxia and retinitis pigmentosa (maternal)
Onset: Infancy or childhood
Disease characteristics: May cause vision problems, lack of coordination and mental retardation. This syndrome may represent a less severe form of MILS.

PEO: Progressive external ophthalmoplegia (sporadic) (maternal) (mendelian)
Onset: Usually in adolescence or early adulthood; slow progression.
Disease characteristics: May cause paralysis of eye muscles, drooping eyelids, muscle weakness and fatigue.

Pearson syndrome: (sporadic)
Onset: Childhood
Disease characteristics: Severe anemia and pancreas malfunction; children who survive the disease may develop KSS as adolescents.

When the breakdown products of the food that we eat enter the mitochondria for processing, they're passed along a well-orchestrated assembly line made up of hundreds of proteins, each with a specific role to play in the energy production process. Raw materials enter the beginning of the assembly line, and ATP energy molecules come out the other side.

The major steps in the energy extraction process are (see the following illustration):
  1. import and export of materials, such as fat and sugar derivatives, to and from the mitochondria
  2. the breakdown of fatty acids through beta-oxidation and the removal of electrons in the citric acid cycle
  3. the passage of electrons through the major complexes of the respiratory chain, or electron transport chain, and
  4. the manufacture of ATP by ATP synthase.
Diagram: the energy extraction process inside the mitochondrion.When any one of these steps is blocked, usually because a genetic defect has prevented the manufacture of a protein required for that step, mitochondrial disease can occur. The body can't function properly because the cell's ability to make energy is reduced or stopped, and metabolic intermediates and toxic by-products begin to build up.

The energy shortage in the tissues is the major cause of muscle weakness, fatigue and problems in the heart, kidneys, eyes and endocrine system. The buildup of toxic intermediates can be responsible for liver problems, muscle cramps, brain dysfunction or even greater mitochondrial damage. Many times these two types of problems reinforce one another, each making the other worse. (The specific problems and symptoms that occur in mitochondrial disorders, and their management, will be discussed in greater detail in Part 2 of this series.)

Salvatore DiMauro, a neurologist at Columbia University in New York, says that, although there are many different types of defects that cause mitochondrial disorders, the term mitochondrial encephalomyopathy has come to refer only to disorders of the respiratory chain (numbers 3 and 4 in the illustration). (The respiratory chain is part of the cell and has nothing to do with a person's breathing.)

The respiratory chain consists of four large protein complexes: I, II, III and IV (cytochrome c oxidase, or COX), ATP synthase, and two small molecules that ferry around electrons, coenzyme Q10 and cytochrome c. The respiratory chain is the final step in the energy-making process in the mitochondrion where most of the ATP is generated; as DiMauro puts it, it's "the business end of mitochondrial metabolism." Mitochondrial encephalomyopathies that can be caused by deficiencies in one or more of the specific respiratory chain complexes include MELAS, MERFF, Leigh's syndrome, KSS, Pearson, PEO, NARP, MILS and MNGIE.
:: Story Continue on next Screen ::