Mitochondrial Disorders

What are Mitochondrial Disorders?

Mitochondria, often called the “powerhouses” of cells, are small structures within cells that provide the energy for all cellular activity. When mitochondria do not function properly they are unable to provide the necessary energy for the cell and disease can develop. Some of the most well known mitochondrial disorders are:

  1. MELAS (Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes);
  2. MERRF (Myoclonic Epilepsy Ragged Red Fibers);
  3. NARP (Neuropathy; Ataxia; Retinitis Pigmentosa);
  4. MNGIE (Myoneurogenic Gastrointestinal Encephalopathy);
  5. LHON (Leber’s Hereditary Optic Neuropathy);
  6. KSS- Kearns Sayre Syndrome; and
  7. Leigh’s Syndrome.

The most common symptoms of mitochondrial disorders are:

  1. muscle weakness,
  2. exercise intolerance,
  3. fatigue,
  4. cognitive difficulties, and
  5. neurological problems.

The primary reason for poorly functioning mitochondria is the presence of mitochondrial DNA (mtDNA) mutations. All cells, except for egg and sperm cells, have two copies of DNA, one inherited from the mother and one from the father. Mitochondria, however, have their own DNA, all inherited from the mother. When each mitochondrion divides to make two new mitochondria, the copies of DNA are divided randomly between the new mitochondria. If the DNA inherited from the mother is defective (i.e. carries a mutation), all or some of the DNA in the newly formed mitochondria may be defective, leading to mitochondria that may eventually function improperly.

Sometimes mutations in mitochondrial DNA (mtDNA) also occur spontaneously without anyone in the family having had one before, however most mutations begin with someone in a family and are commonly transmitted through the maternal lineage (maternal inheritance), as described above. As a result, these mutations can be found in several different individuals from many generations in one family. The child’s mother may or may not have symptoms, but if she carries a mitochondrial mutation it will be transmitted to all of her offspring. A father of a child can carry a mutation and also be affected by a disease but he will not carry the mutation to his children. It is difficult to estimate the population frequency of mitochondrial disorders, but reports have estimated the prevalence to be as high as 5.7 per 100,000 in the population over 14 years of age.

Types of Mitochondrial Disorders

Currently there are several known and established mitochondrial disorders. Scientists continue to discover new mutations in the mitochondrial DNA with the goal of characterizing unique disorders resulting from these mutations.

A description of the most well known mitochondrial disorders is below:

    MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) is a disorder that affects several body systems and usually has its onset in childhood. It is characterized by a progressive encephalopathy and stroke-like episodes leading to disability. MELAS is caused by a genetic mutation and has been associated with at least 6 different point mutations on mitochondrial DNA (mt DNA). The most common mutation for MELAS is an A-to-G switch at nucleotide 3243 in the strand of mitochondrial DNA. Clinical symptoms are determined by various factors including the amount (percentage) of point mutations in each organ (including the brain).
    In individuals affected by MELAS, early psychomotor development, involving physical and mental processes, is usually normal, but short stature is common. The first onset of symptoms is frequently between the ages of two and ten years. Common initial symptoms include seizures, recurrent headaches, lack of appetite (anorexia), and recurrent vomiting. Inability to exercise and limb weakness can also be early signs of MELAS. Seizures are often associated with stroke-like episodes of weakness on one side of the body that may come and go over time or cortical blindness. These stroke-like episodes may be associated with altered consciousness and may be recurrent. The combined effects of the stroke-like episodes may gradually impair motor abilities, vision, and mental functioning, often by adolescence or young adulthood. Sensorineural hearing loss is common. People affected by MELAS typically also show elevated levels of lactic acid (lactic acidosis) in the blood.
    MERFF is characterized by myoclonus (twitching or spasms of muscle); epilepsy (seizure disorder); cerebellar dysfunction displayed as ataxia (defective muscle coordination) and gait (walking) disorder; dementia (memory problems); and optic atrophy (the loss of some or most of the fibers of the optic nerve). Also common is polyneuropathy (disorder of the peripheral nerves) causing distal sensory loss; hearing loss; and myopathy (muscle problems). Weakness is usually proximal (closest to the center of the body) and affected people may experience muscle pain either while resting or during exercise, cramps, and fatigue. Short stature and lipomata (fatty tumors) also occur in about 10% of people with MERRF.
    NARP is a disorder characterized by proximal and distal weakness (closest and farthest from the center of the body); sensory neuropathy (nerve disease) resulting in reduced vibration; reduced tendon reflexes, particularly at the ankle; and retinitis pigmentosa (a condition characterized by widespread pigmentary changes in the retina) resulting in reduced night vision. Other features of NARP include dementia (memory problems), seizures (common in early onset, tonic-clonic later), developmental delay, and dystonia (impaired muscle tone).
    MNGIE typically appears during the second through fifth decades of life and is a multisystem disorder causing visceral neuropathy characterized by diarrhea, constipation, and/or gastroparesis resulting in nausea, vomiting, weight loss, and malabsorption (inadequate absorption of nutrients from the intestinal tract). Many people also experience Borborygmi (rumbling in the stomach), feel full quickly when eating, and may have diverticulitis (pain caused by pouches formed in the colon). Ocular symptoms include ophthalmoplegia (paralysis of eye muscles), ptosis (drooping eyelids) and degeneration of the retina. Thin appearance and ongoing weight loss are clinical features of MNGIE, as is short stature and neuropathy (disease of the nerve). Pain may be experienced, along with progressive weakness and lack of reflexes. Hearing loss is also common, as is leukoencephalopathy (destruction of nerve fiber covering). Normal intelligence is common with MNGIE; dementia (memory problems) does not occur.
    Leber’s hereditary optic neuropathy (LHON) is a condition that affects predominantly young adult males and involves the degeneration of retinal ganglion cells (RGCs) and their axons within the retina of the eye that leads to an acute loss of central vision. LHON is usually due to one of three disease causing mitochondrial DNA (mtDNA) point mutations.
    People with LHON experience an acute onset of visual loss, generally first in one eye and then a few weeks later in the other. This eventually evolves to very severe optic atrophy (the loss of some or most of the fibers of the opticnerve) and permanent decrease of visual acuity. In the acute stage, which may last a few weeks, the affected eye demonstrates an edematous (swollen) appearance of the nerve fiber layer, which can be seen on an eye examination, just before or after the onset of visual loss. Examination reveals decreased visual acuity, loss of color vision and a cecocentral scotoma (area of visual loss surrounded by area of well preserved vision).
    Kearns-Sayre syndrome (KSS) is a rare neuromuscular disorder with onset usually before the age of 20. It is the result of abnormalities in the DNA of mitochondria – small rod-like structures found in every cell of the body that produce the energy that drives cellular functions. The mitochondrial diseases correlate with specific DNA mutations that cause problems with many of the organs and tissues in the body. KSS is characterized by progressive limitation of eye movements until there is complete immobility, accompanied by eyelid droop (ptosis). It is also associated with abnormal accumulation of pigmented material on the membrane lining the eyes. Additional symptoms may include mild skeletal muscle weakness, heart block (a cardiac conduction defect), short stature, hearing loss, an inability to coordinate voluntary movements (ataxia), impaired cognitive function, and diabetes. Seizures are infrequent. Several endocrine disorders can also be associated with KSS.
    Leigh’s syndrome usually has its onset during the first year of life, but can occur later. It is characterized by hypotonia (low tone) and episodes of vomiting, ataxia, choreoarthetosis, hyperventilations, encephalopathy associated with loss of verbal milestones, spasticity, abnormal breathing rhythm, and hearing loss, ataxia, systagmus, dystonia, visual loss, peripheral neuropathy. Signs and symptoms may manifest with stress such as an intercurrent infection and carbohydrate intolerance. Motor and intellectual regression occurs.


The evaluation of a patient for mitochondrial disease can encompass several tests. The standard set of examinations used in most cases include the following:

  1. Neurological History and Examination
  2. Medical and family history – including pedigree analysis
  3. Tissue sample for mitochondrial DNA analysis
  4. Muscle biopsy
  5. General and specialized blood tests
  6. Other diagnostic tests, as indicated

Tissue samples can be sent to Columbia University for mitochondrial DNA analysis.

Please Contact

The H. Houston Merritt Center for Neuromuscular and Mitochondrial Disorders
Tel: 1-212-305-3947
Fax: 212-305-3986