Leigh disease

Definition

Leigh syndrome is an early onset, progressive neurological disease that involves defects in the normal function of the mitochondria. The mitochondrion is a small organelle located in most cells and is responsible for producing energy for cells and tissues throughout the body.

Description

Leigh syndrome is caused by defective cellular respiration that supplies many tissues with energy. The disorder is severe and can be particularly difficult for family members, as infants are among the severely affected. Leigh syndrome is also known as necrotizing encephalopathy .

Demographics

Leigh syndrome is a very rare disease that affects different peoples relatively equally. Some studies have shown that more males are affected than females.

Causes and symptoms

In Leigh syndrome, symptoms usually develop within the first year of life; rarely, symptoms can develop during later childhood. The infant usually initially develops symptoms that include hypotonia (decreased muscle tone), vomiting, and ataxia (balance or coordination abnormalities). Overall, failure to grow and thrive is usually the primary reason parents seek medical help. Eventually, the infant experiences seizures , lactic acidosis (an excess of lactic acid, a normal product of carbohydrate metabolism, in the body), and respiratory and kidney impairment.

Various abnormalities of the eyes are also common in Leigh syndrome. Ophthalmoplegia (paralysis of some or all of the muscles of the eye) is a typical finding, along with optic atrophy (degeneration of the optic nerve) and pigmentary retinopathy, a disorder that eventually leads to blindness.

On the cellular level, persons with Leigh syndrome have an inability to produce ATP (an energy source for the cell) in the mitochondria. Tissues that are not provided with adequate energy replenishment usually die. Irreversible damage can occur first in cells requiring much energy, such as the brain, leading to mental impairments and developmental delay. Many parts of the brain are affected by the lack of ATP in Leigh disease, including the basal ganglia, which helps regulate motor performance; the brainstem, which controls the functions of breathing, swallowing, seeing, and hearing; and the cerebellum , which coordinates balance and voluntary muscle movement.

Several genetic causes explain how persons develop Leigh disease, and several genes are involved. These genes include defects found in nuclear DNA as well as the smaller, less widely known mitochondrial DNA. Genes from both genomes contribute to the normal function of the mitochondria. Mutations in genes from the nuclear and the mitochondrial DNA have both been implicated in Leigh disease.

Diagnosis

In general, diagnosis of Leigh syndrome is often difficult due to the broad variability in clinical symptoms as well as the many different genetic explanations that cause this disease. Genetic testing for specific nuclear or mitochondrial DNA mutation is helpful in this regard.

Laboratory studies can assist in the diagnosis of Leigh syndrome. A muscle biopsy often determines if there are abnormalities associated with the mitochondria. Additionally, as the mitochondria are responsible for producing energy, a deficiency in a protein complex that has an important function in the mitochondria is often detected. In Leigh syndrome, this deficiency is found in one of five complexes that make up the mitochondrial respiratory system. One of these complexes, complex IV, or cytochrome c oxidase (COX), is commonly deficient. Although a COX deficiency is associated with Leigh syndrome, it can also indicate other mitochondrial abnormalities. Similarly, there are mutations found in other complexes that can cause Leigh syndrome.

Treatment team

Treatment for Leigh syndrome is aimed at easing the disease-related symptoms and involves neurologists, pediatricians, clinical geneticists, nurses, and other related caretakers. Psychological counseling and support for family members caring for a child with Leigh disease is often encouraged.

Treatment

Currently, there is no treatment that is effective in slowing the progression of Leigh disease. Thiamine or vitamin B1 is usually given. Sodium bicarbonate may also be prescribed to help manage lactic acidosis.

Recovery and rehabilitation

As there is no cure for Leigh disease and the nature of the disorder is rapidly progressive, maintaining function for as long as possible is the primary focus rather than recovery. Physical therapists often assist in exercises designed to maintain strength and range of motion. As the disease progresses, occupational therapists can provide positioning devices for comfort.

Clinical trials

As of early 2004, there are no clinical trials to treat or cure Leigh syndrome. However, studies are underway to better understand all mitochondrial diseases in an effort to identify treatments and, eventually, a cure.

Prognosis

Soon after the onset of symptoms, the progression of Leigh disease is unrelentingly rapid. Death usually occurs from respiratory failure within two years following the initial symptoms, and usually by age six.

Resources

BOOKS

Icon Health Publicaitons. The Official Parent's Sourcebook on Leigh's Disease: A Revised and Updated Directory for the Internet Age. San Diego: Icon Group International, 2002.

PERIODICALS

Schmiedel, J., S. Jackson, J. Schafer, and H. Reichmann. "Mitochondrial Cytopathies." Neurol. 250, no. 3 (March 2003): 267–77.

DiMauro, S., A. L. Andreu, and D. C. De Vivo. "Mitochondrial Disorders." J Child Neurol. 17, Suppl. 3 (December 2002): 3S35–45; 3S46–47.

OTHER

"NINDS Leigh's Disease Information Page." National Institute of Neurological Disorders and Stroke. February 10, 2004 (April 4, 2004). <http://www.ninds.nih.gov/health_and_medical/disorders/leighsdisease_doc.htm>.

ORGANIZATIONS

The National Leigh's Disease Foundation. P.O. Box 2222, Corinth, MS 38834. (601) 286-2551 or (800) 819-2551.

United Mitochondrial Disease Foundation. 8085 Saltsburg Road, Suite 201, Pittsburgh, PA 15239. (412) 793-8077; Fax: (412) 793-6477. [email protected]. <http://www.umdf.org/>.

Bryan Richard Cobb, PhD