Information on the following diseases can be found in the Related Disorders section of this report:

• Wernicke encephalopathy
• Kufs disease
• Batten disease
• Tay-Sachs disease
• Sandhoff disease
• Niemann-Pick disease
• Alpers disease

The symptoms of classical Leigh's disease (infantile necrotizing encephalopathy), a rapidly progressive neurological disorder, usually begin between the ages of 3 months and 2 years. In most children, the first noticeable sign is the loss of previously acquired motor skills. When there is early onset (i.e., 3 months), loss of head control and poor sucking ability may be the first noticeable symptoms. This may be accompanied by a profound loss of appetite, recurrent vomiting, irritability, continuous crying and possible seizure activity. Delays in reaching developmental milestones may also occur. Affected infants may fail to grow and gain weight at the expected rate (failure to thrive).

If the onset of Leigh's disease is later in infancy (i.e., 24 months), affected children may experience difficulty articulating words (dysarthria) and coordinating voluntary movements such as walking or running (ataxia). Previously acquired intellectual skills may diminish and mental retardation may also occur.

Progressive neurological deterioration associated with Leigh's disease is marked by a variety of symptoms including generalized weakness, lack of muscle tone (hypotonia), clumsiness, tremors, muscle spasms (spasticity) that result in slow, stiff movements of the legs, and/or the absence of tendon reflexes. Further neurological development is delayed.

Episodes of lactic acidosis may occur and are characterized by abnormally high levels of acidic waste products in the blood, brain, and other tissues of the body. Periodically, levels of carbon dioxide in the blood may also be abnormally elevated (hypercapnia). Lactic acidosis and hypercapnia can lead to psychomotor regression and respiratory, heart, or kidney impairment.

Children with Leigh's disease usually develop respiratory problems including the temporary cessation of spontaneous breathing (apnea), difficulty breathing (dysapnea), abnormally rapid breathing (hyperventilation), and/or abnormal breathing patterns (Cheyne-Stokes). Some infants may also experience difficulty swallowing (dysphagia). Visual problems may include abnormally rapid eye movements (nystagmus), sluggish pupils, crossed eyes (strabismus), paralysis of certain eye muscles (ophthalmoplegia), deterioration of the nerves of the eyes (optic atrophy), and/or visual impairment leading to blindness.

Leigh's disease may also affect the heart. Some children with this disorder may have abnormal enlargement of the heart (hypertrophic cardiomyopathy) and overgrowth of the fibrous membrane that divides the various chambers of the heart (asymmetric septal hypertrophy). Disease affecting the nerves outside of the central nervous system (peripheral neuropathy) may eventually occur, causing progressive weakness of the arms and legs.

The symptoms of the X-linked infantile form of Leigh's disease are similar to those of classical Leigh's disease. The symptoms of the adult-onset form of Leigh's disease (subacute necrotizing encephalomyelopathy), a very rare form of the disorder, generally begin during adolescence or early adulthood. Initial symptoms are generally related to vision and may include such abnormalities as blurred "filmy" central visual fields (central scotoma), colorblindness, and/or progressive visual loss due to degeneration of the optic nerve (bilateral optic atrophy). The neurological problems associated with the disease progress slowly in this form of the disorder. At about 50 years of age, affected individuals may find it progressively difficult to coordinate voluntary movements (ataxia). Additional late symptoms may include partial paralysis and involuntary muscle movements (spastic paresis), sudden muscle spasms (clonic jerks), grand mal seizures, and/or varying degrees of dementia.

Several different types of genetically determined metabolic defects can lead to Leigh's disease. Leigh’s disease may be caused by a deficiency of one or a number of different enzymes (e.g., mitochondrial respiratory chain enzymes or enzymes of the pyruvate dehydrogenase complex). These enzyme deficiencies are caused by changes (mutations) in one of several different disease genes (genetic heterogeneity). These mutations may be inherited as an autosomal recessive trait, an X-linked recessive trait, or as a mutation found within the DNA of mitochondria. In some cases of Leigh’s disease, no genetic cause can be identified.

The classical form of Leigh's disease is inherited as an autosomal recessive trait and has been linked to a genetic defect in one of several different genes. These genes cause either a deficiency of the enzyme pyruvate dehydrogenase, or an abnormality in other enzymes that activate pyruvate dehydrogenase.

Genetic diseases are determined by two genes, one received from the father and one from the mother. Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25 percent with each pregnancy. The risk to have a child who is a carrier like the parents is 50 percent with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25 percent.

Other genetically based enzyme deficiencies (i.e., NADH-CoQ and cytochrome C oxidase) have also been implicated as a cause of some cases of autosomal recessive Leigh's disease. These specific enzyme deficiencies have been linked to several different genes. For example, mutations of the SURF1 gene located on chromosome 9 causes Leigh’s disease associated with cytochrome C oxidase deficiency. All of these different genetic defects seem to have a common effect on the central nervous system, resulting in progressive neurological deterioration.

There is also evidence in the medical literature for an X-linked recessive form of Leigh's disease. This form of the disease has been linked to a specific genetic defect in a gene known as E1-alpha subunit of the pyruvate dehydrogenase complex that is located on the short arm (p) of the X chromosome (Xp22.2-22.1). X-linked recessive disorders are conditions that are coded on the X chromosome. Females have two X chromosomes, but males have one X chromosome and one Y chromosome. Therefore, in females, disease traits on the X chromosome can be masked by the normal gene on the other X chromosome. Since males only have one X chromosome, if they inherit a gene for a disease present on the X, it will be expressed. Men with X-linked disorders transmit the gene to all their daughters, who are carriers, but never to their sons. Women who are carriers of an X-linked disorder have a 50 percent risk of transmitting the carrier condition to their daughters, and a 50 percent risk of transmitting the disease to their sons.

In some cases, Leigh's disease may be inherited from the mother as a mutation (change in genetic material) found within the DNA of mitochondria. Mitochondria, found by the hundreds within every cell of the body, regulate the production of cellular energy and carry the genetic blueprints for this process within their own unique DNA (mtDNA). The mitochondrial DNA instructions from the father are carried by sperm cells. During the process of fertilization, these instructions break off from the sperm cell and are lost. As a result, all human mtDNA comes from the mother. An affected mother will pass the traits to all of her children, but only the daughters will pass the mutation(s) onto the next generation.

The genetic mutations that are present in the mtDNA may outnumber the normal copies of the genes. Symptoms may not occur until mutations are present in a significant percentage of the mitochondria. The uneven distribution of normal and mutant mtDNA in different tissues of the body can affect different organ systems in individuals from the same family and can result in a variety of symptoms in affected family members.

The specific mtDNA defect that may be responsible for some cases of Leigh's disease (mtDNA nt 8993) is associated with a gene known as ATPase 6 (complex V deficiency of the mitochondrial respiratory chain [ATPase deficiency]). These cases are sometimes referred to as maternally inherited Leigh’s syndrome (MILS) or mtDNA-associated Leigh’s disease.

Some researchers believe that cases of adult-onset Leigh's disease may be inherited as an autosomal dominant trait. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child.

The classical form of Leigh's disease develops during infancy (infantile necrotizing encephalopathy) and usually begins between the ages of 3 months and 2 years. This form of the disease affects males and females in equal numbers.

In cases of Leigh's disease that are inherited as an X-linked recessive trait, the symptoms typically develop during infancy. Almost twice as many males as females are affected by this form of the disease.

In some rare cases, Leigh's disease may begin during late adolescence or early adulthood (adult-onset subacute necrotizing encephalomyelopathy). In these cases, which affect twice as many males as females, the progression of the disease is slower than the classical form of the disease.

Researchers once believed that the classical form of Leigh’s disease accounted for approximately 80 percent of cases. Recently, however, researchers have determined that mtDNA-associated Leigh’s disease occurs more often than originally believed and may account for as much as 30 percent of cases of Leigh’s disease. In the medical literature, the prevalence of Leigh’s disease has been estimated at 1 in 36,000-40,000 live births.

Symptoms of the following disorders can be similar to those of Leigh's disease. Comparisons may be useful for a differential diagnosis:

Wernicke syndrome and Korsakoff syndrome are related disorders that often occur due to a deficiency of thiamine (vitamin B1). Wernicke’s syndrome, also known as Wernicke encephalopathy, is a neurological disease characterized by the clinical triad of confusion, the inability to coordinate voluntary movement (ataxia), and eye (ocular) abnormalities. Korsakoff’s syndrome is a mental disorder characterized by disproportionate memory loss in relation to other mental aspects. When these two disorders occur together, the term Wernicke-Korsakoff syndrome is used. In the United States, most cases occur in alcoholics. Some researchers believe Wernicke and Korsakoff syndromes are separate yet related disorders; others believe them to be different stages of the same disorder or disease spectrum. Wernicke syndrome is considered the acute phase with a shorter duration and more serious symptoms. Korsakoff syndrome is considered the chronic phase and is a long-lasting condition. (For more information on this disorder, choose "Wernicke" as your search term in the Rare Disease Database.)

Batten disease, a rare genetic disorder, belongs to a group of progressive degenerative neurometabolic disorders known as the neuronal ceroid lipofuscinoses. These disorders share certain similar symptoms and are distinguished in part by the age at which such symptoms appear. Batten disease is considered the juvenile form of the neuronal ceroid lipofuscinoses (NCLs). The NCLs are characterized by abnormal accumulation of certain fatty, granular substances (i.e., pigmented lipids [lipopigments] ceroid and lipofuscin) within nerve cells (neurons) of the brain as well as other tissues of the body that may result in progressive deterioration (atrophy) of certain areas of the brain, neurological impairment, and other characteristic symptoms and physical findings. The symptoms of Batten disease usually become apparent between 5 and 15 years of age when progressive loss of vision, seizures, and progressive neurological degeneration develop. In some cases, initial symptoms may be more vague and include clumsiness, balance problems and behavioral or personality changes. Batten disease is inherited as an autosomal recessive trait and occurs most in families of Northern European or Scandinavian ancestry. (For more information on this disorder, choose "Batten" as your search term in the Rare Disease Database.)

Tay-Sachs disease is a rare, neurodegenerative disorder in which deficiency of an enzyme (hexosaminidase A) results in excessive accumulation of certain fats (lipids) known as gangliosides in the brain and nerve cells. This abnormal accumulation of gangliosides leads to progressive dysfunction of the central nervous system. This disorder is categorized as a lysosomal storage disease. Lysosomes are the major digestive units in cells. Enzymes within lysosomes break down or "digest" nutrients, including certain complex carbohydrates and fats. Symptoms associated with Tay-Sachs disease may include an exaggerated startle response to sudden noises, listlessness, loss of previously acquired skills (i.e., psychomotor regression), and severely diminished muscle tone (hypotonia). With disease progression, affected infants and children may develop cherry-red spots within the middle layer of the eyes, gradual loss of vision, and deafness, increasing muscle stiffness and restricted movements (spasticity), eventual paralysis, uncontrolled electrical disturbances in the brain (seizures), and deterioration of cognitive processes (dementia). The classical form of Tay-Sachs disease occurs during infancy; an adult form (late-onset Tay-Sachs disease) may occur anytime from adolescence to the mid 30s. Tay-Sachs disease is inherited as an autosomal recessive trait. (For more information on this disorder, choose "Tay-Sachs" as your search term in the Rare Disease Database.)

Neuropathy, ataxia and retinitis pigmentosa (NARP) syndrome is a rare genetic disorder. It is characterized by nerve disease affecting the nerves outside of the central nervous system (peripheral neuropathy), an impaired ability to coordinate voluntary movements (ataxia), an eye condition known as retinitis pigmentosa (RP), and a variety of additional abnormalities. RP is a general term for a group of vision disorders that cause progressive degeneration of the membrane lining the eyes (retina) resulting in visual impairment. The specific symptoms of NARP syndrome in each individual vary greatly from case to case. The disorder is a maternally inherited mitochondrial disease. NARP syndrome is caused by a specific mutation affecting the mitochondrial gene known as the ATPase 6 gene. This mutation can also cause a specific subtype of Leigh’s disease known as maternally inherited Leigh’s syndrome (MILS). In fact, when individuals have more than 90 percent of mutated mitochondrial DNA (mtDNA) in their cells, they are classified as having MILS and not NARP syndrome. Most individuals with NARP syndrome have 70-80 percent of mutated mtDNA. (For more information on this disorder, choose "NARP" as your search term in the Rare Disease Database.)

Diagnosis
The diagnosis of Leigh's disease may be confirmed by a thorough clinical evaluation and a variety of specialized tests, particularly advanced imaging techniques. Magnetic resonance imaging (MRI) or computed tomography (CT) scans of the brain may reveal abnormal areas in certain parts of the brain (i.e., basal ganglia, brain stem, and gray matter). An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures.

Small or large cysts may be present in the cerebral cortex of the brain. Laboratory tests may reveal high levels of acidic waste products in the blood (lactic acidosis) as well as elevated levels of pyruvate and alanine. Blood sugar (glucose) may be slightly lower than normal. The enzyme pyruvate carboxylase may be absent from the liver and an inhibitor of thiamine triphosphate (TTP) production may be present in the blood and urine of affected individuals. Some children with Leigh's disease may have detectable deficiencies of the enzymes pyruvate dehydrogenase complex or cytochrome C oxidase.

Treatment
The treatment of Leigh’s disease is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, cardiologists, neurologists, specialists who assess and treat hearing problems (audiologists), eye specialists, and other health care professionals may need to systematically and comprehensively plan an effective child’s treatment.

The most common treatment for Leigh's disease is the administration of thiamine (Vitamin B1) or thiamine derivatives. Some people with this disorder may experience a temporary symptomatic improvement and a slight slowing of the progression of the disease. In those patients with Leigh's disease who also have a deficiency of pyruvate dehydrogenase enzyme complex, a high fat, low carbohydrate diet may be recommended.

Oral sodium bicarbonate or sodium citrate may be prescribed for some children with Leigh's disease to help reduce abnormally high acid levels in the blood and to reduce the accumulation of lactic acid in the brain. The intravenous infusion of tris-hydroxymethyl aminomethane (THAM) may help to control acute episodes of lactic acidosis. This medication may avoid the sodium overload that is frequently associated with the administration of sodium bicarbonate.

Services that benefit people who are visually impaired may also be helpful for some people with Leigh's disease. Genetic counseling is recommended for families of affected individuals with this disorder. Other treatment is symptomatic and supportive.

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
Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, in the main, contact:
www.centerwatch.com

Research is ongoing into possible causes of biochemical and genetic factors that may contribute to the development of Leigh's disease.

Clinical trials are underway to study stable isotope technique in glucogenesis and Krebs cycle, and patient response to treatment. Interested persons may wish to contact:

W.N. Paul Lee, M.D.
Harbor University of CA
Los Angeles Medical Center
Dept. of Pediatrics, Box 16
1000 W. Carson St.
Torrance, CA 90509
(310) 533-2503

Researchers at the University of Florida are conducting an ongoing clinical trial to investigate the long-term safety and effectiveness of dichloroacetate (DCA) for the treatment of children, between the ages of three months and 18 years, affected by various forms of congenital lactic acidosis (CLA). DCA is an investigational drug that may benefit children with CLA by decreasing the acidity in their blood and by preventing or decreasing neurological damage. Congenital lactic acidosis is characterized by excessive amounts of lactic acid in the blood that may occur in association with a number of diseases including: Pyruvate Dehydrogenase (PDH) Deficiency, Complex I Abnormalities, Complex IV Abnormalities, Cytochrome C Oxidase (COX) Deficiency, Leigh's Disease, Neuropathy Ataxia and Retinitis Pigmentosa (NARP) , Myoclonic Epilepsy and Ragged-Red Fibers (MERRF), and Mitochondrial Encephalopathy with Lactic Acidosis and Stroke-like Episodes (MELAS) . In addition to the clinical studies, the University has an international registry of individuals and families affected by congenital lactic acidosis. For more information on this study, contact:

Leigh Ann Perkins, R.N.
Nurse Coordinator
DCA/CLA Clinical Trial
University of Florida
Box 100226
Gainesville, FL 32610
Tel: (352) 392-2321
Fax: (352) 846-0990
email: perkila@medicine.ufl.edu
http://cla-dca.gcrc.ufl.edu

L-Carnitine and Coenzyme Q10 are being tested as a possible treatments for mitochondrial disorders. More studies are needed to determine the long-term safety and effectiveness of these treatments.

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Rahman S, et al., Leigh syndrome: clinical features and biochemical and DNA abnormalities. Ann Neurol. 1996;39:343-51.

Robinson BH. Prenatal diagnosis of mitochondrial disease. Mitochondrial News. 1999;4.

Zhu Z, et al., SURF1, encoding a factor involved in the biogenesis of cytochrome c oxidase, is mutated in Leigh syndrome. Nat Genet. 1998;20:337-43.

Thorburn DR. Leigh syndome: clinical features and biochemical and DNA abnormalities. Mitochondrial News. 1998;3:1, 7-10.

Santorelli FM, The mutation at nt 8993 of mitochondrial DNA is a common cause of Leigh's syndrome. Ann Neurol. 1993;34:827-34.

Matthews PM, et al., Molecular genetic characterization of an X-linked form of Leigh's syndrome. Ann Neurol. 1993;33:652-5.

Ciafaloni E, et al., Maternally inherited Leigh syndrome. J Pediatr. 1993;122:419-22.

Morris SA, et al., Infant onset subacute necrotizing encephalomyelopathy (leigh's disease). J Paediatr Child Health. 1993;29:363-7.

Macaya A, et al., Disorders of movement in Leigh syndrome. Neuropediatrics. 1993;24:60-7.

Tatch Y, et al., Heteroplasmic mtDNA mutation (T----G) AT 8993 can cause Leigh disease when the percentage of abnormal mtDNA is high. Am J Hum Genet.1992;50:852-8.

Sperl W, et al., Diagnostic criteria in classical infantile subacute necrotizing encephalomyelopathy (Leigh's disease). Klin Padiatr. 1989;201:86-92.

Fulham M, et al., Diagnostic clues in an adult case of Leigh's disease. Med J Aust. 1988;149:320-2.

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FROM THE INTERNET
Thornburn DR, Rahman S. Updated:02/03/2006. Mitochondrial DNA-Associated Leigh Disease and NARP. In: GeneReviews at GeneTests: Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997-2003. Available at http://www.genetests.org.

Lombes A. Leigh Disease. Orphanet encyclopedia, July 2006. Available at: http://www.orpha.net/consor/cgi-bin/OC_Exp.php?Lng=GB&Expert=506 Accessed on: August 30, 2006.

McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:256000; Last Update:03/17/2006. Available at: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=256000 Accessed on: August 30, 2006.

McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:308930; Last Update:07/15/2006. Available at: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=308930 Accessed on: August 30, 2004.

McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:161700; Last Update:02/23/2000. Available at: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=161700 Accessed on: August 30, 2004.

National Institute of Neurological Disorders and Stoke (NINDS). Leigh’s Disease Information Page. February 7, 2006. Available at: http://www.ninds.nih.gov/disorders/leighsdisease/leighsdisease.htm Accessed On: August 30, 2006.