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Leigh Syndrome

NORD is very grateful to Peter W. Stacpoole, PhD, MD, Professor of Medicine, Biochemistry and Molecular Biology, College of Medicine, University of Florida, for assistance in the preparation of this report.

Synonyms of Leigh Syndrome

  • classical Leigh syndrome
  • Leigh necrotizing encephalopathy
  • Leigh's disease
  • necrotizing encephalomyelopathy of Leigh's
  • SNE
  • subacute necrotizing encephalopathy

Disorder Subdivisions

  • adult-onset subacute necrotizing encephalomyelopathy
  • infantile necrotizing encephalopathy
  • X-linked infantile nectrotizing encephalopathy

General Discussion

Leigh syndrome is a rare genetic neurometabolic disorder. It is characterized by the degeneration of the central nervous system (i.e., brain, spinal cord, and optic nerve). The symptoms of Leigh syndrome usually begin between the ages of three months and two years. Symptoms are associated with progressive neurological deterioration and may include loss of previously acquired motor skills, loss of appetite, vomiting, irritability, and/or seizure activity. As Leigh syndrome progresses, symptoms may also include generalized weakness, lack of muscle tone (hypotonia), and episodes of lactic acidosis, which may lead to impairment of respiratory and kidney function.

Several different genetically determined enzyme defects can cause the syndrome, initially described over 60 years ago. Most individuals with Leigh syndrome have defects of mitochondrial energy production, such as deficiency of an enzyme of the mitochondrial respiratory chain complex or the pyruvate dehydrogenase complex. In most cases, Leigh syndrome is inherited as an autosomal recessive trait. However, X-linked recessive and mitochondrial inheritance are additional modes of transmission.

Symptoms

The symptoms of classical Leigh syndrome (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 syndrome is later in childhood (e.g., 24 months), a child 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 syndrome 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 lactic acid 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 syndrome 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 syndrome 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 syndrome are similar to those of classical Leigh syndrome. The symptoms of the adult-onset form of Leigh syndrome (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.

Causes

Several different types of genetically determined metabolic defects can lead to Leigh syndrome. The condition 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 syndrome, no genetic cause can be identified.

The classical form of Leigh syndrome 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 information is contained in two types of DNA: nuclear DNA (nDNA) is contained in the nucleus of a cell and is inherited from both biological parents. Mitochondrial DNA (mtDNA) is contained in the mitochondria of cells and is inherited exclusively from the child's mother. Genetic diseases due to nDNA mutations (change in genetic material), 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 nDNA-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 syndrome. These specific enzyme deficiencies have been linked to several different genes. For example, mutations of the SURF1 gene located on chromosome 9 causes Leigh syndrome 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 a nDNA X-linked recessive form of Leigh syndrome. This form of the disease has been linked to a specific 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 syndrome may be inherited from the mother as a mutation 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 mtDNA from the father is carried by sperm cells. However, during the process of fertilization, the father's mtDNA is 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 syndrome (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 syndrome (MILS) or mtDNA-associated Leigh syndrome.

Some researchers believe that cases of adult-onset Leigh syndrome may be inherited as an autosomal dominant trait, due to a nDNA mutation. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. Because the condition is due to a nDNA mutation, the abnormal gene can be inherited from either parent, or can be the result of a new nDNA mutation 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.

Affected Populations

The classical form of Leigh syndrome 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 syndrome 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 syndrome 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 syndrome accounted for approximately 80 percent of cases. In the medical literature, the prevalence of Leigh syndrome has been estimated at 1 in 36,000-40,000 live births.

Related Disorders

Symptoms of the following disorders can be similar to those of Leigh syndrome. 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 syndrome known as maternally inherited Leigh 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.)

Standard Therapies

Diagnosis
The diagnosis of Leigh syndrome 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 syndrome may have detectable deficiencies of the enzymes pyruvate dehydrogenase complex or cytochrome C oxidase.

Treatment
There are no proven therapies for Leigh Syndrome of any type and that treatment recommendations are based primarily on open label studies, case reports and personal observations. The treatment of Leigh syndrome 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 syndrome 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 syndrome who also have a deficiency of pyruvate dehydrogenase enzyme complex, a high fat, low carbohydrate diet may be recommended.

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

Investigational Therapies

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, contact:
www.centerwatch.com

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.

A phase three trial of coenzyme Q10 sponsored by the FDA Orphan Products division, Tishcon Corp and University of Florida Clinical Research Centers funded by the National Institutes of Health is on-going. For more information contact:

Kathryn St. Croix
Email: stcroixk@ufl.edu
Phone: (352) 273-9023

Contact for additional information about Leigh syndrome:

Peter W. Stacpoole, PhD, MD
Professor of Medicine, Biochemistry and Molecular Biology
College of Medicine
P.O. Box 100226
University of Florida
Gainesville, FL 32610
Phone: 352-273-9599
Fax: 352-273-9013

Leigh Syndrome Resources

NORD Member Organizations:

(To become a member of NORD, an organization must meet established criteria and be approved by the NORD Board of Directors. If you're interested in becoming a member, please contact Susan Olivo, Membership Manager, at solivo@rarediseases.org.)

Other Organizations:

References

TEXTBOOKS
Chakraborthy P, Feigenbaum A, Robinson B. Human Cytochrome Oxidase Deficiency. NORD Guide to Rare Disorders. Philadelphia, PA: Lippincott Williams & Wilkins: 2003:436.

Lyon G, Adams RD, Kolodny EH. Eds. Neurology of Hereditary Metabolic Diseases in Childhood. 2nd ed. New York, NY: McGraw-Hill Companies; 1996:94-9.

JOURNAL ARTICLES
Nesbitt V, Morrison PJ, Crushell E, et al. The clinical spectrum of the m.10191T>C mutation in complex I-deficient Leigh syndrome. Dev Med Child Neurol. 2012, In press. PMID: 22364517.

Tuppen HA, Hogan VE, He L, et al. The p.M292T NDUFS2 mutation causes complex I-deficient Leigh syndrome in multiple families. Brain. 2010;133(10):2952-63.

Friedman SD, Shaw DW, Ishak G, Gropman AL, Saneto RP. The use of neuroimaging in the diagnosis of mitochondrial disease. Dev Disabil Res Rev. 2010;16(2):129-35.

van Riesen AK, et al., Maternal segmental disomy in Leigh syndrome with cytochrome c oxidase deficiency caused by homozygous SURF1 mutation. Neuropediatrics. 2006;37:88-94.

Schiff M, Miné M, Brivet M, et al. Leigh's disease due to a new mutation in the PDHX gene. Ann Neurol. 2006;59(4):709-14.

Van Maldergem L, Trijbels F, DiMauro S, et al. Coenzyme Q-responsive Leigh's encephalopathy in two sisters. Ann Neurol. 2002;52(6):750-4.

Makino M, Horai S, Goto Y, Nonaka I. Mitochondrial DNA mutations in Leigh syndrome and their phylogenetic implications. J Hum Genet. 2000;45(2):69-75.

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

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

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.

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

INTERNET
Thorburn DR, Rahman S. (Updated May 3, 2011). Mitochondrial DNA-Associated Leigh Disease and NARP. In: GeneReviews at GeneTests: Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2012. Available at http://www.genetests.org. Accessed April 2, 2012.

Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Leigh Syndrome; LS. Entry No: 256000. Last Edited March 20, 2012. Available at: http://www.ncbi.nlm.nih.gov/omim/. Accessed April 2, 2012.

Leigh's Disease Information Page. National Institute of Neurological Disorders and Stroke (NINDS). http://www.ninds.nih.gov/disorders/leighsdisease/leighsdisease.htm. Last updated December 16, 2011. Accessed April 2, 2012.

Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Necrotizing Encephalomyelopathy, Subacute, Of Leigh, Adult. Entry No: 161700. Last Edited October 13, 2011. Available at: http://www.ncbi.nlm.nih.gov/omim/. Accessed April 2, 2012.

Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Leigh Syndrome, X-linked. Entry No: 308930. Last Edited March 31, 2009. Available at: http://www.ncbi.nlm.nih.gov/omim/. Accessed April 2, 2012.

Lombes A. Leigh Disease. Orphanet encyclopedia. http://www.orpha.net/consor/cgi-bin/OC_Exp.php?Lng=GB&Expert=506. Last Updated July 2006. Accessed April 2, 2012.

The information in NORD’s Rare Disease Database is for educational purposes only. It should never be used for diagnostic or treatment purposes. If you have questions regarding a medical condition, always seek the advice of your physician or other qualified health professional. NORD’s reports provide a brief overview of rare diseases. For more specific information, we encourage you to contact your personal physician or the agencies listed as “Resources” on this report.

Report last updated: 2013/03/20 00:00:00 GMT+0

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