Leigh syndrome

Definition

Leigh syndrome is a rare inherited neurometabolic disorder characterized by degeneration of the central nervous system (brain, spinal cord, and optic nerve), meaning that it gradually loses its ability to function properly.

Description

First described in 1951, Leigh syndrome usually occurs between the ages of three months and two years. The disorder worsens rapidly; the first signs may be loss of head control, poor sucking ability and loss of previously acquired motor skills, meaning the control of particular groups of muscles. Loss of appetite, vomiting, seizures, irritability, and/or continuous crying may accompany these symptoms. As the disorder becomes worse, other symptoms such as heart problems, lack of muscle tone (hypotonia), and generalized weakness may develop, as well as lactic acidosis, a condition by which the body produces too much lactic acid. In rare cases, Leigh syndrome may begin late in adolescence or early adulthood, and in these cases, the progression of the disease is slower than the classical form.

The disorder usually occurs in three stages, the first between eight and 12 months involving vomiting and failure to thrive, the second in infancy, characterized by loss of motor ability, eye problems and respiratory irregularity. The third stage occurs between two and 10 years of age and is characterized by hypotonia and feeding difficulties.

In most cases, Leigh syndrome is inherited as an autosomal recessive genetic trait. However, X-linked recessive, autosomal dominant, and mitochondrial inheritance can also occur. Several different types of genetic enzyme defects are thought to cause Leigh syndrome, meaning that the disorder may be caused by defective enzymes, the proteins made by the body to speed up the biochemical reactions required to sustain life.

Commonly known as Leigh's disease, Leigh syndrome is also known as Leigh necrotizing encephalopathy, necrotizing encephalomyelopathy of Leigh's and subacute necrotizing encephalopathy (SNE). When it occurs in adolescence and adulthood, it may be called adult-onset subacute necrotizing encephalomyelopathy.

Genetic profile

Several different types of genetic metabolic defects are thought to lead to Leigh syndrome. A deficiency of one or a number of different enzymes may be the cause.

Classic Leigh syndrome

The usual form of Leigh syndrome is inherited as an autosomal recessive genetic trait. It has been linked to a genetic defect in one of two genes known as E2 and E3, which cause either a deficiency of the enzyme pyruvate dehydrogenase, or an abnormality in other enzymes that make pyruvate dehydrogenase work. Other cases of autosomal recessive Leigh syndrome are associated with other genetic enzyme deficiencies (i.e., NADH-CoQ and Cytochrome C oxidase), although the gene or genes responsible for these deficiencies are not known. All of these different genetic defects seem to have a common effect on the central nervous system.

In autosomal recessive inheritance, a single abnormal gene on one of the autosomal chromosomes (one of the first 22 "non-sex" chromosomes) from both parents can cause the disease. Both of the parents must be carriers in order for the child to inherit the disease and neither of the parents has the disease (since it is recessive).

A child whose parents are carriers of the disease has a 25% chance of having the disease; a 50% chance of being a carrier of the disease, meaning that he is not affected by the disease, and a 25% chance of receiving both normal genes, one from each parent, and being genetically normal for that particular trait.

X-linked Leigh syndrome

Evidence also exists for an X-linked recessive form of Leigh syndrome, which has been linked to a specific defect in a gene called E1-alpha, a part of the enzyme pyruvate dehydrogenase.

X-linked recessive disorders are conditions that are coded on the X chromosome . All humans have two chromosomes that determine their gender: females have XX, males have XY. X-linked recessive, also called sexlinked, inheritance affects the genes located on the X chromosome. It occurs when an unaffected mother carries a disease-causing gene on at least one of her X chromosomes. Because females have two X chromosomes, they are usually unaffected carriers. The X chromosome that does not have the disease-causing gene compensates for the X chromosome that does. Generally for a woman to have symptoms of the disorder, both X chromosomes would have the disease-causing gene. That is why women are less likely to show such symptoms than males.

If a mother has a female child, the child has a 50% chance of inheriting the disease gene and being a carrier who can pass the disease gene on to her sons. On the other hand, if a mother has a male child, he has a 50% chance of inheriting the disease-causing gene because he has only one X chromosome. If a male inherits an X-linked recessive disorder, he is affected. All of his daughters will also be carriers.

Mitochondrial Leigh syndrome

Evidence also exists that Leigh syndrome may be inherited in some cases from the mother as a DNA mutation inside mitochondria. Hundreds of tiny mitochondria are contained in every human cell. They control the production of cellular energy and carry the genetic code for this process inside their own special DNA, called mtDNA. The mtDNA instructions from the father are carried by sperm cells, and during fertilization, these instructions break off from the sperm cell and are lost. All human mtDNA, therefore comes from the mother. The specific mtDNA defect that is thought to be responsible for some cases of Leigh syndrome, mtDNA nt 8993, is associated with the ATPase 6 gene. An affected mother passes it along to all of her children, but only the daughters will pass the mutation onto the next generation.

When mutations occur on mtDNA, the resulting genes may outnumber the normal ones. And until mutations are present in a significant percentage of the mitochondria, symptoms may not occur. Uneven distribution of normal and mutant mtDNA in different tissues of the body means that different organ systems in individuals from the same family may be affected, and a variety of symptoms may result in affected family members.

Adult–onset Leigh syndrome

In cases of adult-onset Leigh syndrome, the disorder may be inherited in yet another way, as an autosomal dominant genetic trait. In autosomal dominant inheritance, a single abnormal gene on one of the autosomal chromosomes (one of the first 22 "non-sex" chromosomes) from either parent can cause the disease. One of the parents will have the disease (since it is dominant) and will be the carrier. Only one parent needs to be a carrier in order for the child to inherit the disease. A child who has one parent with the disease has a 50% chance of also having the disease.

Demographics

Leigh syndrome is very rare. It is thought that the classic form of the disorder accounts for approximately 80% of cases and affects males and females in equal numbers. In both X-linked Leigh syndrome and adult-onset Leigh syndrome, almost twice as many males as females are affected. In adult-onset cases, progression of the disease is slower than the classical form.

Signs and symptoms

The symptoms of developmental delay, hypotonia, and lactic acidosis are present in almost all cases of Leigh syndrome. Other symptoms that may occur with the disorder are:

• Respiratory: Hyperventilation, breathing arrest (apnea), shortness of breath (dyspnea), respiratory failure. Respiratory disturbance may occur in as many as 70% of cases.
• Neurological: Muscle weakness, clumsiness, shaking, failure of muscular coordination (ataxia).
• Ocular: Abnormal eye movements, sluggish pupils, blindness.
• Cardiovascular: heart disease and malformation.
• Seizures may also occur.

Diagnosis

The diagnosis of Leigh syndrome is usually made by clinical evaluation and a variety of tests.

Advanced imaging techniques

The main body part affected is the nerve cells (gray matter) of the brain with areas of dead nerve cells (necrosis) and cell multiplication (capillary proliferation) in the lowest part of the brain (brain stem). A CT scan or magnetic resonance imaging MRI of the brain may reveal these abnormalities. Also, cysts may be present in the outer portion of the brain (cerebral cortex).

Laboratory testing

Biochemical findings are high levels of pyruvate and lactate in the blood and slightly low sugar (glucose) levels in the blood and cerebrospinal fluid (CSF), a clear fluid that bathes the brain and spinal cord. Laboratory tests may reveal high levels of acidic waste products in the blood, indicative of lactic acidosis as well as high levels of pyruvate and alanine. The enzyme pyruvate carboxylase may be absent from the liver. An inhibitor of thiamine triphosphate (TTP) production may be present in the blood and urine of affected individuals. Blood glucose may be somewhat lower than normal. Some children with the disorder may have detectable deficiencies of the enzymes pyruvate dehydrogenase complex or cytochrome C oxidase.

Related disorders

Symptoms of other disorders are very similar to those of Leigh syndrome, and comparisons may be useful to distinguish between them. These disorders are:

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

Prenatal testing

Genetic counseling may be of benefit for families with a history of Leigh syndrome. Prenatal testing is available to assist in prenatal diagnosis. Prior testing of family members is usually necessary for prenatal testing.

Either chorionic villus sampling (CVS) or amniocentesis may be performed for prenatal testing. CVS is a procedure to obtain chorionic villi tissue for testing. Examination of fetal tissue can reveal information about the changes that lead to Leigh syndrome. Chorionic villus sampling can be performed at 10–12 weeks pregnancy.

Amniocentesis is a procedure that involves inserting a thin needle into the uterus, into the amniotic sac, and withdrawing a small amount of amniotic fluid. DNA can be extracted from the fetal cells contained in the amniotic fluid and tested. Amniocentesis is performed at 15–18 weeks pregnancy.

Tissue obtained from CVS or in amniotic fluid that shows evidence of the genetic abnormalities responsible for Leigh syndrome confirms the diagnostic. Other forms of prenatal testing may be available for Leigh syndrome.

Treatment and management

The most common treatment for the disorder is the prescription of thiamine or vitamin B1. This may result in a temporary improvement of the symptoms and slightly slow the progress of the disease.

Patients lacking the pyruvate dehydrogenase enzyme complex may benefit from a high-fat, low-carbohydrate diet.

To treat lactic acidosis, oral sodium bicarbonate or sodium citrate may also be prescribed. To control severe lactic acidosis, intravenous infusion of tris-hydroxy-methyl aminomethane (THAM) may be beneficial. Both treatments help reduce abnormally high acid levels in the blood and the accumulation of lactic acid in the brain.

If eye problems occur, the individual with Leigh syndrome may benefit from treatment from an ophthalmologist.

Treatment should also include assistance with locating support resources for the family and the individual with Leigh syndrome.

Prognosis

Prognosis for individuals with classical Leigh syndrome is poor. Death usually occurs within a few years, although patients may live to be 6 or 7 years of age. Some patients have survived to the mid-teenage years. Children who survive the first episode of the disease may not fully recover physically and neurologically. In addition, they are likely to face successive bouts of devastating illness that ultimately cause death.

Resources

BOOKS

Jorde, L. B., et al., eds. Medical Genetics. 2nd ed. St. Louis: Mosby, 1999.

ORGANIZATIONS

Arc (a National Organization on Mental Retardation). 1010 Wayne Ave., Suite 650, Silver Spring, MD 20910. (800) 433-5255. <http://www.thearclink.org>.

Association for Neuro-Metabolic Disorders. 5223 Brookfield Lane, Sylvania, OH 43560-1809. (419) 885-1497.

Children Living with Inherited Metabolic Diseases. The Quadrangle, Crewe Hall, Weston Rd., Crewe, Cheshire, CW1-6UR. UK 127 025 0221. Fax: 0870-7700-327. <http://www.climb.org.uk>.

Children's Brain Disease Foundation. 350 Parnassus Ave., Suite 900, San Francisco, CA 94117. (415) 566-5402.

Epilepsy Foundation of America. 4351 Garden City Dr., Suite 406, Landover, MD 20785-2267. (301) 459-3700 or (800) 332-1000. <http://www.epilepsyfoundation.org>.

Lactic Acidosis Support Trust. 1A Whitley Close, Middlewich, Cheshire, CW10 0NQ. UK (016) 068-37198.

March of Dimes Birth Defects Foundation. 1275 Mamaroneck Ave., White Plains, NY 10605. (888) 663-4637. resourcecenter@modimes.org. <http://www.modimes.org>.

National Institute of Neurological Disorders and Stroke. 31 Center Drive, MSC 2540, Bldg. 31, Room 8806, Bethesda, MD 20814. (301) 496-5751 or (800) 352-9424. <http://www.ninds.nih.gov>.

National Organization for Rare Disorders (NORD). PO Box 8923, New Fairfield, CT 06812-8923. (203) 746-6518 or (800) 999-6673. Fax: (203) 746-6481. <http://www.rarediseases.org>.

United Mitochondrial Disease Foundation. PO Box 1151, Monroeville, PA 15146-1151. (412) 793-8077. Fax: (412) 793-6477. <http://www.umdf.org>.

WEBSITES

Online Mendelian Inheritance in Man. <http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?db=OMIM>.

Jennifer F. Wilson, MS