Gale Encyclopedia of Genetic Disorder / Gale Encyclopedia of Genetic Disorders, Two Volume Set - Volume 1 - A-L - I

Leber congenital amaurosis

K E Y T E R M S

Autosomal recessive—A pattern of genetic inheritance where two abnormal genes are needed to display the trait or disease.

Braille—An alphabet represented by patterns of raised dots which may be felt with the fingertips. It is the main method of reading used by the blind today.

Carrier—A person who possesses a gene for an abnormal trait without showing signs of the disorder. The person may pass the abnormal gene on to offspring.

Computed tomography (CT) scan—An imaging procedure that produces a three-dimensional picture of organs or structures inside the body, such as the brain.

Electroretinography (ERG)—A diagnostic test that records electrical impulses created by the retina when light strikes it.

Mutation—A permanent change in the genetic material that may alter a trait or characteristic of an individual, or manifest as disease, and can be transmitted to offspring.

Occipital lobe—An anatomical subdivision, located at the back of the brain, that contains the visual cortex.

Oculo-digital reflex—A reflex causing an individual to press on their eyes with their fingers or fists.

Retina—The light-sensitive layer of tissue in the back of the eye that receives and transmits visual signals to the brain through the optic nerve.

Visual cortex—The area of the brain responsible for receiving visual stimuli from the eyes and integrating it to form a composite picture of an object.

not be confused with another disorder of sight, Leber optic atrophy, that was also discovered by Theodor Leber.

Genetic profile

Mutations in any one of at least six different gene groups may result in LCA. Each of the known genes produce proteins, which are located within the retinal rod and cone cells. These proteins participate in the detection of an incoming stimulus of light and the subsequent transmission of signals out of the retinal cells to the

visual cortex of the brain. The different types of LCA and the corresponding genetic abnormality is described in the table below. These six identified mutations likely account for less than half of all diagnosed cases of LCA, and thus, there are additional mutations resulting in LCA that remain to be discovered.

LCA is a genetic condition and can be inherited or passed on in a family. The genetic defects for the disorder are all inherited as autosomal recessive traits, meaning that two mutant genes of the same group are needed to display the disease. A person who carries one mutant gene does not display the disease and is called a carrier. A carrier has a 50% chance of transmitting the gene to their children, who must inherit the same defective gene from each parent to display the disease. Since there are different genes that are responsible for causing LCA, two individuals with different types of LCA will have an unaffected child, as it is impossible for the child to inherit two of the same type of defective genes from the parents.

Demographics

LCA has been reported to account for at least 5% of all cases of inborn blindness, but several reports suggest that is an underestimation. In 1957, scientific investigators reported that one form of LCA was responsible for 10% of blindness in Sweden. Several years later, similar rates of LCA were found in people living in the Netherlands. While this suggests that the geographical distribution of LCA is not uniform and may be higher in certain ethnic groups, a comprehensive study has never been performed.

Signs and symptoms

Because there are different types of LCA, there is considerable variation in the symptoms experienced by an affected infant. Most infants with LCA are often blind at birth or lose their sight within the first few years of life, however some people with LCA may have residual vision. In these patients, visual acuity is usually limited to the level of counting fingers or detecting hand motions or bright lights, and patients are extremely farsighted. There may be some small improvement in vision during the first decade of life as the visual system reaches maturity, but it is uncommon for children to be able to navigate without assistance or to be able to read print.

Other symptoms of LCA may include crossed eyes, sluggish pupils, rapid involuntary eye movements, unusual sensitivity to light, and the clouding of the lenses of the eyes. Many children with LCA habitually press on their eyes with their fists or fingers. This habitual pressing on the eyes is known as an oculo-digital reflex and

may represent an instinctual attempt to provide the eveloping visual cortex of the brain with a stimulus to replace the loss of normal visual stimuli. As a result of this behavior, the eyes may become thin and conical in shape and appear sunken or deep. In some cases, LCA is associated with hearing loss, epilepsy, decreased coordination, kidney problems, or heart abnormalities. Mental retardation may be present in approximately 20% of individuals affected with LCA.

Diagnosis

Infants are usually brought to medical attention within the first six months of life when parents note a lack of visual responsiveness and the unusual roving eye movements characteristic of the disease. As with any evidence of loss of vision, a prompt and thorough evaluation is initiated to determine the cause of the visual defect, and steps may include physical tests designed to measure brain and eye function, CT scans (a method using x rays controlled by a sophisticated computer) of the brain and eye, and even tests to look for genetic and metabolic causes of blindness.

Eye examinations of infants with LCA usually reveal a normal appearing retina. By early adolescence, however, various changes in the retinas of patients with LCA become readily apparent; blood vessels often become narrow and constricted, and a variety of color changes can also occur in the retina and its supportive tissue.

One of the most important tests in diagnosing LCA is called electroretinography (ERG). This test measures electrical impulses which are produced in the retina when light is sensed by the rod and cone cells. It is useful in distinguishing whether blindness is due to a problem in the retina versus a problem in the visual cortex of the brain. When ERG tests are performed on people with LCA, there is no recordable electrical activity arising from the eye, indicating the problem is based in the retina rather than in the brain.

Thus, an absence of activity on ERG, combined with the absence of diagnostic signs of other conditions which result in blindness, point to a diagnosis of LCA. Although several abnormal genes have been identified which are responsible for LCA, genetic analysis and prenatal diagnosis is rarely performed outside of research studies.

Treatment and management

Currently, there is no treatment for LCA, and thus, patient and family education and adaptive assistance is critical. Some people with remaining vision may benefit from vision-assistance technology such as electronic, computer-based, and optical aids, but severely visually-

TABLE 1

Location of genetic abnormality for specific types of Leber congenital amaurosis

impaired individuals often utilize traditional resources such as canes and companion-guide dogs. Orientation and mobility training, adaptive training skills, job placement and income assistance are available through hospital physical and occupation therapy programs and various community resources. It should be noted that up to 20% of patients with LCA may have associated mental retardation and will require additional adaptive and vocational assistance.

Most people with LCA are unable to read print and instead utilize braille, an alphabet represented by raised dots that can be felt with the fingertips. People with LCA often attend schools specially designed to meet the needs of visually-impaired students and may require modifications to their home and work environments in order to accommodate their low or absent vision. As almost all patients with LCA are legally blind, they will not be able to drive or operate heavy machinery. Genetic counseling may assist affected individuals with family planning.

Scientists have isolated several mutant genes that can each cause LCA. Ongoing scientific research is directed toward understanding how these genes function in the retina and toward locating the remaining genes that cause LCA. With this information, scientists can better develop a means of prevention and treatment. A dramatic example of this principle was provided in 2000, when researchers were able to restore vision in mice with LCA2. By giving oral doses of a chemical compound derived from vitamin A, the scientists were able to restore the animals’ visual functions to almost normal levels after just two days. The researchers report that they will attempt the same experiments in dogs with LCA2 before trying the treatment in humans. It should be noted that LCA2 causes only 10% of the known cases of LCA, and the treatment in this experimental study does not work for other types of LCA.

amaurosis congenital Leber

Lebers hereditary optic atrophy

Prognosis

While children born with LCA may have variable symptoms and differing levels of visual acuity, they can lead productive and healthy lives with adaptive training and assistance. In those patients who do not have associated problems with their brain, heart, or kidney, lifespan is approximately the same as the general population, otherwise the prognosis is variable and depends on the extent of the complication.

Resources

BOOKS

“Disorders of Vision” In Nelson Textbook of Pediatrics, edited by R. E. Behrman. Philadelphia: W. B. Saunders, 2000, pp. 1900-1928.

PERIODICALS

Dharmaraj, S. R., et al. “Mutational Analysis and Clinical Correlation in Leber Congenital Amaurosis.” Ophthalmic Genetics 21 (September 2000): 135-150.

Gamm, D. M., and A.T. Thliveris. “Implications of Genetic Analysis in Leber Congenital Amaurosis.” Archives of Ophthalmology 119 (March 2001): 426-427.

Lambert, S. R., A. Kriss, and D. Taylor. “Vision in Patients with Leber Congenital Amaurosis.” Archives of Ophthalmology 11 (February 1997): 293294.

Perrault, I. “Leber Congenital Amaurosis.” Molecular Genetics and Metabolism 68 (October 1999): 200-208.

ORGANIZATIONS

Foundation Fighting Blindness. Executive Plaza 1, Suite 800, 11350 McCormick Rd., Hunt Valley, MD 21031-1014. (888) 394-3937. http://www.blindness.org .

WEBSITES

“Entry 20400: Leber Congenital Amaurosis, Type 1.” OMIM—

Online Mendelian Inheritance in Man. http://www.ncbi

.nlm.nih.gov/entrez/dispomim.cgi?id 20400 .

Leber’s Links: Leber’s Congenital Amaurosis. http://www

.freeyellow.com/members4/leberslinks/index.html .

Oren Traub, MD, PhD

Lebers hereditary optic neuropathy see

Lebers hereditary optic atrophy

I Lebers hereditary optic atrophy

Definition

Lebers hereditary optic atrophy is a painless loss of central vision (blurring of objects and colors appearing

less vivid) that usually begins between the ages of 25 and 35 (but can occur at any age) and leads to legal blindness. Other minor problems may be present such as tremors, numbness or weakness in arms and legs, or loss of ankle reflexes. It was first described in 1871 by Theodore Leber and is the most common cause of optic atrophy.

Description

Lebers hereditary optic atrophy is also called Lebers hereditary optic neuropathy or LHON. The beginning of visual blurring in both eyes is called the acute phase of LHON. In about half the patients, both eyes are affected at the same time. In the remainder of patients, central vision is lost in one eye over a period of a few weeks, then a month or two later, the second eye is affected. Once both eyes are affected, a few weeks usually pass before the eyesight stops getting worse. Other less common patterns of central vision loss in LHON can be very sudden loss in both eyes, or very gradual loss occuring over several years. After the acute phase, there is rarely any significant change in eyesight during the remainder of the person’s life. People with LHON are usually left with some peripheral vision, which is seeing around the edges, or out of the corner of the eye. This final phase is called the atrophic phase because the optic discs are atrophic (cells have wasted away) and rarely change.

The optic disc is the center part of the retina (back of the eye) and is where the clearest vision—both in detail and color—comes from. The retina is what interprets what a person sees and sends this message to their brain, along the pathway known as the optic nerve. In LHON, both the retina and the optic nerve stop working properly. The rest of the eye works normally, so that light enters the eye through the pupil (black circle in the center of the iris, the colored part of the eye) as it should. However, even though the light is focused on the retina properly, in LHON, this information isn’t converted into signals for the brain to process. When a person wears prescription glasses, the purpose is to help focus light properly on the retina. In LHON, light is already focused as it should be, so glasses will not improve vision. Magnifying glasses and telescopes do help, however, because they make things look bigger. When a person looks through a magnifier or telescope they use more of their retina to see, and some undamaged cells of the retina may be able to provide some information to the brain.

Suddenly losing vision is a shock. Patients diagnosed with LHON may feel they have no useful sight left, and often, their family and friends treat them as the stereotypic blind person. In reality, LHON usually leaves an affected person with some useable vision. A variety of visual aids are available to enhance this.

atrophy optic hereditary Lebers

Lebers hereditary optic atrophy

• G3460A

Not all persons who have one of these mutations will develop LHON, since it is thought that additional genetic or environmental factors are necessary to develop central vision loss. In general, males with one of these mutations have a 40% lifetime risk to develop symptoms of LHON, while females have a 10% risk, although the actual risk varies slightly from mutation to mutation. In addition, the older a person in whom a mutation has been identified becomes without symptoms, the less likely they will lose their vision at all. If a person is going to experience vision loss from LHON, the majority of people with a mutation will express symptoms by the age of 50 years.

Environmental factors that can reduce the blood supply to the retina and optic nerve, and ‘trigger’ the vision loss in LHON to begin, include heavy drinking or smoking, exposure to poisonous fumes such as carbon monoxide, high levels of stress, and certain medications. A person in whom a mutation has been identified is considered more susceptible to some of these exposures and are advised not to smoke and to moderate their alcohol intake if they are asymptomatic.

The other important concept to understand in relation to mitochondrial disease is that mitochondria are only inherited from the mother. Therefore, a woman with a mitochondrial mutation (whether she has symptoms or not) will pass it to all of her offspring. Sons who inherit the mutation will not pass it to any of their children, while daughters who inherit the mutation will pass it to all of their children. This is in contrast to nuclear DNA, where half the genetic material is inherited from each parent.

Demographics

Males have LHON more often than females, however, females may develop LHON at a slightly older age and may have more severe symptoms, including a multiple sclerosis-like illness. Multiple sclerosis is a progressive degeneration of nerve cells that causes episodes of muscle weakness, dizziness, and visual disturbances, followed by remission. The onset of LHON usually occurs by 50 years if a mitochondrial DNA mutation is present, although it can present as late as the sixth or seventh decade of life.

Signs and symptoms

Symptoms of LHON include a painless sudden loss of central vision, both in visual detail and color, in both eyes over a period of weeks to months. Peripheral vision (seeing out of the corner of the eye) remains. Additional

symptoms involving the neurological system may be present such as tremors, numbness or weakness in arms or legs, or loss of ankle reflexes. Symptoms vary by gender and type of mutation present. The following mutations are frequently identified and well understood:

•G11778A—the most common mutation and usually the most severe vision loss

•T14484C—usually has the best long term prognosis or outcome

•G3460A—has an intermediate presentation

Persons who have a multiple sclerosis-like illness can have any of the three mutations. This phenomena–where different mutations give different clinical outcomes–is called a genotype-phenotype correlation. The word genotype describes the specific findings in DNA, while the word phenotype is used to describe the clinical presentation.

Diagnosis

Suspicion of LHON is usually made by an ophthlamologist after a complete eye examination. Genetic testing for the presence/absence of mitochondrial mutations can then be performed from a small blood sample. After a symptomatic person with LHON in a family has been identified to have a mitochondrial mutation, other asymptomatic at-risk relatives can also be tested. At-risk relatives would include the affected persons’ mother, siblings, and the offspring of any females found to have the mutation. Testing for asymptomatic children who are atrisk is not currently offered since no treatment is available for LHON; these individuals could opt for testing upon becoming a legal adult (i.e. reaching 18 years of age). Prenatal diagnosis for LHON is presently not available in the United States, but may be offered elsewhere. With genetic testing for LHON, it is important to remember that the presence of a mitochondrial mutation does not predict whether the condition will occur at all, the age at which it will begin, the severity, or rate of progression.

Treatment and management

There is no proven treatment available for LHON, although some studies report benefit from various vitamin therapies or other medications. Management of LHON is supportive, utilizing visual aids such as magnifiers.

Prognosis

The loss of central vision tends to remain the same (legally blind) over a lifetime once a person with LHON has reached the atrophic phase.

Resources

ORGANIZATIONS

International Foundation for Optic Nerve Disease. PO Box 777, Cornwall, NY 12518. http://www.ifond.org .

United Mitochondrial Diseases Foundation. PO Box 1151, Monroeville, PA 15146-1151. http://www.umdf.org .

WEBSITES

Leber’s Optic Neuropathy.http://www.leeder.demon.co.uk/pages/lhonhome.htm .

Catherine L. Tesla, MS, CGC

I 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 chracterized 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

syndrome Leigh

Leigh syndrome

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 car-

rier 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 adultonset 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 lev-

syndrome Leigh

Leri-Weill dyschondrosteosis

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-hydrox- ymethyl 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 ophthamologist.

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

LEOPARD syndrome see Multiple lentigines syndrome

Leprechaunism see Donohue syndrome

I Leri-Weill dyschondrosteosis

Definition

Leri-Weill dyschondrosteosis (LWD) is a rare form of dwarfism. It is characterized by short forearms and lower legs as well as a certain arm-bone abnormality (Madelung deformity).

Description

LWD was first described by A. Leri and J. Weill in 1929. Other names for LWD include Leri-Weill syndrome (LWS), dyschondrosteosis (DCO), and Madelung deformity.

Genetic profile

LWD appears to be caused by several genetic factors. Many forms of LWD are caused by a mutation (change) in a gene called SHOX (for “short stature homeo box” gene). SHOX is located on the X chromosome. In the cases of LWD in which a specific mutation or change cannot be found in the SHOX gene, another gene may be responsible for the problems in bone devel-

opment. The involvement of another gene or some other factor would not be surprising, as a person’s height is determined by the interaction of many genes and environmental factors.

Leri-Weill dyschondrosteosis can appear in an individual but not be found in his or her parents. A new, isolated type of LWD is called denovo LWD. A person with denovo LWD has a 50% chance of having children with the syndrome.

Family members with the syndrome can be affected very differently. For example, some family members may have proportional dwarfism, with no visible arm-bone abnormality, while other family members may have very short (mesomelic) arms and legs and severe Madelung arm-bone abnormality. Such differences in physical findings within the same family are known as intrafamilial variability.

Studies in 1998 and 1999 suggested that another form of severe dwarfism, Langer mesomelic dysplasia, is the result of inheriting two copies of the mutated gene that causes LWD. Langer mesomelic dysplasia is characterized by extremely short stature along with underdeveloped or missing arm bones.

Demographics

The ethnic origins of individuals affected by LWD are varied. LWD does not appear to be more common in any specific country.

Signs and symptoms

Most individuals affected by Leri-Weill dyschrondrosteosis have short stature based on their shortened lower legs and forearms, normal head size, and Madelung deformity. One recent study found that some males have overdeveloped muscles (or muscular hypertrophy). Depending on the individual, LWD can result in severe to very mild symptoms (variable expression). Females affected by LWD tend to have the more severe effects of LWD.

Some individuals with LWD have symptoms not part of the LWD features. These features, such as mental retardation and skin disorders, are believed to be caused by abnormalities in genes close to the mutated SHOX gene. Individuals with other symptoms as well as LWD are said to be affected by an Xp22.3 contiguous gene syndrome. The name refers to a syndrome caused by the deletion or incorrect working of several genes found side-by-side on the X chromosome.

Diagnosis

Diagnosis of LWD is usually made from physical examination by a medical geneticist, and by studies of x

K E Y T E R M S

Madelung’s deformity—A forearm bone malformation characterized by a short forearm, arched or bow shaped radius, and dislocation of the ulna.

Mesomelia—Shortness of the portion of arm connecting the elbow to the wrist or forearm.

rays of the legs and arms. Madelung deformity of the arms is generally not visible in children through physical exam, but the first signs of the abnormality, such as bowing of the forearm bone, can be identified by x ray between ages two and five years.

Although one gene has been found to cause LWD, diagnostic genetic testing in affected individuals or in fetuses is not available in 2001.

Treatment and management

At this time there is no specific therapy that removes, cures, or repairs all signs of the disorder. Some progress in increasing height has been made by growth hormone (GH) supplementation in affected children. However, this treatment causes disproportionate growth, with longer arms and trunk and shorter legs.

Prognosis

The severity of effects of LWD varies widely, so prognoses for people with the syndrome also vary. Severe Madelung deformity may require surgery. However, individuals with LWD have an excellent prognosis, and most have normal lives.

Resources

BOOKS

Charles, I., et al. Dwarfism: The Family and Professional

Guide. Short Stature Foundation Press, 1994.

Rieser, Patricia, and Heino F. L. Mayer-Bahlburg. Short & Okay: A Guide for Parents of Short Children. Human Growth Foundation.

ORGANIZATIONS

Human Growth Foundation. 997 Glen Cove Ave., Glen Head, NY 11545. (800) 451-6434. Fax: (516) 671-4055.http://www. hgf1@hgfound.org .

International Center for Skeletal Dysplasia. Saint Joseph’s Hospital, 7620 York Rd., Towson, MD 21204. (410) 3371250.

Little People of America, Inc. National Headquarters, PO Box 745, Lubbock, TX 79408. (806) 737-8186 or (888) LPA2001. lpadatabase@juno.com. http://www.lpaonline

.org .

dyschondrosteosis Weill-Leri