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Aniridia, cerebellar ataxia, and mental deficiency, also known as Gillespie syndrome, is an extremely rare inherited disorder that is characterized by the absence, in whole (aniridia) or part (partial aniridia), of the colored portion (iris) of the eye; impaired coordination of voluntary movements due to underdevelopment (hypoplasia) of the brain’s cerebellum (cerebellar ataxia); and mental retardation. The condition usually affects both eyes (bilateral) but a few cases have been reported in which only one eye is affected. Some individuals with this syndrome also exhibit a delay in the acquisition of skills requiring coordination of muscular and mental activity (psychomotor retardation). AMD is thought to be inherited as an autosomal recessive genetic trait and is extremely rare, with only 20 to 30 cases reported in the medical literature.

Aniridia-cerebellar ataxia-mental deficiency, also known as Gillespie syndrome, is an extremely rare heterogeneous, inherited in either an autosomal dominant or autosomal recessive manner inherited disorder that is characterized by malformations of the eye, partial aniridia (meaning that part of the iris is missing), ataxia (motor and coordination problems), neuromuscular abnormalities, developmental delays, and/or mental retardation. Some affected individuals may also exhibit additional physical abnormalities.

Causes

The disorder aniridia, cerebellar ataxia, and mental deficiency are thought to be inherited as autosomal recessive genetic traits, but researchers have not yet been able to establish the mode of inheritance conclusively. The genetics of the disorder are not well understood at this time.

Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 11p13” refers to band 13 on the short arm of chromosome 11. The numbered bands specify the location of the thousands of genes that are present on each chromosome.

Genetic diseases are determined by the combination of genes for a particular trait that is on the chromosomes received from the father and 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 of 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% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% 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%. The risk is the same for males and females.

All individuals carry a few abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.

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% for each pregnancy regardless of the sex of the resulting child.

Related Disorders

Marinesco-Sjogren Syndrome is a rare inherited disorder that is characterized by impaired coordination of voluntary movement due to underdevelopment (hypoplasia) of the cerebellum (cerebellar ataxia), clouding of the lens of both eyes (bilateral cataracts), involuntary movements of the eyes (nystagmus), difficulty speaking due to an impaired ability to control the muscles enabling speech (dysarthria), and/or mild mental retardation. Many affected individuals exhibit additional physical abnormalities. Marinesco-Sjogren Syndrome is inherited as an autosomal recessive genetic trait. (For more information on this disorder, choose “Marinesco-Sjogren” as your search term in the Rare Disease Database.)

In Aniridia, Type II, a rare vision disorder that is present at birth (congenital), affected individuals exhibit partial or nearly complete absence (aplasia) of the colored portion (iris) of the eye (aniridia). Vision may range from nearly normal to poor, depending upon the severity of the aniridia. In many cases, affected infants may also exhibit clouding of the lens of the eyes (cataracts) and/or repeated, involuntary eye movements (nystagmus). During late childhood or early adolescence, the pressure of the fluid in the eyes may become abnormally high (glaucoma) in some affected individuals, potentially leading to progressive loss of vision. Aniridia, Type II may occur randomly, for no apparent reason (sporadic); cases, where a familial pattern has been identified, show that the disorder may be inherited as an autosomal dominant genetic trait. In both sporadic and familial cases of Aniridia, Type II, abnormalities (mutations) of a gene called PAX6, which has been located on the short arm (p) of chromosome 11 (11p13), are believed to play a role in causing the disorder. (At least four types of Aniridia are thought to exist. Aniridia, Type I is marked by incomplete expression of the disorder. In Type III, Aniridia occurs in association with mental retardation. Aniridia, Type IV is associated with Wilms’ Tumor, abnormalities of the reproductive and urinary (genitourinary) tracts, and possible mental retardation; this association of symptoms is called “WAGR Syndrome.

Symptoms

The eye abnormality most frequently associated with this disorder is the partial or complete absence of the colored portion (iris) of the eye, resulting in poor vision. Both eyes are usually affected (bilateral). The inner edge of the iris that normally surrounds the pupil (pupillary margin of the iris) may be absent, as may be the circular band of muscle fibers in the iris that reduces the size of the pupil (sphincter pupillae) in response to light. In many cases, people with aniridia may also exhibit repeated, involuntary movements of the eye (nystagmus). In addition, during late childhood or early adolescence, the pressure of the fluid in the eye may become abnormally high (glaucoma) in some individuals with aniridia, potentially leading to progressive loss of vision.

Individuals with an aniridia-cerebellar ataxia-mental deficiency may also have additional eye abnormalities, such as excessive widening (dilatation) of the pupils (mydriasis) and/or extreme sensitivity to light (photophobia). In addition, they may exhibit droopy eyelids (ptosis); inward deviation of one eye (esotropia), resulting in double vision (diplopia); and/or farsightedness (hypermetropia), causing blurred vision, eye strain, and/or difficulty in viewing close objects.

Aniridia-cerebellar ataxia-mental deficiency is also characterized by neuromuscular abnormalities, such as an impaired ability to coordinate voluntary movement due to incomplete development (hypoplasia) of the cerebellum (cerebellar ataxia). The cerebellum is the part of the brain that plays a role in maintaining balance and posture as well as coordinating voluntary movement. People with this disorder may walk unsteadily and have difficulty positioning their feet and turning (cerebellar gait); they may also speak slowly and haltingly, with pauses between each syllable (scanning speech). Affected individuals may also exhibit severely diminished muscle tone (hypotonia). The cerebellar ataxia does not seem to worsen over time in individuals with this disorder (non-progressive cerebellar ataxia);, in some cases, the control of certain voluntary movements may improve with age.

People with this disorder may also exhibit developmental abnormalities, such as a delay in the acquisition of skills requiring the coordination of muscular and mental activity (psychomotor retardation). As a result, they may achieve certain developmental milestones (e.g., crawling, walking, speaking, etc.) later than normally expected. Mild to moderate mental retardation may also be present.

In rare cases, individuals with an aniridia-cerebellar ataxia-mental deficiency may have additional physical abnormalities. For example, affected individuals have exhibited skeletal malformations, such as fusion of certain bones in the spinal column of the neck (cervical vertebrae), flat feet (pes planus), and/or feet with heels that are abnormally turned inward and soles that are flexed (equinovarus clubfeet). Other features have included heart abnormalities, such as a heart murmur, and/or abnormal narrowing of the opening between the heart’s right ventricle and the artery that supplies blood to the lung (pulmonary stenosis).

Diagnosis

The diagnosis of aniridia, cerebellar ataxia, and mental deficiency may be made at birth if the newborn (neonate) presents with a partial absence of the iris in association with hypotonia. Although partial aniridia may be obvious at birth, the other symptoms may not become apparent until later in the child’s development. Therefore, the disorder usually is not diagnosed until early childhood, based upon a thorough clinical evaluation, a detailed patient history, specialized laboratory tests, and advanced imaging techniques.

Examination of the eyes using a slit-lamp and an instrument that measures certain angles in the eye (gonioscope), and reveals any remnants of iris tissue that may be present, help to establish and confirm a diagnosis of partial aniridia. If involuntary movements of the eye (nystagmus) occur in association with aniridia, the ophthalmologist will record eye movements to determine the exact type of nystagmus present.

Cerebellar ataxia due to underdevelopment of the cerebellum (cerebellar hypoplasia) may be confirmed by imaging techniques such as CT (computerized tomography) scanning and MRI (magnetic resonance imaging). During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of tissue structure. During MRI, a magnetic field and radio waves are used to create cross-sectional images of different organs of the body.

Treatment

The treatment of ACAMD is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, physicians who diagnose and treat diseases of the eye (ophthalmologists), specialists who assess and correct vision problems with corrective lenses (optometrists), physical therapists, and others may need to work together to ensure a comprehensive approach to treatment.

Early intervention is also important in ensuring that affected children with cerebellar ataxia, developmental delays, and mental retardation reach their potential. Special services that may be beneficial to affected children may include physical therapy, special remedial education, speech therapy, and other medical, social, and/or vocational services.

Genetic counseling will also be of benefit to affected families. Another treatment is symptomatic and supportive.