Aniridia, cerebellar ataxia, mental deficiency (ACAMD) is an extremely rare inherited disorder that involves eye abnormalities, problems with balance and coordinating movements (ataxia), and mild to moderate intellectual disability.
Aniridia may be broadly divided into hereditary and sporadic forms. Hereditary aniridia is usually transmitted in an autosomal dominant manner (each offspring has a 50% chance of being affected), although rare autosomal recessive forms (such as Gillespie syndrome) have also been reported.
Gillespie syndrome is characterized by aniridia, which is the absence of the colored part of the eye (the iris). In most affected individuals, only part of the iris is missing (partial aniridia) in both eyes, but in some affected individuals, partial aniridia affects only one eye, or the entire iris is missing (complete aniridia) in one or both eyes. The absence of all or part of the iris can cause blurry vision (reduced visual acuity) and increased sensitivity to light (photophobia). Rapid, involuntary eye movements (nystagmus) can also occur in Gillespie syndrome.
The balance and movement problems in Gillespie syndrome result from underdevelopment (hypoplasia) of a part of the brain called the cerebellum. This abnormality can cause delayed development of motor skills such as walking. In addition, difficulty controlling the muscles in the mouth can lead to delayed speech development. The difficulties with coordination generally become noticeable in early childhood when the individual is learning these skills. People with Gillespie syndrome usually continue to have an unsteady gait and speech problems. However, the problems do not get worse over time, and in some cases they improve slightly.
Other features of Gillespie syndrome can include abnormalities in the bones of the spine (vertebrae) and malformations of the heart.
ACAMD 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.
Malformations of the eye:
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 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 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 the 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 fact, in some cases, the control of certain voluntary movements may improve with age.
Developmental delays and/or Mental retardation:
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 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).
The disorder aniridia, cerebellar ataxia and mental deficiency is thought to be inherited as an autosomal recessive genetic trait, 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. It has been estimated that Gillespie syndrome accounts for about 2 percent of cases of aniridia.
Gillespie syndrome can be caused by mutations in the PAX6 gene. The PAX6 gene provides instructions for making a protein that is involved in early development, including the development of the eyes and brain. The PAX6 protein attaches (binds) to specific regions of DNA and regulates the activity of other genes.
The diagnosis of aniridia, cerebellar ataxia and mental deficiency may be made at birth if the newborn (neonate) presents with 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.
The eyes are examined using a slit-lamp and an instrument that measures certain angles in the eye (gonioscope), and to reveal 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.
The treatment of ACAMD is conducted with the specific symptoms that are present in each individual. Pediatricians, physicians who diagnose and treat diseases of the eye (ophthalmologists), specialists who assess and correct visual 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 for affected families. Other treatment is symptomatic and supportive.
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