Disease Definitions - For Physicians
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Angelman syndrome (AS) is a neurodevelopmental disorder characterized by mental retardation, severe speech/language delays, ataxia, seizures, and a happy disposition with episodes of spontaneous laughter.
The genetic basis of AS is complex with at least 4 mechanisms that render the individual without a functional copy of the UBE3A gene. UBE3A, located on chromosome 15q11-13, is expressed only from the maternally-inherited chromosome (parent-of-origin specific gene expression is a phenomenon known as imprinting). Deletion of the maternal chromosome 15q11-13 accounts for approximately 70% of AS. The other mechanisms (uniparental disomy for the paternally-inherited chromosome 15; imprinting center defect causing inactivation of the maternally-inherited UBE3A; or mutation within the maternally-inherited UBE3A ) account for 15-20% of cases. Approximately 10-15% of cases are diagnosed clinically and do not have a molecularly defined basis.
Symptoms of AS include functionally severe developmental delay, absent or nearly absent speech, ataxia of gait, microcephaly, seizures, hypermotoric activity, drooling, sleep disturbance, attraction to or fascination with water, feeding problems, and happy demeanor with excitable personality.
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Angelman Syndrome Foundation
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Prader-Willi syndrome (PWS) is a congenital condition characterized by obesity, hypotonia, mild mental retardation and hypogonadism.
PWS is the result of the loss of several genes on the chromosome 15 inherited from the father. This loss is typically due to a small chromosomal deletion that arose spontaneously in one of the father's germ cells. If the same chromosomal region is deleted in the chromosome 15 inherited from the mother, this results in a much different syndrome called Angelman syndrome. This phenomenon, where there is a difference in the expression of the genes inherited from the father and the mother, is called "genomic imprinting". Most of our genes are not subject to "imprinting", but a defect in the imprinting process is known to be involved in several birth defects, such as PWS.
Signs of PWS are typically seen at birth. This includes hypotonia and failure-to-thrive (FTT). Most PWS babies need assistance with feeding for several months including widened formula bottle nipples as well as nasal gastric (NG) or oral gastric (OG) tubes. Some infants will have a prolonged FTT phase and require gastrostomy tube feeding. Male infants frequently have undescended testicles. Typically the PWS infant is slower to achieve developmental milestones including sitting, walking and talking. At around 18-36 months of age the PWS child starts gaining weight rapidly. If not appropriately controlled, the child can become morbidly obese. Compounding the weight problem is the development of an insatiable appetite which can begin anywhere from 3 to 12 years of age.
Affected children have an intense craving for food and will do almost anything to get it. This results in uncontrollable weight gain. Morbid obesity (the degree of obesity that seriously affects health) may lead to respiratory failure with hypoxia (low blood oxygen levels), cor pulmonale (right-sided heart failure), and death. Access to food must be closely monitored.
Almost all individuals with PWS have some degree of learning difficulties and will need special help in school. The average IQ is 60-70 with a range of 40-105. Those individuals with a normal IQ typically have learning disabilities. In addition, many individuals with PWS have behavioral problems which can be responsive to behavioral management and medications. There is also delayed and incomplete development of secondary sexual characteristics including puberty. Almost all individuals with PWS are infertile, but there have been a few rare cases of females becoming pregnant.
Frequently the diagnosis of PWS is not made until the child is several years of age. However, with the increased awareness of PWS and the good genetic tests now available, many physicians are making the diagnosis of PWS early in infancy. Making a diagnosis at an early age allows physicians to begin management sooner thus minimizing many, but not all, of the problems with PWS. Generally there are a number of health care professionals involved in the care of the child with PWS. This typically includes a geneticist, endocrinologist, nutritionist and behavioral therapist, as well as the primary care physician. It may also include a psychiatrist, orthopedist and neurologist.
While PWS is suspected on clinical grounds, it is confirmed by specialized genetic testing which, when properly used, can pick up virtually all cases of PWS. There are 3 main molecular classes of PWS. The most common is a 3-5 million base pair deletion of the proximal portion of the paternally inherited chromosome 15 long arm. This accounts for approximately 70 % of cases. The next most common (20% of cases) are the patients with a maternal uniparental disomy where there are 2 normal chromosome 15s, but they are both inherited from the mother with no paternal contribution. The least common (5%) are the imprinting defect patients. DNA methylation analysis will pick up all 3 molecular classes, but it will not distinguish among the molecular classes. This requires further genetic testing that is probably best done under the supervision of a geneticist. For a more detailed description of the genetics please refer to the following web site: http://www.geneclinics.org/profiles/pws/
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Rett syndrome is a childhood neurodevelopmental disorder characterized by apparently normal early development followed by loss of purposeful use of the hands, distinctive hand movements, slowed brain and head growth, gait abnormalities, seizures, and mental retardation. It affects females almost exclusively.
The course of Rett syndrome, including the age of onset and the severity of symptoms, varies from child to child. Before the symptoms begin, however, the child appears to grow and develop normally. Then, gradually, mental and physical symptoms appear. Hypotonia (loss of muscle tone) is usually the first symptom. As the syndrome progresses, the child loses purposeful use of her hands and the ability to speak. Other early symptoms may include problems crawling or walking and diminished eye contact. The loss of functional use of the hands is followed by compulsive hand movements such as wringing and washing. The onset of this period of regression is sometimes sudden.
Another symptom, apraxia - the inability to perform motor functions - is perhaps the most severely disabling feature of Rett syndrome, interfering with every body movement, including eye gaze and speech.
Individuals with Rett syndrome often exhibit autistic-like behaviors in the early stages. Other symptoms may include toe walking; sleep problems; wide-based gait; teeth grinding and difficulty chewing; slowed growth; seizures; cognitive disabilities; and breathing difficulties while awake such as hyperventilation, apnea (breath holding), and air swallowing.
Diagnostic Criteria for Rett Syndrome | Contact Registry for this Disorder | Find a Clinical Trial | Back to Top | International Rett Syndrome Organization
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