Chromosome abnormalities
Angus Clarke, Alex Murray, Julian Sampson in Harper's Practical Genetic Counselling, 2019
It is a fundamental fact of genetics that a child usually receives one copy of each chromosome pair from each parent (i.e. one of each autosome and one sex chromosome), but occasionally this does not happen; when both copies originate from one parent, this is termed uniparental disomy.This may have no harmful effects, in which case it will usually be unrecognised, but problems may arise if either of the following is true:The transmitted copies both carry a recessive mutated gene present in heterozygous state in the parent.(This has occurred in rare cases of cystic fibrosis.)Part of the chromosome shows ‘genetic imprinting’ (see Chapter 2), so that either two inactivated chromosome regions or two functioning copies are transmitted when we usually have only a single functioning copy.Prader-Willi and Angelman syndromes provide the clearest examples of uniparental disomy in conjunction with imprinting, although this is less common than microdeletions. Recurrence is very unlikely with any form of uniparental disomy. Now that responsible genes have been identified in the critical region of chromosome 15, it is usually possible to determine the genetic basis of Prader-Willi syndrome or of Angelman syndrome. The causes of Angelman syndrome are more complex and varied: mutation in the maternally inherited UBE3A gene will lead to Angelman syndrome, just as with a deletion of the maternal 15q, paternal disomy 15 or a disturbance of the local imprinting mechanism. Uniparental disomy for chromosome 14 is also associated with disorders of fetal growth and development, whether the disomy is paternal or maternal, and can very occasionally arise in association with a Robertsonian translocation involving chromosome 14. When a Robertsonian translocation carrier is identified with involvement of chromosome 14 or 15, and her or his fetus appears to be an unaffected carrier of the translocation, prenatal molecular studies may be indicated to exclude the small risk of pathogenic uniparental disomy (UPD).
Animal Models of Down Syndrome and Other Genetic Diseases Associated with Mental Retardation
Merlin G. Butler, F. John Meaney in Genetics of Developmental Disabilities, 2019
Angelman syndrome (AS) is a disorder characterized by microcephaly, severe mental retardation, minimal or absent speech, hyperactivity, sleep disturbance, seizures, hypertonia, gait ataxia, hand flapping, and a happy disposition with frequent inappropriate outbursts of laughter (147,148). The majority of patients (70%) with AS have ~4 Mb interstitial deletions of the maternal HSA15 (q11.2-q13) (149). Although several genes have been located in this region, loss-of-function mutations in UBE3A, a gene encoding a ubiquitin protein ligase, found in clinically typical AS patients indicate that the main aspects of the phenotype are attributable to maternal deficiency for this locus (150,151). UBE3A is expressed only from the maternally inherited HSA15 and is imprinted within the brain (152,153). Therefore, inheritance of a UBE3A mutation from the mother causes AS, but inheritance from the father has no detectable effect on the child. Other genetic causes of AS are paternal uniparental disomy (UPD) (in 2–3% of cases), in which the child inherits both copies of HSA15 from the father, and an “imprinting defect” (in 3–5% of cases) in which the allele inherited from the mother functions in the same way that a paternal HSA15 should function and is not active. Some AS individuals with imprinting defects have very small deletions of a region called the AS-imprinting center (IC) (154,155) which regulates the activity of UBE3A from a distant location by an unknown mechanism. To model AS in mice and to clarifyREFERENCES the relationship between imprinting and UBE3A functions, two groups created mice with a null mutation for Ube3a (156,157). Whereas mice with paternal deficiency of Ube3a were essentially similar to wild-type mice, the phenotype of mice with maternal deficiency resembled that of human AS. They exhibited motor dysfunction, inducible seizures, and a context-dependent learning deficit (156,157). The absence of detectable expression of Ube3a in hippocampal neurons and Purkinje cells in mice with maternal deficiency correlated with neurological and cognitive impairments, and LTP in the hippocampus was severely impaired.
Dictionary of Eponymous Syndromes and Diseases
Timothy G Barrett, Anthony D Lander, Vin Diwakar in A Paediatric Vade-Mecum, 2002
Good prognosis. Alexander disease: leukodystrophy of unknown aetiology associated with progressive developmental delay and unresponsive seizures. Death by 5 years of age. Allagille syndrome: AD. Intrahepatic cholestasis, dysmorphism (broad forehead, bullous nose, pointed chin), posterior embryotoxin , peripheral pulmonary artery stenosis. Allgrove syndrome: ACTH resistance, achalasia of the cardia, and alacrima. Alport syndrome: sensorineural deafness and progressive nephropathy, presenting with asymptomatic microscopic haematuria. XL dominant or AD. Males develop end-stage renal failure in their twenties or thirties. Females have normal lifespan and subclinical hearing loss. Angelman syndrome: commonest pattern of inheritance is paternal uniparental disomy. Jerky ataxic arm movements, paroxysms of inappropriate laughter, developmental delay, seizures, characteristic facies (microbrachycephaly, maxillary hypoplasia, blond hair (65%), prognathism, occipital flattening). An example of genetic imprinting (cf. Prader–Willi syndrome, when the same defect is inherited from the mother). Apert syndrome: AD craniosynostosis (acrocephaly), midface hypoplasia, developmental delay, syndactyly and broad distal phalanx of thumb and big toe. Non-skeletal malformations (cardiac, respiratory and renal) must be evaluated. Asperger syndrome: an autistic condition affecting the development of social interaction, communication and imagination. Asperger syndrome applies to those with milder learning difficulties, who have better language development and who try to make social contacts, but in naive and inappropriate ways. Bardet–Biedl syndrome (Laurence–Moon–Biedl syndrome): AR. Hypogenitalism, retinitis pigmentosa, polydactyly, early-onset resistant obesity and mild/severe learning difficulties. In boys, gynaecomastia. In girls, amenorrhoea and lack of breast development.
Using Behavioral Approaches to Assess Memory, Imitation and Motor Performance in Children with Angelman Syndrome: Results of a Pilot Study
Published in Developmental Neurorehabilitation, 2019
Purpose: This study was designed to assess memory, imitation of motor actions and motor performance by 12 children (age range 40–151 months) with Angelman syndrome (AS), a rare neurogenetic disorder associated with learning and memory impairments. Methods: Children’s functioning was assessed at several time points over a 3-month period. Results: Memory and motor performance tests had acceptable test-retest and inter-rater reliability whereas the motor imitation test did not. Children were able to recall action sequences after a 24-h delay. Memory and motor performance scores were correlated with children’s chronological age and raw scores on subdomains of the Vineland-II. Conclusions: These behavioral tests require further development and evaluation but may show promise to accompany standardized assessments that are currently in use with children with AS.
Parents' Priorities for AAC and Related Instruction for their Children with Angelman Syndrome
Published in Augmentative and Alternative Communication, 2010
Stephen N. Calculator, Tibbany Black
This investigation examined the extent to which a set of 98 best practices in AAC, previously agreed upon by a panel of experts in AAC and inclusive education, reflected the actual preferences of 32 parents of children diagnosed with Angelman Syndrome. Parents' responses were examined in relation to whether their children were currently in mostly integrated (MI) settings with children without disabilities, or mostly segregated settings with other children with disabilities. With two exceptions, both groups, regardless of their children's current placements, viewed the practices favorably. When asked to prioritize the most important communication skills they wished their children to attain, all of the most frequently cited priorities were reflected in items contained in the questionnaire, supporting the social validity of the questionnaire as truly reflecting parents' priorities for AAC instruction. Implications of this investigation are discussed, along with next steps.
Uroflowmetric assessment in participants with Angelman syndrome
Published in Developmental Neurorehabilitation, 2015
Maartje Radstaake, Robert Didden, Alexander von Gontard, Leopold M. G. Curfs
Objective: To asses possible bladder dysfunctions and lower urinary tract symptoms (LUTS) in individuals with Angelman syndrome (AS), since remarkable voiding characteristics were found in previous studies on toilet training and incontinence in AS. Method: Uroflowmetric analysis, a non-invasive technique to assess the voiding pattern, was conducted in six participants with AS. Results: Pathological uroflow patterns were found in five participants; staccato flows in three participants, interrupted flows in one and both interrupted and staccato flows in another participant. Small quantities or urine were found in four participants, large amounts in one and one participant had normal voided volumes. Conclusions: Results indicate that different conditions such as dysfunctional voiding are present in AS and future studies should further assess these in greater detail. Possible treatment of LUTS and incontinence includes adequate liquid intake, timed voidings, treatment of constipation, and allowing enough time on toilet to stimulate relaxation.
Related Knowledge Centers
- Ataxia
- Chromosome Disorders
- Mental Retardation
- Muscle Hypotonia
- Multiple Abnormalities
- Movement Disorders
- Dyskinesias