Angelman Syndrome (Happy Puppet Syndrome)

Italian: Ritratto di fanciullo con disegno A child with a drawing  [1]

Angelman syndrome is a rare genetic disorder characterized by severe intellectual and developmental disability, sleep disorder, frequent and sometimes inappropriate laughter, seizures, jerky movements and ataxia. It is named after the British pediatrician, Dr. Harry Angelman, who first described it in 1965.

Angelman Syndrome is triggered by the following process: congenital.

Presentation

Patients diagnosed with Angelman syndrome will commonly present with the following signs and symptoms:

psychiatrical
Inappropriate Laughter
  • Excessive and inappropriate laughter is a telltale sign.[mentalhelp.net]
  • Introduction Angelman syndrome (AS) is characterized by moderate to severe mental retardation, absence of speech, tremor, ataxia, abnormal gait, inappropriate laughter, sleep disturbance and seizures.[hmg.oxfordjournals.org]
  • Therapy may also help reduce negative behaviors, such as inappropriate laughter and hyperactivity.[livingnaturally.com]
  • Patients with AS have a characteristic behavioural phenotype with jerky movements, frequent and sometimes inappropriate laughter, a love of water, and sleep disorder.[jmg.bmj.com]
  • more...
  • musculoskeletal
    Muscle Hypotonia
    • Alternative eponyms Happy puppet syndrome Related people Harry Angelman A chromosome 15 disorder comprising microcephaly with mental retardation, epilepsy, ataxic gait or complete inability to walk, muscle hypotonia, EEG abnormalities, and peculiar facies[whonamedit.com]
  • more...
  • neurologic
    Seizure
    • Medication is typically advisable to those with seizure disorders.[en.wikipedia.org]
    • Any of the seizure medications for the types of seizures in AS may be tried.[epilepsy.com]
    • Seizures Seizures are present in 85% of patients within the first three years of life[ 17 ], although less than 25% develop seizures during the first year[ 18 ].[ijponline.biomedcentral.com]
    • Generalised tonic-clonic seizures and focal (partial) seizures are less common.[epilepsy.org.uk]
    • Update : After almost a year with no seizures, they're back again: Four seizures in the space of two weeks.[armyofangels.org]
    Myoclonic Jerking
    • The types of seizures include myoclonic (‘jerks’), atonic or astatic (‘drops’) and tonic (‘stiffening’) seizures.[epilepsy.org.uk]
    • Recently Elia [ 26 ] by polygraphic studies, documented that myoclonic jerks are not correlated with EEG paroxysmal abnormalities.[ijponline.biomedcentral.com]
    Hyperreflexia
    • Diminished muscle tone (hypotonia) of the trunk, increased muscle tone (hypertonia) of the arms and legs, and abnormally exaggerated or brisk reflex responses (hyperreflexia) may also occur.[rarediseases.org]
  • more...
  • Entire body system
    Epilepsy
    • The clinic includes specialists in epilepsy, sleep, gastroenterology and nutrition, neuropsychology, psychiatry and genetics.[massgeneral.org]
    • If you would like to know more about epilepsy in general, please contact Epilepsy Action.[epilepsy.org.uk]
    • Genetic mechanisms that underlie epilepsy.[genedx.com]
    • Learn more about the Rare Epilepsy Network Authored By: Elaine Kiriakopoulos MD, MSc Drug Resistant and Rare Epilepsies Editor Our Mission The mission of the Epilepsy Foundation is to lead the fight to overcome the challenges of living with epilepsy and[epilepsy.com]
    • This condition is a neurogenetic disorder characterised by developmental delay, absence of speech, motor impairment, epilepsy and a peculiar behavioural phenotype.[amazon.com]
  • more...
  • Workup

    Children with Angelman syndrome will typically present clinically with obvious developmental delays, microcephaly, movement disorders, impaired balance, and seizure disorders. This constellation of signs and symptoms is very suggestive of the syndrome clinically. The following tests may be used to confirm the diagnosis of Angelman syndrome:

    • Chromosome analysis or karyotyping: This is the direct microscopic examination of the chromosomes to determine and identify any defects in the morphology and size of the sampled chromosomes.
    • Fluorescence in situ hybridization (FISH): This fluorescence assay will demonstrate the defective long arm of chromosome 15 in Angelman syndrome.
    • DNA methylation test: This test reveals any gene imprinting defects by the use of methylation techniques. Angelman syndrome will show the absence of the maternal gene copy and expression within the brain tissues.
    • UBE3A gene sequencing: This a specific test that demonstrates the presence of gene mutation within the maternal copy of the gene found in a chromosome subset.

    Treatment

    The gene defect in Angelman syndrome is irreparable; thus, there is no known cure for this rare syndrome. Treatment will only focus on the management of the medical and developmental problems of the affected child. Because of the complexity of the problems involved in Angelman syndrome, a multidisciplinary approach is often times imperative in the management of the disease. The following treatment modalities are available for Angelman syndrome:

    • Anti-convulsant medications: This therapy is given to control the seizure disorders associated with Angelman syndrome. 
    • Physical therapy: Patients with Angelman syndrome may learn to walk promptly and balance with the help of physical therapy and rehabilitation.
    • Speech therapy: Speech therapy among patients with the syndrome may hasten communication problems. Patients may be taught sign language if verbal communication is not achieved [10].
    • Behavioral therapy: This will help children with Angelman syndrome to control hyperactivity and hasten developmental delays.

    Prognosis

    The majority of patients with Angelman syndrome will have progressive developmental delay, speech dysfunctions, and motor difficulties till adulthood. However, these patients will have a normal lifespan without any developmental regression as they chronologically age. The prompt diagnosis of Angelman syndrome coupled with a customized interventional therapy and support improves the prognosis among patients. Female patients with Angelman syndrome have been observed to be prone to obesity and worsening of scoliosis [7].

    Complications

    Mental Retardation
    • Eventually, this delay is recognized as severe mental retardation.[encyclopedia.com]
    • retardation conditions more types...»[rightdiagnosis.com]
    • Medical Dictionary : a genetic disorder characterized by severe mental retardation, seizures, ataxic gait, jerky movements, lack of speech, microcephaly, and frequent smiling and laughter Biographical Note for angelman syndrome Angelman , Harry (1915–[merriam-webster.com]
    • Characteristic features of this condition include developmental delay or mental retardation, severe speech impairment, seizures, small head size (microcephaly), and problems with movement and balance (ataxia).[hon.ch]
    • American Journal of Mental Retardation, 111 (5), 311–321.[link.springer.com]
    Epilepsy
    • The clinic includes specialists in epilepsy, sleep, gastroenterology and nutrition, neuropsychology, psychiatry and genetics.[massgeneral.org]
    • If you would like to know more about epilepsy in general, please contact Epilepsy Action.[epilepsy.org.uk]
    • Genetic mechanisms that underlie epilepsy.[genedx.com]
    • Learn more about the Rare Epilepsy Network Authored By: Elaine Kiriakopoulos MD, MSc Drug Resistant and Rare Epilepsies Editor Our Mission The mission of the Epilepsy Foundation is to lead the fight to overcome the challenges of living with epilepsy and[epilepsy.com]
    • This condition is a neurogenetic disorder characterised by developmental delay, absence of speech, motor impairment, epilepsy and a peculiar behavioural phenotype.[amazon.com]

    Etiology

    Angelman syndrome results from the maternal gene deletion of the locus UBE3A located at the long arm of chromosome 15 (15q11-13) [2]. Studies have demonstrated that Angelman syndrome is closely associated with the intracytoplasmic sperm injection (ICSI) procedures with in vitro fertilization (IVF) techniques used for male infertility [3]. The genetic etiology in Angelman syndrome is brought about by the imprinting defects during the DNA gene expression of the maternal chromosome subset.

    Epidemiology

    The international incidence of Angelman syndrome as a molecular gene defect is approximately 1 case per 300,000 genetic diseases. The syndrome is further evident with an overall incidence rate of 1 case per 12,000 to 20,000 population. Mothers undergoing assistive IVF hormonal steroid therapy have an increased risk of giving birth to an infant afflicted with Angelman syndrome to more than 12.5 times compared to normal unassisted births [4].

    Sex distribution
    Age distribution

    Pathophysiology

    The main pathophysiology of Angelman syndrome stems out from the absence of the maternal gene contribution in the long arm of the chromosome 15 [5]. Other possible genetic causes of the syndrome include genetic translocation, uniparental disomy, and single gene mutation within the chromosome. The subsequent deletion of the gene within the long arm of chromosome 15 will result in the non-expression of the UBE3A gene needed in the DNA methylation during the ubiquitin pathway.

    Recent studies have postulated that the absence of the UBE3A gene will lead to the impairment of the hippocampus memory and cognitive functioning that assists in the learning process, and the synaptic plasticity that controls movements and balance. One of the pathognomonic signs of Angelman syndrome is the characteristic electroencephalogram changes in the prefrontal leads suggesting that the pathogenesis of the syndrome could possibly be associated with some abnormalities in the neurophysiology of the brain [6].

    Prevention

    In few cases of Angelman syndrome, there has been an observable genetic transmission pattern noted. Genetic counselling may be needed to prevent the recurrence of the disease in the family lineage.

    Summary

    Angelman syndrome is an uncommon genetic disorder presenting with developmental delays and neurologic impairments. Patients with Angelman syndrome are observably happy and excitable people with frequent outburst of laughter [1]. Developmental delays with this syndrome are observable between the first 6 to 12 months of life while seizure ensues around 2 to 3 years of age. Majority of patients with Angelman syndrome will have microcephaly and recurrent bouts of seizures that starts beyond the age of two years old.

    Despite their coarse anatomic features and severe neurologic impairments, patients suffering from Angelman syndrome have a comparatively similar life expectancy compared to the normal population. The goal in the management of Angelman syndrome focuses on the patient’s neurological dysfunctions and developmental delays.

    Patient Information

    Definition

    Angelman syndrome is a rare genetic disorder characterized by intellectual disability, developmental delay, microcephaly, speech impairment, and movement disorders.

    Cause

    Angelman syndrome results from the maternal gene deletion of the locus UBE3A located at the long arm of chromosome 15 (15q11-13). Some less common genetic causes include genetic translocation, uniparental disomy, and single gene mutation.

    Symptoms

    Patients will physically present with microcephaly, with observable speech, developmental, and movement impairments.

    Diagnosis

    Clinical history, physical examination and neurologic examinations may clinch the diagnosis of Angelman syndrome. Confirmatory test like karyotyping, FISH, DNA methylation tests, and gene sequencing may also be implored.

    Treatment and follow-up

    Patients are treated with anti-convulsant therapy, physical and speech therapy, and behavioral therapy.

    Other symptoms

    Abnormal Sleep-Wake Cycles
    • Patients may also exhibit wide mouths with unusual tongue/mouthing behaviors, hypopigmentation, and abnormal sleep-wake cycles.[dnatesting.uchicago.edu]
    • Sleep disturbances such as a decreased need for sleep and disrupted or abnormal sleep/wake cycles (e.g., awaking at night or rising earlier than normal) are frequent findings in children with Angelman syndrome.[rarediseases.org]
    • Sleep Sleep disorders are also common, often characterised by abnormal sleep-wake cycles. [ 6 ] The sleep disorders may be related to abnormal serum melatonin profiles. [ 7 ] Poor sleep does not significantly interfere with daytime alertness.[patient.info]
    • Many children have a decreased need for sleep and abnormal sleep/wake cycles.[encyclopedia.com]
    Easily Excitable
    • Children with Angelman syndrome may be easily excited, hypermotoric and hyperactive.[rarediseases.org]
    • Features seen consistently include: Severe problems with developmental delay Balance or movement problems (unsteady walking, tremor) Behaviorally, the child may have frequent laughing or smiling with a happy sociable demeanor and be easily excitable More[epilepsy.com]
    • These include: frequent laughter and smiling, often with little stimulus being easily excitable, often flapping the hands being restless (hyperactive) having a short attention span problems sleeping and needing less sleep than other children a particular[nhs.uk]
    • Sufferers present a happy demeanour, so are often smiling or laughing, and tend to be easily excited.[dailymail.co.uk]
    Excessive Drooling
    • Additional findings include excessive drooling, crossed eyes (strabismus), lack of normal color of the (hypopigmentation) of the skin, eyes and hair due to lack of certain melanin pigments.[rarediseases.org]

    Self-assessment

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    References

    1. Williams CA, Zori RT, Hendrickson J. Angelman syndrome. Curr Probl Pediatr 1995; 25(7): 216–231.
    2. Kishino T, Lalande M, Wagstaff J. UBE3A/E6-AP mutations cause Angelman syndrome. Nat Genet 1997; 15(1): 70–73.
    3. Cox GF, Bürger J, Lip V. Intracytoplasmic sperm injection may increase the risk of imprinting defects. Am J Hum Genet 2002; 71(1): 162–164.
    4. Doornbos ME, Maas SM, McDonnell J, Vermeiden JP, Hennekam RC. Infertility, assisted reproduction technologies and imprinting disturbances: a Dutch study. Hum Reprod 2007; 22(9): 2476–2480.
    5. White HE, Durston VJ, Harvey JF, Cross NC. Quantitative analysis of SRNPN gene methylation by pyrosequencing as a diagnostic test for Prader-Willi syndrome and Angelman syndrome. Clin. Chem. 200 652 (6): 1005–13.
    6. Dan, B., Angelman syndrome: Current understanding and research prospects. Epilepsia, 2009. 50(11): p. 2331–2339.
    7. Laan LA, den Boer AT, Hennekam RC, Renier WO, Brouwer OF. Angelman syndrome in adulthood. Am. J. Med. Genet. 1996 66 (3): 356–60.
    8. Williams CA, Angelman H, Clayton-Smith J et al. Angelman syndrome: consensus for diagnostic criteria. Angelman syndrome Foundation. Am. J. Med. Genet. 1995 56.
    9. Buntinx IM, Hennekam RC, Brouwer OF et al. Clinical profile of Angelman syndrome at different ages. American Journal of Medical Genetics 1995 56 (2): 176–83.
    10. Andersen WH, Rasmussen RK, Strømme P. Levels of cognitive and linguistic development in Angelman syndrome: a study of 20 children. Logopedics, phoniatrics, vocology 2001 26 (1): 2–9.

    • SLC9A6 Mutations Cause X-Linked Mental Retardation, Microcephaly, Epilepsy, and Ataxia, a Phenotype Mimicking Angelman Syndrome - GD Gilfillan, KK Selmer, I Roxrud, R Smith - The American Journal of , 2008 - Elsevier
    • Angelman syndrome in three siblings: characteristic epileptic seizures and EEG abnormalities - T Sugimoto, A Yasuhara, T Ohta, N Nishida - , 2005 - Wiley Online Library
    • Angelman (“happy puppet”) syndrome—seven new cases documented by cerebral computed tomography: review of the literature - A Dörries, HL Spohr, J Kunze - European journal of pediatrics, 1988 - Springer
    • 11. Late effects of cancer therapy - ER Morgan, M Haugen - Diagnostic and Therapeutic Advances in , 1997 - books.google.com
    • SLC9A6 Mutations Cause X-Linked Mental Retardation, Microcephaly, Epilepsy, and Ataxia, a Phenotype Mimicking Angelman Syndrome - GD Gilfillan, KK Selmer, I Roxrud, R Smith - The American Journal of , 2008 - Elsevier
    • A 5-kb imprinting center deletion in a family with Angelman syndrome reduces the shortest region of deletion overlap to 880 bp - K Buiting, C Lich, S Cottrell, A Barnicoat, B Horsthemke - Human genetics, 1999 - Springer

    Media References

    1. Italian: Ritratto di fanciullo con disegno A child with a drawing  , Public Domain

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