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Angelman Syndrome

Happy Puppet Syndrome

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.


Presentation

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

Epilepsy
  • Mean SCQ score for individuals without epilepsy was 13.6 (SD   6.7) and with epilepsy 17.0 (SD   5.6; p  0.17); 58% used fewer than 20 signs to communicate.[ncbi.nlm.nih.gov]
  • RESULTS: All patients with AS based on a deletion had epilepsy. Epilepsy was present in 3/4 children with UBE3A mutation, and 4/5 with pUPD. Onset of epilepsy occurred earlier in deletion cases compared to pUPD or UBE3A mutations cases.[ncbi.nlm.nih.gov]
  • Epilepsy Behav. 2017 Mar;68:45-50. doi: 10.1016/j.yebeh.2016.12.018. Epub 2017 Jan 19.[ncbi.nlm.nih.gov]
  • The aim of this study was to assess the long-term outcome of epilepsy, sleep disorders, and EEG in a vast series of AS subjects.[ncbi.nlm.nih.gov]
  • Epilepsy is characterized by atypical absences, erratic myoclonus, and occasional tonic-clonic seizures.[ncbi.nlm.nih.gov]
Macrostomia
  • Most patients of this age group show at least 8 of the major characteristics (bursts of laughter, happy disposition, hyperactive behaviour, microcephaly, brachycephaly, macrostomia, tongue protrusion, mandibular prognathism, widely spaced teeth, stiff[ncbi.nlm.nih.gov]
  • Moreover, she had facial dysmorphic features such as microbrachycephaly, mid-facial hypoplasia, macrostomia and prominent mandible.[ncbi.nlm.nih.gov]
  • Generally from 1 year of age, the typical features of AS develop: severe intellectual deficit, absent speech, outbursts of laughter with hand flapping, microcephaly, macrostomia, maxillary hypoplasia, prognathia and neurological problems with a puppet-like[orpha.net]
Muscle Hypotonia
  • Cerebellar ataxia, muscle hypotonia and tremor, though constant in childhood, tend to be attenuated in adulthood.[ncbi.nlm.nih.gov]
  • HYPOTONIA ; and a peculiar facies.[hon.ch]
Lordosis
  • Other musculoskeletal abnormalities less frequently reported in the literature include scoliosis, excessive lumbar lordosis, and pes planus.[ncbi.nlm.nih.gov]
Broad Nasal Bridge
  • PTHS is characterized by severe mental retardation, a wide mouth plus other distinctive facial features (fleshy lips, beaked nose, broad nasal bridge) and breathing abnormalities.[ncbi.nlm.nih.gov]
Beak Nose
  • PTHS is characterized by severe mental retardation, a wide mouth plus other distinctive facial features (fleshy lips, beaked nose, broad nasal bridge) and breathing abnormalities.[ncbi.nlm.nih.gov]
Beaked Nose
  • PTHS is characterized by severe mental retardation, a wide mouth plus other distinctive facial features (fleshy lips, beaked nose, broad nasal bridge) and breathing abnormalities.[ncbi.nlm.nih.gov]
Narrow Face
  • Interestingly, this investigation found that certain typical features of mouth breathing syndrome, such as long and narrow faces, open mouth, shortened upper lip, lowered mandible position, shadows under the eyes (infraorbital cyanosis), muscular hypotonia[ncbi.nlm.nih.gov]
Easily Excitable
  • Children with Angelman syndrome may be easily excited, hypermotoric and hyperactive. They are active explorers and often may appear to be constantly in motion.[web.archive.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]
  • Sufferers present a happy demeanour, so are often smiling or laughing, and tend to be easily excited.[dailymail.co.uk]
Inappropriate Laughter
  • Angelman syndrome is characterized by mental retardation, seizures, ataxia, inappropriate laughter, lack of speech, a particular facial appearance, and generally a chromosome 15q11-q13 deletion.[ncbi.nlm.nih.gov]
  • Given the patient's relatively mild developmental impairment, without clinical evidence of seizures, gait disturbance or inappropriate laughter, the diagnosis of AS was not initially suspected.[ncbi.nlm.nih.gov]
  • laughter and happy disposition.[ncbi.nlm.nih.gov]
  • Excessive and inappropriate laughter is a telltale sign. The actual number of cases of Angelman syndrome is unknown. Some estimates are 1 in 15,000 babies have Angelman syndrome. Others estimate 1 in 30,000.[mentalhelp.net]
  • 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.[symptoma.com]
Nocturnal Enuresis
  • What is New: • Children and teens with AS are at special risk for incontinence, but older persons are also affected. • Comorbid epilepsy is significantly associated not only with nocturnal enuresis (NE) but also with daytime urinary incontinence (DUI)[ncbi.nlm.nih.gov]
  • In both groups, nocturnal enuresis was the most common form of incontinence. More incontinence was seen in individuals with AS who were younger, had a lower level of adaptive functioning and/or had epilepsy.[ncbi.nlm.nih.gov]
Seizure
  • , 7 (30%) had a decrease in seizure frequency, and only 1 (4%) did not have enough information to determine seizure control post-initiation.[ncbi.nlm.nih.gov]
  • The other seizure types were isolated generalized myoclonus and tonic seizures. None of the patients experienced atypical absence seizures. Levetiracetam therapy was effective in controlling the myoclonic events in 2 of the 3 patients.[ncbi.nlm.nih.gov]
  • Extensor and flexor spasms are not typically described seizure types in Angelman syndrome, and our patient's seizures responded well to a combination of valproic acid and clonazepam.[ncbi.nlm.nih.gov]
  • The low glycemic index treatment also provided effective seizure control with minimal side effects.[ncbi.nlm.nih.gov]
  • The results of this study indicate that epilepsy severity may assume a bimodal age distribution: seizures are typically most severe in early childhood but may recur in adulthood.[ncbi.nlm.nih.gov]
Abnormal Sleep-Wake Cycles
  • Sleep disorders are also common, often characterized by abnormal sleep-wake cycles. Movement disorders are nearly universal in Angelman syndrome, most frequently presenting with ataxia and tremor.[ncbi.nlm.nih.gov]
  • The consensus guidelines for Angelman syndrome (AS) consider abnormal sleep-wake cycles and diminished need for sleep as associated features.[ncbi.nlm.nih.gov]
  • Patients may also exhibit wide mouths with unusual tongue/mouthing behaviors, hypopigmentation, and abnormal sleep-wake cycles. Older patients may experience obesity.[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.[web.archive.org]
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.[web.archive.org]
Myoclonic Jerking
  • In addition, there was improvement in the myoclonic jerks, sleep pattern, and developmental progress. Corticosteroids appeared to have a broad benefit on the epileptic encephalopathy.[ncbi.nlm.nih.gov]
  • She was initially treated with vigabatrin which resulted in worsening of myoclonic jerks. Fluorometric in situ hybridization revealed a chromosomal deletion at region 15q11-13.[ncbi.nlm.nih.gov]
  • The types of seizures include myoclonic (‘jerks’), atonic or astatic (‘drops’) and tonic (‘stiffening’) seizures. Generalised tonic-clonic seizures and focal (partial) seizures are less common.[epilepsy.org.uk]
Cogwheel Rigidity
  • Two intellectually disabled adults with Angelman Syndrome are reported who developed intermittent episodes of a severe resting tremor, cogwheel rigidity and bradykinesia in their late teens.[ncbi.nlm.nih.gov]

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.
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.[web.archive.org]

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].

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.

References

Article

  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.

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Last updated: 2019-06-28 11:44