Miguelez, J., et al. “P04.22: Case report: diagnosis of 3 cases or no words at all.

However, receptive language skills

Angelman syndrome

of anencephaly/exencephaly at 8–10 weeks.” Ultrasound (listening to and understanding the speech of others)
in Obstetrics and Gynaecology 44.S1 (2014): 207. and non-verbal communication are not as severely
Panduranga, C., et al. “Anencephaly: A pathological study affected.
of 41 cases.” Journal of the Scientific Society 39.2
(2012): 81. Individuals with AS have a balance disorder,
causing unstable and jerky movements. This typically
“Pregnancy termination following prenatal diagnosis of
anencephaly or spina bifida: A systematic review of the
includes gait ataxia (a slow, unbalanced way of walking)
literature.” Birth Defects Research Part A: Clinical and and tremulous movements of the limbs.
Molecular Teratology 94.11 (2012): 857. AS is also associated with a unique “happy”
Youngblood, Monica E., et al. “2012 Update on global behavior, which may be the best-known feature of the
prevention of folic acid-preventable spina bifida and condition. This may include frequent laughter or smil-
anencephaly.” Birth Defects Research Part A: Clinical ing, often with no apparent stimulus. Children with
and Molecular Teratology 97.10 (2013): 658. AS often appear happy, excited, and active. They may
ORGANIZAT
A IONS
AT also sometimes flap their hands repeatedly. Generally,
they have a short attention span. These characteristic
March of Dimes Birth Defects Foundation. 1275
Mamaroneck Ave., White Plains, NY 10605. (914)
behaviors led to the original name of this condition,
997-4488. resourcecenter@modimes.org. http:// the “happy puppet” syndrome. However, this name is
www.modimes.org. no longer used, as it is considered insensitive to AS
National Center on Birth Defects and Developmental Dis-
individuals and their families.
abilities, Division of Birth Defects and Developmental
Disabilities. Mail-Stop E87, 1600 Clifton Rd. Atlanta, Genetic profile
GA 30333 http://www.cdc.gov/ncbddd/birthdefects/
Anencephaly.html. The genetics of AS are complex. There are at least
five different genetic abnormalities that can cause the
National Birth Defects Prevention Network. Atlanta, GA.
(770) 488-3550 http://www.nbdpn.org.
condition, all of which involve a specific region of the
chromosome 15 inherited from the mother. This region
Roger E. Stevenson, MD is designated 15q11-13 (bands 11 through 13 on the
long arm of chromosome 15). The fact that AS occurs
Rosalyn E. Carson–DeWitt, MD
only when there are abnormalities in this region of the
Deborah L. Nurmi, MS
maternal copy of chromosome 15 reflects a unique
phenomenon known as imprinting. Imprinting is a
chemical modification of DNA that acts as an “iden-
tification tag,” indicating which parent contributed the
chromosome. Imprinted genes or chromosome regions
■ Angelman syndrome are expressed or not expressed depending on which
parent transmitted the chromosome. Abnormalities
Definition in the paternally (from the father) inherited 15q11-
Angelman syndrome (AS) is a genetic condition 13 region cause a different genetic condition called
that causes severe intellectual disability, severe speech Prader-Willi syndrome.
impairment, and a characteristic happy and excitable
Chromosome deletion
demeanor.
The most common cause of AS is a small dele-
Description tion (missing piece) in the maternally inherited chro-
mosome 15. Specifically, the deletion occurs within
Individuals with AS show evidence of delayed 15q11-13. Approximately 70% of AS individuals have
development by 6–12 months of age. Eventually, this this deletion.
delay is recognized as severe intellectual disability.
Unlike some genetic conditions causing severe intel- UBE3A mutation
lectual disability, AS is not associated with devel-
In approximately 11% of AS cases, there is a muta-
opmental regression (loss of previously attained
tion within the maternally inherited UBE3A gene.
developmental milestones).
All the genetic mechanisms leading to AS appear to
Severe speech impairment is a striking feature of compromise expression of this gene, which is located
AS. Speech is almost always limited to a few words within the 15q11-13 region. This gene is considered to

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 Angelman syndrome
Angelman Syndrome

1. Etiology: Deletion, Uniparental Disomy or Unkown 2. Etiology: UBE3A mutation, Imprinting mutation or Unknown

88y d.71y d.83y 78y d.71y d.88y d.62y 75y

Colon Liver Stroke
cancer cirrhosis

61y 54y 49y 46y 39y 63y 60y 48y 39y

36y 23y 18y 12y 25y 21y 17y 14y 12y d.2mos
Congenital
heart defect

2
2y

Angelman syndrome: pedigree analysis chart (Illustration by GGS Information Services. Gale, a part of Cengage Learning.)

be the “critical gene” responsible for AS, although its material), an inversion (in which a piece of a chromo-
specific function is unknown. some breaks and rejoins in the opposite orientation),
or another disturbance of the chromosome structure
Uniparental disomy involving the maternal 15q11-15q13. This mechanism
Some cases of AS result from inheritance of both is responsible for about 1% of AS cases.
chromosomes in the 15 pair from the father, an unu-
Unknown mechanism(s)
sual genetic phenomenon known as uniparental dis-
omy. In this circumstance, there is no chromosome 15 In about 10%–15% of individuals with AS, no
from the mother. Approximately 7% of AS cases result genetic cause can be identified. This may reflect mis-
from this mechanism. diagnosis or the presence of additional, unrecognized
mechanisms leading to AS.
Imprinting defect
Approximately 3% of AS cases result from an Demographics
imprinting defect on the maternally inherited chro-
AS has been reported in individuals of diverse
mosome 15. As noted above, imprinting is a chemical
ethnic backgrounds. The incidence of the condition is
modification to the DNA that serves as a marker indi-
estimated at 1 in 10,000 to 1 in 30,000.
cating the parent of origin and controls gene expres-
sion. If there is defective imprinting on the maternally
inherited 15, then the genes in the 15q11-15q13 region Signs and symptoms
may not be expressed, leading to AS. The first abnormalities noted in an infant with AS
are often delays in motor milestones (those related to
Chromosome rearrangement
physical skills, such as sitting up or walking), muscu-
Rarely, AS may be caused by chromosomal breaks lar hypotonia (poor muscle tone), and speech impair-
that occur in the maternally inherited 15q11-13 region. ment. Some infants seem unaccountably happy and
The breaks may occur as the result of a transloca- may exhibit fits of laughter. By age 12 months, 50% of
tion (in which two chromosomes break and exchange infants with AS have microcephaly (a small head size).

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 Tremulous movements are often noted during the first 15  chromosomes (with no number 15 chromosome
Angelman syndrome

year of life. from the mother), or a defective imprinting mecha-

Seizures occur in 80% of children with AS, usually nism, DNA methylation studies will be abnormal and
by three years of age. No major brain lesions are typi- indicate AS. This test detects the majority (approxi-
cally seen on cranial imaging studies. mately 78%) of cases of AS. Additional studies are
then required to determine which of these three mech-
The achievement of walking is delayed, usually anisms led to AS development.
occurring between two-and-a-half and six years of
age. The child with AS typically exhibits a jerky, stiff
UBE3A mutation analysis
gait, often with uplifted and bent arms. About 10%
of individuals with AS do not walk. Additionally, Direct DNA testing of the UBE3A gene is neces-
children may have drooling, protrusion of the tongue, sary to detect cases of AS caused by mutations in this
hyperactivity, and a short attention span. gene. Cases of AS caused by UBE3A mutations usu-
Many children have a decreased need for sleep and ally have a normal imprinting pattern.
abnormal sleep/wake cycles. This problem may emerge
in infancy and persist throughout childhood. Upon Fluorescent in situ hybridization (FISH)
awakening at night, children may become very active FISH studies may be necessary to detect chro-
and destructive to bedroom surroundings. mosome rearrangements that disrupt the 15q11-q13
The language impairment associated with AS is region on the maternal copy of chromosome 15. The
severe. Most children with AS fail to learn appropriate FISH method is a special way of checking for the
and consistent use of more than a few words. Recep- presence, absence, or rearrangement of very small
tive language skills are less severely affected. Older pieces of chromosomes. FISH testing can also read-
children and adults are able to communicate by using ily detect AS caused by chromosome deletions, which
gestures or communication boards (special devices account for approximately 70% of AS cases. FISH
bearing visual symbols that correspond to commonly testing is often performed following an abnormal
used expressions or words). methylation study to determine whether a chromo-
Some individuals with AS caused by a deletion of some deletion accounts for the abnormal methyla-
the 15q11-q13 chromosomal region may have a lighter tion pattern.
skin complexion than would be expected given their
family background. Treatment and management
There is no specific treatment for AS. A variety
Diagnosis of symptomatic management strategies may be offered
The clinical diagnosis of AS is made on the basis for hyperactivity, seizures, intellectual disability, speech
of physical examination and medical and developmen- impairment, and other medical problems.
tal history. Confirmation requires specialized labora- The typical hyperactivity in AS may not respond
tory testing. to traditional behavior modification strategies. Chil-
There is no single laboratory test that can identify dren with AS may have a decreased need for sleep and
all cases of AS. Several different tests may be per- a tendency to awaken during the night. Drug therapy
formed to look for the various genetic causes of AS. may be prescribed to counteract hyperactivity or aid
When positive, these tests are considered diagnostic sleep. Most families make special accommodations
for AS. for their child by providing a safe yet confining envi-
ronment.
DNA methylation studies Seizures in AS are usually controllable with one
or more anti-seizure medications. In some individu-
DNA methylation studies determine whether the
als with severe seizures, dietary manipulations may be
normal imprinting pattern associated with the mater-
tried in combination with medication.
nal (mother’s) copy of the number 15 chromosome
is present. The 15q11-q13 region is differently meth- Children with AS appear to benefit from targeted
ylated (or “imprinted”) depending on which parent educational training. Physical and occupational
contributed the chromosome. If an individual has therapy may improve the disordered, unbalanced
a deletion of this region on the maternal chromo- movements typical of AS. Children with a severe bal-
some 15, paternal uniparental disomy of the number ance disorder may require special supportive chairs.

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 WEBSITES

Ankylosing spondylitis
QU ES T I O N S TO #105830, “Angelman Syndrome; AS.” Online Mendelian
A SK YO U R D O C TOR Inheritance in Man (OMIM). http://www.omim.org/
entry/105830 (accessed June 9, 2015).
• At what point do you recommend surgery rather Dagli, Aditi I., Mueller, Jennifer, and Charles A. Williams.
than medication for gastric reflux? “Angelman Syndrome.” National Center for Biotech-
• What will be the long-term benefit of speech nology Information. http://www.ncbi.nlm.nih.gov/
books/NBK1144 (accessed June 9, 2015).
therapy?
• What is the surgical risk for scoliosis repair? ORGANIZAT
A ION
AT
Angelman Syndrome Foundation, Inc. 414 Plaza Drive, Suite
• At what age should I take my child to an oph-
209, Westmont, IL 60559. (800) IF-ANGEL or (630)
thalmologist (eye doctor)?
734-9267. Fax: (630) 655-0391. info@angelman.org.
http://www.angelman.org.

Speech therapy is often directed towards the develop- Jennifer Ann Roggenbuck, MS, CGC
ment of nonverbal communication strategies, such as
picture cards, communication boards, or basic sign-
ing gestures.
Individuals with AS may be more likely to develop
particular medical problems, which are treated accord-
ingly. Newborn babies may have difficulty feeding, ■ Ankylosing spondylitis
and special bottle nipples or other interventions may Definition
be necessary. Gastroesophageal reflux (heartburn)
Ankylosing spondylitis (AS) is a relatively com-
may lead to vomiting or poor weight gain and may
mon disease that causes inflammation of the area
be treated with drugs or surgery. Constipation is a
where ligaments and tendons insert into the bone.
frequent problem and is treated with laxative medi-
The inflammatory process eventually leads to reduced
cations. Many individuals with AS have strabismus
mobility or immobility of affected joints. Specific
(crossed eyes), which may require surgical correction.
joints are characteristically involved, notably in the
Orthopedic problems, such as tightening of tendons or
spine and pelvis.
scoliosis, are common. These problems may be treated
with physical therapy, bracing, or surgery.
Description
Prognosis Ankylosing spondylitis belongs to a group of
disorders called the seronegative spondyloarthropa-
Individuals with AS have significant intellectual
thies. Each disease in this group is characterized by
disability and speech impairment that are considered
arthritis affecting the spine, as well as the absence of
to occur in all cases. However, they do have the capac-
rheumatoid factor, a diagnostic marker that is pre-
ity to learn and should receive appropriate educational
sent in rheumatoid arthritis and helps distinguish
training.
it from the group of diseases that includes AS. AS
Young people with AS typically have good physi- affects primarily the spine and the sacroiliac joint
cal health aside from seizures. Although lifespan data where the spine meets the hips. Progressive symp-
are not available, the lifespan of people with AS is toms eventually result in fusion of these joints, pain,
expected to be normal. and markedly decreased joint mobility. AS is con-
sidered an autoimmune disease, meaning that symp-
Resources toms are the result of the action of the immune sys-
PERIODICALS tem of the body against its own tissues. Although the
Bird, Lynne M. “Angelman Syndrome: Review of Clinical exact mode of action is unknown, there is a strong
and Molecular Aspects.” Application of Clinical association between AS and a specific type of human
Genetics 7 (2014): 93–104. leukocyte antigen, HLA-B27. HLA are genetically-
Tan, Wen-Hann, et al. “Angelman Syndrome: Mutations determined proteins that play an important role in
Influence Features in Early Childhood.” American the functioning of the immune response of the body,
Journal of Medical Genetics Part A 155, no. 1 (January in that they enable the immune system to distinguish
2011): 81–90. between its own cells and foreign cells. Therefore,

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