Systematic Review of the Clinical and Genetic Aspects of Prader-Willi Syndrome

A Biochemistry Journal Report on DNA Genetic Anomalies

GROUP 7
VASQUEZ, Jorina M.
VICTA, Carlson P.
VILLANUEVA, Anne Monique A.
VILLEGAS-LEOBRERA, Beverly Anne C.
VIRTUSIO, Denice Odil Z.
ZARATE, Miriam Tarah T.
ZOLETA, Mishael V.
December 9, 2015

I. BRIEF INTRODUCTION
In 1887, Langdon Down described the first patient with Prader-Willi syndrome as an adolescent
girl with mental impairment, short stature, hypogonadism, and obesity and attributed these
symptoms to polysarcia. In 1956, Prader et al reported a series of patients with similar
phenotypes. In 1981, Ledbetter et al identified deletions located between bands 15q11 and
15q13 and determined it to be the site for Prader-Willi syndrome.
Prader-Willi syndrome is characterized by severe infantile hypotonia with poor suck and failure
to thrive; hypogonadism causing genital hypoplasia and pubertal insufficiency; characteristic
facial features; early-childhood onset obesity and hyperphagia; developmental delay/mild
intellectual disability; short stature; and a distinctive behavioral phenotype. Sleep abnormalities
and scoliosis are common. Growth hormone insufficiency is frequent, and replacement therapy
provides improvement in growth, body composition, and physical attributes. Management is
otherwise largely supportive. Consensus clinical diagnostic criteria exist, but diagnosis should
be confirmed through genetic testing.
Prader-Willi syndrome is due to absence of paternally expressed imprinted genes at 15q11.2q13 through paternal deletion of this region (6575% of individuals), maternal uniparental
disomy 15 (2030%), or an imprinting defect (13%). Parent-specific DNA methylation analysis
will detect >99% of individuals. However, additional genetic studies are necessary to identify the
molecular class. There are multiple imprinted genes in this region, the loss of which contribute
to the complete phenotype of Prader-Willi syndrome. However, absence of a small nucleolar
organizing RNA gene, SNORD116, seems to reproduce many of the clinical features. Sibling
recurrence risk is typically <1%, but higher risks may pertain in certain cases. Prenatal
diagnosis is available.
The condition is rare, affecting no more than one in every 15,000 children born in England. Boys
and girls of all ethnic backgrounds may be affected.

FIGURE 1. Genetic mechanisms of Prader- Willi syndrome.

Pathophysiology
Most cases of Prader-Willi syndrome that involve deletions, unbalanced translocations, and
uniparental (maternal) disomy are sporadic. Monozygotic twins are concordantly affected.
Approximately 70% of Prader-Willi syndrome cases arise from deletion of band 15q11-13 on
chromosome 15. Maternal uniparental disomy caused by chromosomal nondisjunction accounts
for 28% of Prader-Willi syndrome cases. Less than 1% of patients have mutations isolated to the

imprinting center, which carries a risk of recurrence. Buiting et al have suggested that deletions
solely localized to the imprinting center may be due to a failure to erase the maternal imprint
during spermatogenesis.
Several genes have been mapped to the 15q11.2-13 region, including the SNRPNgene, P gene
(type II oculocutaneous albinism), UBE3A gene (encodes a ubiquitin-protein ligase involved in
intracellular protein turnover), and necdin gene (codes for a nuclear protein expressed
exclusively in the differentiated mouse brain). Mutations associated with the
maternal UBE3A gene result in Angelman syndrome.
The role of ghrelin in the satiety defect found in Prader-Willi syndrome is a subject of active
investigation. In 2002, Cummings et al reported significantly elevated ghrelin levels (4.5-fold
higher) in individuals with Prader-Willi syndrome. Haqq et al reported improvement in ghrelin
levels after octreotide infusion but no significant improvement in postprandial suppression of
ghrelin levels. After correction of relative hypoinsulinemia, Goldstone et al reported a residual
1.3-fold to 1.6-fold elevation in fasting ghrelin levels and a 1.2-fold to 1.5-fold elevation in
postprandial ghrelin levels in adults with Prader-Willi syndrome.
II. DEFINITION OF TERMS

Neonatal hypotonia is one of the hallmark features of this disorder and is a valuable clue
to initiate diagnostic testing.

Head-lag position in traction is noted.

The first stage of PWS in infancy is characterized by lethargy, marked hypotonia, global
developmental delay, and small genitalia with frequent cryptorchidism.

Poor suck (with requirement of gavage feedings), and weak cry may also be exhibited by
the infant.

Body fat in excess in infants with PWS have been documented by skinfold
measurements, dual energy x-ray absorptiometry, and double labeled water.

Lean body mass are decreased in PWS infants, correlating it with a 30% lower energy
expenditure compared to healthy individuals.

III. CLINICAL MANIFESTATIONS

1. Characteristics of PWS in the newborn and infant period

Neonatal hypotonia is one of the hallmark features of this disorder and is a valuable clue
to initiate diagnostic testing.

Head-lag position in traction is noted.

The first stage of PWS in infancy is characterized by lethargy, marked hypotonia, global
developmental delay, and small genitalia with frequent cryptorchidism.

Poor suck (with requirement of gavage feedings), and weak cry may also be exhibited by
the infant.

Body fat in excess in infants with PWS have been documented by skinfold
measurements, dual energy x-ray absorptiometry, and double labeled water.

Lean body mass are decreased in PWS infants, correlating it with a 30% lower energy
expenditure compared to healthy individuals.

FIGURE 2. Hypotonia of infancy in patients with Prader-Willi Syndrome.

2. Dysmorphic features

Narrow bifrontal diameter

Almond-shaped palpebral fissures

Narrow nasal bridge

Thin upper lip with a down-turned mouth

Shorter total hand size, narrow palms with hypoplastic hypothenar bulges, and short feet
with short toes

Fair hair and hypopigmentation of the eyes and skin relative to other family members are
frequently observed in patients with deletion-type PWS; less common in patients with
uniparental disomy.

FIGURE 3. Facial features of a Prader-Willi patient.

3. Developmental and cognitive delays

Gross motor and language milestones are delayed

Early milestones are reached on average at double the normal age (e.g., sitting at 12
months, walking at 24 months, and words spoken at 2 years).

Cognitive disability is evident by school age. Most patients with the syndrome are mildly
mentally retarded (mean intelligence quotient (IQ): 60-70 score).

40% have borderline mental retardation or low-normal intelligence and approximately

20% have moderate retardation.

Impaired physical function in PWS patients during childhood is most often related to
body composition abnormalities and hypotonia.

4. Hyperphagia and Obesity

Hyperphagia begins when patient experience an insatiable appetite.

Hyperphagia is hypothalamic in origin caused by lack of sense of satiety.

Food intake will increase, and if not controlled central obesity will develop.

Having low metabolic rate, decreased activity level which results in decreased total
caloric requirement.

Studies showed that their body composition has increased body fat and reduced muscle
mass.

5. Sleep Abnormalities

Patients with PWS has sleep-disordered breathing, such as disruptions of the normal
sleep cycle and sleep apnea, a condition in which breathing pauses during sleep.

These disorders can result in excessive daytime sleepiness

Obesity can worsen the sleep disorder.

6. Behavioral and Psychiatric Disturbances

Patients with PWS may at times be stubborn, angry, controlling or manipulative.

They may throw temper tantrums, especially when denied food.

They may not tolerate changes in their routine. They may also develop obsessivecompulsive or repetitive behaviors, or both.

Other mental health disorders, such as skin picking, may develop.

7. Endocronological Abnormalities
1. Obesity

Obesity in PWS is the major cause or morbidity and mortality; cardiorespiratory failure,
cor pulmunale exacerbated by central and obstructive apnea, septicemia due to skin infections
and pneumonia.
2. Growth deficiency
Short stature may be observed, due to lack of growth hormone exacerbated bylack of
pubertal growth spurt.

3. Hypogonadism
Hypogonadism is a consistent feature in both men and women with PWS. This is
manifested as genital hypoplasia throughout life, incomplete pubertal development, and
infertility in the vast majority of cases.
Molecular and Genetic Basis of PWS:

A genomic disorder
Results from alteration in the structure of a genome (an epigenetic phenomenon) and
not a specific change in the DNA sequence.
Various genomic changes lead to loss of expression of paternally expressed genes on
chromosomes 15q11.2-q13, through loss or failure of expression;
Due to maternal contribution has been programmed by epigenetic factors (eg: DNA
methylation) to be silenced.
First known examples of human diseases involving imprinted genes.

Structure and Genes in the 15q11-q13 Region:

1. Microdeletions of the chromosome region 15q11-q13

A 57-Mb de novo deletion of the proximal region of the paternal chromosome

15, which includes the entire imprinted domain plus several non-imprinted genes,
is found in the majority (~70%) of patients with PWS.

Molecular level, usually 2 classes of deletions (class I and II) can be

distinguished, 1 spanning from BP1 to BP3 and the other from BP2 to BP3

A precise localization of the deletion breakpoints and the determination of the

deletion sizes have been performed by array-CGH analysis recently

2. Uniparental disomy of chromosome 15

Second most common genetic abnormality in PWS (~2530%) is a maternal

uniparental disomy of chromosome 15, occurring mostly due to maternal meiotic
nondisjunction followed by mitotic loss of the paternal chromosome 15 after
fertilization.

Upd mat leads to the lack of expression of imprinted genes that are active on the
paternal chromosome only.

3. Imprinting defect

Disruption of the imprinting process on the paternally inherited chromosome 15 is

the third molecular mechanism underlying PWS.

This disruption is present in approximately 25% of individuals.

Most imprinting defects are epigenetic (epimutations) and demonstrate a

maternal-only DNA methylation pattern despite the presence of both parental
alleles (biparental).

DNA sequence changes are not found in these epimutations; they are thought to
be random stochastic errors occurring during spermatogenesis in the fathers

By contrast, approximately 15% of individuals with an imprinting defect are found

to have a very small deletion in the PWS imprinting center region located at the 5
end of the SNRPN gene.

Diagnostic Testing:
Parent-of-origin-specific DNA methylation can be used to confirm the clinical diagnosis of
PWS patients in all 3 molecular classes (deletion of 15q11-q13, uniparental disomy, and
imprinting defect).
The most widely used DNA methylation test targets the 5 end of the SNRPN locus.
The promoter region of SNRPN is unmethylated on the paternally expressed allele and
methylated on the maternally repressed allele.
Normal individuals have both a methylated and an unmethylated allele, whereas
individuals with PWS have only the maternally methylated allele.
DNA methylation cannot distinguish this molecular class.
Deletion of the paternally contributed 15q11.2q13 is typically diagnosed using the
SNRPN fluorescence in situ hybridization probe32).
Chromosome analysis should be included in testing for a deletion, as occasionally the
deletion is the result of a chromosomal translocation.

Maternal uniparental disomy is diagnosed using DNA polymorphism analysis of the

proband and parental DNA.

Treatment
Patients who suffer from PWS frequently require medical care for their symptoms which
include constant monitoring for scoliosis and therapy for behavioral issues.
However, there are no medications that effectively address hyperphagia for patients with
PWS. Sex steroid implementation improves secondary sex characteristics but may
aggravate behavioral disorders.
GH Therapy
Growth hormone therapy is advised for children with genetically confirmed PWS and the
evidence of growth failure.
Patients eligible for GH therapy have to periodically receive tests that confirm growth
hormone deficiency, GH response testing, tests for low IGF-1 level, and physical
examination for abnormal body composition with high fat mass and low lean body mass.

Documented improvements in response to GH therapy are linear growth, physical

appearance, functional muscle mass, and infant neurodevelopment.
Treatment also appears to improve behavior in some patients. However, GH does not
appear to enhance the development of scoliosis.
Recommended dose is 1 mg/m2 per day.
Some pediatricians advise a lower dose for infants, starting at 0.25-0.30mg/m2 per day.

Evaluation and monitoring of effects of GH therapy are important, especially for infants
and toddlers, for possible non-GH-related abnormalities and unresponsiveness to
treatment.
Early start of treatment beneficially and significantly alters the natural history of PWS by
reducing body fat and improving muscle strength physical function.
There have been no severe side effects for GH therapy.

Concerns in GH therapy

Children with PWS are at risk of developing sleep-disordered breathing secondary to

both deficient autonomic sleep control and upper airway obstruction.
A causal relationship between GH and sudden death has not been demonstrated,
although important concerns over safety have been raised.
Concerns over possible worsening of obstruction are justified in the obese group, and
patients with PWS require careful dietary, ENT, and respiratory evaluation before starting
treatment with GH.
It has been suggested that GH exacerbates preexisting gas-exchange deficiencies in 3
ways: by stimulating adenotonsillar hypertrophy, increasing the basal metabolic rate with
a resultant rise in oxygen demand, and normalizing previously decreased hydration with
an augmentation of the volume load.

VI. COMPLICATIONS AND PROGNOSIS

Diminished sensitivity to pain

Diminished capacity to vomit, may delay diagnosis of underlying diseases

Hypogonadism Behavior issues Morbid Obesity Shorter life expectancy and affect
quality of life Speech therapy

Need additional physical activity

Need individual attention

VI. CONCLUSION
History of PWS suggest that a multidisciplinary professional, parental, societal, and
environmental approach to the management of these patients is required for overcoming the
many challenges of reducing morbidity and mortality and improving patient quality of life. GH
replacement therapy in PWS has resulted in drastic improvements. However, much is yet to be
learned about this complex disorder. We still do not know the precise gene/s responsible for the
phenotype.
REFERENCES
1. Jin, K.D. (2011). Systematic review of the Clinical and Genetic aspects of Prader-Willi
Syndrome. Retrieved from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3077502/
2. PraderWilli
Syndrome
(December
8,
2015).
http://emedicine.medscape.com/article/947954-overview

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from