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

A Biochemistry Journal Report on DNA Genetic Anomalies

GROUP 7VASQUEZ, 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 15q11.2-q13 through paternal deletion of this region (65–75% of individuals), maternal uniparental disomy 15 (20–30%), or an imprinting defect (1–3%). 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 obsessive-

compulsive or repetitive behaviors, or both.  Other mental health disorders, such as skin picking, may develop.

7. Endocronological Abnormalities

1. ObesityObesity 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 deficiencyShort stature may be observed, due to lack of growth hormone exacerbated bylack of

pubertal growth spurt.

3. HypogonadismHypogonadism 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 5–7-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 (~25–30%) 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 2–5% 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 15q11.2–q13 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. Prader- Willi Syndrome (December 8, 2015). Retrieved from http://emedicine.medscape.com/article/947954-overview