Prader-Willi Syndrome: Underlying Causes, Natural History, and Management

Prader–Willi syndrome is considered a very rare disease, with a prevalence of 1 in 10,000–30,000 births worldwide.[4,6] Based on a study of a large US administrative medical claims database, researchers estimated a US prevalence of 1 in 37,000 persons, or approximately 8,900 patients in 2018. The proportion of males and females with the disorder is equal. Furthermore, there seems to be no disproportion of one race or ethnicity across patients with Prader–Willi syndrome.[7]

Annual mortality of patients with Prader–Willi syndrome is at least three times greater than that of the general population (2.7% vs. 0.8%).[8] Median age at death was 30 years, and respiratory complications were the most common cause of death (>50%), with cardiovascular issues the second most common cause.[4]

Prader–Willi syndrome is caused by a genetic abnormality in chromosome 15, specifically an absence of expression of paternal genes from chromosome 15q11.2-q13.[6] In most cases of Prader–Willi syndrome (60%–70%), at least 13 genes in this region inherited from the father are not expressed (called “genomic imprinting”).[9,10] In other words, the genes on the paternal copy have been deleted, and the genes on the maternal copy are inactive.[3] The second most common cause (up to 35%) is related to maternal disomy 15—both copies of chromosome 15 are from the mother; thus, the paternal expression of these genes is again missing.[10]

For the remaining individuals, a defect in the activity of imprinted genes on chromosome 15 is responsible for the phenotype. Recently, research has uncovered how individual imprinted genes, like SNORD116, affect the phenotype and the principal manifestations of the disorder.[11] The genes MAGEL2 and NECDIN have been implicated in the regulation of appetite, neurodevelopment, and growth.[3]

Our ability to identify genes or gene combinations that may result in atypical or milder cases of Prader–Willi syndrome is improving rapidly. Next-generation sequencing and exciting gene-editing techniques are revealing new potential molecular pathways that account for the manifestations of Prader–Willi syndrome.[3]

The gene dysfunction in Prader–Willi syndrome results in neuromuscular as well as endocrine abnormalities, with wide-ranging effects. From the neuromuscular standpoint, this includes dystonia, behavioral issues, and cognitive deficits. The endocrine effects range from short stature to eating disorders, hypogonadism, and developmental delays.[3,9]

The first symptom of Prader–Willi syndrome is seen almost universally: Severe hypotonia occurs immediately after birth and during the neonatal period.[9] Typical signs of Prader–Willi syndrome exhibited neonatally include:[9]

• Feeding difficulties
• Thickened saliva
• Lethargy
• Small genitalia (both in males and females)
• Cryptoorchidism (males)

The early feeding difficulties may seem ironic, as hyperphagia (followed soon by obesity) inevitably arises in children 4 to 8 years of age. In addition, young children with the disorder exhibit developmental delay, short stature or abnormal slow growth (with growth hormone and insulin-like growth factor-1 deficiency), small hands and feet, hypogonadism, narrow bifrontal diameter, and almond-shaped palpebral fissures.[9]

Endocrine abnormalities are commonly cited in studies of Prader–Willi syndrome, specifically hypothalamic dysfunction. This abnormality may be the underlying cause of patients’ hyperphagia, in addition to an instability in body temperature, a high pain threshold, and sleep-disordered breathing. By the time they reach adulthood, 25% of patients have type 2 diabetes mellitus.[9]

Behavioral problems, such as temper tantrums, outbursts, and skin picking, are often noted. These are concomitant with mild intellectual/cognitive impairment.[9]

Age at diagnosis was shown to be a significant factor in avoiding obesity (or later onset of obesity) and other comorbidities. In one 2019 study, patients were diagnosed at a mean age of 3.1 years.[12] On the other hand, a small study from France found that diagnosis was made a median 18 days after birth.[13] Researchers believe it is critical to identify Prader–Willi syndrome earlier, during the newborn period, to institute a treatment plan as early as possible.[12]

Unfortunately, there is no standard criteria for diagnosing Prader–Willi syndrome prenatally. Although reduced fetal activity, small fetus for gestational age, and non–term delivery have been noted, these are nonspecific signs.[14]

Initial signs and symptoms upon delivery should raise suspicions as to the genetic basis of the disorder. At birth, hypotonia, craniofacial abnormalities (including dolichocephaly, narrow minimal frontal diameter, strabismus, almond-shaped eyes), poorly sucking reflexes and associated feeding difficulty, and hypogonadism are evident.[14]

The presence of hypotonia and feeding problems at birth to age 2 years should prompt confirmatory genetic and molecular testing. This includes DNA methylation analysis and identification of the chromosome 15 deletion or other chromosome 15 anomalies. Additional analysis may be required to determine the type of deletion and its size.[3]

Researchers describe up to four nutritional phases (and additional subphases) in Prader–Willi syndrome, starting with difficulty feeding (phase 1) until weight gain begins at around 2 years of age (phase 2). By age 8, patients exhibit hyperphagia and lack of satiety (phase 3). In phase 4, patients are obese but they can experience satiety.[4,14]

Along with the nutritional issues in young patients, behavioral issues, slow intellectual growth, and the complications of hypothyroidism, such as short stature and low muscle mass, will also be of concern. In a study of children between 3 and 7 years of age with Prader–Willi syndrome, administration of growth hormone over 8 years enabled 60% to reach normal height.[15] Overall, 91% of patients used growth hormone.[16]

There are limited data on patient outcomes over time. One global patient registry, begun in 2015, had approximately 1,700 patients, but it significantly is overrepresented by younger patients and those in North America.[7] Yet, this registry has provided some important information about patient development and milestones. For example, 81% of the patients with Prader–Willi syndrome have graduated high school.

Disrupted sleep patterns seems to be common in these patients, and it may be associated with psychiatric and behavioral challenges, such as anxiety, depression, and psychosis.[17] Of those responding to sleep surveys through the Global Prader–Willi Syndrome Registry, 70% had sleep issues, including excessive daytime sleepiness, narcolepsy, and cataplexy. An additional 61% had sleep apnea.[18]

In another study based on the registry, 40% of patients reported strabismus, and over 90% were diagnosed with the disorder by age 5. Other vision issues, such as myopia, hyperopia, astigmatism, and amblyopia were cited as well.[19]

As patients age, a large proportion live in Prader–Willi syndrome specific settings; 40% of those ages 25 to 39 years live in group homes, and the percentage increases with age. Thirty-four percent of those over 18 years of age live in an independent house or apartment with support.[20]

The hyperphagia and its associated obesity that appears in early childhood are responsible for many complications as the patients enter adulthood. Prader–Willi syndrome has been identified as the most common known genetic cause of life-threatening obesity.[14] Type 2 diabetes is common, along with respiratory issues, cardiac disorders, and gastrointestinal problems. Indeed, patients with Prader–Willi syndrome have reduced lifespans, with an average age of only 29.5 years reported in 2017.[21]

Actual causes of death in one large survey were as follows:[21]

• Respiratory failure (31%)
• Cardiac (16%)
• Gastrointestinal (10%)
• Infection (9%)
• Obesity (7%)
• Pulmonary embolism (7%)
• Choking (6%)
• Accidents (6%)

A substantial proportion of medical research in chronic treatment of Prader–Willi syndrome has focused on hyperphagia and obesity prevention and management. Not only was this the cause of life-threatening outcomes, but it corresponds to the greatest unmet needs named by parents and caregivers of these young patients.[10]

Several compounds have been tested for effectiveness in reducing hyperphagia and inducing weight loss in patients with Prader–Willi syndrome. These included oxytocin, a neuropeptide; beloranib, a methionine aminopeptidase-2 inhibitor; setmelanotide, a melanocortin-4 receptor agonist; exenatide, a glucagon-like peptide-1 approved to treat diabetes mellitus; and livoletide, an inactive ghrelin analogue. Though theoretically promising, none of these agents reduced hyperphagia and obesity rates along with an acceptable side-effect profile.[10]

The benzothiadiazine molecule diazoxide choline had been approved by the Food and Drug Administration (FDA) since the 1970s for the treatment of hypoglycemia caused by the excessive production of insulin. Recently, this agent became the first drug approved by the FDA for the treatment of hyperphagia in patients with Prader–Willi syndrome.[10]

The approval of this oral, controlled-release agent was based on the results of two investigations. The first was a double-blind, placebo-controlled, phase 2 trial of 127 patients with Prader–Willi syndrome (≥ 4 years of age) with moderate-to-severe hyperphagia, based on the scores of a validated questionnaire. Patients were randomized 2:1 to receive diazoxide choline or placebo, respectively. Although it was not found in the primary analysis to be effective in patients with moderate hyperphagia, it did produce significant reductions in patients with severe hyperphagia (P =.023) and in results generated prior to the COVID-19 pandemic (P =.037).[22]

A second investigation of diazoxide choline was a long-term open-label study of 125 patients participating in the phase 3 trial.[22] Patients received the product for up to 52 weeks in the earlier trial or joined the open-label extension trial. Researchers found significant improvements in all patients’ hyperphagia survey scores (P < .0001) and greatest improvement in those with severe hyperphagia. In terms of secondary endpoints, lean body mass increased across the population (P < .0001) and, aggressive behaviors, anxiety, irritability, and depression were all decreased at 52 weeks (P < .0001). The most common adverse events were hypertrichosis (60%), peripheral edema (30%), and hyperglycemia (22%), but they caused discontinuation in fewer than 10% of participants.

Currently, there is no treatment for the underlying genetic basis for the disorder.

CLINICAL TRIALS

Foundation for Prader–Willi Research

Prader–Willi Syndrome Association – USA

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