Prader‑Willi Syndrome / Angelman Syndrome (Prader‑Willi / Angelman syndrome)

Alternate Names of the Diseases

Prader‑Willi Syndrome (PWS)
This name comes from the fact that the syndrome was first reported in the 1960s by Swiss physicians Dr. Prader and Dr. Willi. In Japanese it is sometimes written as “プラダーウィリー症候群.” In Japan, it is registered as a designated intractable disease (No. 193), and is eligible for support systems such as medical expense subsidies.

Angelman Syndrome (AS)
The name derives from British pediatrician Dr. Harry Angelman, who in 1965 reported three children who shared common features. Initially, the name “happy puppet syndrome” was used, but due to criticisms of discriminatory connotations, it is no longer used.

Both disorders are very unusual genetic diseases caused by abnormalities in “imprinted genes” located in the same region (15q11‑q13) of chromosome 15. What is particularly notable is that depending on whether the abnormality is on the chromosome inherited from the father or from the mother, the symptoms are entirely different.

In other words, even with the same region affected:

• Abnormality inherited from father → Prader‑Willi Syndrome
  
• Abnormality inherited from mother → Angelman Syndrome
  

This is why these disorders are sometimes called “mirror‑image genetic disorders.”

Overview of the Diseases

Prader‑Willi Syndrome (PWS) and Angelman Syndrome (AS) are both rare genetic disorders that present with characteristic developmental and physical abnormalities from the newborn or infant period. Both arise from defects in the “imprinting” regulatory mechanism of genes on chromosome 15.

In PWS, infants are born with hypotonia (low muscle tone), difficulty with feeding, and often inadequate weight gain. Around age 3, hyperphagia (abnormally increased appetite) begins, tending toward severe obesity. Additionally, intellectual disability, short stature, endocrine (sex hormone) abnormalities, and restrictive or ritualistic behavior are seen, demanding ongoing medical and welfare support across many domains.

On the other hand, in AS, even if a child appears relatively healthy at first, from around 6 months onward motor development delays become evident. Over time, severe intellectual disability, very limited or absent verbal communication, impaired ambulation, epilepsy (seizures), etc., emerge. Moreover, because these children often smile a lot, are energetic, and have difficulty staying calm, they have sometimes been described as having an “angelic smile,” but their daily life typically involves a high degree of care dependence.

Currently, there is no cure for either disorder. However, early diagnosis and appropriate interventions can alleviate symptoms and improve quality of life. In recent years, research in gene therapy and behavioral-modulating drugs has advanced, offering hope for effective therapeutic approaches in the future.

Thus, although PWS and AS stem from the same chromosomal region, clinically they present entirely different challenges and support needs, requiring deep understanding and tailored approaches from families and caregivers.

Causes and Diagnostic Methods

Both disorders occur due to abnormalities in genetic imprinting.

• PWS: A deletion or inactivation in the paternally derived 15q11‑q13 region.
  
• AS: A deletion or dysfunction in the maternally derived UBE3A gene or other related genes.
  

Specific causes may include chromosomal deletions, uniparental disomy (both chromosomes inherited from one parent), gene mutations, or imprinting defects.

Diagnostic methods include:

• DNA methylation testing (to assess imprinting status)
  
• Genetic analysis (to detect deletions, duplications, or point mutations)
  
• Chromosomal microarray analysis
  
• As necessary, supplementary tests such as electroencephalography (EEG), brain MRI, endocrine studies, etc.
  

Symptoms and Management Methods

Prader‑Willi Syndrome (PWS)

Symptoms

• Neonatal period: hypotonia, feeding difficulties, poor weight gain
  
• From early childhood onward: hyperphagia, obesity, short stature, gonadal dysfunction, intellectual developmental delay, behavioral abnormalities
  
• Adulthood: lifestyle diseases (type 2 diabetes, hypertension, cardiovascular disease), osteoporosis, psychiatric issues
  

Management Methods

• Dietary restriction and exercise therapy (to control hyperphagia)
  
• Growth hormone therapy (to improve height, muscle strength, body composition)
  
• Developmental support and early intervention (speech therapy, occupational therapy, physical therapy)
  
• Behavioral support and psychological care (to address ritualistic behaviors, emotional instability)
  
• Respiratory and sleep management
  
• Endocrine management (sex hormones, diabetes, etc.)
  

In 2025, the U.S. approved a new appetite‑suppressing drug Vykat XR, raising expectations for future treatments.

Angelman Syndrome (AS)

Symptoms

• Developmental delay and severe intellectual disability
  
• Language impairment (nearly nonverbal)
  
• Motor ataxia (walking difficulties)
  
• Seizures (epilepsy)
  
• Frequent smiling, easily excitable behavior
  
• Microcephaly, characteristic facial features
  

Management Methods

• Antiepileptic drugs to control seizures
  
• Physical therapy, occupational therapy, speech therapy
  
• Augmentative and alternative communication support (AAC)
  
• Interventions for sleep and behavioral disorders (environmental modifications and medications)
  
• Long-term systems for life care and assistive support
  
• Research into gene therapy is ongoing。

Future Outlook

Prader‑Willi Syndrome (PWS)

The long-term outlook for PWS can be substantially altered by early diagnosis and multidisciplinary intervention. In particular, obesity-related complications (type 2 diabetes, hypertension, cardiovascular disease, obstructive sleep apnea) can be life‑threatening; thus, how well these are prevented or managed is key to the prognosis.

Medical Outlook

• Introduction of growth hormone therapy (GH) not only helps with height, but also increases muscle strength, reduces adipose tissue, maintains bone density, and thus may improve mobility and quality of life
  
• However, the challenges of weak respiratory function and difficulty in dietary control persist, necessitating careful monitoring and management by families
  
• The emergence of new drugs like Vykat XR (FDA‑approved in 2025) offers a sign that direct treatment for the core issue—“irrepressible appetite (hunger)”—may become feasible, potentially suppressing the onset of obesity‑related complications
  

Life & Social Outlook

• For individuals with severe intellectual or behavioral impairments, independent living is often difficult, and group homes or welfare facilities may be chosen
  
• In milder to moderate cases, day support centers or employment support facilities may allow continued engagement with society
  
• In education, options include special needs schools or inclusive education combining regular classes with support classes
  
• Because of strong behavioral routines and insistence on routines, families and support persons need to continuously attend to environmental arrangement and psychological care
  

Family & Support Systems

• The psychological and financial burden on parents and siblings is considerable; utilization of family support systems (respite care, counseling, financial subsidies) is essential
  
• In Japan, combining the intractable disease medical subsidy system, disability welfare services, and adult guardianship systems is necessary to design comprehensive long-term life plans
  
• In an aging society, planning for the “after parents are gone” scenario is also a critical issue to address early
  

Research & Future Hopes

• Research is underway on gene editing, neuromodulatory agents, and symptom‑specific therapeutic approaches
  
• Overseas, there are early deployments of AI‐ and IoT‑based remote monitoring and life support technologies, with potential future adoption in Japan
  
• In the long run, innovative treatments aiming to restore gene function (e.g. epigenetic therapies) may become practically available
  

Angelman Syndrome (AS)

As AS centers on severe intellectual and motor impairment, lifelong assistance and medical-welfare support are necessary. Although life-threatening complications are less common compared to PWS, with proper medical care and life support, many cases can maintain relatively stable living conditions.

Medical Outlook

• For severe epilepsy, quality of life can deteriorate greatly, so careful selection and ongoing adjustment of antiepileptic drugs is critically important
  
• Sleep disorders, gastrointestinal dysfunction, motor problems, vision and hearing issues may also occur; an individualized multidisciplinary management system is required
  
• Recently, approaches that leverage neural plasticity (the brain’s adaptability) for training interventions, and EEG‑based intervention research, have attracted attention
  

Life & Social Outlook

• Although often severely impaired, many individuals engage in community welfare or educational settings, benefitting from their tendency to smile and interact with others
  
• Because verbal expression is extremely limited, introduction of AAC (augmentative and alternative communication) tools is key to supplementing their ability to communicate wishes
  
• Sensory integration therapies (e.g. using music, rhythm, tactile stimulation) have shown effectiveness in some cases, and support approaches that emphasize “sensing and responding” are recommended
  

Family & Support Systems

• Chronic sleep disturbance or reversed sleep–wake patterns can lead to persistent sleep deficiency and caregiver fatigue; support systems involving professional collaboration are indispensable
  
• Ongoing sharing of information and coordination of care plans among daycare, preschools, schools, welfare facilities is essential
  
• In adulthood, utilization of regional life support centers and welfare‐type facilities for disabled children becomes important in creating a life environment aligned with the person’s own style
  

Research & Future Hopes

• Among the genetic anomalies in AS, the loss of function in the maternal UBE3A gene is a key focus, and clinical trials of gene therapy and epigenetic drugs targeting this are underway overseas
  
• Animal experiments have succeeded in artificially “activating” the paternal UBE3A gene, which brings the possibility of a curative therapy one step closer
  
• In Japan, clinical genetics specialists and neuro‑pediatricians have organized study groups, participated in international collaborative research, and intensified outreach efforts
  

A key commonality of both disorders is that early diagnosis and intervention have a profound impact on subsequent quality of life. For families, although these are lifelong conditions requiring ongoing support, the progress of medicine and improvement in social systems promise that the range of possible options will continue to expand.