Conditions · Pediatrics and neonatology
Prader–Willi and Angelman syndromes (imprinting) !
Prader–Willi and Angelman syndromes come from the same chromosome 15 region: Prader–Willi when the father's copy fails, Angelman when the mother's copy fails.
Updated 2026-11-01
Structures involved
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Why it happens
- Genomic imprinting: Prader–Willi and Angelman
- Nonclassic inheritance: repeat expansions, mitochondrial genes, imprinting, mosaicism
- Obesity: leptin, adipokines and its consequences
- Functions of the hypothalamus
- Epigenetics: DNA and histone methylation
What it is
Two neurodevelopmental syndromes caused by loss of imprinted genes in 15q11–q13: Prader–Willi (paternal genes; hypotonia, then hyperphagia and obesity) and Angelman (maternal UBE3A gene; severe intellectual disability, absent speech, ataxia and seizures).
Who gets it
Prader–Willi syndrome affects roughly 1 in 10,000 to 30,000 people and Angelman syndrome about 1 in 12,000 to 20,000, without sex or ethnic predominance. Most cases are sporadic. They are classic examination examples of genomic imprinting.
Causes
- Prader–Willi: deletion of the paternal 15q11–q13 region (about 70%), maternal uniparental disomy (about 25%), or an imprinting defect
- Angelman: deletion of the maternal 15q11–q13 region (about 70%), mutation of the maternal UBE3A gene, paternal uniparental disomy or an imprinting defect
- Most cases arise from random events at conception; some imprinting or UBE3A mutations can be inherited
Risk factors
- Usually none identifiable (sporadic)
- A parent carrying a balanced chromosome 15 rearrangement or an imprinting centre mutation
- Assisted reproductive techniques have been linked to imprinting disorders in some studies
Pathophysiology
Imprinting means some genes are expressed from only one parent's copy, the other being silenced by methylation. In Prader–Willi, the active paternal genes (including the SNORD116 cluster) are lost; hypothalamic dysfunction then disturbs satiety, growth hormone secretion, gonadotropins and temperature control. In Angelman, neurons lose UBE3A, which in the brain is expressed only from the maternal copy, impairing synaptic function and causing the neurological picture.
Classification
- Prader–Willi syndrome: deletion, maternal uniparental disomy or imprinting defect
- Angelman syndrome: maternal deletion, UBE3A mutation, paternal uniparental disomy or imprinting defect
Symptoms and signs
- Prader–Willi in infancy: severe hypotonia, weak suck and poor feeding, often needing tube feeding
- Prader–Willi from early childhood: hyperphagia with food seeking, leading to obesity if food is not controlled
- Prader–Willi: short stature, small hands and feet, almond-shaped eyes, narrow forehead
- Prader–Willi: hypogonadism (cryptorchidism, small genitals, delayed puberty) and mild to moderate intellectual disability
- Prader–Willi: temper outbursts, stubbornness, skin picking and obsessive traits
- Angelman: developmental delay noticed at 6 to 12 months; severe intellectual disability with minimal or no speech
- Angelman: ataxic, jerky gait and tremulous limbs; frequent laughter and smiling with an excitable manner
- Angelman: seizures, microcephaly and sleep problems
Diagnosis
- Clinical
- Suspected from a floppy newborn with feeding problems (Prader–Willi) or from severe delay, absent speech, ataxia, happy demeanour and seizures (Angelman). Clinical scoring criteria exist for both.
- Tests
- DNA methylation analysis of 15q11–q13 is the first test and detects most cases of both syndromes. Further tests define the mechanism (FISH or microarray for deletion, uniparental disomy studies, imprinting centre analysis, UBE3A sequencing in Angelman with normal methylation). EEG in Angelman shows characteristic patterns. Prader–Willi follow-up includes glucose, thyroid and hormone studies.
- Imaging
- Not diagnostic. Polysomnography for sleep apnoea, spine X-rays for scoliosis, bone densitometry in adolescents and adults with Prader–Willi.
Differential diagnosis
- Other causes of neonatal hypotonia: spinal muscular atrophy, congenital myopathies, myotonic dystrophy, sepsis
- Other genetic obesity syndromes and hypothalamic obesity
- Rett syndrome, Pitt-Hopkins and Mowat-Wilson syndromes (Angelman-like)
- Autism spectrum disorder and cerebral palsy
Goal of treatment
No cure: management is lifelong and multidisciplinary, aimed at preventing obesity and its complications in Prader–Willi, controlling seizures and supporting communication in Angelman, and maximising each person's development and safety.
Treatment
- Lifestyle
- Prader–Willi: strict control of food access and environment, a structured low-energy diet and daily physical activity from early childhood.
- Medical
- Growth hormone therapy in Prader–Willi improves body composition, muscle tone and height; sex hormone replacement for hypogonadism. Antiseizure medicines in Angelman, plus treatment of sleep problems.
- Rehabilitation
- Early intervention: physical, occupational and speech therapy; augmentative communication in Angelman; behavioural support.
- Follow-up
- Monitoring of weight, glucose, sleep apnoea, scoliosis, thyroid function and bone density; genetic counselling for families.
Complications
- Morbid obesity, type 2 diabetes, obstructive sleep apnoea and cor pulmonale (Prader–Willi)
- Choking and gastric rupture after food binges (Prader–Willi)
- Scoliosis and osteoporosis
- Drug-resistant epilepsy and status epilepticus (Angelman)
- Infertility from hypogonadism (Prader–Willi)
- Psychiatric problems, including psychosis in some adults with Prader–Willi
Prognosis
In Angelman syndrome life expectancy appears near normal, but the person needs lifelong care. In Prader–Willi syndrome, survival depends mainly on obesity control; obesity-related heart and breathing problems and choking are leading causes of early death.
Test yourself
Think of the answer, then tap the question to see it.
Which chromosome region is involved in both Prader–Willi and Angelman syndromes?
Chromosome 15q11–q13, an imprinted region.
Loss of which parent's genes causes Prader–Willi syndrome?
Loss of the paternally expressed genes, by paternal deletion or maternal uniparental disomy.
Which gene is lost in Angelman syndrome?
The maternally expressed UBE3A gene in neurons.
What is the first-line genetic test when either syndrome is suspected?
DNA methylation analysis of 15q11–q13, which detects most cases.
How does Prader–Willi syndrome typically change from infancy to childhood?
From severe hypotonia and poor feeding in infancy to hyperphagia and obesity in childhood.
Related conditions
- Obesity
- Type 2 diabetes mellitus
- Obstructive sleep apnoea
- Cryptorchidism (undescended testis)
- Male hypogonadism
- Scoliosis
- Epilepsy and seizures
- Autism spectrum disorder (ASD)
Educational information, not medical advice. For any symptom, see a health professional.
Sources: Prader-Willi syndrome (MedlinePlus Genetics (U.S. National Library of Medicine), 2024); Angelman syndrome (MedlinePlus Genetics (U.S. National Library of Medicine), 2024).
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