Prader-Willi and Angelman syndromes — formative SAQs

SAQ 1 (10 marks)

A two-week-old neonate is referred for profound hypotonia, poor feeding, and a weak cry. Birth weight was at the 10th centile. He requires nasogastric feeding. Examination reveals a narrow bifrontal diameter, almond-shaped palpebral fissures, a thin upper lip, bilateral cryptorchidism, and acromicria. A standard karyotype has been reported as normal. [1] [3]

a) Give the most likely diagnosis and explain why a normal karyotype does not exclude it. Name the first-tier molecular test you will order. (3 marks) [1] [4]

b) Describe the three molecular subtypes of this syndrome, their approximate relative frequencies, and the mechanism by which each produces the phenotype. (3 marks) [3] [4]

c) Outline the syndrome-specific management plan for this child across infancy and childhood, naming four domains that require active intervention. (2 marks) [1] [7]

d) Explain why molecular subtype determination is essential for genetic counselling, and state the recurrence risk for each subtype. (2 marks) [4]

SAQ 2 (10 marks)

A three-year-old girl is referred for severe global developmental delay. She has minimal speech but seems to understand simple commands. She walks with a wide-based, ataxic gait and frequently holds her arms uplifted and flexed. Her parents describe her as always happy and laughing. She developed seizures at 18 months, currently treated with valproate but with ongoing myoclonic jerks. She has microcephaly and fair skin relative to her parents. [2] [6]

a) Give the most likely diagnosis and describe the molecular mechanism. Name the first-tier test and the result you expect. (3 marks) [2] [4]

b) If the first-tier test returns normal, name the next investigation and explain why approximately 10 per cent of these patients have a normal methylation result. (2 marks) [2] [4]

c) Outline the multidisciplinary management plan for this child, naming four key domains. (2 marks) [6]

d) Discuss the emerging precision medicine approaches for this syndrome, including the molecular rationale for unsilencing the paternal allele. (3 marks) [9]

Marking guide

SAQ 1. The most likely diagnosis is Prader-Willi syndrome (loss of paternal expression at 15q11-q13). A standard karyotype does not detect the imprinting error — the chromosomes look structurally normal because the genes are present but silenced by methylation. The first-tier test is methylation-specific PCR or MS-MLPA of the SNRPN locus, which shows only the maternal methylation pattern (absent paternal pattern), confirming the diagnosis. The three molecular subtypes are: paternal deletion of 15q11-q13 (approximately 70 per cent, a de novo interstitial deletion), maternal uniparental disomy (approximately 25 per cent, two maternal copies and no paternal copy), and imprinting-centre defect (approximately 5 per cent, paternal allele silenced without deletion or UPD). Management across infancy and childhood includes neonatal feeding support (nasogastric feeding), strict dietary and environmental control of hyperphagia from early childhood (locked food, structured meals, behavioural strategies), growth hormone therapy (improves body composition, height, lean mass, and cognitive outcomes, with surveillance for sleep apnoea and scoliosis), endocrine management (hypogonadism, hypothyroidism), and behavioural and developmental support (early intervention, individualised education, speech and occupational therapy). Recurrence risk: deletion and UPD are sporadic (less than 1 per cent); imprinting-centre defect can carry up to 50 per cent recurrence if a parent carries the defect — hence subtype determination is the counselling answer. [1] [3] [4] [7]

SAQ 2. The most likely diagnosis is Angelman syndrome (loss of maternal UBE3A expression in the brain at 15q11-q13). The mechanism is genomic imprinting: in neurons, the paternal UBE3A allele is silenced by the antisense transcript UBE3A-ATS, so loss of the maternal allele eliminates functional UBE3A protein in the brain. The first-tier test is methylation-specific PCR or MS-MLPA of SNRPN, which shows only the paternal methylation pattern (absent maternal pattern) in the deletion, UPD, and imprinting-defect forms. If methylation is normal, the next test is UBE3A sequencing, because approximately 10 per cent of AS cases are caused by a UBE3A point mutation — these have intact imprinting and a normal methylation pattern. The UBE3A mutation form carries a 50 per cent recurrence risk if the mother is a carrier. Multidisciplinary management includes anticonvulsant optimisation (valproate, levetiracetam, clonazepam, possibly a ketogenic diet), augmentative and alternative communication (AAC, sign language, picture-based systems — because expressive language is minimal but receptive language is relatively preserved), motor and physical therapy (gait, balance, tone), and sleep management (melatonin, behavioural strategies). Emerging precision medicine includes antisense oligonucleotides that block UBE3A-ATS to unsilence the intact paternal UBE3A allele, restoring functional UBE3A protein in the brain — this is the molecular rationale for gene-therapy approaches, currently in clinical development. [2] [4] [6] [9]