Aetiology

Prader-Willi syndrome (PWS) was the first condition in humans to be attributed to an error in genomic imprinting. Almost all cases are sporadic and approximately 70% of cases are attributed to a paternal deletion of genes on chromosome 15q11-q13. The remainder of cases are predominantly attributed to maternal disomy of chromosome 15.[4] Very rarely, familial cases have been identified in which the affected individual has inherited a microdeletion of the imprinting centre from the father via the paternal grandmother. In these families there is a recurrence risk of 50% in any additional children.[13][14][15]

Risk factors that may lead to increased susceptibility to inheriting the condition include:

  • Older maternal age (>35 years), due to increased risk of maternal meiosis (non-sdisjunction) errors and trisomy rescue (leading to maternal disomy of chromosome 15) occurring in early pregnancy[16]

  • Occupations associated with hydrocarbon exposure in fathers of affected patients[17]

  • Conception occurring via assisted reproductive technology methods due to a possible increased risk of occurrence of genomic imprinting errors.[18]

Pathophysiology

Development of PWS is attributed to the loss of gene expression, which is normally paternally inherited, from the chromosome 15q11-q13 region due to errors in genomic imprinting.[17] These genes are normally present but inactivated on the maternal chromosome 15.[14] The majority of cases are due to a deletion of the 5-7 Mb in 15q11.2-q13 region.

The 15q11.2-q13 region can be loosely separated into four subregions:[19]

  • Proximal non-imprinted region with four biparentally expressed genes, located between break point 1 and break point 2

  • PWS paternal-only expressed region with the protein coding genes MKRN3, MAGEL2, NECDIN, and SNURF-SNRPN, five snoRNA genes (HBII-436, HBII-13, HBII-438, HBII-85, and HBII-52), and several antisense transcripts (including one to UBE3A)

  • Angelman syndrome (AS) region containing the preferentially maternally expressed genes UBE3A (the mutation of which is known to cause AS) and ATP10A[20]

  • Distal non-imprinted region with three GABA receptor genes, the HERC gene, and the oculocutaneous albinism type 2 (OCA2) gene.

The specific genes involved in PWS and their exact functions are still unclear. Although a single gene mutation that explains all features of PWS has not been identified, the snoRNA gene HBII-85 is thought to play a significant role.[21]

Many aspects of the PWS phenotype are thought to be attributed to hypothalamic dysfunction, although how this is linked to the genetic abnormality is not understood. Disruption to hypothalamic pathways including those related to satiety control may lead to some phenotypical features of PWS including hyperphagia, regulation of food intake, and issues related to behaviour.[22] It has also been hypothesised that patients with PWS may also have decreased mitochondrial function.[23]

Classification

Prader-Willi syndrome genetic subtypes

There are three molecular classes of Prader-Willi syndrome:[4] ​

  • Paternal 15q11-q13 deletion (approximately 70% of cases), which is divided into the following subgroups:

    • type 1 deletion (approximately 6 Mb)

    • type 2 deletion (approximately 4.5 mb)

    • atypical deletions

  • Maternal disomy of chromosome 15 (approximately 30% of cases), which is divided into the following subgroups:

    • heterodisomy

    • isodisomy

  • Genomic imprinting centre defects (rare).

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