Seizures more likely in PWS caused by genetic deletion mutations

Early detection of seizure disorders may improve quality of life, researchers say

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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About every 10th person with Prader-Willi syndrome (PWS) experiences epilepsy or fever-induced seizures, and more likely so if the disease is caused by a specific type of mutation, a review study has found.

Also, this type of mutation — deletions in a segment of chromosome 15 and the most common PWS cause — increases the likelihood of fever-induced seizures by nearly four times compared with the second-most genetic cause, called maternal uniparental disomy.

These findings suggest genetic information could help predict how likely someone with PWS is to experience epilepsy or febrile seizures, and enable steps toward improving care. However, “more studies or larger sample sizes are needed,” researchers wrote.

The study, “Prevalence and genotypic associations of epilepsy in Prader-Willi Syndrome: A systematic review and meta-analysis,” was published in Epilepsy & Behavior.

Every person has 23 pairs of chromosomes, which are rodlike structures where genes are located, with one chromosome inherited from the mother and one from the father. PWS, a disease marked by physical, behavioral, and metabolic abnormalities, is caused by mutations that affect a specific region in the paternal copy of chromosome 15.

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PWS most commonly caused by 15q11-q13 deletion

PWS is most commonly caused by a genetic deletion, also known as 15q11-q13 deletion, where that section of DNA is entirely missing. PWS can also be caused by maternal uniparental disomy, where both chromosome 15 copies are inherited from the mother, or due to an imprinting defect that inactivates the paternal chromosome 15.

“Although there has been increasing interest in seizures and epileptic disorders in PWS in recent years, the actual prevalence is still unknown, and knowledge is limited to single studies with necessarily limited sample sizes,” the researchers wrote.

“Furthermore, it is not known whether genotype [genetic profile] determines the risk of seizure disorders,” they added.

Now, a team of researchers in Spain has systematically analyzed data from published studies up to November 2023 reporting rates of epilepsy or febrile seizures in people diagnosed with PWS. Febrile seizures, or those triggered by a rapid rise in body temperature, can occur at any age, but are more common in children.

A total of 15 studies — including a total of 1,969 patients, from birth to 66 years old — were included in the qualitative analysis. Six studies were from the Americas (five from the U.S.), four from Asia, three from Europe, and one from Oceania, and one study described data from the Global PWS Registry (mainly from the U.S.).

Among patients with available genetic data, 904 had a genetic deletion, 499 had maternal uniparental disomy, and 38 had errors in genomic imprinting.

All but two of these 15 studies were included in the final meta-analysis to assess the pooled frequency of epilepsy and febrile seizures in PWS.

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Epilepsy, febrile seizures occur at higher rates in PWS patients

Data showed epilepsy occurred in 11% of patients and febrile seizures in 9%. Both of these rates were higher than in the general population, the researchers wrote.

However, “there was some discrepancy in the prevalence [number of cases] of epilepsy and febrile seizures between the different studies due to limited sample sizes, which means that small variations in cases can significantly alter the final estimate,” they added.

Consistent with previous findings, epilepsy was more common in patients with a 15q11-q13 deletion than in those with maternal uniparental disomy (12% vs. 4%). While “there was a clear trend towards a doubling of risk in participants with deletions,” this association did not reach statistical significance, the researchers wrote.

“Further studies are needed to confirm this, which could stratify the risk of patients according to genotype,” the team wrote.

Febrile seizures were also more common in patients with 15q11-q13 deletions (17% vs. 3%), reflecting a significantly higher risk, by nearly fourfold, relative to those with maternal uniparental disomy.

“There were no sex differences in the prevalence of epilepsy and febrile seizures,” the team wrote.

“PWS has not traditionally been considered a syndrome with an increased risk of seizures and epilepsy,” but “confirmation of the association between epilepsy and genotype could improve knowledge of the prognosis of these patients and, ultimately, their management,” the researchers wrote.

“Active search and early detection of seizure disorders should improve the quality of life of these patients,” they concluded.