Prader–Willi syndrome: Symptoms and topiramate response in light of genetics

Frontiers in Neuroscience

Neuroscience

Mimi-Caterina Turtulici¹  Cécile Louveau¹  Anton Iftimovici²  Marie-Odile Krebs²  Boris Chaumette³  Angèle Consoli⁴  Muriel Coupaye⁵  Christine Poitou⁵ 

[1] Centre de Référence pour les Maladies Rares à expression Psychiatrique, GHU Paris Psychiatrie et Neurosciences, Paris, France;Centre de Référence pour les Maladies Rares à expression Psychiatrique, GHU Paris Psychiatrie et Neurosciences, Paris, France;Institute of Psychiatry and Neuroscience of Paris (IPNP), INSERM U1266, Université Paris Cité, Paris, France;Centre de Référence pour les Maladies Rares à expression Psychiatrique, GHU Paris Psychiatrie et Neurosciences, Paris, France;Institute of Psychiatry and Neuroscience of Paris (IPNP), INSERM U1266, Université Paris Cité, Paris, France;Department of Psychiatry, McGill University, Montréal, QC, Canada;Department of Child and Adolescent Psychiatry, Pitié-Salpêtrière Hospital, Paris, France;GRC-15, Dimensional Approach of Child and Adolescent Psychotic Episodes, Faculté de Médecine, Sorbonne Université, Paris, France;Nutrition Department, Rare Diseases Center of Reference “Prader–Willi Syndrome and Obesity With Eating Disorders” (PRADORT), Assistance Publique-Hôpitaux de Paris, Pitié-Salpêtrière Hospital, INSERM, Nutriomics, Sorbonne Université, Paris, France;

关键词: Prader–Willi;    topiramate;    treatment;    genetics;    deletion;    disomy;    personalized medicine;   

DOI  :  10.3389/fnins.2023.1126970

 received in 2022-12-18, accepted in 2023-01-17,  发布年份 2023

来源: Frontiers

【 摘 要 】

IntroductionPrader–Willi Syndrome (PWS) is a rare genetic condition, which affects one in 25,000 births and results in various phenotypes. It leads to a wide range of metabolic and endocrine disorders including growth delay, hypogonadism, narcolepsy, lack of satiety and compulsive eating, associated with mild to moderate cognitive impairment. Prognosis is especially determined by the complications of obesity (diabetes, cardiorespiratory diseases) and by severe behavioral disorders marked by impulsivity and compulsion. This heterogeneous clinical picture may lead to mis- or delayed diagnosis of comorbidities. Moreover, when diagnosis is made, treatment remains limited, with high interindividual differences in drug response. This may be due to the underlying genetic variability of the syndrome, which can involve several different genetic mutations, notably deletion or uniparental disomy (UPD) in a region of chromosome 15. Here, we propose to determine whether subjects with PWS differ for clinical phenotype and treatment response depending on the underlying genetic anomaly.MethodsWe retrospectively included all 24 PWS patients who were referred to the Reference Center for Rare Psychiatric Disorders (GHU Paris Psychiatrie and Neurosciences) between November 2018 and July 2022, with either deletion (N = 8) or disomy (N = 16). The following socio-demographic and clinical characteristics were recorded: age, sex, psychiatric and non-psychiatric symptoms, the type of genetic defect, medication and treatment response to topiramate, which was evaluated in terms of eating compulsions and impulsive behaviors. We compared topiramate treatment doses and responses between PWS with deletion and those with disomy. Non-parametric tests were used with random permutations for p-value and bootstrap 95% confidence interval computations.ResultsFirst, we found that disomy was associated with a more severe clinical phenotype than deletion. Second, we observed that topiramate was less effective and less tolerated in disomy, compared to deletion.DiscussionThese results suggest that a pharmacogenomic-based approach may be relevant for the treatment of compulsions in PWS, thus highlighting the importance of personalized medicine for such complex heterogeneous disorders.

【 授权许可】

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Copyright © 2023 Louveau, Turtulici, Consoli, Poitou, Coupaye, Krebs, Chaumette and Iftimovici.