Randomized, Placebo Controlled Double-blind Study of the Efficacy of Topiramate on the Symptoms of Irritability - Impulsivity, Overeating and Self-harm in a Population of Patients Suffering From Prader Willi Syndrome Over 8 Weeks

Scientific background and justification of the study :

Patients with a rare disease are often challenging to treat when considering psychotropic treatment for behavioral or psychiatric manifestations. There is an important lack of clear data or treatment guidelines for treating behavioral disturbance in patients with intellectual disabilities. Prader Willi syndrome (PWS) is a paradigmatic example of such a disease. It is a rare disease with an estimated prevalence of 1:25,000 at birth. PWS is a genetic disease located on chromosome 15 (15 q11-q13). Imprinting silence the normal genes on 15 q11-Q13, rendering them non-functional, with the paternal non-imprinted genes being deleted. The imprinting effect in this region explains why approximately 60 to 70% of patients with PWS have a paternal deletion of 15q11-q13 (2). An additional 25 to 35 % of patients have two copies of maternal chromosome 15 (uniparental disomy). Rarely, PWS may be associated with translocation, mutation, or other anomalies. Angelman Syndrome, which has primarily been associated with autism spectrum disorders, involves the same genetic region and is commonly associated to mutations of the maternal allele of the UB3a gene or rare deletions. .

PWS patients present in a neonatal hypotonic state with deficit of sucking and eating refusal which progresses to with hyperphagia and obsession with food in infancy or adolescence. In addition, patients have distinct facial features, such as a narrow forehead, almond-shaped eyes, and a triangular mouth, as well as a short stature, related to growth hormone deficiency and small hands and feet. Puberty is often delayed or incomplete, and most affected individuals are unable to have children. This eating disorder is more similar to an addictive disorder to food than a traditional eating disorder. PWS leads to severe obesity, which is a major issue associated with quality of life and medical prognosis.

Psychiatric and cognitive symptoms in patients with PWS are severe and have an important impact on social and interpersonal life. Patients with PWS often have mild to moderate intellectual disability (ID), with learning impairments and poor academic achievement. They have particular difficulties in mathematics, calculation, and abstraction, which may be related to under-diagnosed neuro-visual impairments. There is a large individual heterogeneity of language impairments, primarily in morphosyntaxic abilities. Behavioral impairments predominately include temper outbursts, impulsivity, emotional liability and aggressive behavior , as well as self-injury behavior, such as compulsively picking the skin and mucosa (rectal picking), which may lead to a severe wound and severe infections. Patients with disomy as a group have more severe overall symptoms than patients with a deletion.

Regarding the relationship between PWS and schizophrenia spectrum disorders (SSDs), 5 studies have utilized standardized psychometric tools to assess psychiatric diagnoses. SSDs are primarily, but not exclusively, associated with disomy, and the clinical diagnosis may be complicated. Considering that disomy represents only 20%, at most, of patients, SSDs affect less than 20% of patients with PWS, most likely approximately 17% or 15%. There are few studies in the field of behavioral treatment in PWS they suggests that risperidone for psychotic symptoms associated with disomy, and N-acetylcysteine for skin picking might be efficient. Moreover and despite many study limitations, the investigators identified promising treatment effects with topiramate for self-injury and impulsive/aggressive behaviors. To date there is only one study (open trial) for topiramate in PWS.