The role of PREPL in the pathophysiology of PWS: evaluation of a novel therapeutic approach for the treatment of hypotonia

A remarkable clinical resemblance between Prader-Willi syndrome (PWS) and hypotonia-cystinuria syndrome (HCS) was observed in our multidisciplinary clinic for PWS in our center. All HCS patients were initially referred for genetic analysis of PWS. Patients with either syndrome suffer from weakness and poor sucking in the newborn period. This improves spontaneously but overeating and rapid weight gain develop in childhood. A growth delay is also seen in both disorders. Mental development is abnormal both in HCS and PWS, although the mental problems in HCS are less pronounced.

We have recently found that the weakness in HCS is caused by a defect in communication between the motor nerve and the muscle, and this communication is also abnormal in PWS. We showed that inactivation of the gene PREPL is responsible for these symptoms in HCS, and suspect PREPL also plays a role in PWS. 4- and 16-fold reduction of PREPL in muscle biopsies of 2 PWS patients appear to confirm this suspicion. We observed serendipitously that treatment with a certain antibiotic improves the weakness of HCS patients for a prolonged period of time and we suspect that it may also help children with PWS.

The studies we plan to conduct aim to validate this novel therapy to treat hypotonia in PWS. We will evaluate if this antibiotic improves muscle weakness in infants with PWS as it does in HCS patients. We will also confirm diminished presence of PREPL in muscle and blood of PWS patients and in a mouse model of PWS. Furthermore, we want to evaluate the details of the defect in communication between the motor nerve and the muscle in the PWS mouse model. This will be done with electrical measurements in muscle biopsies.

This project is in loving memory of baby Violet Ai Xin Hasenmyer, a life that was lost too soon, but a life that was not without purpose or joy.

Research Outcomes: 

PREPL deficiency: delineation of the phenotype and development of a functional blood assay. Régal L, Mårtensson E, Maystadt I, Voermans N, Lederer D, Burlina A, Juan Fita MJ, Hoogeboom AJM, Olsson Engman M, Hollemans T, Schouten M, Meulemans S, Jonson T, François I, Gil Ortega D, Kamsteeg EJ, Creemers JWM.  Genetics in Medicine. 2017 Jul 20. 

Funded Year:


Awarded to:

John Creemers, Ph.D.




University of Leuven, Belgium

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