Rapamycin. The mTOR pathway, known through its role in Tuberous Sclerosis Complex (TSC), becomes increasingly important in epilepsy. A wide range of epilepsies caused by brain malformations are due to mutations in genes involved in this pathway, and several neurodevelopmental disorders associated with macrocephaly, intellectual disability and epilepsy are known, where components of this pathway are altered due to germline mutations. For one of these disorders named PMSE (polyhydramnios, megalencephaly and symptomatic epilepsy), a recent paper in Science Translational Medicine reports the effects of treatment with rapamycin, an mTOR inhibitor. The results demonstrate that personalized medicine might in part be promising, asexisting drugs can be used in rare genetic diseases.
Pretzel Syndrome. Due to the peculiar positioning of the legs due to the muscular hypotonia in combination with connective tissue problems, children with mutations in the STRADA/LYK5 gene can twist themselves into a pretzel-like configuration. Hence, STRADA deficiency is sometimes referred to as Pretzel Syndrome. The recessive disease, caused by a small deletion of the STRADA gene, is exclusively found in the Old Order Mennonites, a distinct religious community in Lancaster County, Central Pennsylvania. Recessive disorders are regularly observed in these communities including homozygous CNTNAP2 mutations in recessive symptomatic focal epilepsy in the Amish. In 2007, Puffenberger and colleagues identified STRADA as the causative gene in a disease that was referred to a polyhydramnios, megalencephaly and symptomatic epilepsy (PMSE). PMSE leads to severe intellectual disability, lack of active speech and intractable epilepsy.
The mTOR pathway in PMSE. The STRADA/LYK5 protein was found to be involved in cellular signaling involved in neuronal proliferation. One of these pathways, the mTOR pathway, plays a central role in neuronal proliferation. Somatic mutations, i.e. mutations only affecting a subset of cells, as well as germline mutations, affecting all cells of the body, are found in neurodevelopmental disorders in mTOR pathway genes including mutations in TSC1/TSC2 and PTEN. The mTOR pathway, referring to the mammalian target of rapamycin, is actually named after the drug that is used to influence dysregulations in this signaling cascade. Rapamycin or sirolimus is approved for the treatment of so-called subependymal giant-cell astrocytomas (SEGA) in TSC. As sirolimus is a well-tolerated immunosuppressant, the indications are currently expanding beyond SEGA to other areas of mTOR dysregulation. In their current paper, Parker and colleagues investigate the effect on PMSE due to STRADA mutations. STRADA deficiency leads to a continuous overactivation of the mTOR pathway, as this protein is involved in negatively regulating the effect of external stimuli on mTOR.
Zero seizures. Parker and colleagues investigated the effect of sirolimus in PMSE after thoroughly assessing the effect of mTOR suppression through this drug in the a mouse model for PMSE and in skin fibroblasts. As the mouse model recapitulates some of the neuronal migration deficits, it was ideally suited to test the effect of sirolimus. Parker and colleagues found that much of the disorganized neuronal migration is reversed through sirolimus. In skin fibroblasts, the continuous activation of the mTOR pathway could be attenuated through sirolimus. In their clinical study, sirolimus was well tolerated by 5 patients with PMSE who were treated as toddlers. None of the patients had major side effects. Interestingly, the seizure frequency in all patients dropped to virtually zero with only a single seizure reported during a 12 month observation period. There was some suggestion that cognition also improved, but this effect was much less evident than the reduction in seizure frequency. All patients were treated at the average age of 3 years, a time when seizures are usually very frequent and treatment resistant in PMSE patients. In summary, targeted treatment with PMSE drastically reduced the seizure frequency, and patients became virtually seizure-free.
Lessons to be learned. The report by Parker and colleagues offers the following lessons. First, personalized medicine does not necessarily mean that expensive drugs will need to be custom designed. In some cases, existing drugs may find a new purpose once the disease mechanism is understood. It can be assumed that with the paper by Parker and colleagues, sirolimus therapy in PMSE will soon become commonplace. Secondly, in complex neurodevelopmental disorders, seizures may be an “easy target”, while other features of a genetic disease including intellectual disability, autism or absent speech, will be much harder to tackle. This underlines the potential role of such personalized medicine approaches in patients with difficult-to-treat epilepsies.