Clinical report
Compassionate use of everolimus for refractory epilepsy in a patient with MTOR mosaic mutation

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Abstract

The MTOR gene encodes the mechanistic target of rapamycin (mTOR), which is a core component of the PI3K-AKT-mTOR signaling pathway. Postzygotic MTOR variants result in various mosaic phenotypes, referred to in OMIM as Smith-Kinsgmore syndrome or focal cortical dysplasia. We report here the case of a patient, with an MTOR mosaic gain-of-function variant (p.Glu2419Lys) in the DNA of 41% skin cells, who received compassionate off-label treatment with everolimus for refractory epilepsy. This 12-year-old-girl presented with psychomotor regression, intractable seizures, hypopigmentation along Blaschko's lines (hypomelanosis of Ito), asymmetric regional body overgrowth, and ocular anomalies, as well as left cerebral hemispheric hypertrophy with some focal underlying migration disorders. In response to the patient's increasingly frequent epileptic seizures, everolimus was initiated (after approval from the hospital ethics committee) at 5 mg/day and progressively increased to 12.5 mg/day. After 5 months of close monitoring (including neuropsychological and electroencephalographic assessment), no decrease in seizure frequency was observed. Though the physiopathological rationale was good, no significant clinical response was noticed under everolimus treatment. A clinical trial would be needed to draw conclusions, but, because the phenotype is extremely rare, it would certainly need to be conducted on an international scale.

Introduction

The MTOR gene encodes the mechanistic target of rapamycin (mTOR), a highly conserved serine-threonine kinase and core component of the MTORC1 and MTORC2 complexes. The PI3K-AKT-mTOR signaling pathway is essential for cell growth, protein synthesis, autophagy, and cytoskeletal dynamics (Jacinto et al., 2004; Thoreen et al., 2012; Zoncu et al., 2011). The term “mTORopathies” has been used to characterize the clinical syndromes in which mTOR regulation is altered (Griffith and Wong, 2018). Dysregulation, such as hyperactivation of the mTOR pathway, can lead to various phenotypes. These include cortical development malformations that result in neurological abnormalities, including drug-resistant seizures (Crino, 2015). In this context, the inhibition of mTOR signaling with rapamycin has become an increasingly common therapeutic approach in patients with epilepsy (Meng et al., 2013).

The most extensively reported use of mTOR inhibitors for the control of intractable seizures associated with mTORopathies is for tuberous sclerosis complex (TSC) (OMIM #191100 and OMIM #613254). EXIST-3, a recent, double-blind, randomized controlled trial of everolimus in TSC, reported that 40% of patients in the high-exposure group (everolimus target trough 9–15 ng/ml) showed a clinical response (i.e. defined as >50% reduction in seizure frequency from baseline) compared with 28% of patients in the low-exposure group (target trough 3–7 ng/ml), and only 15% in the placebo group (French et al., 2016). Because studies have demonstrated that mTOR inhibitors can be used with partial success in TSC-related seizures, additional trials have been conducted in patients with other mTORopathies that have common physiopathological mechanisms (i.e. upregulation of the mTOR signaling pathway) (Parker et al., 2013; Xu et al., 2019). For instance, one study that explored the effects of rapamycin in polyhydramnios, megalencephaly, and symptomatic epilepsy (PMSE) syndrome reported a major decrease in the frequency of seizures (i.e. during the 12 months of treatment, four of five patients were seizure-free and the fifth had only one seizure) (Parker et al., 2013). Recently, a case report described the efficacy of rapamycin for intractable seizures in an infant diagnosed with hemimegalencephaly and a mosaic MTOR mutation present in 16% of reads, found following deep-sequencing of brain tissue after surgery. While awaiting hemispherectomy, rapamycin treatment led to >50% reduction in seizures and the total seizure burden after 1 week of treatment (Xu et al., 2019). However, there is still limited clinical data concerning the efficacy of mTOR inhibitors in non-TSC epilepsy with MTOR mutation (Griffith and Wong, 2018).

Here, we describe the case of a patient with a mosaic MTOR mutation associated with hypomelanosis of Ito (HMI), asymmetric regional body overgrowth and left cerebral hemispheric hypertrophy with some focal underlying migration disorders who received compassionate off-label treatment with everolimus for intractable seizures and psychomotor regression.

Section snippets

Case report

The patient was a 12-year-old female with a clinical diagnosis of severe syndromic HMI. She was the third and only affected child of non-consanguineous parents. Since birth, she had linear hypomelanosis along Blaschko's lines (Fig. 1A) combined with left corporal hemihypertrophy, hemimegalencephaly and hypotonia with spina bifida occulta. Her developmental milestones were delayed, with the ability to sit acquired only at the age of four, a severe language delay and autistic-like behavior.

Results

Treatment was initiated at 5 mg/day and further increased to 12.5 mg/day. The aim was to obtain a blood dosage between 5 and 15 μg/L (Fig. 2B). The patient experienced a few mild adverse events (diarrhea, alopecia and acne) (Fig. 2C). Some adverse events were only noted for few days, whereas asthenia was constant during all the everolimus period treatment. Blood count normalized at the everolimus end period. After five months of treatment, the number of seizures increased (120 seizures/month

Discussion

In this case of intractable seizures with a mosaic MTOR mutation, everolimus treatment showed no beneficial effect, even though the rapamycin-sensitivity of the activating MTOR mutation of the patient was confirmed in vitro and in vivo (Urano et al., 2007; Wagle et al., 2014). Indeed, sensitivity to rapamycine of yeast cells carrying the p.Glu2419Lys have been demonstrated in vitro (Urano et al., 2007), and later Wagle et al. demonstrated sensitivity to everolimus in a patient with an advanced

CRediT authorship contribution statement

Nawale Hadouiri: Formal analysis, Writing - original draft, Writing - review & editing. Veronique Darmency: Conceptualization, Investigation, Writing - review & editing. Laurent Guibaud: Data curation, Formal analysis, Writing - review & editing. Alexis Arzimanoglou: Data curation, Formal analysis, Investigation, Methodology, Writing - review & editing. Arthur Sorlin: Conceptualization, Writing - review & editing. Virginie Carmignac: Conceptualization, Writing - review & editing. Jean-Baptiste

Declaration of competing interest

The authors declare no conflict of interest.

Acknowledgements

We wish to thank the patient involved in the study and her family. This work was supported by the Conseil Régional de Bourgogne through the Plan d'Actions Régional pour l'Innovation (PARI 2015) and the European Union through the Programme Opérationnel (PO) de Fonds européen de développement régional (FEDER) - Fonds Social Européen (FSE) Bourgogne 2014/2020 programs.

We would also like to thank Suzanne Rankin (CHU Dijon Bourgogne) for proofreading and editing the manuscript.

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