Orphanet Journal of Rare Diseases (May 2019)

Safety and efficacy of mTOR inhibitor treatment in patients with tuberous sclerosis complex under 2 years of age – a multicenter retrospective study

  • Afshin Saffari,
  • Ines Brösse,
  • Adelheid Wiemer-Kruel,
  • Bernd Wilken,
  • Paula Kreuzaler,
  • Andreas Hahn,
  • Matthias K. Bernhard,
  • Cornelis M. van Tilburg,
  • Georg F. Hoffmann,
  • Matthias Gorenflo,
  • Sven Hethey,
  • Olaf Kaiser,
  • Stefan Kölker,
  • Robert Wagner,
  • Olaf Witt,
  • Andreas Merkenschlager,
  • Andreas Möckel,
  • Timo Roser,
  • Jan-Ulrich Schlump,
  • Antje Serfling,
  • Juliane Spiegler,
  • Till Milde,
  • Andreas Ziegler,
  • Steffen Syrbe

DOI
https://doi.org/10.1186/s13023-019-1077-6
Journal volume & issue
Vol. 14, no. 1
pp. 1 – 13

Abstract

Read online

Abstract Background Tuberous sclerosis complex (TSC) is a multisystem disease with prominent neurologic manifestations such as epilepsy, cognitive impairment and autism spectrum disorder. mTOR inhibitors have successfully been used to treat TSC-related manifestations in older children and adults. However, data on their safety and efficacy in infants and young children are scarce. The objective of this study is to assess the utility and safety of mTOR inhibitor treatment in TSC patients under the age of 2 years. Results A total of 17 children (median age at study inclusion 2.4 years, range 0–6; 12 males, 5 females) with TSC who received early mTOR inhibitor therapy were studied. mTOR inhibitor treatment was started at a median age of 5 months (range 0–19 months). Reasons for initiation of treatment were cardiac rhabdomyomas (6 cases), subependymal giant cell astrocytomas (SEGA, 5 cases), combination of cardiac rhabdomyomas and SEGA (1 case), refractory epilepsy (4 cases) and disabling congenital focal lymphedema (1 case). In all cases everolimus was used. Everolimus therapy was overall well tolerated. Adverse events were classified according to the Common Terminology Criteria of Adverse Events (CTCAE, Version 5.0). Grade 1–2 adverse events occurred in 12 patients and included mild transient stomatitis (2 cases), worsening of infantile acne (1 case), increases of serum cholesterol and triglycerides (4 cases), changes in serum phosphate levels (2 cases), increase of cholinesterase (2 cases), transient neutropenia (2 cases), transient anemia (1 case), transient lymphopenia (1 case) and recurrent infections (7 cases). No grade 3–4 adverse events were reported. Treatment is currently continued in 13/17 patients. Benefits were reported in 14/17 patients and included decrease of cardiac rhabdomyoma size and improvement of arrhythmia, decrease of SEGA size, reduction of seizure frequency and regression of congenital focal lymphedema. Despite everolimus therapy, two patients treated for intractable epilepsy are still experiencing seizures and another one treated for SEGA showed no volume reduction. Conclusion This retrospective multicenter study demonstrates that mTOR inhibitor treatment with everolimus is safe in TSC patients under the age of 2 years and shows beneficial effects on cardiac manifestations, SEGA size and early epilepsy.

Keywords