A case report: New-onset refractory status epilepticus in a patient with FASTKD2 -related mitochondrial disease.

Objectives: New-onset refractory status epilepticus (NORSE) is associated with high morbidity and mortality. Despite extensive work-up, the underlying etiology remains unknown in 50% of affected individuals. Mitochondrial disorders represent rare causes of NORSE. Biallelic variants in FASTKD2 were reported as a cause of infantile encephalomyopathy with refractory epilepsy.
Case Description: In the study, we report a previously healthy 14-year-old with a new, homozygous FASTKD2 variant presenting with NORSE. Following a seizure-free period of 7 years, he experienced another super-refractory SE and subsequently developed drug-resistant focal epilepsy, mild myopathy, optic atrophy, and discrete psychomotor slowing. Structural MRI at the time of NORSE showed right temporo-parieto-occipital FLAIR hyperintensity and diffusion restriction, with extensive right hemispheric atrophy at the age of 22 years. Whole-exome sequencing revealed a novel homozygous loss of function variant [c.(1072C>T);(1072C>T)] [p.(Arg358Ter);(Arg358Ter)] in FASTKD2 (NM_001136193), resulting in a premature termination codon in the protein-coding region and loss of function of FASTKD2. Oxidative phosphorylation (OXPHOS) in muscle and skin fibroblasts was unremarkable.
Conclusion: This is the first case of a normally developed adolescent with a new homozygous loss of function variant in FASTKD2 , manifesting with NORSE. The phenotypical spectrum of FASTKD2-related mitochondrial disease is heterogeneous, ranging from recurrent status epilepticus and refractory focal epilepsy in an adolescent with normal cognitive development to severe forms of infantile mitochondrial encephalopathy. Although mitochondrial diseases are rare causes of NORSE, clinical features such as young age at onset and multi-system involvement should trigger genetic testing. Early diagnosis is essential for counseling and treatment considerations.
Competing Interests: AA-R reports travel support and speaker's honoraria from Eisai, outside the submitted work. ML reports a travel grant from UCB Pharma and a speaker's honorarium from Eisai, outside the submitted work. GK reports travel support from UCB, Eisai and Cyberonics and speaker's honoraria from Eisai, outside the submitted work. CN reports consulting honorarium from Epilog NV, outside the submitted work. ET reports personal fees from EVER Pharma, Marinus, Argenx, Arvelle/Angelini, Epilog, Medtronic, MedScape, Bial–Portela & Cª, NewBridge, GL Pharma, GlaxoSmithKline, Hikma, Boehringer Ingelheim, LivaNova, Eisai, UCB, Biogen, Genzyme Sanofi, GW Pharmaceuticals/Jazz, and Actavis outside the submitted work; his institution has received grants from Biogen, UCB Pharma, Eisai, Red Bull, Merck, Bayer, the European Union, FWF Osterreichischer Fond zur Wissenschaftsforderung, Bundesministerium fur Wissenschaft und Forschung, and Jubilaumsfond der Österreichischen Nationalbank outside the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
(Copyright © 2023 Astner-Rohracher, Mauritz, Leitinger, Rossini, Kalss, Neuray, Retter, Wortmann, Achleitner, Mayr and Trinka.)