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

Abstract

ObjectivesNew-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 descriptionIn 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.ConclusionThis 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.

Expanding the genetic spectrum of mitochondrial diseases in Tunisia: novel variants revealed by whole-exome sequencing

“…To gain further insights into the phenotypic spectrum associated with the FASTKD2 gene, we compiled information about all reported cases carrying variants in this gene (see Supplementary File; Supplementary Table S2). Summing up the data of the nine patients belonging to seven families with FASTKD2 variants, we found that there is high variability in both the genetic and phenotypic spectra with lactic acidosis and stroke-like episodes (MELAS) (Yoo et al, 2017;Shah and Balasubramaniam, 2021), infant-onset encephalomyopathy (Ghezzi et al, 2008;Wei et al, 2020), and new-onset refractory status epilepticus (Astner-Rohracher et al, 2023). The disease onset for P3 occurred at 7 months, whereas for all reported patients, it ranged from 6 months to 14 years.…”

DHEA down-regulates mitochondrial dynamics and promotes apoptosis of lung adenocarcinoma cells through FASTKD2

“…The relationship between FASTKD2 gene and mitochondrial dynamics related genes was found. FASTKD2 belongs to the protein family containing fast kinase domain, which is located in mitochondria [31] . As a component of functional protein ribonucleic acid module, FASTKD2 is an essential gene for translation and transcription in mitochondria.…”

Review and standard operating procedures for collection of biospecimens and analysis of biomarkers innew onsetrefractory status epilepticus

“…63,64 Whole genome sequencing may allow the identification of the concerned variants, but muscle biopsy and skin fibroblasts could provide additional information by looking at the function of the respiratory chain complexes. 63,65 Previous recommendations suggest cutting the muscle tissue into several pieces for formalin fixation, glutaraldehyde fixation, and rapid freezing in isopentane. 65 We cannot yet provide specific recommendations for rare patients with NORSE due to mitochondrial disorders.…”

“…Other biological samples might be of interest for patients with NORSE, for diagnosis or research purposes. Mitochondrial disorders were reported as a cause of NORSE for a few patients 63,64 . Whole genome sequencing may allow the identification of the concerned variants, but muscle biopsy and skin fibroblasts could provide additional information by looking at the function of the respiratory chain complexes 63,65 .…”