UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.

Mitochondrial disorders (MIDs) are frequently multisystemic in nature and cause significant morbidity and mortality. Accurate assessment of mitochondrial disease prevalence has been difficult in the past. Primary MIDs are due to mutations in mitochondrial DNA (mtDNA) or nuclear DNA (nDNA)-located genes. Here we report cases of two siblings who presented to the pediatric emergency department with status epilepticus. Initially, the elder sibling was treated for metabolic encephalopathy and viral encephalitis, during his admission to the hospital. On treatment with multiple antiepileptic drugs, the status epilepticus subsided. A provisional diagnosis of mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes was made. Magnetic resonance imaging showed diffusion restriction in the left temporal lobe, insular cortex, and left lentiform nucleus, which completely resolved on follow-up after 1 month. His sudden demise in May 2019 due to status epilepticus, and a similar case presentation in his younger sibling, prompted us to do a genetic analysis test. The exome sequence revealed FASTKD2 mutation, a rare variant. This case report helps in increasing the awareness among the clinicians about the clinical presentation of FASTKD2 mutation case.