Infection-Induced Elevated Plasma Perampanel in a Patient with Hemimegalencephaly.

Perampanel is a noncompetitive, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid glutamate receptor antagonist. Herein, we report a case of increased perampanel plasma concentration and impaired consciousness triggered by an infection. The patient had refractory epilepsy associated with hemimegalencephaly. During adolescence, perampanel (maximum dose, 10 mg, oral), valproic acid, clobazam, and lacosamide were administered for seizure control. He was admitted to our hospital with high fever, impaired consciousness, and elevated perampanel plasma level (from 1,300 to 1,790 ng/mL), but with no increase in the concentration of other antiseizure medications. Further examinations (blood, cerebrospinal fluid, brain magnetic resonance images, and electroencephalogram) revealed no physical cause for impaired consciousness. After discontinuation of perampanel, his level of consciousness gradually improved. The pharmacokinetics of perampanel may be modified by both hemimegalencephaly and infection, resulting in an elevated plasma concentration of perampanel. This case underlines the importance of monitoring perampanel plasma concentration in patients with underlying brain disease who develop an infection.

POLR1C variants dysregulate splicing and cause hypomyelinating leukodystrophy.

OBJECTIVE: To further clarify the molecular pathogenesis of RNA polymerase III (Pol III)-related leukodystrophy caused by biallelic POLR1C variants at a cellular level and potential effects on its downstream genes. METHODS: Exome analysis and molecular functional studies using cell expression and long-read sequencing analyses were performed on 1 family with hypomyelinating leukodystrophy showing no clinical and MRI findings characteristic of Pol III-related leukodystrophy other than hypomyelination. RESULTS: Biallelic novel POLR1C alterations, c.167T>A, p.M56K and c.595A>T, p.I199F, were identified as causal variants. Functional analyses showed that these variants not only resulted in altered protein subcellular localization and decreased protein expression but also caused abnormal inclusion of introns in 85% of the POLR1C transcripts in patient cells. Unexpectedly, allelic segregation analysis in each carrier parent revealed that each heterozygous variant also caused the inclusion of introns on both mutant and wild-type alleles. These findings suggest that the abnormal splicing is not direct consequences of the variants, but rather reflect the downstream effect of the variants in dysregulating splicing of POLR1C, and potentially other target genes. CONCLUSIONS: The lack of characteristic clinical findings in this family confirmed the broad clinical spectrum of Pol III-related leukodystrophy. Molecular studies suggested that dysregulation of splicing is the potential downstream pathomechanism for POLR1C variants.