Enasidenib-induced hepatitis in an individual with Type II D2-hydroxyglutaric aciduria

Authors

Jessica I. Gold, Division of Medical Genetics, Department of Pediatrics Northwell Health New York New York USA.
Arianna K. Stefanatos, Department of Child and Adolescent Psychiatry and Behavioral Sciences Children's Hospital of Philadelphia Philadelphia Pennsylvania USA.
Jamie L. Fraser, Prenatal Pediatrics Institute Children's National Hospital Washington DC USA.
Adeline Vanderver, Division of Neurology, Department of Pediatrics Children's Hospital of Philadelphia Philadelphia Pennsylvania USA.
Sanmati Cuddapah, Section of Biochemical Genetics, Division of Genetics, Department of Pediatrics Children's Hospital of Philadelphia Philadelphia Pennsylvania USA.

Document Type

Journal Article

Publication Date

5-1-2024

Journal

JIMD reports

Volume

65

Issue

3

DOI

10.1002/jmd2.12421

Keywords

IDH2 inhibitor; Type II D2‐hydroxyglutaric aciduria; novel treatment; organic acidurias

Abstract

Type II D-2-Hydroxyglutaric aciduria (T2D2HGA) is caused by a gain-of-function pathogenic variant in Isocitrate Dehydrogenase 2 (IDH2). Patients with T2D2HGA commonly present with developmental delay, seizures, cardiomyopathy, and arrhythmias. The recently approved IDH2-inhibitor Enasidenib targets the p.Arg140Gln pathogenic variant and decreases production of D2HGA. We present a 7-year-old female with T2D2HGA due to the p.Arg140Gln variant. She was diagnosed at 3-years-old after presenting with global developmental delay, leukoencephalopathy, communicating hydrocephalus, seizures, and dilated cardiomyopathy. At age 3 years 11 months, 50 mg Enasidenib daily was initiated. Primary outcomes included seizure frequency, hospital admissions, development, and cardiac structure. Laboratories were monitored biweekly for common Enasidenib side effects. Our patient tolerated Enasidenib well. Urine 2-HGA decreased significantly from 244 mg/g creatinine to undetectable within 2 weeks of treatment. Inpatient admissions decreased from 8 during the 2 years preceding treatment to 1 during treatment. She has been seizure-free since Enasidenib initiation. Echocardiography showed improvement in dilated cardiomyopathy with normal left ventricular systolic function. Developmental assessment demonstrated improvements in gross motor, fine motor, language, and socialization domains. Treatment was complicated by mild elevations in alanine transaminase (118 IU/L, range 0-28) and creatine kinase (334 U/L, range 45-198) that resolved by decreasing Enasidenib dosing frequency to three times weekly. Enasidenib is a viable treatment for Type II D2HGA with benefits including developmental gains, fewer acute medical interventions, and cardiomyopathy improvement. While drug-induced hepatitis is a novel adverse effect of Enasidenib, it can be ameliorated by decreasing dose frequency.

APA Citation

Gold, Jessica I.; Stefanatos, Arianna K.; Fraser, Jamie L.; Vanderver, Adeline; and Cuddapah, Sanmati, "Enasidenib-induced hepatitis in an individual with Type II D2-hydroxyglutaric aciduria" (2024). GW Authored Works. Paper 4989.
https://hsrc.himmelfarb.gwu.edu/gwhpubs/4989

Department

Pediatrics