Thermolabile polymorphism of carnitine palmitoyltransferase 2: A genetic risk factor of overall acute encephalopathy

Akiko Shibata; Mariko Kasai; Ai Hoshino; Taku Miyagawa; Hiroshi Matsumoto; Gaku Yamanaka; Kenjiro Kikuchi; Ichiro Kuki; Akira Kumakura; Shinya Hara; Takashi Shiihara; Sawako Yamazaki; Masayasu Ohta; Takanori Yamagata; Jun-Ichi Takanashi; Masaya Kubota; Akira Oka; Masashi Mizuguchi

doi:10.1016/j.braindev.2019.07.008

Thermolabile polymorphism of carnitine palmitoyltransferase 2: A genetic risk factor of overall acute encephalopathy

Brain Dev. 2019 Nov;41(10):862-869. doi: 10.1016/j.braindev.2019.07.008. Epub 2019 Jul 24.

Authors

Akiko Shibata¹, Mariko Kasai², Ai Hoshino³, Taku Miyagawa⁴, Hiroshi Matsumoto⁵, Gaku Yamanaka⁶, Kenjiro Kikuchi⁷, Ichiro Kuki⁸, Akira Kumakura⁹, Shinya Hara¹⁰, Takashi Shiihara¹¹, Sawako Yamazaki¹², Masayasu Ohta¹³, Takanori Yamagata¹⁴, Jun-Ichi Takanashi¹⁵, Masaya Kubota¹⁶, Akira Oka¹⁷, Masashi Mizuguchi³

Affiliations

¹ Department of Developmental Medical Sciences, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. Electronic address: asasano-tky@umin.ac.jp.
² Department of Developmental Medical Sciences, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
³ Department of Developmental Medical Sciences, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
⁴ Sleep Disorders Project, Department of Psychiatry and Behavioral Sciences, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan; Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
⁵ Department of Pediatrics, National Defense Medical College, Saitama, Japan.
⁶ Department of Pediatrics, Tokyo Medical University, Tokyo, Japan.
⁷ Division of Neurology, Saitama Children's Medical Center, Saitama, Japan.
⁸ Department of Pediatrics, Osaka City General Hospital, Osaka, Japan.
⁹ Department of Pediatrics, Kitano Hospital, Osaka, Japan.
¹⁰ Department of Pediatrics, TOYOTA Memorial Hospital, Aichi, Japan.
¹¹ Department of Neurology, Gunma Children's Medical Center, Gunma, Japan.
¹² Department of Pediatrics, Niigata Minami Hospital, Niigata, Japan.
¹³ Department of Pediatrics, Aiseikai Memorial Ibaraki Welfare Medical Center, Ibaraki, Japan.
¹⁴ Department of Pediatrics, Jichi Medical University, Tochigi, Japan.
¹⁵ Department of Pediatrics, Tokyo Women's Medical University Yachiyo Medical Center, Chiba, Japan.
¹⁶ Division of Neurology, National Center for Child Health and Development, Tokyo, Japan.
¹⁷ Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

PMID: 31351739
DOI: 10.1016/j.braindev.2019.07.008

Abstract

Objectives: Acute encephalopathy is an acute brain dysfunction after preceding infection, consisting of multiple syndromes. Some syndromes, such as acute encephalopathy with biphasic seizures and late reduced diffusion (AESD), are severe with poor outcome, whereas others, such as clinically mild encephalitis/encephalopathy with reversible splenial lesion (MERS), are mild with favorable outcome. Previous study reported the association of the thermolabile polymorphism in Carnitine Palmitoyltransferase 2 (CPT2) gene and severe syndromes of acute encephalopathy. To further explore the pathogenetic role of CPT2 in acute encephalopathy, we conducted a case-control association study of a typical thermolabile CPT2 polymorphism, rs2229291, in 416 patients of acute encephalopathy, including both severe and mild syndromes.

Methods: The case cohort consisted of 416 patients, including AESD, MERS, and other syndromes. The control subjects were 100 healthy Japanese. rs2229291 was genotyped by Sanger sequencing. Genetic distribution was compared between the patients and controls using Cochran-Armitage trend test.

Results: Minor allele frequency of rs2229291 was significantly higher in AESD (p = 0.044), MERS (p = 0.015) and entire acute encephalopathy (p = 0.044) compared to the controls. The polymorphism showed no significant association with influenza virus, or with outcome.

Conclusions: This study provided evidence that CPT2 is a susceptibility gene for overall acute encephalopathy, including both severe and mild syndromes, and suggested that impairment of mitochondrial metabolism is common to various syndromes of acute encephalopathy.

Keywords: Acute encephalitis with refractory; Acute encephalopathy; Acute encephalopathy with biphasic seizures and late reduced diffusion; Acute necrotizing encephalopathy; Carnitine palmitoyltransferase 2; Clinically mild encephalitis/encephalopathy with reversible splenial lesion; Energy failure; Genetic risk factor; Predisposing factor; Repetitive partial seizures/febrile infection-related epileptic syndrome; Susceptibility gene; Thermolability.

MeSH terms

Alleles
Brain Diseases / genetics*
Carnitine O-Palmitoyltransferase / deficiency
Carnitine O-Palmitoyltransferase / genetics*
Case-Control Studies
Child, Preschool
Encephalitis
Female
Gene Frequency / genetics
Genome-Wide Association Study / methods
Genotype
Humans
Infant
Japan
Male
Polymorphism, Genetic / genetics
Risk Factors
Seizures

Substances

Carnitine O-Palmitoyltransferase