title: Fatal viral infection-associated encephalopathy in two Chinese boys: a genetically determined risk factor of thermolabile carnitine palmitoyltransferase II variants.
abstract: Influenza-associated encephalopathy (IAE) is a potentially fatal neurological complication of influenza infection usually in the presence of high and persistent fever. Thermolabile carnitine palmitoyltransferase II enzyme (CPT-II) predisposes IAE, so far only described in Japanese. As the genetic origins of Japanese and Chinese are alike, similar genetic risk factors in CPT-II are expected. We report the first two unrelated Chinese patients of thermolabile CPT-II variants that underlain the persistent high fever-triggered viral infection-associated encephalopathy, multi-organ failure and death. Elevated (C16:0+C18:1)/C2 acylcarnitines ratio and the CPT2 susceptibility variant allele [p.Phe352Cys; p.Val368Ile] were detected. The asymptomatic family members of one patient also had abnormal long-chain acylcarnitines. In our experience of biochemical genetics, the elevated (C16:0+C18:1)/C2 acylcarnitines ratio is unusual and specific for thermolabile CPT-II variants. Allele frequency of [p.Phe352Cys; p.Val368Ile] among Hong Kong Chinese was 0.104, similar to Japanese data, and [p.Phe352Cys] has not been reported in Caucasians. This may explain the Asian-specific phenomenon of thermolabile CPT-II-associated IAE. We successfully demonstrated the thermolabile CPT-II variants in patients with viral infection-associated encephalopathy in another Asian population outside Japanese. The condition is likely under-recognized. With our first cases, it is envisaged that more cases will be diagnosed in subsequent years. The exact pathogenic mechanism of how other factors interplay with thermolabile CPT-II variants and high fever leading to IAE, is yet to be elucidated. Fasting and decreased intake during illness may aggravate the disease. Further studies including high risk and neonatal screening are warranted to investigate its expressivity, penetrance and temperature-dependent behaviors in thermolabile CPT-II carriers. This may lead to discovery of the therapeutic golden window by aggressive antipyretics and L-carnitine administration in avoiding the high mortality and morbidity of IAE.
authors.affiliation: Chemical Pathology Laboratory, Department of Pathology, Princess Margaret Hospital, Hong Kong SAR, China.
authors.forename: Chloe Miu
authors.initials: CM
authors.lastname: Mak
authors.forename: Ching-wan
authors.initials: CW
authors.lastname: Lam
authors.forename: Nai-chung
authors.initials: NC
authors.lastname: Fong
authors.forename: Wai-kwan
authors.initials: WK
authors.lastname: Siu
authors.forename: Han-chih Hencher
authors.initials: HC
authors.lastname: Lee
authors.forename: Tak-shing
authors.initials: TS
authors.lastname: Siu
authors.forename: Chi-kong
authors.initials: CK
authors.lastname: Lai
authors.forename: Chun-yiu
authors.initials: CY
authors.lastname: Law
authors.forename: Sui-fun
authors.initials: SF
authors.lastname: Tong
authors.forename: Wing-tat
authors.initials: WT
authors.lastname: Poon
authors.forename: David Shu-yan
authors.initials: DS
authors.lastname: Lam
authors.forename: Ho-leung
authors.initials: HL
authors.lastname: Ng
authors.forename: Yuet-ping
authors.initials: YP
authors.lastname: Yuen
authors.forename: Sidney
authors.initials: S
authors.lastname: Tam
authors.forename: Tak-lun
authors.initials: TL
authors.lastname: Que
authors.forename: Ngai-shan
authors.initials: NS
authors.lastname: Kwong
authors.forename: Albert Yan-wo
authors.initials: AY
authors.lastname: Chan
mesh_terms: D019943:Amino Acid Substitution; D001483:Base Sequence; D002331:Carnitine / Q000031:analogs & derivatives / Q000378:metabolism; D002334:Carnitine O-Palmitoyltransferase / Q000235:genetics / Q000378:metabolism*; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D018792:Encephalitis, Viral / Q000150:complications / Q000201:enzymology* / Q000235:genetics; D004795:Enzyme Stability; D005192:Family Health; D017809:Fatal Outcome; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006801:Humans; D007251:Influenza, Human / Q000150:complications*; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D012307:Risk Factors; D013696:Temperature
chemical_list: C116917:acylcarnitine; D002334:Carnitine O-Palmitoyltransferase; D002331:Carnitine