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.

Prognosis of 18 H7N9 Avian Influenza Patients in Shanghai

“…Aside from fulminant pneumonia, respiratory failure and ARDS [2], H7N9 was characterized by extrapulmonary manifestation such as rhabdomyolysis and encephalopathy [2]–[4]. In an epidemiological study involving 82 patients, H7N9 was found to prevail in elderly male with substantial co-morbidities and historical livestock exposure or poultry industry engagement [5].…”

Human Genetic Determinants of Viral Diseases

“…IAE patients often display abnormal acylcarnitine fatty acid chain lengths, which suggest a potential aberration in lipid metabolism (21). A candidate gene approach in Japanese and Chinese cohorts demonstrated that IAE is reproducibly associated with several specific polymorphisms in the carnitine palmitoyltransferase II (CPT11) gene (21, 94, 171). The amino acid changes within CPTII result in decreased enzymatic activity at 41°C, consistent with a buildup of long chain fatty acids in the serum of affected patients upon onset of fever (171).…”

Host genetics of severe influenza: from mouse Mx1 to human IRF7

“…More interestingly, regulatory SNPs affecting expression of surfactant proteins, SFPTA (rs1965708 and rs1059046) in a Spanish cohort and in SFPTB (rs1130866) in a Chinese cohort [113,114], were associated with severe pH1N1 2009 influenza. Independent studies of Japanese and Chinese children who developed severe and/or fatal influenza-associated encephalopathy found significant association with exonic variants in CPT2 that result in thermolabile proteins that are hypomorphic during fever [115,116]. However overall, population-based studies have been underpowered and unreplicated and have not yet revealed major genetic determinants of severe influenza [110].…”