ORPHA: 263524;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1p32.3 | {Encephalopathy, acute, infection-induced, 4, susceptibility to} | 614212 | Autosomal dominant; Autosomal recessive | 3 | CPT2 | 600650 |
A number sign (#) is used with this entry because of evidence that susceptibility to infection-induced acute encephalopathy-4 (IIAE4) is conferred by heterozygous or homozygous variation in the CPT2 gene (600650) on chromosome 1p32.
Acute encephalopathy is a severe neurologic complication of an infection that usually occurs in children. It is characterized by a high-grade fever accompanied within 12 to 48 hours by febrile convulsions, often leading to coma, multiple-organ failure, brain edema, and high morbidity and mortality. The infections are usually viral, particularly influenza, although other viruses and even mycoplasma have been found to cause the disorder (summary by Chen et al., 2005; Shinohara et al., 2011).
For a discussion of genetic heterogeneity of susceptibility to acute infection-induced encephalopathy, see 610551.
Chen et al. (2005) found that 41.2% of 34 Japanese children with influenza-associated acute encephalopathy had increased serum acylcarnitine ratios, suggesting a defect of mitochondrial long-chain fatty acid metabolism. Elevated acylcarnitine ratios at the time of high-grade fever significantly decreased after a return to normal temperature in all of the follow-up patients. The family of 1 girl, who had a fatal outcome, was studied in detail. The child was found to be heterozygous for a thermolabile allele in the CPT2 gene (F352C and V368I; 600650.0018). She had significantly increased serum acylcarnitine levels during febrile convulsions. Her 2 unaffected brothers, who were heterozygous for the allele, and their father, who was homozygous for the allele, had slightly increased serum acylcarnitine compared to normal values in the nonfebrile state. The mother, who was heterozygous for only the 368I substitution, had normal acylcarnitine levels in the nonfebrile state.
Mak et al. (2011) reported 2 unrelated Chinese boys from Hong Kong with fatal virally-induced acute encephalopathy. The infectious agents were Coxsackie virus group A in 1 patient and influenza A, subtype H1 in the other. Both patients had high fever, seizures, and rapid deterioration with cerebral edema and multiorgan failure. Plasma acylcarnitines were increased in all mutation carriers, including asymptomatic parents.
Among 29 Japanese patients with infection-induced acute encephalopathy, Shinohara et al. (2011) found significantly higher frequency of the 352C variant in exon 4 of the CPT2 gene (600650.0018) compared to controls (27.6 vs 13.5%, odds ratio of 2.44, p = 0.011). All patients with 352C had the 368I allele and the 647M allele (CIM haplotype). There was no difference in allele frequency between patients with a clinical diagnosis of acute necrotizing encephalopathy and those with acute encephalopathy with biphasic seizures and late reduced diffusion, and there was no correlation between good and poor prognosis. Pathogens included influenza, adenovirus, HHV6, mycoplasma, and rotavirus.
Mak et al. (2011) found that 2 unrelated Chinese boys from Hong Kong with fatal virally-induced acute encephalopathy were heterozygous for variant F352C and homozygous for variant V368I in the CPT2 gene.
Kubota et al. (2012) found that serum ATP levels in 10 patients with a clinical diagnosis of infection-induced acute encephalopathy were significantly lower during the episode compared to the convalescent phase and were lower compared to 9 patients with febrile seizures. The authors postulated that decreased ATP may reflect systemic mitochondrial dysfunction, including an inability to maintain the blood-brain barrier, which may lead to acute hypoxic insult or brain edema.
Chen, Y., Mizuguchi, H., Yao, D., Ide, M., Kuroda, Y., Shigematsu, Y., Yamaguchi, S., Yamaguchi, M., Kinoshita, M., Kido, H. Thermolabile phenotype of carnitine palmitoyltransferase II variations as a predisposing factor for influenza-associated encephalopathy. FEBS Lett. 579: 2040-2044, 2005. [PubMed: 15811315] [Full Text: https://doi.org/10.1016/j.febslet.2005.02.050]
Kubota, M., Chida, J., Hoshino, H., Ozawa, H., Koide, A., Kashii, H., Koyama, A., Mizuno, Y., Hoshino, A., Yamaguchi, M., Yao, D., Yao, M., Kido, H. Thermolabile CPT II variants and low blood ATP levels are closely related to severity of acute encephalopathy in Japanese children. Brain Dev. 34: 20-27, 2012. [PubMed: 21277129] [Full Text: https://doi.org/10.1016/j.braindev.2010.12.012]
Mak, C. M., Lam, C., Fong, N., Siu, W., Lee, H. H., Siu, T., Lai, C., Law, C., Tong, S., Poon, W., Lam, D. S., Ng, H, Yuen, Y., Tam, S., Que, T., Kwong, N., Chan, A. Y. Fatal viral infection-associated encephalopathy in two Chinese boys: a genetically determined risk factor of thermolabile carnitine palmitoyltransferase II variants. J. Hum. Genet. 56: 617-621, 2011. [PubMed: 21697855] [Full Text: https://doi.org/10.1038/jhg.2011.63]
Shinohara, M., Saitoh, M., Takanashi, J., Yamanouchi, H., Kubota, M., Goto, T., Kikuchi, M., Shiihara, T., Yamanaka, G., Mizuguchi, M. Carnitine palmitoyl transferase II polymorphism is associated with multiple syndromes of acute encephalopathy with various infectious diseases. Brain Dev. 33: 512-517, 2011. [PubMed: 20934285] [Full Text: https://doi.org/10.1016/j.braindev.2010.09.002]