Variable Presentation and Reduced Penetrance in Autosomal Dominant Acute Necrotizing Encephalopathy Related to RANBP2 Variant

Abstract

Acute necrotizing encephalopathy (ANE) is clinically characterized by fever, acute alteration of consciousness, seizures, and rapid progression to coma within days of onset of a viral illness occurring in healthy children without evidence of central nervous system infection. Brain magnetic resonance imaging (MRI) shows multiple symmetrical lesions affecting primarily the thalami but also brain stem, putamina, periventricular white matter, and cerebellum. Most cases of ANE are sporadic and nonrecurrent. However, a missense variant in RANBP2 has been identified in some families with recurrent ANE (OMIM # 608033), also named autosomal dominant ANE (ADANE). Clinical manifestation, clinical course, and brain MRI imaging findings of six affected members of two distinct families with ADANE were described. Sequencing revealed heterozygous c.1754C > T variant in RANBP2 (p.Thr585Met) in affected and asymptomatic family members. Only few ADANE families have been reported and it is the first description in South America. Differential diagnosis of Leigh disease and acute disseminated encephalomyelitis is discussed. Our report reinforces incomplete penetrance of ADANE and intrafamilial phenotypic variability of outcome.

Keywords

acute necrotizing encephalopathy - RANBP2 - autosomal dominant - acute disseminated encephalomyelitis (ADEM)

Publikationsverlauf

Eingereicht: 29. August 2020

Angenommen: 13. November 2020

Artikel online veröffentlicht:
07. Januar 2021

• References

• 1 Rezaei A, Kamali K, Haghbin S, Inaloo S. Acute necrotizing encephalopathy of childhood. J Pediatr Neurol 2014; 12 (02) 95-99
• 2 Wong AM, Simon EM, Zimmerman RA, Wang HS, Toh CH, Ng SH. Acute necrotizing encephalopathy of childhood: correlation of MR findings and clinical outcome. AJNR Am J Neuroradiol 2006; 27 (09) 1919-1923
• 3 Skelton BW, Hollingshead MC, Sledd AT, Phillips CD, Castillo M. Acute necrotizing encephalopathy of childhood: typical findings in an atypical disease. Pediatr Radiol 2008; 38 (07) 810-813
• 4 Mastroyianni SD, Gionnis D, Voudris K, Skardoutsou A, Mizuguchi M. Acute necrotizing encephalopathy of childhood in non-Asian patients: report of three cases and literature review. J Child Neurol 2006; 21 (10) 872-879
• 5 Kirton A, Busche K, Ross C, Wirrell E. Acute necrotizing encephalopathy in caucasian children: two cases and review of the literature. J Child Neurol 2005; 20 (06) 527-532
• 6 Neilson DE, Eiben RM, Waniewski S. et al. Autosomal dominant acute necrotizing encephalopathy. Neurology 2003; 61 (02) 226-230
• 7 Neilson DE, Adams MD, Orr CM. et al. Infection-triggered familial or recurrent cases of acute necrotizing encephalopathy caused by mutations in a component of the nuclear pore, RANBP2 . Am J Hum Genet 2009; 84 (01) 44-51
• 8 Singh RR, Sedani S, Lim M, Wassmer E, Absoud M. RANBP2 mutation and acute necrotizing encephalopathy: 2 cases and a literature review of the expanding clinico-radiological phenotype. Eur J Paediatr Neurol 2015; 19 (02) 106-113
• 9 Sell K, Storch K, Hahn G. et al. Variable clinical course in acute necrotizing encephalopathy and identification of a novel RANBP2 mutation. Brain Dev 2016; 38 (08) 777-780
• 10 Lee YJ, Hwang SK, Lee SM, Kwon S. Familial acute necrotizing encephalopathy with RANBP2 mutation: the first report in Northeast Asia. Brain Dev 2017; 39 (07) 625-628
• 11 Denier C, Balu L, Husson B. et al. Familial acute necrotizing encephalopathy due to mutation in the RANBP2 gene. J Neurol Sci 2014; 345 (1-2): 236-238
• 12 Iyer G, Utage P, Bailur S, Utage A, Srirambhatla A, Hasan Q. Familial acute necrotizing encephalopathy: evidence from next generation sequencing of digenic inheritance. J Child Neurol 2020; 35 (06) 393-397