Profile of Indian Children with Childhood Ataxia and Central Nervous System Hypomyelination/Vanishing White Matter Disease: A Single Center Experience from Southern India

Abstract

Background Childhood ataxia with central nervous system hypomyelination (CACH) is a recently described childhood inherited white matter disease, caused by mutations in any of the five genes encoding eukaryotic translation initiation factor (eIF2B).

Methods Retrospective review of the charts of children with CACH was performed from January 2014 to March 2020 at tertiary care center from Southern India. Diagnosis was based on magnetic resonance imaging (MRI) criteria or genetic testing.

Results Total number of children with CACH enrolled were 18. Male/female ratio was 10:8. Mean age of presentation was 37.11 months (range =  6–144 months). Affected siblings were seen in five (28%) cases. All children had spasticity, ataxia, and diffuse white matter changes with similar signal as cerebrospinal fluid on all pulse sequences on MRI brain. Of the 18 children, only nine are alive. Duration of illness among deceased children was 9.6667 months (range = 2–16 months). Waxing and waning of symptoms were seen in seven cases. Genetic analysis of EIF2B gene was performed in five cases, among which three mutations were novel.

Conclusion A diagnosis of childhood ataxia with central nervous system hypomyelination should be considered in patients presenting with acute onset neuroregression following infection or trauma with associated neuroimaging showing classical white matter findings.

Keywords

EIF2B - childhood ataxia with central hypomyelination - vanishing white matter disease

Authors' Contributions

V.K.G. involved in supervision, guidance, and review of the manuscript. V.M.S. and B.N. were dedicated in the management of the child and the preparation of manuscript. M.B. supported in diagnosis and preparation of the manuscript. S.K.S. contributed in the diagnosis and management of the child. N.B. has given valuable inputs in the management of this child.

Publication History

Received: 10 May 2020

Accepted: 28 June 2020

Article published online:
27 July 2020

• References

• 1 van der Knaap MS, Barth PG, Gabreëls FJM. et al. A new leukoencephalopathy with vanishing white matter. Neurology 1997; 48 (04) 845-855
• 2 Schiffmann R, Moller JR, Trapp BD. et al. Childhood ataxia with diffuse central nervous system hypomyelination. Ann Neurol 1994; 35 (03) 331-340
• 3 Hanefeld F, Holzbach U, Kruse B, Wilichowski E, Christen HJ, Frahm J. Diffuse white matter disease in three children: an encephalopathy with unique features on magnetic resonance imaging and proton magnetic resonance spectroscopy. Neuropediatrics 1993; 24 (05) 244-248
• 4 Van der Knaap MS, Kamphorst W, Barth PG, Kraaijeveld CL, Gut E, Valk J. Phenotypic variation in leukoencephalopathy with vanishing white matter. Neurology 1998; 51: 540-547
• 5 Vermeulen G, Seidl R, Mercimek-Mahmutoglu S, Rotteveel JJ, Scheper GC, van der Knaap MS. Fright is a provoking factor in vanishing white matter disease. Ann Neurol 2005; 57 (04) 560-563
• 6 Kaczorowska M, Kuczynski D, Jurkiewicz E, Scheper GC, van der Knaap MS, Jozwiak S. Acute fright induces onset of symptoms in vanishing white matter disease-case report. Eur J Paediatr Neurol 2006; 10 (04) 192-193
• 7 Leegwater PA, Vermeulen G, Könst AA. et al. Subunits of the translation initiation factor eIF2B are mutant in leukoencephalopathy with vanishing white matter. Nat Genet 2001; 29 (04) 383-388
• 8 van der Knaap MS, Leegwater PA, Könst AA. et al. Mutations in each of the five subunits of translation initiation factor eIF2B can cause leukoencephalopathy with vanishing white matter. Ann Neurol 2002; 51 (02) 264-270
• 9 van der Knaap MS, Fogli A, Boespflug-Tanguy O. et al. Childhood ataxia with central nervous system hypomyelination/vanishing white matter. 2003. Feb 20 [Updated 2019 Apr 4]. In: Adam MP, Ardinger HH, Pagon RA. et al., editors. GeneReviews® [Internet]. Seattle, WA: University of Washington; 1993-2020
• 10 Labauge P. Magnetic resonance findings in leucodystrophies and MS. Int MS J 2009; 16 (02) 47-56
• 11 Serafini G, Pompili M, Innamorati M. et al. White matter hyperintensities and self-reported depression in a sample of patients with chronic headache. J Headache Pain 2012; 13 (08) 661-667
• 12 Schiffmann R, van der Knaap MS. Invited article: an MRI-based approach to the diagnosis of white matter disorders. Neurology 2009; 72 (08) 750-759
• 13 Hyun SE, Choi BS, Jang JH, Jeon I, Jang DH, Ryu JS. Correlation between vanishing white matter disease and novel heterozygous EIF2B3 variants using next-generation sequencing: a case report. Ann Rehabil Med 2019; 43 (02) 234-238
• 14 Gulati S, Jain P, Chakrabarty B, Kumar A, Gupta N, Kabra M. The spectrum of leukodystrophies in children: experience at a tertiary care centre from North India. Ann Indian Acad Neurol 2016; 19 (03) 332-338
• 15 Ravishankar S, Sinha S, Taly AB, Panicker J. Vanishing white matter disease: Phenotypic, MR imaging and H spectroscopic observation. Ann Indian Acad Neurol 2006; 9: 172-174
• 16 Gowda VK, Srinivasan VM, Bhat M, Benakappa A. Case of childhood ataxia with central nervous system hypomyelination with a novel mutation in EIF2B3 gene. J Pediatr Neurosci 2017; 12 (02) 196-198
• 17 Lee HN, Koh SH, Lee KY, Ki CS, Lee YJ. Late-onset vanishing white matter disease with compound heterozygous EIF2B5 gene mutations. Eur J Neurol 2009; 16 (03) e42-e43
• 18 Maletkovic J, Schiffmann R, Gorospe JR. et al. Genetic and clinical heterogeneity in eIF2B-related disorder. J Child Neurol 2008; 23 (02) 205-215
• 19 Güngör G, Güngör O, Çakmaklı S. et al. Vanishing white matter disease with different faces. Childs Nerv Syst 2020; 36 (02) 353-361
• 20 Turón-Viñas E, Pineda M, Cusí V. et al. Vanishing white matter disease in a spanish population. J Cent Nerv Syst Dis 2014; 6: 59-68
• 21 Hamilton EMC, van der Lei HDW, Vermeulen G. et al; VWM Research Group. natural history of vanishing white matter. Ann Neurol 2018; 84 (02) 274-288
• 22 Fontenelle LM, Scheper GC, Brandão L, van der Knaap MS. Atypical presentation of vanishing white matter disease. Arq Neuropsiquiatr 2008; 66 (3A) 549-551
• 23 Barros SR, Parreira SCR, Miranda AFB, Pereira AMB, Campos NMP. New insights in vanishing white matter disease: isolated bilateral optic neuropathy in adult onset disease. J Neuroophthalmol 2018; 38 (01) 42-46
• 24 van der Knaap MS, Pronk JC, Scheper GC. Vanishing white matter disease. Lancet Neurol 2006; 5 (05) 413-423
• 25 Zhou L, Zhang H, Chen N. et al. Similarities and differences between infantile and early childhood onset vanishing white matter disease. J Neurol 2018; 265 (06) 1410-1418
• 26 van der Lei HD, Steenweg ME, Barkhof F. et al. Characteristics of early MRI in children and adolescents with vanishing white matter. Neuropediatrics 2012; 43 (01) 22-26
• 27 Singh RR, Livingston J, Lim M, Berry IR, Siddiqui A. An unusual neuroimaging finding and response to immunotherapy in a child with genetically confirmed vanishing white matter disease. Eur J Paediatr Neurol 2017; 21 (02) 410-413
• 28 Wilson CJ, Pronk JC, Van der Knaap MS. Vanishing white matter disease in a child presenting with ataxia. J Paediatr Child Health 2005; 41 (1-2): 65-67