<%server.execute "isdev.asp"%> Case of childhood ataxia with central nervous system hypomyelination with a novel mutation in EIF2B3 gene Gowda VK, Srinivasan VM, Bhat M, Benakappa A - J Pediatr Neurosci
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CASE REPORT
Year : 2017  |  Volume : 12  |  Issue : 2  |  Page : 196-198
 

Case of childhood ataxia with central nervous system hypomyelination with a novel mutation in EIF2B3 gene


1 Department of pediatric Neurology, Indira Gandhi Institute of Child Health, Bengaluru, Karnataka, India
2 Department of Pediatrics, Indira Gandhi Institute of Child Health, Bengaluru, Karnataka, India
3 Department of Neuroradiology, National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka, India

Date of Web Publication10-Aug-2017

Correspondence Address:
Vykuntaraju K Gowda
Bangalore Child Neurology and Rehabilitaion Center, No 8/A 1st Main, 1st Cross, Near Adhichunchanagiri Choultry, Vijayanagar, Bengaluru - 560 104, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jpn.JPN_183_16

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   Abstract 

A 4-year-old boy presented with loss of motor milestones following viral fever. On examination, the child had increased tone and exaggerated deep tendon reflexes. Magnetic resonance imaging of the brain showed white matter hyperintensities on T2-weighted images, which revealed partial inversion on fluid-attenuated inversion recovery images. Clinical exome sequencing revealed a novel homozygous mutation c.1270T>G: pCys424Gly in exon 11 of the EIF2B3 gene. This novel mutation is reported in this article along with a literature review.


Keywords: Childhood ataxia with central nervous system hypomyelination, EIF2B3 gene mutation, Indian, leukodystrophy, vanishing white matter disease


How to cite this article:
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;12:196-8

How to cite this URL:
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 [serial online] 2017 [cited 2022 Jan 26];12:196-8. Available from: https://www.pediatricneurosciences.com/text.asp?2017/12/2/196/212804



   Introduction Top


Vanishing white matter (VWM) disease or childhood ataxia with central nervous system hypomyelination (CACH) was first described by van der Knaap et al. in a series of nine children describing the clinical and radiological manifestation.[1] VWM disease is central nervous system white matter disease due to demyelination characterized by episodic deterioration following insults such as head trauma, infection with fever, and acute fright.[2] The phenotype of disease varies from mild adult-onset disease to most severe congenital form.[3] VWM disease is caused by mutation in the EIF2B15 gene encoding the subunits of the EIF2B.[3] We report the case of VWM disease with novel EIF2B3 mutation.


   Case Report Top


A 4-year-old boy born to a second-degree consanguineous marriage with normal birth history presented with regression of motor milestones. The regression occurred following an episode of febrile episode at 3 years 6 months when the child lost walking, sitting, and neck control over a period of 2 weeks. The child had two episodes of seizures with fever. On examination, the head circumference was 48 cm with weight of 14 kg. There were no neurocutaneous markers. There was increased tone of all four limbs with exaggerated deep tendon reflexes with extensor plantar response.

On investigations, complete blood count, liver function test, renal function test, serum ammonia, and serum lactate were all normal. Electroencephalogram done was normal. Axial T2-weighted image in magnetic resonance imaging (MRI) of the brain showed periventricular and lobar hyperintensities [Figure 1]a which revealed partial inversion on fluid-attenuated inversion recovery images [Figure 1]b. Axial T2-weighted image showed diffuse white matter hyperintensities [Figure 2]a and [Figure 2]b. Axial T2-weighted images demonstrated bilateral central tegmental tract (white arrow) hyperintensities [Figure 3]a and cerebellar white matter (white triangle) hyperintensities [Figure 3]b. Based on clinical features and MRI of the brain, we considered possibilities of CACH. Clinical exome sequencing revealed a novel homozygous mutation c.1270T>G: pCys424Gly in exon 11 of the EIF2B3 gene.
Figure 1: (a) Axial T2-weighted image of magnetic resonance imaging of brain showing periventricular and lobar hyperintensities which reveal partial inversion on fluid-attenuated inversion recovery images in (b)

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Figure 2: (a and b) Axial T2-weighted image of magnetic resonance imaging of brain showing diffuse white matter hyperintensities

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Figure 3: (a) Axial T2-weighted image of magnetic resonance imaging of brain demonstrating bilateral central tegmental tract (white arrow) hyperintensities and (b) showing cerebellar white matter (white triangle) hyperintensities

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   Discussion Top


VWM disease is one of the common leukodystrophies.[4] Earlier cases have been reported from Europe, China, Japan, and India.[5] VWM disease is characterized by progressive ataxia and spasticity and periods of acute deterioration precipitated by febrile illness or head trauma. We suspected VWM disease based on clinical features and MRI findings. We confirmed on genetic testing. Mutations in the EIF2B1, EIF2B2, EIF2B3, EIF2B4, and EIF2B5 genes cause VWM disease. Mutation has been identified in all five of the genes of eIF2B protein. About 65% of mutation occurs in the EIF2B5 gene.[6] Approximately 4% to 7% of mutations in VWM disease are due to EIF2B3.[7] Wu et al. reported mutation in EIF2B3 account for 20% of the Chinese pediatric cases.[8] We report a novel mutation in this gene in a child with mild phenotype of VWM disease.

We are earlier reported case of VWM disease associated with ptosis and myoclonic seizures.[5] Fogli et al. found that 87% of 78 families with VWM disease had a mutation in four of the EIF2B genes. Sixty-two percent had mutation in the EIF2B5 gene. Three families (4%) had mutations in the EIF2B3 gene. Mean onset of disease was at 3.9 years. The disease severity ranged from no neurological signs to death. There was no correlation between type of gene mutation and age of onset or disease severity.[7] van der Lei et al. identified mutation in the EIF2B5 gene in 68% of 184 patients from a large database of VWM disease patients.[9] Matsukawa et al. reported adult-onset VWM disease with homozygous mutation in the EIF2B3 (L27Q; 606273.0005) gene.[10] La Piana et al. reported adult-onset VWM disease due to novel EIF2B3 mutation.[11] Mutations due to EIF2B3 gene are milder phenotype and indicate longer survival rate.


   Conclusion Top


Homozygous mutation c.1270T>G: pCys424Gly in exon 11 of the EIF2B3 gene may be a causative factor for VWM disease. This can be used for novel diagnostic and prognostic marker in white matter diseases.

Acknowledgment

The authors are grateful to InterpretOmics India Pvt. Ltd., Bengaluru, Karnataka, India, for performing the genetic testing.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
   References Top

1.
van der Knaap MS, Barth PG, Gabreëls FJ, Franzoni E, Begeer JH, Stroink H, et al. Anew leukoencephalopathy with vanishing white matter. Neurology 1997;48:845-55.  Back to cited text no. 1
    
2.
Bugiani M, Boor I, Powers JM, Scheper GC, van der Knaap MS. Leukoencephalopathy with vanishing white matter: A review. J Neuropathol Exp Neurol 2010;69:987-96.  Back to cited text no. 2
[PUBMED]    
3.
Pavitt GD, Proud CG. Protein synthesis and its control in neuronal cells with a focus on vanishing white matter disease. Biochem Soc Trans 2009;37(Pt 6):1298-310.  Back to cited text no. 3
    
4.
van der Knaap MS, Breiter SN, Naidu S, Hart AA, Valk J. Defining and categorizing leukoencephalopathies of unknown origin: MR imaging approach. Radiology 1999;213:121-33.  Back to cited text no. 4
    
5.
Sharma S, Arya R, Raju KN, Kumar A, Scheper GC, van der Knaap MS, et al. Vanishing white matter disease associated with ptosis and myoclonic seizures. J Child Neurol 2011;26:366-8.  Back to cited text no. 5
[PUBMED]    
6.
Pronk JC, van Kollenburg B, Scheper GC, van der Knaap MS. Vanishing white matter disease: A review with focus on its genetics. Ment Retard Dev Disabil Res Rev 2006;12:123-8.  Back to cited text no. 6
    
7.
Fogli A, Schiffmann R, Bertini E, Ughetto S, Combes P, Eymard-Pierre E, et al. The effect of genotype on the natural history of eIF2B-related leukodystrophies. Neurology 2004;62:1509-17.  Back to cited text no. 7
    
8.
Wu Y, Pan Y, Du L, Wang J, Gu Q, Gao Z, et al. Identification of novel EIF2B mutations in Chinese patients with vanishing white matter disease. J Hum Genet 2009;54:74-7.  Back to cited text no. 8
    
9.
van der Lei HD, van Berkel CG, van Wieringen WN, Brenner C, Feigenbaum A, Mercimek-Mahmutoglu S, et al. Genotype-phenotype correlation in vanishing white matter disease. Neurology 2010;75:1555-9.  Back to cited text no. 9
    
10.
Matsukawa T, Wang X, Liu R, Wortham NC, Onuki Y, Kubota A, et al. Adult-onset leukoencephalopathies with vanishing white matter with novel missense mutations in EIF2B2, EIF2B3, and EIF2B5. Neurogenetics 2011;12:259-61.  Back to cited text no. 10
    
11.
La Piana R, Vanderver A, van der Knaap M, Roux L, Tampieri D, Brais B, et al. Adult-onset vanishing white matter disease due to a novel EIF2B3 mutation. Arch Neurol 2012;69:765-8.  Back to cited text no. 11
    


    Figures

  [Figure 1], [Figure 2], [Figure 3]


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