Conversion of a Normal MRI into an MRI Showing a Cystic Leukoencephalopathy is not a Known Feature of Vanishing White Matter

“Vanishing white matter” (VWM) or “childhood ataxia with central hypomyelination” (CACH) is an autosomal recessive disorder (OMIM 603896), related to mutations in either one of the five genes encoding translation initiation factor eIF2B (EIF2B1-5) [3] [6]. The disease most often has a childhood onset [4] [5]. Patients have been reported who underwent MRI in the presymptomatic stage and in all patients reported so far, the presymptomatic MRI already showed extensive cerebral white matter abnormalities, although not necessarily with signs of white matter rarefaction and cystic degeneration [5] [7].

Ding XQ et al. describe a child in whom the initial MRI was normal and who subsequently developed an extensive cerebral leukoencephalopathy with cystic changes [1]. The authors suspected VWM and sequenced the genes EIF2B1-5, which revealed one heterozygous mutation in EIF2B4. The authors do not state which mutation. They do not mention analysis of control chromosomes or evolutionary conservation of the affected residue to make it unlikely that the change is a benign polymorphism. Despite the fact that two mutations, one for both alleles, should be found for genetic confirmation, the authors establish a diagnosis of VWM and conclude that the MRI can be normal in VWM in the presymptomatic stage.

It is not only the normal initial MRI that is atypical for VWM in this patient. The clinical picture dominated by seizures is unusual. Restriction of the diffusion is not an MRI feature commonly observed in VWM. The white matter rarefaction and cystic degeneration in VWM occurs in a diffuse, melting away-like fashion, leaving behind radiating stripes of preserved perivascular tissue, not observed in the present patient. There are in general no lesions with a border of restricted diffusion and a cystic center in VWM, as observed in the present patient. Sparing of the occipital and temporal white matter is not a known feature of VWM. In fact, the MRI features observed in the patient of the paper of Ding et al. are suggestive of a mitochondrial defect rather than VWM [8].

It is important to note that the authors have not provided genetic confirmation of the diagnosis. They have at most shown that the patient is carrier of a mutation in EIF2B4. Confirmation of the diagnosis would include demonstration of mutations in one of the eIF2B genes for both alleles [3] [6], or reduced eIF2B activity [2], or both. A definitive diagnosis is particularly important when it comes to adding new features to the known VWM phenotype.

References

• 1 Ding XQ, Goerg M, Eckert B, Ohlenbusch A, Kohlschutter A, Gaertner J. et al . Rapidly progressive vanishing white matter disease in a child with previously inconspicuous brain MRI.  Neuropediatrics. 2006;  37 253-256
• 2 Fogli A, Schiffmann R, Hugendubler L, Combes P, Bertini E, Rodriquez D. et al . Decreased guanine nucleotide exchange factor activity in eIF2B-mutated patients.  Eur J Hum Genet. 2004;  12 561-566
• 3 Leegwater PAJ, Vermeulen G, Könst AAM, Naidu S, Mulders J, Visser A. et al . Subunits of the translation initiation factor eIF2B are mutated in leukoencephalopathy with vanishing white matter.  Nature Genet. 2001;  29 383-388
• 4 Schiffmann R, Moller JR, Trapp BD, Shih HH, Farrer RG, Katz DA. et al . Childhood ataxia with diffuse central nervous system hypomyelination.  Ann Neurol. 1994;  35 331-340
• 5 Knaap MS Van der, Barth PG, Gabreëls FJM, Franzoni E, Begeer JH, Stroink H. et al . A new leukoencephalopathy with vanishing white matter.  Neurology. 1997;  48 845-855
• 6 Knaap MS Van der, Leegwater PA, Könst AAM, Visser A, Naidu S, Oudejans CBM. et al . Mutations in each of the five subunits of translation initiation factor eIF2B can cause leukoencephalopathy with vanishing white matter.  Ann Neurol. 2002;  51 264-270
• 7 Knaap MS Van der, Valk J. Magnetic resonance of myelination and myelin disorders. 3rd edition Springer, Heidelberg 2005
• 8 Knaap MS Van der, Pronk JC, Scheper GC. Vanishing white matter disease.  Lancet Neurol. 2006;  5 413-423

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