AANP-OREN American Association of Neuropathologists Online Resource for Education in Neuropathology

 49th Annual Diagnostic Slide Session, 2008 Case 1

Contributor: Carrie A. Mohila MD PhD1, James M. Powers MD2, Gert C. Scheper PhD3, Marjo S. van der Knaap MD PhD3, C. Harker Rhodes MD PhD1.  1Department of Pathology, Dartmouth-Hitchcock Medical Center, Lebanon, NH; 2Department of Pathology, University Rochester Medical Center, Rochester, NY; 3Department of Child Neurology VU Medical Center, Amsterdam, The Netherlands

Moderator: Anthony Yachnis, M.D. Manager and Editor: Leroy R Sharer, M.D.

Diagnosis: Vanishing white matter (VWM) disease.  PDF File

 

Comment: As mentioned in the protocol, grossly there was massive cystic degeneration of the white matter (see below).  This condition often has clinical onset following head trauma, as in this patient.  Oligodendroglial cells appear to be increased in the white matter in some regions, while in other areas oligos are lost because of apoptosis.  In answer to a question, the Presenter reported that the patient’s ovaries were normal at autopsy.

 

  Gross photograph of the brain at autopsy.

 

From the Presenter: Genetic studies revealed that this patient was compound heterozygous for two mutations in the gene EIF2B5: 338G>A mutation leading to the substitution of arginine for histidine in eIF2B  at position 113 (R113H), and 1015C>T mutation leading to the substitution of arginine for tryptophan in eIF2B  at position 339 (R339W). Both mutations have been described many times in other VWM patients. Two-thirds of VWM patients have mutations in EIF2B5.  The R113H mutation occurs in approximately 40% of all VWM patients and has been correlated with adult onset and milder clinical manifestation with slower rate of progression of disease.  Two cases of R113H/R339W compound heterozygous mutations in VWM patients have been reported previously.

 

References:

  1. Fogli A, Boespflug-Tanguy O: The large spectrum of eIF2B-related diseases. Biochem Soc Trans 2006; 34:22-29.

  2. Powers JM, Kamphorst W, van der Knaap MS: Vanishing white matter disease. In: Pathology and Genetics: Developmental Neuropathology, Golden J, Harding B, Eds., International Society of Neuropathology, Allen Press (Basel), 2004, pp: 325-330.

  3. Scali O, Di Perri C, Federico A: The spectrum of mutations for the diagnosis of vanishing white matter disease. Neurol Sci 2006; 27:271-277.

  4. van der Knaap MS, Pronk JC, Scheper GC: Vanishing white matter disease. Lancet Neurol 2006; 5:413-423.

  5. van Kollenburg B, van Dijk J, Garbern J, Thomas AA, Scheper GC, Powers JM, van der Knaap MS: Glia-specific activation of all pathways of the unfolded protein response in vanishing white matter disease. J Neuropathol Exp Neurol 2006;65:707-715.