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Keywords:

  • action myoclonus;
  • brown pigment;
  • cerebellar cortex;
  • cerebral cortex;
  • neurodegeneration;
  • progressive myoclonus epilepsy;
  • SCARB2;
  • seizure

Aims

Mutations in the SCABR2 gene cause a rare autosomal recessive disease, progressive myoclonus epilepsy (PME) with or without renal failure, the former also being designated action myoclonus-renal failure syndrome. Although reported cases have been accumulating, only a few have described its neuropathology. We studied two Japanese patients with PME without renal failure, in whom the ages at onset and disease durations were 45 and 20 years, and 14 and 8.5 years, respectively.

Methods

Sequencing and restriction analysis of the SCARB2 gene and neuropathological examination with immunohistochemistry were performed.

Results

Gene analyses revealed novel homozygous frame-shift and nonsense mutations in the SCARB2 gene. Both cases exhibited deposition of brown pigment in the brain, especially the cerebellar and cerebral cortices. Ultrastructurally, the pigment granules were localized in astrocytes. Neuronal loss and gliosis were also evident in the brain, including the pallido-luysian and cerebello-olivary systems. The spinal cord was also affected. Such changes were less severe in one patient with late-onset disease than in the other patient with early-onset disease. In brain and kidney sections, immunostaining with an antibody against the C-terminus of human SCARB2 revealed decreased levels and no expression of the protein, respectively.

Conclusions

The frame-shift mutation detected in the patient with late-onset disease is a hitherto undescribed, unique type of SCABR2 gene mutation. The present two patients are the first reported to have clearly demonstrated both extraneuronal brown pigment deposition and system neurodegeneration as neuropathologic features of PME with SCABR2 mutations.