These authors contributed equally to this work.
Progressive myoclonus epilepsy: extraneuronal brown pigment deposition and system neurodegeneration in the brains of Japanese patients with novel SCARB2 mutations
Version of Record online: 1 JUL 2014
© 2013 British Neuropathological Society
Neuropathology and Applied Neurobiology
Volume 40, Issue 5, pages 551–563, August 2014
How to Cite
Fu, Y.-J., Aida, I., Tada, M., Tada, M., Toyoshima, Y., Takeda, S., Nakajima, T., Naito, H., Nishizawa, M., Onodera, O., Kakita, A. and Takahashi, H. (2014), Progressive myoclonus epilepsy: extraneuronal brown pigment deposition and system neurodegeneration in the brains of Japanese patients with novel SCARB2 mutations. Neuropathology and Applied Neurobiology, 40: 551–563. doi: 10.1111/nan.12057
- Issue online: 1 JUL 2014
- Version of Record online: 1 JUL 2014
- Accepted manuscript online: 10 MAY 2013 05:24AM EST
- Manuscript Accepted: 30 APR 2013
- Manuscript Received: 16 DEC 2012
- Ministry of Education, Culture, Sports, Science, and Technology, Japan. Grant Number: 23240049
- brown pigment;
- cerebellar cortex;
- cerebral cortex;
- progressive myoclonus epilepsy;
Mutations in the SCARB2 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.
Sequencing and restriction analysis of the SCARB2 gene and neuropathological examination with immunohistochemistry were performed.
Gene analyses revealed novel homozygous frameshift 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 pallidoluysian 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.
The frameshift mutation detected in the patient with late-onset disease is a hitherto undescribed, unique type of SCARB2 gene mutation. The present two patients are the first reported to have clearly demonstrated both extraneuronal brown pigment deposition and system neurodegeneration as neuropathological features of PME with SCARB2 mutations.