title: Progressive myoclonus epilepsy: extraneuronal brown pigment deposition and system neurodegeneration in the brains of Japanese patients with novel SCARB2 mutations.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  Sequencing and restriction analysis of the SCARB2 gene and neuropathological examination with immunohistochemistry were performed.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors: Department of Pathology, Brain Research Institute, University of Niigata, Niigata, Japan.
authors: Yong-Juan
authors: YJ
authors: Fu
authors: Izumi
authors: I
authors: Aida
authors: Masayoshi
authors: M
authors: Tada
authors: Mari
authors: M
authors: Tada
authors: Yasuko
authors: Y
authors: Toyoshima
authors: Shigeki
authors: S
authors: Takeda
authors: Takashi
authors: T
authors: Nakajima
authors: Haruhiko
authors: H
authors: Naito
authors: Masatoyo
authors: M
authors: Nishizawa
authors: Osamu
authors: O
authors: Onodera
authors: Akiyoshi
authors: A
authors: Kakita
authors: Hitoshi
authors: H
authors: Takahashi
mesh_terms: D000328:Adult; D044466:Asian People; D001253:Astrocytes / Q000648:ultrastructure*; D001921:Brain / Q000648:ultrastructure*; D018389:Codon, Nonsense; D005260:Female; D016368:Frameshift Mutation; D006801:Humans; D007564:Japan; D051907:Lysosomal Membrane Proteins / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D020191:Myoclonic Epilepsies, Progressive / Q000235:genetics* / Q000473:pathology*; D010375:Pedigree; D011689:Purkinje Cells / Q000648:ultrastructure*; D051116:Receptors, Scavenger / Q000235:genetics*; D055815:Young Adult
chemical_list: D018389:Codon, Nonsense; D051907:Lysosomal Membrane Proteins; D051116:Receptors, Scavenger; C074299:SCARB2 protein, human
keywords: SCARB2; brown pigment; cerebellar cortex; cerebral cortex; neurodegeneration; progressive myoclonus epilepsy