title: Extensive aggregation of α-synuclein and tau in juvenile-onset neuroaxonal dystrophy: an autopsied individual with a novel mutation in the PLA2G6 gene-splicing site.
abstract: BACKGROUND
  Infantile neuroaxonal dystrophy (INAD) is a rare autosomal-recessive neurodegenerative disorder. Patients with INAD usually show neurological symptoms with infant onset and die in childhood. Recently, it was reported that mutations in the PLA2G6 gene cause INAD, but neuropathological analysis of genetically confirmed individuals with neuroaxonal dystrophy has been limited.
  
  
  RESULTS
  Here, we report a Japanese individual with neuroaxonal dystrophy associated with compound heterozygous mutations in the PLA2G6 gene. A novel splice-site mutation resulting in skipping and missense mutations (p.R538C) in exon 9 was identified in the patient. This patient initially presented with cerebellar ataxia at the age of 3 years, which was followed by symptoms of mental retardation, extrapyramidal signs, and epileptic seizure. The patient survived until 20 years of age. Neuropathological findings were characterized by numerous axonal spheroids, brain iron deposition, cerebellar neuronal loss, phosphorylated alpha-synuclein-positive Lewy bodies (LBs), and phosphorylated-tau-positive neurofibrillary tangles. In particular, LB pathology exhibited a unique distribution with extremely severe cortical involvement.
  
  
  CONCLUSIONS
  Our results support a genetic clinical view that compound heterozygous mutations with potential residual protein function are associated with a relatively mild phenotype. Moreover, the severe LB pathology suggests that dysfunction of the PLA2G6 gene primarily contributes to LB formation.
authors.affiliation: Institute for Medical Science of Aging, Aichi Medical University, Aichi, Japan. myoshida@aichi-med-u.ac.jp.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Riku
authors.forename: Takeshi
authors.initials: T
authors.lastname: Ikeuchi
authors.forename: Hiroyo
authors.initials: H
authors.lastname: Yoshino
authors.forename: Maya
authors.initials: M
authors.lastname: Mimuro
authors.forename: Kazuo
authors.initials: K
authors.lastname: Mano
authors.forename: Yoji
authors.initials: Y
authors.lastname: Goto
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Hattori
authors.forename: Gen
authors.initials: G
authors.lastname: Sobue
authors.forename: Mari
authors.initials: M
authors.lastname: Yoshida
mesh_terms: D017668:Age of Onset; D044466:Asian People / Q000235:genetics; D015153:Blotting, Western; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D004252:DNA Mutational Analysis; D017809:Fatal Outcome; D054522:Group VI Phospholipases A2 / Q000235:genetics*; D006801:Humans; D007564:Japan; D008279:Magnetic Resonance Imaging; D008297:Male; D020125:Mutation, Missense; D019150:Neuroaxonal Dystrophies / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D015899:Tomography, Emission-Computed, Single-Photon; D055815:Young Adult; D051844:alpha-Synuclein / Q000378:metabolism*; D016875:tau Proteins / Q000378:metabolism*
chemical_list: C054369:MAPT protein, human; C497604:SNCA protein, human; D051844:alpha-Synuclein; D016875:tau Proteins; D054522:Group VI Phospholipases A2; C516475:PLA2G6 protein, human