title: Autosomal-recessive complicated spastic paraplegia with a novel lysosomal trafficking regulator gene mutation.
abstract: BACKGROUND
  Autosomal-recessive hereditary spastic paraplegias (AR-HSP) consist of a genetically diverse group of neurodegenerative diseases characterised by pyramidal tracts dysfunction. The causative genes for many types of AR-HSP remain elusive. We tried to identify the gene mutation for AR-HSP with cerebellar ataxia and neuropathy.
  
  
  METHODS
  This study included two patients in a Japanese family with their parents who are first cousins. Neurological examination and gene analysis were conducted in the two patients and two normal family members. We undertook genome-wide linkage analysis employing single nucleotide polymorphism arrays using the two patients' DNAs and exome sequencing using one patient's sample.
  
  
  RESULTS
  We detected a homozygous missense mutation (c.4189T>G, p.F1397V) in the lysosomal trafficking regulator (LYST) gene, which is described as the causative gene for Chédiak-Higashi syndrome (CHS). CHS is a rare autosomal-recessive syndrome characterised by hypopigmentation, severe immune deficiency, a bleeding tendency and progressive neurological dysfunction. This mutation was co-segregated with the disease in the family and was located at well-conserved amino acid. This LYST mutation was not found in 200 Japanese control DNAs. Microscopic observation of peripheral blood in the two patients disclosed large peroxidase-positive granules in both patients' granulocytes, although they had no symptoms of immune deficiency or bleeding tendency.
  
  
  CONCLUSIONS
  We diagnosed these patients as having adult CHS presenting spastic paraplegia with cerebellar ataxia and neuropathy. The clinical spectrum of CHS is broader than previously recognised. Adult CHS must be considered in the differential diagnosis of AR-HSP.
authors: Division of Neurology, Department of Internal Medicine, Jichi Medical University School of Medicine, Tochigi, Japan.
authors: Haruo
authors: http://orcid.org/0000-0003-0628-7164
authors: H
authors: Shimazaki
authors: Division of Neurology, Department of Internal Medicine, Jichi Medical University School of Medicine, Tochigi, Japan.
authors: Junko
authors: J
authors: Honda
authors: Division of Neurology, Department of Internal Medicine, Jichi Medical University School of Medicine, Tochigi, Japan.
authors: Tametou
authors: T
authors: Naoi
authors: Division of Neurology, Department of Internal Medicine, Jichi Medical University School of Medicine, Tochigi, Japan.
authors: Michito
authors: M
authors: Namekawa
authors: Department of Neurology, Tokyo Metropolitan Neurological Hospital, Tokyo, Japan.
authors: Imaharu
authors: I
authors: Nakano
authors: Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine, Nagano, Japan.
authors: Masahide
authors: M
authors: Yazaki
authors: Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine, Nagano, Japan.
authors: Katsuya
authors: K
authors: Nakamura
authors: Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine, Nagano, Japan.
authors: Kunihiro
authors: K
authors: Yoshida
authors: Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine, Nagano, Japan.
authors: Shu-ichi
authors: S
authors: Ikeda
authors: Department of Neurology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
authors: Hiroyuki
authors: H
authors: Ishiura
authors: Department of Neurology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
authors: Yoko
authors: Y
authors: Fukuda
authors: Department of Neurology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
authors: Yuji
authors: Y
authors: Takahashi
authors: Department of Neurology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
authors: Jun
authors: J
authors: Goto
authors: Department of Neurology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
authors: Shoji
authors: S
authors: Tsuji
authors: Department of Neurology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi, Japan.
authors: Yoshihisa
authors: Y
authors: Takiyama
mesh_terms: D044466:Asian People / Q000235:genetics; D002524:Cerebellar Ataxia / Q000150:complications / Q000235:genetics; D002609:Chediak-Higashi Syndrome / Q000150:complications / Q000235:genetics*; D008040:Genetic Linkage / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D015419:Spastic Paraplegia, Hereditary / Q000150:complications / Q000235:genetics*; D033921:Vesicular Transport Proteins / Q000235:genetics*
chemical_list: C102161:LYST protein, human; D033921:Vesicular Transport Proteins
keywords: CEREBELLAR ATAXIA; NEUROGENETICS; NEUROPATHY; SPASTICITY