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Research paper
Autosomal-recessive complicated spastic paraplegia with a novel lysosomal trafficking regulator gene mutation
  1. Haruo Shimazaki1,
  2. Junko Honda1,
  3. Tametou Naoi1,
  4. Michito Namekawa1,
  5. Imaharu Nakano2,
  6. Masahide Yazaki3,
  7. Katsuya Nakamura3,
  8. Kunihiro Yoshida3,
  9. Shu-ichi Ikeda3,
  10. Hiroyuki Ishiura4,
  11. Yoko Fukuda4,
  12. Yuji Takahashi4,
  13. Jun Goto4,
  14. Shoji Tsuji4,
  15. Yoshihisa Takiyama5
  1. 1Division of Neurology, Department of Internal Medicine, Jichi Medical University School of Medicine, Tochigi, Japan
  2. 2Department of Neurology, Tokyo Metropolitan Neurological Hospital, Tokyo, Japan
  3. 3Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine, Nagano, Japan
  4. 4Department of Neurology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
  5. 5Department of Neurology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi, Japan
  1. Correspondence to Dr Haruo Shimazaki, Division of Neurology, Department of Internal Medicine, Jichi Medical University School of Medicine, Yakushiji 3311-1, Shimotsuke, Tochigi 329-0498, Japan; hshimaza{at}


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.


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