title: Molecular and functional studies of retinal degeneration as a clinical presentation of SACS-related disorder.
abstract: BACKGROUND
  ARSACS (autosomal-recessive spastic ataxia of Charlevoix-Saguenay) is a neurodegenerative disorder caused by SACS gene mutations and characterized by a triad of symptoms: early-onset cerebellar ataxia, spasticity and peripheral neuropathy. A characteristic retinal nerve fiber hypertrophy has been reported in several individuals with ARSACS.
  
  
  METHODS
  We describe a patient with a unique clinical presentation of ataxia, nystagmus, dysarthria, hearing impairment, and retinal degeneration. Whole-exome-sequencing was performed as well as morphological studies in the patient's fibroblasts.
  
  
  RESULTS
  A compound heterozygosity for a novel D3269N and N2380K mutations in the SACS gene was found. The parents are carriers. Morphological studies revealed a dramatic decrease in the number of cell mitochondria as well as a difference in mitochondrial network morphology.
  
  
  CONCLUSIONS
  Retinal degeneration has never been reported in ARSACS. Since sacsin is involved in the mitochondrial fusion-fission process, we speculate that defected fission process may be responsible for an impaired mitochondrial function and retinal degeneration. Our patient has a unique clinical presentation of SACS mutations inconsistent with the classic ARSACS triad but also different from the "atypical" presentations described in the literature. Further studies are necessary to clarify the factors that modify the SACS related phenotype.
authors.affiliation: Pediatric Neurology Unit, Wolfson Medical Center, Holon, Israel; Metabolic-Neurogenetic Clinic, Wolfson Medical Center, Holon, Israel; Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
authors.forename: Lubov
authors.initials: L
authors.lastname: Blumkin
authors.affiliation: William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: Teisha
authors.initials: T
authors.lastname: Bradshaw
authors.affiliation: Metabolic-Neurogenetic Clinic, Wolfson Medical Center, Holon, Israel; Institute of Medical Genetics, Wolfson Medical Center, Holon, Israel; Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
authors.forename: Marina
authors.initials: M
authors.lastname: Michelson
authors.affiliation: Molecular Genetics Laboratory, Wolfson Medical Center, Holon, Israel.
authors.forename: Tal
authors.initials: T
authors.lastname: Kopler
authors.affiliation: Toldot Genetics Ltd., Tel Aviv, Israel.
authors.forename: Dvir
authors.initials: D
authors.lastname: Dahari
authors.affiliation: Pediatric Neurology Unit, Wolfson Medical Center, Holon, Israel; Metabolic-Neurogenetic Clinic, Wolfson Medical Center, Holon, Israel; Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
authors.forename: Tally
authors.initials: T
authors.lastname: Lerman-Sagie
authors.affiliation: Metabolic-Neurogenetic Clinic, Wolfson Medical Center, Holon, Israel; Institute of Medical Genetics, Wolfson Medical Center, Holon, Israel; Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
authors.forename: Dorit
authors.initials: D
authors.lastname: Lev
authors.affiliation: William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: J Paul
authors.initials: JP
authors.lastname: Chapple
authors.affiliation: Metabolic-Neurogenetic Clinic, Wolfson Medical Center, Holon, Israel; Toldot Genetics Ltd., Tel Aviv, Israel; Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel. Electronic address: leshinsky@wolfson.health.gov.il.
authors.forename: Esther
authors.initials: E
authors.lastname: Leshinsky-Silver
mesh_terms: D002648:Child; D006360:Heat-Shock Proteins / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D008297:Male; D008928:Mitochondria / Q000473:pathology; D009128:Muscle Spasticity / Q000150:complications* / Q000235:genetics*; D009154:Mutation; D010641:Phenotype; D012162:Retinal Degeneration / Q000235:genetics*; D020754:Spinocerebellar Ataxias / Q000150:complications / Q000151:congenital* / Q000235:genetics
chemical_list: D006360:Heat-Shock Proteins; C404403:SACS protein, human
keywords: ARSACS; Ataxia; Hearing loss; Night blindness; Retinal degeneration; SACS