title: SPG15 is the second most common cause of hereditary spastic paraplegia with thin corpus callosum.
abstract: OBJECTIVE
  Hereditary spastic paraplegias (HSPs) are very heterogeneous inherited neurodegenerative disorders. Our group recently identified ZFYVE26 as the gene responsible for one of the clinical and genetic entities, SPG15. Our aim was to describe its clinical and mutational spectra.
  
  
  METHODS
  We analyzed all exons of SPG15/ZFYVE26 gene by direct sequencing in a series of 60 non-SPG11 HSP subjects with associated mental or MRI abnormalities, including 30 isolated cases. The clinical data were collected through the SPATAX network.
  
  
  RESULTS
  We identified 13 novel truncating mutations in ZFYVE26, 12 of which segregated at the homozygous or compound heterozygous states in 8 new SPG15 families while 1 was found at the heterozygous state in a single family. Two of 3 splice site mutations were validated on mRNA of 2 patients. The SPG15 phenotype in 11 affected individuals was characterized by early onset HSP, severe progression of the disease, and mental impairment dominated by cognitive decline. Thin corpus callosum and white matter hyperintensities were MRI hallmarks of the disease in this series.
  
  
  CONCLUSIONS
  The mutations are truncating, private, and distributed along the entire coding sequence of ZFYVE26, which complicates the analysis of this gene in clinical practice. In our series of patients with hereditary spastic paraplegia-thin corpus callosum, the largest analyzed so far, SPG15 was the second most frequent form (11.5%) after SPG11. Both forms share similar clinical and imaging presentations with very few distinctions, which are, however, insufficient to infer the molecular diagnosis when faced with a single patient.
authors.affiliation: INSERM, U975, Paris, France.
authors.forename: C
authors.initials: C
authors.lastname: Goizet
authors.forename: A
authors.initials: A
authors.lastname: Boukhris
authors.forename: D
authors.initials: D
authors.lastname: Maltete
authors.forename: L
authors.initials: L
authors.lastname: Guyant-Maréchal
authors.forename: J
authors.initials: J
authors.lastname: Truchetto
authors.forename: E
authors.initials: E
authors.lastname: Mundwiller
authors.forename: S
authors.initials: S
authors.lastname: Hanein
authors.forename: P
authors.initials: P
authors.lastname: Jonveaux
authors.forename: F
authors.initials: F
authors.lastname: Roelens
authors.forename: J
authors.initials: J
authors.lastname: Loureiro
authors.forename: E
authors.initials: E
authors.lastname: Godet
authors.forename: S
authors.initials: S
authors.lastname: Forlani
authors.forename: J
authors.initials: J
authors.lastname: Melki
authors.forename: M
authors.initials: M
authors.lastname: Auer-Grumbach
authors.forename: J C
authors.initials: JC
authors.lastname: Fernandez
authors.forename: P
authors.initials: P
authors.lastname: Martin-Hardy
authors.forename: I
authors.initials: I
authors.lastname: Sibon
authors.forename: G
authors.initials: G
authors.lastname: Sole
authors.forename: I
authors.initials: I
authors.lastname: Orignac
authors.forename: C
authors.initials: C
authors.lastname: Mhiri
authors.forename: P
authors.initials: P
authors.lastname: Coutinho
authors.forename: A
authors.initials: A
authors.lastname: Durr
authors.forename: A
authors.initials: A
authors.lastname: Brice
authors.forename: G
authors.initials: G
authors.lastname: Stevanin
mesh_terms: D000293:Adolescent; D001921:Brain / Q000000981:diagnostic imaging / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics*; D002648:Child; D003337:Corpus Callosum / Q000000981:diagnostic imaging / Q000473:pathology*; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D009154:Mutation; D049268:Positron-Emission Tomography / Q000379:methods; D012720:Severity of Illness Index; D015419:Spastic Paraplegia, Hereditary / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology*; D015899:Tomography, Emission-Computed, Single-Photon / Q000379:methods
chemical_list: D002352:Carrier Proteins; C528699:ZFYVE26 protein, human