title: Atlastin1 mutations are frequent in young-onset autosomal dominant spastic paraplegia.
abstract: BACKGROUND
  Hereditary spastic paraplegias are disorders that are very heterogeneous, both clinically and genetically. The atlastin1 gene has recently been implicated in SPG3A, a form of autosomal dominant pure spastic paraplegia. Atlastin1 mutations have been identified in 8 families so far.
  
  
  OBJECTIVE
  To determine the relative frequency, phenotype, and mutation spectrum of SPG3A in patients with pure autosomal dominant spastic paraplegia and onset before age 20 years.
  
  
  METHODS
  We sequenced the atlastin1 gene in a large series of patients (31 families) in which mutations in the spastin gene, corresponding to the frequent SPG4 locus, had previously been excluded. The phenotype was compared with 126 SPG4 patients.
  
  
  RESULTS
  We identified 12 families (39%) including 34 patients with 9 different missense atlastin1 mutations, 7 of which are newly described. The main clinical characteristic of these SPG3A patients was pure spasticity with very young onset of symptoms (mean age, 4.6 +/- 3.9 years) and slow progression. However, additional signs such as decreased vibration sense and wasting in lower limbs, sphincter disturbances, and scoliosis were found in a minority of patients. In addition, several gene carriers were clinically affected but still asymptomatic (n = 5) or had no clinical signs (n = 2), indicating incomplete penetrance. Compared with patients from other families meeting the same diagnostic criteria (43 patients) and families with SPG4 (126 patients), the major form of autosomal dominant spastic paraplegia, SPG3A patients had earlier symptom onset, less frequently increased reflexes in the upper limbs, decreased vibration sense in the lower limbs, and fewer sphincter disturbances, but more frequently observed wasting in the lower limbs and scoliosis. These particularities, as well as frequent abnormal motor evoked potentials, could help identify patients to be screened for atlastin1 gene mutations.
  
  
  CONCLUSIONS
  This study enables us to estimate the frequency of the SPG3A mutations in France at 39% in families with young-onset autosomal dominant spastic paraplegia after exclusion of SPG4 cases. So far, most mutations have been private, although they were all found in exons 7, 8, 12, and 13. These exons should be given priority when performing molecular diagnoses for SPG3A.
authors.affiliation: Département de Génétique, Cytogénétique et Embryologie, and INSERM U289, Hôpital Salpêtrière AP-HP, Paris, France.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Dürr
authors.forename: Agnès
authors.initials: A
authors.lastname: Camuzat
authors.forename: Emilie
authors.initials: E
authors.lastname: Colin
authors.forename: Chantal
authors.initials: C
authors.lastname: Tallaksen
authors.forename: Didier
authors.initials: D
authors.lastname: Hannequin
authors.forename: Paula
authors.initials: P
authors.lastname: Coutinho
authors.forename: Bertrand
authors.initials: B
authors.lastname: Fontaine
authors.forename: Annick
authors.initials: A
authors.lastname: Rossi
authors.forename: Roger
authors.initials: R
authors.lastname: Gil
authors.forename: Christophe
authors.initials: C
authors.lastname: Rousselle
authors.forename: Merle
authors.initials: M
authors.lastname: Ruberg
authors.forename: Giovanni
authors.initials: G
authors.lastname: Stevanin
authors.forename: Alexis
authors.initials: A
authors.lastname: Brice
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D002675:Child, Preschool; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics*; D019204:GTP-Binding Proteins; D006801:Humans; D008297:Male; D008565:Membrane Proteins; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D015419:Spastic Paraplegia, Hereditary / Q000235:genetics*
chemical_list: D008565:Membrane Proteins; C440006:ATL1 protein, human; D020558:GTP Phosphohydrolases; D019204:GTP-Binding Proteins