title: Exonic deletions of FXN and early-onset Friedreich ataxia.
abstract: BACKGROUND
  Friedreich ataxia (FA) is the most frequent type of autosomal recessive cerebellar ataxia, occurring at a mean age of 16 years. Nearly 98% of patients with FA present with homozygous GAA expansions in the FXN gene. The remaining patients are compound heterozygous for an expansion and a point mutation. Patients who are compound heterozygous for an exonic deletion and an expansion are exquisitely rare.
  
  
  OBJECTIVE
  To describe 6 patients affected with FA due to an exonic deletion mutation (FAexdel) and to compare these 6 patients with FAexdel with 46 patients consecutively diagnosed with typical FA due to homozygous GAA expansion and whose small expansions were within the same range as that of the expansions of the patients with FAexdel.
  
  
  METHODS
  Description of a series.
  
  
  METHODS
  Academic research.
  
  
  METHODS
  Six patients with FAexdel and 46 patients with typical FA.
  
  
  METHODS
  FXN gene analysis, including assessments of GAA expansion and exon sequencing and determination of exonic copy numbers using multiplex ligation-dependent probe amplification.
  
  
  RESULTS
  We identified 6 patients with FA who presented with the combination of 1 GAA expansion and 1 FXN exonic deletion. The mean (SD) age at onset of the disease was earlier for patients with FAexdel (7 [4] years [range, 3-12 years]) than for patients with typical FA (15 [5] years [range, 6-30 years]) (P = .001), and the median time to confinement to wheelchair was shorter for patients with FAexdel (20 years) than for patients with typical FA (28 years) (P = .002). There was no difference between the mean (SD) size of the expansion for the patients with FAexdel (780 [256] GAA triplet repeat sequences [range, 340-1070 GAA triplet repeat sequences]) and the mean (SD) size of the short expansion for the patients with typical FA (634 [163] GAA triplet repeat sequences [range, 367-1000 GAA triplet repeat sequences]) (P = .10). The mean disease duration before becoming wheelchair bound was shorter for patients with FAexdel (9 years) than for patients with typical FA (13 years), and the incidence of cardiomyopathy was higher for patients with FAexdel (84%) than for patients with typical FA (68%). However, these differences were not significant, probably owing to the small size of the FAexdel group. The other extraneurological signs, such as scoliosis or diabetes mellitus, were particularly frequently observed in the FAexdel group. One patient presented at 9 years of age with severe angina and marked cardiomyopathy that confined her to a wheelchair. Three patients had disabling autonomic disturbances. It appears that exonic deletion significantly contributes to the clinical picture of patients with FA.
  
  
  CONCLUSIONS
  Friedreich ataxia due to an exonic deletion mutation corresponds to an early onset and severe variant of FA. FXN should be investigated for exonic deletion in patients with early-onset FA in which only 1 GAA expansion without a point mutation is found. Patients with FAexdel have to be carefully observed using cardiological, orthopaedic, endocrinological, gastroenterological, and ophthalmological data. Friedreich ataxia due to an exonic deletion mutation should be suspected in young patients presenting with severe scoliosis.
authors.affiliation: Université Pierre et Marie Curie, Centre de Recherche de l’Institut du Cerveau et de la Moelle épinière, Institut National de la Santé et de la Recherche Médicale, France. mathieu.anheim@psl.aphp.fr
authors.forename: Mathieu
authors.initials: M
authors.lastname: Anheim
authors.forename: Louise-Laure
authors.initials: LL
authors.lastname: Mariani
authors.forename: Patrick
authors.initials: P
authors.lastname: Calvas
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Cheuret
authors.forename: Fabien
authors.initials: F
authors.lastname: Zagnoli
authors.forename: Sylvie
authors.initials: S
authors.lastname: Odent
authors.forename: Claire
authors.initials: C
authors.lastname: Seguela
authors.forename: Cecilia
authors.initials: C
authors.lastname: Marelli
authors.forename: Marlène
authors.initials: M
authors.lastname: Fritsch
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Delaunoy
authors.forename: Alexis
authors.initials: A
authors.lastname: Brice
authors.forename: Alexandra
authors.initials: A
authors.lastname: Dürr
authors.forename: Michel
authors.initials: M
authors.lastname: Koenig
mesh_terms: D000328:Adult; D000975:Antioxidants / Q000627:therapeutic use; D009202:Cardiomyopathies / Q000150:complications / Q000188:drug therapy; D018450:Disease Progression; D004576:Electromyography; D005091:Exons / Q000235:genetics*; D005192:Family Health; D005260:Female; D005621:Friedreich Ataxia / Q000188:drug therapy / Q000235:genetics*; D006801:Humans; D033862:Iron-Binding Proteins / Q000235:genetics*; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D017384:Sequence Deletion / Q000235:genetics*; D019680:Trinucleotide Repeat Expansion / Q000235:genetics*; D014451:Ubiquinone / Q000031:analogs & derivatives / Q000627:therapeutic use; D000096923:Frataxin
chemical_list: D000975:Antioxidants; D033862:Iron-Binding Proteins; D014451:Ubiquinone; D000096923:Frataxin; C036619:idebenone