title: Spinocerebellar ataxia 28: a novel AFG3L2 mutation in a German family with young onset, slow progression and saccadic slowing.
abstract: BACKGROUND
  Spinocerebellar ataxia type 28 (SCA28) is related to mutations of the ATPase family gene 3-like 2 gene (AFG3L2). To date, 13 private missense mutations have been identified in families of French, Italian, and German ancestry, but overall, the disorder seems to be rare in Europe. Here, we report a kindred of German ancestry with four affected family members presenting with slowly progressive ataxia, mild pyramidal tract signs and slow saccades.
  
  
  METHODS
  After excluding repeat expansions in the genes for SCA1-3, 6-8, 10, 12, and 17, Sanger sequencing of the coding regions of TTBK2 (SCA11), KCNC3 (SCA13), PRKCG (SCA14), FGF14 (SCA27) and AFG3L2 (SCA28) was performed. The 17 coding exons of AFG3L2 with flanking intronic sequences were amplified by PCR and sequenced on both strands.
  
  
  RESULTS
  Sequencing detected a novel potential missense mutation (p.Y689N) in the C-terminal proteolytic domain, the mutational hotspot of AFG3L2. The online programme "PolyPhen-2" classifies this amino acid exchange as probably damaging (score 0.990). Similarly to most of the published SCA28 mutations, the novel mutation is located within exon 16. Mutations in exon 16 alter the proteolytic activity of the protease AFG3L2 that is highly expressed in Purkinje cells.
  
  
  CONCLUSIONS
  Genetic testing should be considered in dominant ataxia with pyramidal tract signs and saccadic slowing.
authors.affiliation: Institute of Human Genetics, University of Lübeck, Lübeck, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Zühlke
authors.affiliation: Institute of Human Genetics, University of Duisburg-Essen, Essen, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Mikat
authors.affiliation: Department of Neurology, University of Essen, Essen, Germany.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Timmann
authors.affiliation: Institute of Human Genetics, University of Duisburg-Essen, Essen, Germany.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Wieczorek
authors.affiliation: Institute of Human Genetics, University of Lübeck, Lübeck, Germany.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Gillessen-Kaesbach
authors.affiliation: Department of Neurology, Philipps University of Marburg, Baldinger straße, 53043 Marburg, Germany.|Paracelsus-Elena Klinik, Kassel, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Bürk
keywords: AFG3L2; Slow saccades; Spinocerebellar ataxia