Clinical use of frataxin measurement in a patient with a novel deletion in the FXN gene

J Neurol. 2013 Apr;260(4):1116-21. doi: 10.1007/s00415-012-6770-5. Epub 2012 Nov 30.

Abstract

Friedreich ataxia (FRDA) is caused by a GAA expansion in the first intron of the FXN gene, which encodes frataxin. Four percent of patients harbor a point mutation on one allele and a GAA expansion on the other. We studied an Italian patient presenting with symptoms suggestive of FRDA, and carrying a single expanded 850 GAA allele. As a second diagnostic step, frataxin was measured in peripheral blood mononuclear cells, and proved to be in the pathological range (2.95 pg/μg total protein, 12.7 % of control levels). Subsequent sequencing revealed a novel deletion in exon 5a (c.572delC) which predicted a frameshift at codon 191 and a premature truncation of the protein at codon 194 (p.T191IfsX194). FXN/mRNA expression was reduced to 69.2 % of control levels. Clinical phenotype was atypical with absent dysarthria, and rapid disease progression. L-Buthionine-sulphoximine treatment of the proband's lymphoblasts showed a severe phenotype as compared to classic FRDA.

MeSH terms

  • Analysis of Variance
  • Antimetabolites / pharmacology
  • Buthionine Sulfoximine / pharmacology
  • Cell Line, Transformed
  • Family Health
  • Female
  • Frataxin
  • Friedreich Ataxia / genetics*
  • Friedreich Ataxia / pathology
  • Genetic Testing
  • Humans
  • Iron-Binding Proteins / genetics*
  • Iron-Binding Proteins / metabolism*
  • Lymphocytes / drug effects
  • Male
  • Middle Aged
  • RNA, Messenger / metabolism
  • Sequence Deletion / genetics*
  • Severity of Illness Index
  • Trinucleotide Repeat Expansion / genetics
  • Young Adult

Substances

  • Antimetabolites
  • Iron-Binding Proteins
  • RNA, Messenger
  • Buthionine Sulfoximine