Paroxysmal exercise-induced dystonia within the phenotypic spectrum of ECHS1 deficiency

Imagem de Miniatura
Arquivos
art_OLGIATI_Paroxysmal_exerciseinduced_dystonia_within_the_phenotypic_spectrum_of_2016.PDF (3.53 MB)
Citações na Scopus
59
Tipo de produção
article
Data de publicação
2016
Editora
WILEY-BLACKWELL
DOI
Indexadores
Scopus
Web of Science
PubMed
Título da Revista
ISSN da Revista
Título do Volume
Autores
OLGIATI, Simone
SKORVANEK, Matej
QUADRI, Marialuisa
MINNEBOO, Michelle
GRAAFLAND, Josja
BREEDVELD, Guido J.
BONTE, Ramon
OZGUR, Zeliha
HOUT, Mirjam C. G. N. van den
SCHOONDERWOERD, Kees
Autor de Grupo de pesquisa
Editores
Coordenadores
Organizadores
Citação
MOVEMENT DISORDERS, v.31, n.7, p.1041-1048, 2016
Projetos de Pesquisa
Unidades Organizacionais
Fascículo
Resumo
BackgroundECHS1 encodes a mitochondrial enzyme involved in the degradation of essential amino acids and fatty acids. Recently, ECHS1 mutations were shown to cause a new severe metabolic disorder presenting as Leigh or Leigh-like syndromes. The objective of this study was to describe a family with 2 siblings affected by different dystonic disorders as a resulting phenotype of ECHS1 mutations. MethodsClinical evaluation, MRI imaging, genome-wide linkage, exome sequencing, urine metabolite profiling, and protein expression studies were performed. ResultsThe first sibling is 17 years old and presents with generalized dystonia and severe bilateral pallidal MRI lesions after 1 episode of infantile subacute metabolic encephalopathy (Leigh-like syndrome). In contrast, the younger sibling (15 years old) only suffers from paroxysmal exercise-induced dystonia and has very mild pallidal MRI abnormalities. Both patients carry compound heterozygous ECHS1 mutations: c.232G>T (predicted protein effect: p.Glu78Ter) and c.518C>T (p.Ala173Val). Linkage analysis, exome sequencing, cosegregation, expression studies, and metabolite profiling support the pathogenicity of these mutations. Expression studies in patients' fibroblasts showed mitochondrial localization and severely reduced levels of ECHS1 protein. Increased urinary S-(2-carboxypropyl)cysteine and N-acetyl-S-(2-carboxypropyl)cysteine levels, proposed metabolic markers of this disorder, were documented in both siblings. Sequencing ECHS1 in 30 unrelated patients with paroxysmal dyskinesias revealed no further mutations. ConclusionsThe phenotype associated with ECHS1 mutations might be milder than reported earlier, compatible with prolonged survival, and also includes isolated paroxysmal exercise-induced dystonia. ECHS1 screening should be considered in patients with otherwise unexplained paroxysmal exercise-induced dystonia, in addition to those with Leigh and Leigh-like syndromes. Diet regimens and detoxifying agents represent potential therapeutic strategies. (c) 2016 International Parkinson and Movement Disorder Society
Palavras-chave
ECHS1, mutation, dystonia, paroxysmal, exercise-induced
URI
https://observatorio.fm.usp.br/handle/OPI/16492
Referências
  1. Bhatia KP, 2011, MOVEMENT DISORD, V26, P1157, DOI 10.1002/mds.23765
  2. BROWN GK, 1982, PEDIATRICS, V70, P532
  3. Bruno MK, 2007, NEUROLOGY, V68, P1782, DOI 10.1212/01.wnl.0000262029.91552.e0
  4. Erro R, 2014, MOV DISORD CLIN PRAC, V1, P57
  5. Erro R, 2014, MOVEMENT DISORD, V29, P1108, DOI 10.1002/mds.25933
  6. Ferdinandusse S, 2015, ORPHANET J RARE DIS, V10, DOI 10.1186/s13023-015-0290-1
  7. Footitt EJ, 2008, BRIT J ANAESTH, V100, P436, DOI 10.1093/bja/aen014
  8. Gardiner AR, 2015, BRAIN, V138, P3567, DOI 10.1093/brain/awv310
  9. Haack TB, 2015, Ann Clin Transl Neur, V2, P492, DOI 10.1002/acn3.189
  10. Houten SM, 2010, J INHERIT METAB DIS, V33, P469, DOI 10.1007/s10545-010-9061-2
  11. Liu Q, 2012, J MED GENET, V49, P79, DOI 10.1136/jmedgenet-2011-100653
  12. Peters H, 2014, BRAIN, V137, P2903, DOI 10.1093/brain/awu216
  13. Peters H, 2015, MOL GENET METAB, V115, P168, DOI 10.1016/j.ymgme.2015.06.008
  14. Sakai C, 2015, HUM MUTAT, V36, P232, DOI 10.1002/humu.22730
  15. Schneider SA, 2009, MOVEMENT DISORD, V24, P1684, DOI 10.1002/mds.22507
  16. Suls A, 2008, BRAIN, V131, P1831, DOI 10.1093/brain/awn113
  17. Szczaluba K, 2009, PEDIATR NEUROL, V41, P135, DOI 10.1016/j.pediatrneurol.2009.02.013
  18. Tetreault M, 2015, HUM GENET, V134, P981, DOI 10.1007/s00439-015-1577-y
  19. vansVliet R, 2012, NEUROLOGY, V79, P777
  20. Wanders RJA, 2012, J INHERIT METAB DIS, V35, P5, DOI 10.1007/s10545-010-9236-x
  21. Wang K, 2013, BRAIN DEV-JPN, V35, P664, DOI 10.1016/j.braindev.2012.07.018
  22. Weber YG, 2008, J CLIN INVEST, V118, P2157, DOI 10.1172/JCI34438
  23. Yamada K, 2015, J MED GENET, V52, P691, DOI 10.1136/jmedgenet-2015-103231
  24. Yeh TH, 2012, J NEUROL SCI, V323, P80, DOI 10.1016/j.jns.2012.08.015

Coleções
Artigos e Materiais de Revistas Científicas - HC/Outros
Artigos e Materiais de Revistas Científicas - HC/ICHC
Artigos e Materiais de Revistas Científicas - LIM/45