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

Simone Olgiati, Matej Skorvanek, Marialuisa Quadri, Michelle Minneboo, Josja Graafland, Guido J. Breedveld, Ramon Bonte, Zeliha Ozgur, Mirjam C.G.N. van den Hout, Kees Schoonderwoerd, Frans W. Verheijen, Wilfred F.J. van IJcken, Hsin Fen Chien, Egberto Reis Barbosa, Hsiu Chen Chang, Szu Chia Lai, Tu Hsueh Yeh, Chin Song Lu, Yah Huei Wu-Chou, Anneke J A Kievit & 7 others Vladimir Han, Zuzana Gdovinova, Robert Jech, Robert M.W. Hofstra, George J.G. Ruijter, Wim Mandemakers, Vincenzo Bonifati

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Background: ECHS1 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. Methods: Clinical evaluation, MRI imaging, genome-wide linkage, exome sequencing, urine metabolite profiling, and protein expression studies were performed. Results: The 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. Conclusions: The 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.

Original languageEnglish
Pages (from-to)1041-1048
Number of pages8
JournalMovement Disorders
Volume31
Issue number7
DOIs
Publication statusPublished - Jul 1 2016
Externally publishedYes

Fingerprint

Leigh Disease
Mutation
Siblings
Exome
Metabolic Brain Diseases
Dystonic Disorders
Phenotype
Chorea
Proteins
Essential Amino Acids
Dystonia
Virulence
Dystonia 18
Fatty Acids
Fibroblasts
Urine
Genome
Diet
Survival
Enzymes

Keywords

  • dystonia
  • ECHS1
  • exercise-induced
  • mutation
  • paroxysmal

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

Cite this

Olgiati, S., Skorvanek, M., Quadri, M., Minneboo, M., Graafland, J., Breedveld, G. J., ... Bonifati, V. (2016). Paroxysmal exercise-induced dystonia within the phenotypic spectrum of ECHS1 deficiency. Movement Disorders, 31(7), 1041-1048. https://doi.org/10.1002/mds.26610

Paroxysmal exercise-induced dystonia within the phenotypic spectrum of ECHS1 deficiency. / Olgiati, Simone; Skorvanek, Matej; Quadri, Marialuisa; Minneboo, Michelle; Graafland, Josja; Breedveld, Guido J.; Bonte, Ramon; Ozgur, Zeliha; van den Hout, Mirjam C.G.N.; Schoonderwoerd, Kees; Verheijen, Frans W.; van IJcken, Wilfred F.J.; Chien, Hsin Fen; Barbosa, Egberto Reis; Chang, Hsiu Chen; Lai, Szu Chia; Yeh, Tu Hsueh; Lu, Chin Song; Wu-Chou, Yah Huei; Kievit, Anneke J A; Han, Vladimir; Gdovinova, Zuzana; Jech, Robert; Hofstra, Robert M.W.; Ruijter, George J.G.; Mandemakers, Wim; Bonifati, Vincenzo.

In: Movement Disorders, Vol. 31, No. 7, 01.07.2016, p. 1041-1048.

Research output: Contribution to journalArticle

Olgiati, S, Skorvanek, M, Quadri, M, Minneboo, M, Graafland, J, Breedveld, GJ, Bonte, R, Ozgur, Z, van den Hout, MCGN, Schoonderwoerd, K, Verheijen, FW, van IJcken, WFJ, Chien, HF, Barbosa, ER, Chang, HC, Lai, SC, Yeh, TH, Lu, CS, Wu-Chou, YH, Kievit, AJA, Han, V, Gdovinova, Z, Jech, R, Hofstra, RMW, Ruijter, GJG, Mandemakers, W & Bonifati, V 2016, 'Paroxysmal exercise-induced dystonia within the phenotypic spectrum of ECHS1 deficiency', Movement Disorders, vol. 31, no. 7, pp. 1041-1048. https://doi.org/10.1002/mds.26610
Olgiati S, Skorvanek M, Quadri M, Minneboo M, Graafland J, Breedveld GJ et al. Paroxysmal exercise-induced dystonia within the phenotypic spectrum of ECHS1 deficiency. Movement Disorders. 2016 Jul 1;31(7):1041-1048. https://doi.org/10.1002/mds.26610
Olgiati, Simone ; Skorvanek, Matej ; Quadri, Marialuisa ; Minneboo, Michelle ; Graafland, Josja ; Breedveld, Guido J. ; Bonte, Ramon ; Ozgur, Zeliha ; van den Hout, Mirjam C.G.N. ; Schoonderwoerd, Kees ; Verheijen, Frans W. ; van IJcken, Wilfred F.J. ; Chien, Hsin Fen ; Barbosa, Egberto Reis ; Chang, Hsiu Chen ; Lai, Szu Chia ; Yeh, Tu Hsueh ; Lu, Chin Song ; Wu-Chou, Yah Huei ; Kievit, Anneke J A ; Han, Vladimir ; Gdovinova, Zuzana ; Jech, Robert ; Hofstra, Robert M.W. ; Ruijter, George J.G. ; Mandemakers, Wim ; Bonifati, Vincenzo. / Paroxysmal exercise-induced dystonia within the phenotypic spectrum of ECHS1 deficiency. In: Movement Disorders. 2016 ; Vol. 31, No. 7. pp. 1041-1048.
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T1 - Paroxysmal exercise-induced dystonia within the phenotypic spectrum of ECHS1 deficiency

AU - Olgiati, Simone

AU - Skorvanek, Matej

AU - Quadri, Marialuisa

AU - Minneboo, Michelle

AU - Graafland, Josja

AU - Breedveld, Guido J.

AU - Bonte, Ramon

AU - Ozgur, Zeliha

AU - van den Hout, Mirjam C.G.N.

AU - Schoonderwoerd, Kees

AU - Verheijen, Frans W.

AU - van IJcken, Wilfred F.J.

AU - Chien, Hsin Fen

AU - Barbosa, Egberto Reis

AU - Chang, Hsiu Chen

AU - Lai, Szu Chia

AU - Yeh, Tu Hsueh

AU - Lu, Chin Song

AU - Wu-Chou, Yah Huei

AU - Kievit, Anneke J A

AU - Han, Vladimir

AU - Gdovinova, Zuzana

AU - Jech, Robert

AU - Hofstra, Robert M.W.

AU - Ruijter, George J.G.

AU - Mandemakers, Wim

AU - Bonifati, Vincenzo

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N2 - Background: ECHS1 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. Methods: Clinical evaluation, MRI imaging, genome-wide linkage, exome sequencing, urine metabolite profiling, and protein expression studies were performed. Results: The 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. Conclusions: The 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.

AB - Background: ECHS1 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. Methods: Clinical evaluation, MRI imaging, genome-wide linkage, exome sequencing, urine metabolite profiling, and protein expression studies were performed. Results: The 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. Conclusions: The 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.

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KW - ECHS1

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KW - mutation

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