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Benign hereditary chorea: phenotype, prognosis, therapeutic outcome and long term follow-up in a large series with new mutations in the TITF1/NKX2-1 gene
  1. Domitille Gras1,
  2. Laurence Jonard2,
  3. Emmanuel Roze3,4,5,
  4. Sandra Chantot-Bastaraud6,
  5. Jeanette Koht7,
  6. Jacques Motte8,
  7. Diana Rodriguez1,5,9,
  8. Malek Louha2,
  9. Isabelle Caubel10,
  10. Isabelle Kemlin1,
  11. Laurence Lion-François11,
  12. Cyril Goizet12,
  13. Loic Guillot13,
  14. Marie-Laure Moutard1,9,
  15. Ralph Epaud14,
  16. Bénédicte Héron1,9,
  17. Perrine Charles9,15,
  18. Marilyn Tallot1,5,
  19. Agnès Camuzat4,15,
  20. Alexandra Durr4,5,9,15,
  21. Michel Polak16,
  22. David Devos17,
  23. Damien Sanlaville18,19,
  24. Isabelle Vuillaume20,
  25. Thierry Billette de Villemeur1,5,9,
  26. Marie Vidailhet3,4,5,9,
  27. Diane Doummar1,9
  1. 1AP-HP, Service de Neuropédiatrie, Hôpital Trousseau, Paris, France
  2. 2AP-HP, Laboratoire de Biochimie Biologie moléculaire, Hôpital Trousseau, Paris, France
  3. 3AP-HP, Département de Neurologie, Groupe Hospitalier Pitié-Salpêtrière, Paris, France
  4. 4Centre de Recherche de l'Institut du Cerveau et de la Moelle Épinière, UMR-S975, Inserm, U975, CNRS UMR-7225, Paris, France
  5. 5Université Pierre et Marie Curie, Paris, France
  6. 6APHP, Service de Génétique et Embryologie Médicales, Hôpital Trousseau, Inserm U933, UPMC, UMRS933, Paris, France
  7. 7Department of Neurology, Oslo University Hospital, Oslo, Norway
  8. 8Service de Pediatrie, American Memorial Hospital, CHU de Reims, Reims, France
  9. 9Centre de Référence de Neurogénétique, mouvements anormaux, Paris, France
  10. 10Service de Pédiatrie, CH Bretagne Sud, Paris, France
  11. 11Département de Neuropédiatrie, Hôpital Universitaire de Lyon HFME, Lyon, France
  12. 12CHU Bordeaux, Department of Medical Genetics, University Bordeaux Segalen, Laboratoire Maladies Rares: Génétique et Métabolisme (MRGM), Bordeaux Cedex, France
  13. 13Inserm, UMR_938, UPMC, Univ Paris, Paris, France
  14. 14Centre hospitalier intercommunal de Créteil, Service de pédiatrie, Inserm, U955, Université Paris Est, Créteil, France
  15. 15AP-HP, Département de Génétique Hôpital de la Salpêtrière, Paris, France
  16. 16AP-HP Endocrinologie Gynécologie Diabétologie pédiatriques, INSERM U 845, Université Paris Descartes, Paris, France
  17. 17Department of Neurology and Movement Disorders, IMPRT, IFR 114, University of Lille Nord de France, Lille University Hospital, Lille, France
  18. 18Hospices Civils de Lyon, Groupement Hospitalier Est, Service Cytogénétique Constitutionnelle, Bron, France
  19. 19Inserm U1028, CNRS UMR5292, Université Lyon 1, Centre de Recherche en Neurosciences de Lyon, Lyon, France
  20. 20Unité Fonctionnelle de Neurobiologie, Laboratoire de Biochimie et Biologie moléculaire, Hôpital R Salengro, Centre Hospitalier Régional et Universitaire, Lille Cedex, France
  1. Correspondence to D Doummar, Service de Neuropédiatrie, Centre de Référence de Neurogénétique, Hôpital Armand Trousseau, Paris, France; diane.doummar{at}


Background Benign hereditary chorea (BHC) is a rare autosomal dominant disorder characterised by childhood onset that tends to improve in adulthood. The associated gene, NKX2-1 (previously called TITF1), is essential for organogenesis of the basal ganglia, thyroid and lungs. The aim of the study was to refine the movement disorders phenotype. We also studied disease course and response to therapy in a large series of genetically proven patients.

Methods We analysed clinical, genetic findings and follow-up data in 28 NKX2-1 mutated BHC patients from 13 families.

Results All patients had private mutations, including seven new mutations, three previously reported mutations and three sporadic deletions encompassing the NKX2-1 gene. Hypotonia and chorea were present in early infancy, with delayed walking ability (25/28); dystonia, myoclonus and tics were often associated. Attention deficit hyperactivity disorder (ADHD) was present in seven. Among the 14 patients followed-up until adulthood, nine had persistent mild chorea, two had near total resolution of chorea but persistent disabling prominent myoclonus and three recovered completely. Learning difficulties were observed in 20/28 patients, and three had mental retardation. Various combinations of BHC, thyroid (67%) and lung (46%) features were noted. We found no genotype–phenotype correlation. A rapid and sustained beneficial effect on chorea was obtained in 5/8 patients treated with tetrabenazine.

Conclusion Early onset chorea preceded by hypotonia is suggestive of BHC. Associated thyroid or respiratory disorders further support the diagnosis and call for genetic studies. Tetrabenazine may be an interesting option to treat disabling chorea.

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  • Linked article 302834.

  • MV and DD contributed equally to this work.

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval This was a retrospective study in which the data were collected during usual clinical care of the patients.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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