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Neuropathy target esterase impairments cause Oliver–McFarlane and Laurence–Moon syndromes
  1. Robert B Hufnagel1,
  2. Gavin Arno2,
  3. Nichole D Hein3,
  4. Joshua Hersheson4,
  5. Megana Prasad5,
  6. Yvonne Anderson6,7,
  7. Laura A Krueger1,
  8. Louise C Gregory8,
  9. Corinne Stoetzel5,
  10. Thomas J Jaworek9,
  11. Sarah Hull2,
  12. Abi Li4,
  13. Vincent Plagnol10,
  14. Christi M Willen11,
  15. Thomas M Morgan12,
  16. Cynthia A Prows1,
  17. Rashmi S Hegde13,
  18. Saima Riazuddin9,
  19. Gregory A Grabowski1,
  20. Rudy J Richardson3,14,
  21. Klaus Dieterich15,
  22. Taosheng Huang1,
  23. Tamas Revesz4,
  24. J P Martinez-Barbera8,
  25. Robert A Sisk16,17,
  26. Craig Jefferies18,
  27. Henry Houlden4,
  28. Mehul T Dattani8,
  29. John K Fink3,
  30. Helene Dollfus5,19,
  31. Anthony T Moore2,
  32. Zubair M Ahmed9
  1. 1Division of Human Genetics, Cincinnati Children's Hospital, Cincinnati, Ohio, USA
  2. 2UCL Institute of Ophthalmology and Moorfields Eye Hospital, London, UK
  3. 3Department of Neurology, University of Michigan, Ann Arbor, Michigan, USA
  4. 4Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK
  5. 5Laboratoire de génétique Médicale, Université de Strasbourg, FMTS, Strasbourg, France
  6. 6Department of Paediatrics, Taranaki Base Hospital, New Plymouth, New Zealand
  7. 7Liggins Institute, University of Auckland, Auckland, New Zealand
  8. 8Developmental Endocrinology Research Group, Genetics and Epigenetics in Health and Disease Section, Genetics and Genomic Medicine Programme, University College London Institute of Child Health, London, UK
  9. 9Department of Otorhinolaryngology, University of Maryland, Baltimore, Maryland, USA
  10. 10Department of Statistical Genetics, University College London, London, UK
  11. 11Department of Pediatric Ophthalmology, University of Kentucky, Lexington, Kentucky, USA
  12. 12Department of Pediatrics, Vanderbilt University, Nashville, Tennessee, USA
  13. 13Developmental Biology, Cincinnati Children's Hospital, Cincinnati, Ohio, USA
  14. 14Department of Environmental Health Sciences, University of Michigan, Ann Arbor, Michigan, USA
  15. 15Département de Génétique et Procréation, Hôpital Couple Enfant, CHU Grenoble and Grenoble Institut des Neurosciences, Equipe Muscle et Pathologie, Grenoble, France
  16. 16Division of Pediatric Ophthalmology, Cincinnati Children's Hospital, Cincinnati, Ohio, USA
  17. 17Cincinnati Eye Institute, Cincinnati, Ohio, USA
  18. 18Department of Paediatric Endocrinology, Starship Children's Hospital, Auckland, New Zealand
  19. 19Centre de référence pour les Affections Rares Ophtalmologiques CARGO, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
  1. Correspondence to Dr Robert B Hufnagel, Department of Human Genetics, Cincinnati Children's Hospital, 3333 Burnet Avenue ML 4006, Cincinnati, OH 45229, USA; robert.hufnagel{at} Zubair M Ahmed, BioPark I, 801 West Baltimore St, Room 404, Baltimore, MD, 21201, USA;


Background Oliver–McFarlane syndrome is characterised by trichomegaly, congenital hypopituitarism and retinal degeneration with choroidal atrophy. Laurence–Moon syndrome presents similarly, though with progressive spinocerebellar ataxia and spastic paraplegia and without trichomegaly. Both recessively inherited disorders have no known genetic cause.

Methods Whole-exome sequencing was performed to identify the genetic causes of these disorders. Mutations were functionally validated in zebrafish pnpla6 morphants. Embryonic expression was evaluated via in situ hybridisation in human embryonic sections. Human neurohistopathology was performed to characterise cerebellar degeneration. Enzymatic activities were measured in patient-derived fibroblast cell lines.

Results Eight mutations in six families with Oliver–McFarlane or Laurence–Moon syndrome were identified in the PNPLA6 gene, which encodes neuropathy target esterase (NTE). PNPLA6 expression was found in the developing human eye, pituitary and brain. In zebrafish, the pnpla6 curly-tailed morphant phenotype was fully rescued by wild-type human PNPLA6 mRNA and not by mutation-harbouring mRNAs. NTE enzymatic activity was significantly reduced in fibroblast cells derived from individuals with Oliver–McFarlane syndrome. Intriguingly, adult brain histology from a patient with highly overlapping features of Oliver–McFarlane and Laurence–Moon syndromes revealed extensive cerebellar degeneration and atrophy.

Conclusions Previously, PNPLA6 mutations have been associated with spastic paraplegia type 39, Gordon–Holmes syndrome and Boucher–Neuhäuser syndromes. Discovery of these additional PNPLA6-opathies further elucidates a spectrum of neurodevelopmental and neurodegenerative disorders associated with NTE impairment and suggests a unifying mechanism with diagnostic and prognostic importance.

  • Genetics
  • Ophthalmology
  • Neuro endocrinology
  • Dermatology
  • Developmental

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