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Mutations in the oligophrenin-1 gene (OPHN1) cause X linked congenital cerebellar hypoplasia
  1. N Philip1,
  2. B Chabrol2,
  3. A-M Lossi3,
  4. C Cardoso3,
  5. R Guerrini4,
  6. W B Dobyns5,
  7. C Raybaud6,
  8. L Villard3
  1. 1Department of Medical Genetics, Timone Children's Hospital, Rue St-Pierre, 13385 Marseille, France.
  2. 2Department of Paediatric Neurology, Timone Children's Hospital, Rue St-Pierre, 13385 Marseille, France
  3. 3INSERM U491, Faculty of Medecine La Timone, 27 Bd Jean Moulin, 13385 Marseille, France
  4. 4Division of Child Neuropsychiatry, University of Pisa and Research Institute Stella Maris Foundation, Pisa, Italy
  5. 5Departments of Human Genetics, Neurology, and Pediatrics, The University of Chicago, 928 East 58th Street, Chicago, IL 60657, USA
  6. 6Department of Neuroradiology, Timone Children's Hospital, Rue St-Pierre, 13385 Marseille, France
  1. Correspondence to:
 Dr L Villard, INSERM U491, Faculty of Medecine La Timone, 27 Bd Jean Moulin, 13385 Marseille, France;
 laurent.villard{at}medecine.univ-mrs.fr

https://doi.org/10.1136/jmg.40.6.441

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    A number of apparently non-syndromic X linked mental retardation syndromes are associated with subtle but characteristic phenotypic manifestations. Such manifestations can be dysmorphic features but they potentially also extend to abnormal brain morphology. In this latter field, progress in neuroimaging has aided the approach to brain malformations associated with mental retardation hence allowing a new classification of conditions previously described as non-syndromic. This classification is based on very similar brain malformations in affected subjects. Among the many brain malformations that can be associated with mental retardation in affected children, rhombencephalic anomalies are being recognised with increasing frequency. Accordingly, the classification of malformations of the posterior fossa has evolved considerably during the last decade.1–3

    The cerebellum is known to be involved in movement coordination. However, besides its role in the control and integration of motor activity, the cerebellum also represents an essential node in the neural network subserving higher order behaviour.4,5 An abundant circuitry links the cerebellum with associative and paralimbic areas of the cerebral cortex and cerebellar lesions are known to underlie a cognitive syndrome combining impaired affective regulation, fine motor coordination, language fluency, verbal memory, and the ability to plan.4,5

    These fascinating characteristics have led researchers to search for genetic determinants controlling cerebellar development. One way of addressing the genetics of cerebellar development in humans is to study families in which this brain region is abnormally developed. A number of families with X linked congenital cerebellar hypoplasia (CCH) have been reported,6–8 but no disease causing gene has been identified so far.

    We have studied several families with X linked congenital cerebellar hypoplasia (CCH) and mental retardation and we have found different mutations in the oligophrenin-1 (OPHN1) gene. Carrier females are mildly affected and, accordingly, we found that they have a random …

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