Phospholipase C beta 1 deficiency is associated with early-onset epileptic encephalopathy

Manju A. Kurian, Esther Meyer, Grace Vassallo, Neil V. Morgan, Nandhini Prakash, Shanaz Pasha, Nebula A. Hai, Salwati Shuib, Fatima Rahman, Evangeline Wassmer, J. Helen Cross, Finbar J. O'Callaghan, John P. Osborne, Ingrid E. Scheffer, Paul Gissen, Eamonn R. Maher

Research output: Contribution to journalArticle

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Abstract

The epileptic encephalopathies of infancy and childhood are a collection of epilepsy disorders characterized by refractory, severe seizures and poor neurological outcome, in which the mechanism of disease is poorly understood. We report the clinical presentation and evolution of epileptic encephalopathy in a patient, associated with a loss-of-function mutation in the phospholipase C-β 1 gene. We ascertained a consanguineous family containing a male infant who presented with early-onset epileptic encephalopathy for detailed clinical phenotyping and molecular genetic investigation. In addition, a cohort of 12 consanguineous families of children with infantile spasms were analysed for linkage to the phospholipase C-β 1 gene locus. The male infant presented with tonic seizures in early infancy and subsequently developed infantile spasms. Over time, he developed drug-resistant epilepsy associated with severe neurological regression and failure to thrive. Molecular genetic investigation revealed a homozygous loss-of-function 0.5-Mb deletion, encompassing the promoter element and exons 1, 2 and 3 of phospholipase C-β 1 in the index case. Linkage to the phospholipase C-β 1 locus was excluded in the 12 other consanguineous families, consistent with genetic heterogeneity in this disorder. Although phospholipase C-β 1 deficiency has not previously been reported in humans, the Plcb1 homozygote knockout mouse displays early-onset severe tonic seizures and growth retardation, thus recapitulating the human phenotype. Phospholipase C-β 1 has important functions in both hippocampal muscarinic acetylcholine receptor signalling and in cortical development. Thus, the discovery of a phospholipase C-β 1 mutation allows us to propose a novel potential underlying mechanism in early-onset epileptic encephalopathy.

Original languageEnglish
Pages (from-to)2964-2970
Number of pages7
JournalBrain
Volume133
Issue number10
DOIs
Publication statusPublished - 2010
Externally publishedYes

Fingerprint

Phospholipase C beta
Brain Diseases
Type C Phospholipases
Infantile Spasms
Seizures
Molecular Biology
Failure to Thrive
Mutation
Genetic Heterogeneity
Homozygote
Muscarinic Receptors
Knockout Mice
Genes
Exons
Epilepsy
Phenotype

Keywords

  • epileptic encephalopathy
  • hippocampus
  • infantile spasms
  • muscarinic acetylcholine receptor
  • phospholipase C-β 1
  • PLCB1

ASJC Scopus subject areas

  • Clinical Neurology
  • Medicine(all)

Cite this

Kurian, M. A., Meyer, E., Vassallo, G., Morgan, N. V., Prakash, N., Pasha, S., ... Maher, E. R. (2010). Phospholipase C beta 1 deficiency is associated with early-onset epileptic encephalopathy. Brain, 133(10), 2964-2970. https://doi.org/10.1093/brain/awq238

Phospholipase C beta 1 deficiency is associated with early-onset epileptic encephalopathy. / Kurian, Manju A.; Meyer, Esther; Vassallo, Grace; Morgan, Neil V.; Prakash, Nandhini; Pasha, Shanaz; Hai, Nebula A.; Shuib, Salwati; Rahman, Fatima; Wassmer, Evangeline; Cross, J. Helen; O'Callaghan, Finbar J.; Osborne, John P.; Scheffer, Ingrid E.; Gissen, Paul; Maher, Eamonn R.

In: Brain, Vol. 133, No. 10, 2010, p. 2964-2970.

Research output: Contribution to journalArticle

Kurian, MA, Meyer, E, Vassallo, G, Morgan, NV, Prakash, N, Pasha, S, Hai, NA, Shuib, S, Rahman, F, Wassmer, E, Cross, JH, O'Callaghan, FJ, Osborne, JP, Scheffer, IE, Gissen, P & Maher, ER 2010, 'Phospholipase C beta 1 deficiency is associated with early-onset epileptic encephalopathy', Brain, vol. 133, no. 10, pp. 2964-2970. https://doi.org/10.1093/brain/awq238
Kurian MA, Meyer E, Vassallo G, Morgan NV, Prakash N, Pasha S et al. Phospholipase C beta 1 deficiency is associated with early-onset epileptic encephalopathy. Brain. 2010;133(10):2964-2970. https://doi.org/10.1093/brain/awq238
Kurian, Manju A. ; Meyer, Esther ; Vassallo, Grace ; Morgan, Neil V. ; Prakash, Nandhini ; Pasha, Shanaz ; Hai, Nebula A. ; Shuib, Salwati ; Rahman, Fatima ; Wassmer, Evangeline ; Cross, J. Helen ; O'Callaghan, Finbar J. ; Osborne, John P. ; Scheffer, Ingrid E. ; Gissen, Paul ; Maher, Eamonn R. / Phospholipase C beta 1 deficiency is associated with early-onset epileptic encephalopathy. In: Brain. 2010 ; Vol. 133, No. 10. pp. 2964-2970.
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AU - Shuib, Salwati

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AU - Cross, J. Helen

AU - O'Callaghan, Finbar J.

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