Journal Article

Polyhydramnios, megalencephaly and symptomatic epilepsy caused by a homozygous 7-kilobase deletion in <i>LYK5</i>

Erik G. Puffenberger, Kevin A. Strauss, Keri E. Ramsey, David W. Craig, Dietrich A. Stephan, Donna L. Robinson, Christine L. Hendrickson, Steven Gottlieb, David A. Ramsay, Victoria M. Siu, Gregory G. Heuer, Peter B. Crino and D. Holmes Morton

in Brain

Published on behalf of The Guarantors of Brain

Volume 130, issue 7, pages 1929-1941
Published in print July 2007 | ISSN: 0006-8950
Published online May 2007 | e-ISSN: 1460-2156 | DOI: http://dx.doi.org/10.1093/brain/awm100
Polyhydramnios, megalencephaly and symptomatic epilepsy caused by a homozygous 7-kilobase deletion in LYK5

Show Summary Details

Preview

We used single nucleotide polymorphism (SNP) microarrays to investigate the cause of a symptomatic epilepsy syndrome in a group of seven distantly related Old Order Mennonite children. Autozygosity mapping was inconclusive, but closer inspection of the data followed by formal SNP copy number analyses showed that all affected patients had homozygous deletions of a single SNP (rs721575) and their parents were hemizygous for this marker. The deleted SNP marked a larger deletion encompassing exons 9–13 of LYK5, which encodes STE20-related adaptor protein, a pseudokinase necessary for proper localization and function of serine/threonine kinase 11 (a.k.a. LKB1). Homozygous LYK5 deletions were associated with polyhydramnios, preterm labour and distinctive craniofacial features. Affected children had large heads, infantile-onset intractable multifocal seizures and severe psychomotor retardation. We designated this condition PMSE syndrome (polyhydramnios, megalencephaly and symptomatic epilepsy). Thirty-eight percent (N = 16) of affected children died during childhood (ages 7 months to 6 years) from medical complications of the disorder, which included status epilepticus, congestive heart failure due to atrial septal defect and hypernatremic dehydration due to diabetes insipidus. A single post-mortem neuropathological study revealed megalencephaly, ventriculomegaly, cytomegaly and extensive vacuolization and astrocytosis of white matter. There was abundant anti-phospho-ribosomal S6 labelling of large cells within the frontal cortex, basal ganglia, hippocampus and spinal cord, consistent with constitutive activation of the mammalian target of rapamycin (mTOR) signalling pathway in brain.

Keywords: symptomatic epilepsy; mammalian target of rapamycin; Mennonite; single nucleotide polymorphism; syndromic developmental delay; tuberous sclerosis complex

Journal Article.  6259 words.  Illustrated.

Subjects: Neurology ; Neuroscience

Full text: subscription required

How to subscribe Recommend to my Librarian

Users without a subscription are not able to see the full content. Please, subscribe or login to access all content.