Brain Advance Access originally published online on May 23, 2007
Brain 2007 130(7):1929-1941; doi:10.1093/brain/awm100
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Polyhydramnios, megalencephaly and symptomatic epilepsy caused by a homozygous 7-kilobase deletion in LYK5
1Clinic for Special Children, Strasburg, PA, USA, 2Neurogenomics Division, Translational Genomics Research Institute, Phoenix, AZ, USA, 3Pediatric Neurology, Lancaster General Hospital, Lancaster, PA, USA, 4Department of Pathology, London Health Sciences Centre, London, Ontario, Canada, 5Medical Genetics Program, London Health Sciences Centre, London, Ontario, Canada, 6Department of Neurosurgery, University of Pennsylvania, Philadelphia, PA, USA and 7Department of Neurology, University of Pennsylvania, Philadelphia, PA, USA
Correspondence to: Kevin A. Strauss, MD, Clinic for Special Children, 535 Bunker Hill Road, Strasburg, PA 17579, USA E-mail: kstrauss{at}clinicforspecialchildren.org
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.
Key Words: symptomatic epilepsy; mammalian target of rapamycin; Mennonite; single nucleotide polymorphism; syndromic developmental delay; tuberous sclerosis complex
Abbreviations: GFAP, glial acidic fibrillary protein; LFB-CV, luxol fast blue-cresyl violet; mTOR, mammalian target of rapamycin; P-S6, phospho-ribosomal S6 protein; SNP, single nucleotide polymorphism; STK11, serine/threonine kinase 11 (a.k.a. LKB1); STRAD, STE20-related adaptor protein; TSC, tuberous sclerosis complex
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Received September 18, 2006. Revised January 28, 2007. Accepted April 4, 2007.
*These authors contributed equally to this work.