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

Abstract

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.

mTOR Signaling in Epilepsy: Insights from Malformations of Cortical Development

“…2) (Puffenberger et al 2007). PS is characterized by severe intellectual disability, intractable epilepsy, dysmorphic facial features, and megalencephaly with 100% penetrance.…”

“…PS is characterized by severe intellectual disability, intractable epilepsy, dysmorphic facial features, and megalencephaly with 100% penetrance. In the initial report, 38% of children with PS died by age 8 (Puffenberger et al 2007), typically from renal failure or status epilepticus. PS results from a homozygous deletion of exons 9-13 in the STRADa (STRADA) gene identified as a founder mutation in all affected children.…”

“…For example germline mutations in PI3K3R2, PI3KCA, and AKT have been reported in megalencephaly-capillary malformation (MCAP) and megalencephaly-polymicrogyria-polydactyly-hydrocephalus (MPPH) syndromes (Riviere et al 2012; see Mirzaa and Dobyns 2013). As discussed above, STRADA mutations cause megalencephaly in PMSE via activation of mTOR (Puffenberger et al 2007). Recently, megalencephaly and intellectual disability (ME/ intellectual disability [ID]) was reported in a consanguinous family with a TBC1D7 mutation (Capo-Chici et al 2013).…”

C. elegans STRADα and SAD cooperatively regulate neuronal polarity and synaptic organization

“…early embryogenesis versus neural differentiation). Interestingly, human genetic studies have noted that unlike LKB1, mutations in STRAD are not associated with the cancer-developing PeutzJeghers syndrome (Alhopuro et al, 2005;de Leng et al, 2005); instead, a deletion in STRAD leads to distinct clinical features including abnormal brain and craniofacial development (Puffenberger et al, 2007). This might also provide an alternative explanation for the observation in dissociated mouse cortical neurons where the supernumerary axon phenotype induced by LKB1/STRAD co-expression was only partially blocked by siRNA-mediated knock-down of SAD-A and SAD-B (Barnes and Polleux, 2009).…”

Caveat mTOR: aberrant signaling disrupts corticogenesis

“…Imbalance between excitatory and inhibitory systems in the cortex can lead to spontaneous electrical discharge with catastrophic consequences, often in the form of intractable or medication-resistant epilepsy and severe intellectual disability (1). Polyhydramnios, megalencephaly, and symptomatic epilepsy syndrome (PMSE), recently described in an Old Order Mennonite population, is associated with craniofacial dysmorphism (large forehead, widely spaced eyes, and large mouth), an abnormally large brain, and severe, earlyonset intractable epilepsy (2). PMSE in this kindred is caused by homozygous deletion of a portion of the STE20-related kinase adaptor a gene (STRADA; encoding STRADa) on human chromosome 17 (2).…”