Polyhydramnios, megalencephaly and symptomatic epilepsy caused by a homozygous 7-kilobase deletion in LYK5.
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.
Puffenberger
Erik G
EG
Clinic for Special Children, 535 Bunker Hill Road, Strasburg, PA 17579, USA.
Strauss
Kevin A
KA
Ramsey
Keri E
KE
Craig
David W
DW
Stephan
Dietrich A
DA
Robinson
Donna L
DL
Hendrickson
Christine L
CL
Gottlieb
Steven
S
Ramsay
David A
DA
Siu
Victoria M
VM
Heuer
Gregory G
GG
Crino
Peter B
PB
Morton
D Holmes
DH
D000293:Adolescent; D000328:Adult; D001483:Base Sequence; D001921:Brain / Q000002:abnormalities* / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D002874:Chromosome Mapping / Q000379:methods; D004827:Epilepsy / Q000235:genetics* / Q000473:pathology; D017809:Fatal Outcome; D005260:Female; D017353:Gene Deletion; D005838:Genotype; D006801:Humans; D007223:Infant; D008279:Magnetic Resonance Imaging; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010641:Phenotype; D006831:Polyhydramnios / Q000235:genetics* / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D011247:Pregnancy; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D011596:Psychomotor Disorders / Q000235:genetics / Q000473:pathology; D013577:Syndrome; D000099317:Hippo Kinases
D009419:Nerve Tissue Proteins; D017346:Protein Serine-Threonine Kinases; C109163:STK24 protein, human; D000099317:Hippo Kinases