Polyhydramnios, Megalencephaly, And Symptomatic Epilepsy

A number sign (#) is used with this entry because of evidence that polyhydramnios, megalencephaly, and symptomatic epilepsy (PMSE) is caused by homozygous mutation in the STRADA gene (608626) on chromosome 17q23.

Clinical Features

Puffenberger et al. (2007) studied 16 distantly related Old Order Mennonite children with a syndrome they designated PMSE for 'polyhydramnios, megalencephaly, and symptomatic epilepsy.' All affected pregnancies were complicated by polyhydramnios. Spontaneous onset of labor occurred between 25 and 36 weeks' gestation in 12 pregnancies. All but 1 affected child had macrocephaly. Seizures started between 3 and 7 months of age in all patients. These were most commonly complex partial seizures that would occasionally spread to involve 1 or both cerebral hemispheres. All patients had severe psychomotor retardation. Four of the 16 patients had atrial septal defects and 1 developed congestive heart failure at 3 months of age. Diabetes insipidus was present in 2 patients who were formally tested, and 2 additional patients had a clinical history suggestive of an osmoregulatory defect. Two patients had bilateral nephrocalcinosis despite essentially normal urinary calcium levels. Six of the 16 children with PMSE syndrome died between ages 7 months and 6 years. Causes of death were status epilepticus in 2, hypovolemic shock secondary to diabetes insipidus, and leukemia.

Bi et al. (2016) reported a 5-year-old boy, born of consanguineous Indian parents, with clinical and genetic features consistent with PMSE. Prenatal ultrasound showed polyhydramnios as early as 12 weeks. He was born at term with feeding difficulties and poor weight gain. At 3 months of age, he developed seizures, which were initially difficult to control. He had global developmental delay, severe psychomotor retardation, severe hypotonia, and marked joint laxity. At age 5, he could cruise with a walker, but remained nonverbal. He had a thin body habitus with decreased muscle mass and minimal subcutaneous fat, tall forehead, narrow face, highly arched eyebrows, wide mouth, tented upper lip, and hypotonic facies with open mouth and drooling. The patient also had nephrocalcinosis with normal renal size and morphology. Head circumference remained at the 75th percentile. Brain imaging showed periventricular white matter signal abnormalities, and EEG showed multifocal epileptiform discharges and generalized background slowing.

Inheritance

The transmission pattern of PMSE in the families reported by Puffenberger et al. (2007) was consistent with autosomal recessive inheritance.

Molecular Genetics

Puffenberger et al. (2007) used single-nucleotide polymorphism (SNP) microarrays to investigate the genetic basis of the disorder in 7 of the 16 children with PMSE available to them for study. 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 through 13 of the LYK5 gene (608626.0001), which encodes STE20-related adaptor protein (STRAD), a pseudokinase necessary for proper localization and function of serine/threonine kinase 11 (LKB1; 602216).

In an Indian boy with PMSE, Bi et al. (2016) identified a homozygous truncating mutation in the STRADA gene (608626.0002). The mutation was found by whole-exome sequencing and segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed.

Pathogenesis

Puffenberger et al. (2007) reported a postmortem neuropathologic study of 1 of the 16 patients, which revealed megalencephaly, ventriculomegaly, cytomegaly, and extensive vacuolization and astrocytosis of white matter. There was abundant antiphosphoribosomal S6 labeling of large cells within the frontal cortex, basal ganglia, hippocampus, and spinal cord, consistent with constitutive activation of the mammalian target of rapomycin (mTOR; 601231) signaling pathway in brain. Puffenberger et al. (2007) postulated that mTOR is constitutively activated as a result of homozygous LYK5 mutations, and that this leads to inappropriate phosphorylation of p70 S6 kinase (see 608938) and phosphorylated S6 protein (180460). Puffenberger et al. (2007) suggested that the cellular mechanisms leading to abnormal brain development from LYK5 deletions may be similar to those of tuberous sclerosis (TSC; see 191100). In both TSC and PMSE syndrome, proliferation of astrocytes may result from constitutive activation of mTOR, either focally, as in TSC, or diffusely, as in PMSE.

Population Genetics

Puffenberger et al. (2007) stated that developmental delay is the presenting problem for 35% of the approximately 125 Amish and Mennonite patients evaluated each year at the Clinic for Special Children in Lancaster County, Pennsylvania. They genotyped 100 healthy Old Order Mennonite controls for the LYK5 deletion and identified four 7-kb deletion carriers, yielding an estimated carrier frequency for the mutant allele in Lancaster County Old Order Mennonites of approximately 4%.