STRADA – Polyhydramnios, Megalencephaly, and Symptomatic Epilepsy

STRADA (HGNC:30172) encodes a STE20‐related adaptor pseudokinase that regulates the LKB1–mTOR signaling axis. Biallelic loss‐of‐function variants in STRADA cause a rare autosomal recessive neurodevelopmental disorder known as PMSE syndrome (polyhydramnios, megalencephaly, and symptomatic epilepsy, MONDO:0012611). Affected fetuses display prenatal polyhydramnios, and postnatal features include megalencephaly, infantile‐onset drug‐resistant epilepsy, and profound psychomotor delay. Disease onset is typically in utero or early infancy, and without targeted therapy there is high risk of severe comorbidities and early mortality.

Initial evidence arose from a consanguineous Old Order Mennonite kindred in which seven children from a single extended family harbored a homozygous 7-kb deletion spanning exons 9–13 of STRADA, all presenting with PMSE features (7 probands [PMID:17522105]). Parental carriers were hemizygous and asymptomatic, consistent with autosomal recessive inheritance. In 2023, two additional unrelated patients were reported: one bearing a homozygous truncating allele and one a missense variant p.Ser264Arg, both conforming to the PMSE phenotype ([PMID:37722301]).

The variant spectrum is dominated by loss-of-function alleles, including splice‐site, frameshift, nonsense, and multi‐exon deletions. A representative recurrent variant is c.207C>G (p.Tyr69Ter), which abolishes STRADA protein expression. The founder 7-kb deletion in the Mennonite population represents a population‐specific allele with complete penetrance. No dominantly acting variants have been reported, and all pathogenic changes follow an autosomal recessive model.

Functional studies corroborate pathogenicity: postmortem brain tissue from affected Mennonite cases showed constitutive mTOR activation via phosphorylated S6 immunoreactivity ([PMID:17522105]). In yeast, modeling the human p.Ser264Arg change in the SPS1 homolog impaired kinase activation function, confirming missense deleteriousness ([PMID:37722301]). These data demonstrate concordant mechanistic evidence linking STRADA dysfunction to mTOR pathway dysregulation.

Therapeutically, mTOR inhibitors such as sirolimus have been used off‐label in PMSE patients, yielding seizure reduction and improved developmental trajectories in early treatment. This genotype‐directed intervention underscores the value of prompt molecular diagnosis. Overall, the genetic and experimental data establish a Strong clinical validity for STRADA in PMSE syndrome.

Key Take‐home

STRADA genetic testing confirms autosomal recessive PMSE syndrome, guides mTOR inhibitor therapy, and informs prognosis.

References

• Pediatric neurology • 2023 • Electroclinical Features in Two Novel STRADA Patients and a Functional Yeast Assay for the Validation of Missense STRADA Mutations. PMID:37722301
• Brain : a journal of neurology • 2007 • Polyhydramnios, megalencephaly and symptomatic epilepsy caused by a homozygous 7-kilobase deletion in LYK5. PMID:17522105

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