SLC1A1 – Hot water reflex epilepsy

Hot water reflex epilepsy is a form of sensory-triggered epilepsy characterized by seizures upon contact with hot water. Although familial clustering suggests a genetic basis, the molecular etiology remained largely undefined.

Genome-wide linkage in a three-generation family with three affected relatives (PMID:28324217) identified a heterozygous missense SLC1A1 variant, c.520G>A (p.Asp174Asn), which co-segregated with disease.

Subsequent screening of 98 unrelated probands (PMID:28324217) uncovered three rare SLC1A1 missense variants—c.520G>A (p.Asp174Asn), c.751G>A (p.Val251Ile) and c.912A>G (p.Ile304Met)—absent from population databases, supporting allelic heterogeneity.

SLC1A1 encodes the neuronal glutamate transporter EAAC1, which clears extracellular glutamate to prevent excitotoxicity. Loss-of-function of EAAC1 in animal models leads to age-dependent neurodegeneration.

Functional assays in mammalian cells demonstrated that all three variants exhibited reduced glutamate uptake, altered substrate affinity and impaired anion conductance, consistent with a hypomorphic mechanism (PMID:28324217).

Integration of segregation in a multiplex family, replication in multiple probands and concordant functional data supports a moderate clinical validity for SLC1A1 in hot water reflex epilepsy. This association informs genetic testing panels and suggests glutamate transport dysfunction as a therapeutic target.

Key Take-home: Rare heterozygous SLC1A1 missense variants cause hot water reflex epilepsy via partial loss of EAAC1 function.

References

• Human Genetics • 2017 • Rare SLC1A1 variants in hot water epilepsy PMID:28324217

Evidence Based Scoring (AI generated)