SLC12A5 – Epilepsy of Infancy with Migrating Focal Seizures

Epilepsy of infancy with migrating focal seizures (EIMFS) is a rare, early-onset developmental and epileptic encephalopathy characterized by medically refractory seizures, severe psychomotor delay, and migrating focal discharges. SLC12A5 encodes the neuron-specific K^+–Cl^– cotransporter KCC2, which maintains low intracellular chloride critical for GABAergic inhibition. Impairment of KCC2 function disrupts inhibitory neurotransmission and predisposes to hyperexcitability.

Initial series in 2015 identified recessive loss-of-function SLC12A5 alleles in multiple probands with EIMFS ([PMID:26333769]). Subsequent targeted gene panel and exome studies confirmed biallelic SLC12A5 variants across diverse families. These included nonsense, frameshift, splice, and missense changes, establishing a broad variant spectrum.

In a cohort of 11 sporadic and familial EIMFS cases, compound heterozygous SLC12A5 mutations were discovered in four individuals from two families, with segregation in two affected siblings ([PMID:27436767]). Variants included an exon-skipping indel (p.Glu50_Gln93del) paired with p.Ala191Val, and p.Ser323Pro paired with p.Met415Val. A fourth patient harbored p.Trp318Ser and an in-frame p.Ser748del, illustrating allelic heterogeneity.

Case reports describe a non-consanguineous patient with maternally inherited p.Ser399Leu and de novo p.Arg880Leu compound heterozygosity ([PMID:28477354]), and a homozygous c.692G>A (p.Arg231His) variant in a patient with profound intellectual disability and drug-resistant seizures ([PMID:38660387]).

Functional assays including gramicidin-perforated patch-clamp, ammonium flux measurements, and surface immunolabeling demonstrate that E50_Q93del, p.Arg231His, p.Ala191Val, and other mutants exhibit significantly reduced chloride extrusion and decreased KCC2 membrane expression, consistent with impaired inhibitory neurotransmission ([PMID:27436767]; [PMID:38660387]).

Together, these genetic and experimental data support a recessive loss-of-function mechanism for SLC12A5 in EIMFS and justify inclusion of SLC12A5 in diagnostic gene panels for early-onset epileptic encephalopathies. Key take-home: biallelic KCC2 dysfunction underlies EIMFS and can guide molecular diagnosis and potential therapies.

References

• Nature Communications • 2015 • Mutations in SLC12A5 in epilepsy of infancy with migrating focal seizures. PMID:26333769
• Scientific Reports • 2016 • Impaired neuronal KCC2 function by biallelic SLC12A5 mutations in migrating focal seizures and severe developmental delay. PMID:27436767
• Clinical Genetics • 2017 • A de novo missense mutation in SLC12A5 found in a compound heterozygote patient with epilepsy of infancy with migrating focal seizures. PMID:28477354
• Frontiers in Molecular Neuroscience • 2024 • A novel pathogenic SLC12A5 missense variant in epilepsy of infancy with migrating focal seizures causes impaired KCC2 chloride extrusion. PMID:38660387

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