KCNA1 – KCNA1-related developmental and epileptic encephalopathy

The voltage-gated potassium channel gene KCNA1 encodes the Kv1.1 subunit critical for neuronal excitability. Heterozygous and homozygous variants in developmental and epileptic encephalopathy are characterized by early-onset, pharmacoresistant seizures and developmental delay.

Multiple heterozygous de novo variants affecting the pore domain (p.Pro403Ser, p.Pro405Leu, p.Pro405Ser) were identified in four unrelated patients presenting with severe developmental and epileptic encephalopathy (4 probands) (PMID:34778950). An additional de novo pore variant, p.Pro403Ala, was found in a girl with early-onset epilepsy, ataxia and developmental delay (1 proband) (PMID:35897654). A distinct case of neonatal epileptic encephalopathy and dyskinesia was linked to a homozygous pore variant p.Val368Leu (c.1102G>T) in a single patient, demonstrating recessive inheritance (1 proband) (PMID:31586945).

These six unrelated probands harbour loss-of-function (LoF) pore variants in KCNA1, underscoring a spectrum of DEE. All LoF alleles either fully suppressed or markedly reduced Kv1.1-mediated currents in vitro, indicating haploinsufficiency or complete channel loss when homozygous.

Patch-clamp analyses in heterologous systems confirmed that DEE-associated pore variants shifted voltage dependence and slowed activation kinetics of Kv1.1 channels, consistent with a loss-of-function mechanism (PMID:34778950; PMID:35897654; PMID:31586945). Functional concordance across three independent studies supports the pathogenicity of these variants and suggests potential benefit from sodium channel–blocking therapies.

No conflicting or refuting evidence has been reported for KCNA1-associated DEE. The aggregate genetic and experimental data fulfill ClinGen criteria for a Strong gene–disease association.

In summary, KCNA1 loss-of-function variants cause a severe developmental and epileptic encephalopathy spectrum, guiding diagnostic sequencing panels and informing precision treatment strategies targeting Kv1.1 channel dysfunction.

References

• Epilepsia • 2022 • Distinct epilepsy phenotypes and response to drugs in KCNA1 gain- and loss-of function variants. PMID:34778950
• International journal of molecular sciences • 2022 • Clinical and Functional Study of a De Novo Variant in the PVP Motif of Kv1.1 Channel Associated with Epilepsy, Developmental Delay and Ataxia. PMID:35897654
• Journal of medical genetics • 2020 • Complete loss of KCNA1 activity causes neonatal epileptic encephalopathy and dyskinesia. PMID:31586945

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