Key result
The recurrent SCN1A p.R1636Q variant causes a distinct early onset epileptic encephalopathy with mixed loss and gain of function that is partially corrected by oxcarbazepine.
Why the study?
Emerging evidence suggests separate entities of SCN1A-related disorders due to gain-of-function variants rather than loss-of-function variants, prompting characterization of the recurrent p.R1636Q gain-of-function variant.
Observational (n=51)
No
The recurrent SCN1A p.R1636Q variant causes a distinct early-onset epileptic encephalopathy with mixed loss and gain of function that may be partially corrected by oxcarbazepine.
Answers are grounded in this paper and cite their sources.
May guide variant-specific care in SCN1A encephalopathy; hypothesis-generating and requires prospective validation before practice change.
OBJECTIVE: Loss-of-function variants in SCN1A cause Dravet syndrome, the most common genetic developmental and epileptic encephalopathy (DEE). However, emerging evidence suggests separate entities of SCN1A-related disorders due to gain-of-function variants. Here, we aim to refine the clinical, genetic, and functional electrophysiological features of a recurrent p.R1636Q gain-of-function variant, identified in four individuals at a single center. METHODS: β2 subunits, including response to oxcarbazepine. To delineate differences from other SCN1A-related epilepsies, we analyzed electronic medical records. RESULTS: All four individuals had an early onset DEE characterized by focal tonic seizures and additional seizure types starting in the first few weeks of life. Electrophysiological analysis showed a mixed gain-of-function effect with normal current density, a leftward (hyperpolarized) shift of steady-state inactivation, and slower inactivation kinetics leading to a prominent late sodium current. The observed functional changes closely paralleled effects of pathogenic variants in SCN3A and SCN8A at corresponding positions. Both wild type and variant exhibited sensitivity to block by oxcarbazepine, partially correcting electrophysiological abnormalities of the SCN1A p.R1636Q variant. Clinically, a single individual responded to treatment with oxcarbazepine. Across 51 individuals with SCN1A-related epilepsies, those with the recurrent p.R1636Q variants had the earliest ages at onset. SIGNIFICANCE: The recurrent SCN1A p.R1636Q variant causes a clinical entity with a wider clinical spectrum than previously reported, characterized by neonatal onset epilepsy and absence of prominent movement disorder. Functional consequences of this variant lead to mixed loss and gain of function that is partially corrected by oxcarbazepine. The recurrent p.R1636Q variant represents one of the most common causes of early onset SCN1A-related epilepsies with separate treatment and prognosis implications.
No takes yet. Share an insight, caveat, or question.
Clatot et al. (2022) conducted an observational in SCN1A-related developmental and epileptic encephalopathy (n=51). SCN1A p.R1636Q variant vs. Other SCN1A-related epilepsies was evaluated on Age at onset and electrophysiological features. The recurrent SCN1A p.R1636Q variant causes a distinct early onset epileptic encephalopathy with mixed loss and gain of function that is partially corrected by oxcarbazepine.
Synapse has enriched 10 related papers. Consider them for comparative context: