SCAMP5 – Epilepsy

Over the past three years, heterozygous de novo variants in SCAMP5 have emerged as a cause of early-onset epilepsy with severe neurodevelopmental impairment. SCAMP5 encodes a tetraspanin membrane protein involved in synaptic vesicle trafficking at neuronal synapses. Initial multi-patient studies identified four unrelated individuals presenting with focal or generalized seizures, severe intellectual disability, motor regression, absent speech, nonspecific MRI abnormalities and extrapyramidal signs, all harboring the identical SCAMP5 c.538G>T (p.Gly180Trp) variant (PMID:33390987). A subsequent report described two additional unrelated patients with the same de novo variant exhibiting autism spectrum features, intellectual disability and seizures (PMID:31439720).

All six probands presented with seizure onset between 6 and 15 months of age and showed diverse seizure types, including focal-onset, bilateral tonic-clonic and tonic seizures. Electroencephalographic findings ranged from focal or multifocal discharges to secondary generalization. Neuroimaging revealed variable brain anomalies in each patient. Language and motor development were profoundly impaired, with all individuals nonverbal at last follow-up and most exhibiting motor regression. No additional affected relatives were reported, consistent with a fully penetrant autosomal dominant de novo mechanism.

Genetically, the association is supported by six unrelated de novo occurrences of the same missense variant, meeting ClinGen de novo case-level criteria for autosomal dominant disorders. The recurrent c.538G>T (p.Gly180Trp) variant affects a highly conserved glycine residue and accounts for all reported heterozygous pathogenic alleles in SCAMP5 associated with epilepsy and neurodevelopmental delay.

Functional studies in a Drosophila SCAMP orthologue carrying the equivalent p.Gly302Trp mutation demonstrated drastically reduced protein levels and recapitulated neuronal and eye phenotypes akin to SCAMP5 knockdown, consistent with a dominant-negative effect (PMID:31439720). Parallel in vitro assays in tsA-201 cells showed that co-expression of human SCAMP5 p.Gly180Trp fails to suppress T-type calcium channel currents, mirroring loss of channel repression by wild-type SCAMP5 and implicating disrupted vesicular trafficking in pathogenesis (PMID:37389974).

A separate homozygous SCAMP5 p.Arg91Trp variant identified in a consanguineous family causes early-onset epilepsy and juvenile-onset Parkinson disease, suggesting dosage sensitivity of SCAMP5 but a recessive mechanism distinct from the dominant-negative action of p.Gly180Trp (PMID:32020363). These findings do not dispute the dominant-de novo association but highlight allelic heterogeneity and a critical role for SCAMP5 in synaptic function.

In summary, robust clinical and experimental evidence supports a strong gene-disease association between de novo SCAMP5 p.Gly180Trp and autosomal dominant epilepsy with severe neurodevelopmental delay. Functional concordance across models, a recurrent missense change in six independent patients, and lack of segregation in unaffected relatives establish high clinical validity. Key take-home: SCAMP5 c.538G>T (p.Gly180Trp) should be included in diagnostic gene panels for early-onset epilepsy with developmental impairment.

References

• Frontiers in pharmacology • 2020 • Identification of an Identical de Novo SCAMP5 Missense Variant in Four Unrelated Patients With Seizures and Severe Neurodevelopmental Delay. PMID:33390987
• Journal of medical genetics • 2020 • De novo SCAMP5 mutation causes a neurodevelopmental disorder with autistic features and seizures. PMID:31439720
• Human genetics • 2020 • Deficiency of SCAMP5 leads to pediatric epilepsy and dysregulation of neurotransmitter release in the brain. PMID:32020363
• Channels (Austin, Tex.) • 2023 • Secretory carrier-associated membrane protein 5 regulates cell-surface targeting of T-type calcium channels. PMID:37389974

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