SPTAN1 – Developmental and Epileptic Encephalopathy

The nonerythrocytic αII-spectrin gene SPTAN1 encodes a cytoskeletal scaffolding protein essential for neuronal structure and function. Pathogenic heterozygous variants in SPTAN1 have been linked to early infantile epileptic encephalopathy type 5 (DEE5), an autosomal dominant disorder characterized by severe developmental delay, refractory seizures, and brain structural abnormalities such as cerebellar atrophy and heterotopias.

Genetic investigations across multiple cohorts have identified 29 unrelated individuals with de novo SPTAN1 variants, including both missense substitutions and protein-truncating alleles, confirming autosomal dominant inheritance (PMID:34590414).

Affected patients present with a broad clinical spectrum ranging from infantile spasms with profound intellectual disability to later-onset generalized seizures with moderate developmental delay. Consistent neuroimaging findings include cerebellar atrophy, subependymal heterotopias, and hypomyelination, underscoring phenotypic concordance in DEE5 (PMID:34590414).

The variant spectrum encompasses missense changes within spectrin repeat domains and truncating variants predicted to result in haploinsufficiency or dominant-negative effects. For example, the recurrent c.3293G>A (p.Arg1098His) variant disrupts spectrin repeat stability and has been observed in multiple unrelated patients with severe encephalopathy.

Functional studies demonstrate that in-frame C-terminal deletions impair αII-spectrin heterodimer assembly and induce abnormal aggregation in neuronal cells, consistent with a dominant-negative mechanism (PMID:22258530). A murine model carrying the orthologous R1098Q mutation recapitulates progressive ataxia, seizure episodes, and cognitive deficits, further validating pathogenicity in vivo (PMID:36831804).

Collectively, de novo heterozygous SPTAN1 variants produce a dominant spectrinopathy manifesting as developmental and epileptic encephalopathy. Inclusion of SPTAN1 in diagnostic gene panels enhances detection of DEE5 and informs prognosis. Key Take-home: Heterozygous de novo SPTAN1 mutations cause autosomal dominant developmental and epileptic encephalopathy with high diagnostic yield.

References

• Unknown Journal | n.d. | Mutations in SPTAN1 gene, encoding the nonerythrocyte αII-spectrin, are responsible for a severe developmental and epileptic encephalopathy and a wide spectrum of neurodevelopmental disorders. PMID:34590414
• European Journal of Human Genetics | 2012 | Identification of a novel in-frame de novo mutation in SPTAN1 in intellectual disability and pontocerebellar atrophy. PMID:22258530
• Brain Sciences | 2023 | Progressive Ataxia, Memory Impairments, and Seizure Episodes in Spna2 R1098Q Mouse Variant Affecting Alpha II Spectrin's Scaffold Stability. PMID:36831804

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