SPTAN1 – West syndrome

Spectrin alpha-II (SPTAN1) encodes a cytoskeletal scaffolding protein critical for neuronal membrane stability and axon initial segment architecture. Heterozygous de novo variants in SPTAN1 have been identified in patients with West syndrome (West syndrome), an early infantile epileptic encephalopathy characterized by infantile spasms and hypsarrhythmia.

Five unrelated probands harbored distinct de novo heterozygous mutations: c.21A>T (p.Lys7Asn) in a 1-year-old with hypsarrhythmia and hypomyelination (PMID:22656320); an in-frame 3 bp deletion and a 6 bp duplication affecting the spectrin repeat nucleation site (PMID:20493457); and two C-terminal in-frame variants c.6605_6607del (p.Gln2202del) and c.6917GCATGC[3] (p.Arg2308_Met2309dup) in independent cohorts (PMID:22258530). The inheritance is autosomal dominant with all variants confirmed de novo.

No additional affected relatives have been reported beyond the probands, consistent with de novo occurrence in all cases and fulfilling strong genetic evidence for causality. Functional assays demonstrate that mutant alpha-II/β-spectrin heterodimers are thermolabile and prone to aggregation, disrupting ankyrin-G clustering at the axon initial segment and elevating neuronal excitation thresholds (PMID:20493457). Neuronal cell models recapitulate spectrin aggregation and impaired axon initial segment integrity, supporting a dominant-negative mechanism (PMID:22258530). Zebrafish knockdown studies confirm SPTAN1’s indispensable role in CNS myelination, mirroring patient hypomyelination.

The concordance of multiple de novo heterozygous variants in unrelated patients, combined with mechanistic in vitro and in vivo data, establishes a strong gene-disease relationship. SPTAN1 should be included in diagnostic gene panels for West syndrome, enabling precise molecular diagnosis and informed clinical management.

References

• Brain & development • 2013 • Progressive diffuse brain atrophy in West syndrome with marked hypomyelination due to SPTAN1 gene mutation. PMID:22656320
• American journal of human genetics • 2010 • Dominant-negative mutations in alpha-II spectrin cause West syndrome with severe cerebral hypomyelination, spastic quadriplegia, and developmental delay. PMID:20493457
• European journal of human genetics : EJHG • 2012 • Identification of a novel in-frame de novo mutation in SPTAN1 in intellectual disability and pontocerebellar atrophy. PMID:22258530

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