A de novo 9q33.3-q34.11 microdeletion involving STXBP1 has been found in one of 
four individuals (group A) with early-onset West syndrome, severe 
hypomyelination, poor visual attention, and developmental delay. Although 
haploinsufficiency of STXBP1 was involved in early infantile epileptic 
encephalopathy in a previous different cohort study (group B), no mutations of 
STXBP1 were found in two of the remaining three subjects of group A (one was 
unavailable). We assumed that another gene within the deletion might contribute 
to the phenotype of group A. SPTAN1 encoding alpha-II spectrin, which is 
essential for proper myelination in zebrafish, turned out to be deleted. In two 
subjects, an in-frame 3 bp deletion and a 6 bp duplication in SPTAN1 were found 
at the initial nucleation site of the alpha/beta spectrin heterodimer. SPTAN1 
was further screened in six unrelated individuals with WS and hypomyelination, 
but no mutations were found. Recombinant mutant (mut) and wild-type (WT) 
alpha-II spectrin could assemble heterodimers with beta-II spectrin, but 
alpha-II (mut)/beta-II spectrin heterodimers were thermolabile compared with the 
alpha-II (WT)/beta-II heterodimers. Transient expression in mouse cortical 
neurons revealed aggregation of alpha-II (mut)/beta-II and alpha-II 
(mut)/beta-III spectrin heterodimers, which was also observed in lymphoblastoid 
cells from two subjects with in-frame mutations. Clustering of ankyrinG and 
voltage-gated sodium channels at axon initial segment (AIS) was disturbed in 
relation to the aggregates, together with an elevated action potential 
threshold. These findings suggest that pathological aggregation of alpha/beta 
spectrin heterodimers and abnormal AIS integrity resulting from SPTAN1 mutations 
were involved in pathogenesis of infantile epilepsy.