SPTAN1 encephalopathy: distinct phenotypes and genotypes

Abstract

Recent progress in genetic analysis reveals that a significant proportion of cryptogenic epileptic encephalopathies are single-gene disorders. Mutations in numerous genes for early-onset epileptic encephalopathies have been rapidly identified, including in SPTAN1, which encodes α-II spectrin. The aim of this review is to delineate SPTAN1 encephalopathy as a distinct clinical syndrome. To date, a total of seven epileptic patients with four different in-frame SPTAN1 mutations have been identified. The major clinical features of SPTAN1 mutations include epileptic encephalopathy with hypsarrhythmia, no visual attention, acquired microcephaly, spastic quadriplegia and severe intellectual disability. Brainstem and cerebellar atrophy and cerebral hypomyelination, as observed by magnetic resonance imaging, are specific hallmarks of this condition. A milder variant is characterized by generalized epilepsy with pontocerebellar atrophy. Only in-frame SPTAN1 mutations in the last two spectrin repeats in the C-terminal region lead to dominant negative effects and these specific phenotypes. The last two spectrin repeats are required for α/β spectrin heterodimer associations and the mutations can alter heterodimer formation between the two spectrins. From these data we suggest that SPTAN1 encephalopathy is a distinct clinical syndrome owing to specific SPTAN1 mutations. It is important that this syndrome is recognized by pediatric neurologists to enable proper diagnostic work-up for patients.

Critical roles of αII spectrin in brain development and epileptic encephalopathy

“…A potential epilepsy mechanism is disinhibition of cortical pyramidal neurons merization ( Figure 6A) (4). In vitro data suggest that these mutations impair α/β spectrin complex formation (4).…”

“…The most recent genetic study identified 20 patients with pathogenic or likely pathogenic SPTAN1 variants that exhibited a broad spectrum of neurodevelopmental phenotypes, comprising 6 patients with mild to moderate intellectual disability, with or without epilepsy and behavioral disorders, and 14 patients with EIEE, of whom 13 had severe neurodevelopmental impairment and 4 died in early childhood (5). The majority of pathological mutations discovered reside in the last 2 spectrin repeats in the C-terminal region critical for the formation of α/β spectrin heterotetramers, and some lead to aggregation of spectrin complexes in vitro (3,4). Although these observations suggest dominant-negative effects, little is known about the role of αII spectrin in brain development and the pathogenesis of EIEE5-producing SPTAN1 mutations.…”

“…(Glu2207del) and c.6923_6928dup/p. (Arg2308_Met2309dup)] exhibiting a distinctive form of early-onset West syndrome with infantile spasms, severe developmental delay, spastic quadriplegia, poor visual attention, and distinctive MRI features that was termed EIEE5 (MIM 613477) (3,4). The most recent genetic study identified 20 patients with pathogenic or likely pathogenic SPTAN1 variants that exhibited a broad spectrum of neurodevelopmental phenotypes, comprising 6 patients with mild to moderate intellectual disability, with or without epilepsy and behavioral disorders, and 14 patients with EIEE, of whom 13 had severe neurodevelopmental impairment and 4 died in early childhood (5).…”

αII Spectrin Forms a Periodic Cytoskeleton at the Axon Initial Segment and Is Required for Nervous System Function

“…Human mutations in ␣II spectrin cause West syndrome, a severe infantile epilepsy that includes seizures, hypomyelination, and brain atrophy (Saitsu et al, 2010;Writzl et al, 2012;Tohyama et al, 2015). Mice and zebrafish lacking ␣II spectrin are embryonic and larval lethal due to cardiac and nervous system malformations (Voas et al, 2007;Stankewich et al, 2011).…”

9q33.3q34.11 microdeletion: new contiguous gene syndrome encompassing STXBP1, LMX1B and ENG genes assessed using reverse phenotyping

“…4,13 One recent article argues in favor of a dominant-negative effect in at least a subset of SPTAN1 mutations. 14 Reverse phenotyping, consisting in refining the clinical phenotype according to genetic data, allowed us to explain the recurrent malformations in our patients. In this series, we highlighted features of NPS and HHT1 disease after analyzing the gene content of the deletions.…”