Abstracts

Rationale: Recent progress in genetic analysis reveals that a significant part of cryptogenic epileptic encephalopathies is indeed single-gene disorders. We previously reported that in-frame SPTAN1 mutations could cause early-onset West syndrome with severe hypomyelination and developmental delay as a new clinical condition. The phenotypes of patients with SPTAN1 mutations are still under-recognized because the number of patients is small despite the extensive genetic testing for epileptic encephalopathies. SPTAN1 is located at 9q34.11, consists of 53 exons and encodes α-ΙΙ spectrin, The aims of this study are to delineate the electroclinical and neuroradiological features of patients with SPTAN1 mutations and to evaluate phenotype-genotype correlation of patients with SPTAN1 mutations. Methods: Seven patients with epilepsy and SPTAN1 mutation were ascertained. Clinical histories, neurological examinations, and neurophysiological and neuroradiological data were obtained. Phenotype-genotype correlation was evaluated in these seven patients. Results: Six out of seven patients presented intractable infantile spasms with hypsarrhythmia, no visual attention, acquired microcephaly, spastic quadriplegia and severe intellectual disability (ID). In all six patients, brainstem and cerebellar atrophy, cerebral hypomyelination and diffusely reduced white matter were observed on magnetic resonance imaging (MRI). Among them, coloboma-like optic discs and atrial septal defect were observed in one patient, respectively. Two patients had de novo in-frame 3-bp deletion (c.6619_6621del; p.E2207del), another three had de novo in-frame 9-bp duplication (c.6908_6916dup; p.D2303_L2305dup), and other one had de novo in-frame 6 bp duplication (c.6923_6928dup; p.R2308_M2309dup) within the last spectrin repeat. One patient presented generalized epilepsy and pontocerebellar atrophy, but without infantile spasms. In this patient, de novo in-frame 3-bp deletion (c.6605_6607del; p.Q2202del) was identified. All the in-frame SPTAN1 mutations are located at the last two spectrin repeats in C-terminal region. Two patients with duplication mutation in last spectrin showed much more severe phenotypes than those of the patients with p.E2207del mutation, and the mutation in a patient with milder phenotype is located most closely to the N-terminal region. Conclusions: All identified SPTAN1 mutations were in-frame mutation. SPTAN1 encephalopathy reveals distinct phenotypes characterized by intractable infantile spasms with hypsarrhythmia, no visual attention, acquired microcephaly, spastic quadriplegia and severe ID. Brainstem and cerebellar atrophy and cerebral hypomyelination on MRI are specific hallmarks of this disorder. A milder variant is also characterized by generalized epilepsy with pontocerebellar atrophy on MRI. These phenotypes are caused by in-frame SPTAN1 mutations at the last two spectrin repeats in C-terminal region by a dominant negative manner. It is important to recognize this syndrome to make the proper diagnostic work-up for epileptic encephalopathy.