Response to Steroids in IQSEC2-Related Encephalopathy Presenting with Rett-Like Phenotype and Infantile Spasms

Abstract

Introduction IQSEC2-related encephalopathy is an X-linked childhood neurodevelopmental disorder with intellectual disability, epilepsy, and autism. This disorder is caused by a mutation in the IQSEC2 gene, the product of which plays an important role in the development of the central nervous system.

Case Report We describe the symptomatology, clinical course, and management of a 17-month-old male child with a novel IQSEC2 mutation. He presented with an atypical Rett syndrome phenotype with developmental delay, autistic features, midline stereotypies, microcephaly, hypotonia and epilepsy with multiple seizure types including late-onset infantile spasms. Spasms were followed by worsening of behavior and cognition, and regression of acquired milestones. Treatment with steroids led to control of spasms and improved attention, behavior and recovery of lost motor milestone. In the past 10 months following steroid therapy, child lags in development, remains autistic with no further seizure recurrence.

Conclusion IQSEC2-related encephalopathy may present with Rett atypical phenotypes and childhood spasms. In resource-limited settings, steroids may be considered for spasm remission in IQSEC2-related epileptic encephalopathy.

Keywords

IQSEC2 - steroid - autism - stereotypies - epilepsy - Rett

Note

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published, and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Publication History

Received: 29 August 2020

Accepted: 14 October 2020

Article published online:
07 December 2020

• References

• 1 Morleo M, Iaconis D, Chitayat D. et al. Disruption of the IQSEC2 transcript in a female with X;autosome translocation t(X;20)(p11.2;q11.2) and a phenotype resembling X-linked infantile spasms (ISSX) syndrome. Mol Med Rep 2008; 1 (01) 33-39
• 2 Shoubridge C, Tarpey PS, Abidi F. et al. Mutations in the guanine nucleotide exchange factor gene IQSEC2 cause nonsyndromic intellectual disability. Nat Genet 2010; 42 (06) 486-488
• 3 Radley JA, O'Sullivan RBG, Turton SE. et al. Deciphering Developmental Disorders (DDD) Study. Deep phenotyping of 14 new patients with IQSEC2 variants, including monozygotic twins of discordant phenotype. Clin Genet 2019; 95 (04) 496-506
• 4 Barrie ES, Cottrell CE, Gastier-Foster J. et al. Genotype-phenotype correlation: Inheritance and variant-type infer pathogenicity in IQSEC2 gene. Eur J Med Genet 2020; 63 (03) 103735
• 5 Mignot C, McMahon AC, Bar C. et al. IQSEC2-related encephalopathy in males and females: a comparative study including 37 novel patients. Genet Med 2019; 21 (04) 837-849
• 6 Balciuniene J, DeChene ET, Akgumus G. et al. Use of a dynamic genetic testing approach for childhood-onset epilepsy. JAMA Netw Open 2019; 2 (04) e192129
• 7 Tran Mau-Them F, Willems M, Albrecht B. et al. Expanding the phenotype of IQSEC2 mutations: truncating mutations in severe intellectual disability. Eur J Hum Genet 2014; 22 (02) 289-292
• 8 Brown JC, Petersen A, Zhong L. et al. Bidirectional regulation of synaptic transmission by BRAG1/IQSEC2 and its requirement in long-term depression. Nat Commun 2016; 7: 11080
• 9 Heyne HO, Singh T, Stamberger H. et al. EuroEPINOMICS RES Consortium. De novo variants in neurodevelopmental disorders with epilepsy. Nat Genet 2018; 50 (07) 1048-1053
• 10 Choi MH, Yang JO, Min JS. et al. A novel X-linked variant of IQSEC2 is associated with Lennox-Gastaut syndrome and mild intellectual disability in three generations of a Korean family. Genet Test Mol Biomarkers 2020; 24 (01) 54-58
• 11 Zerem A, Haginoya K, Lev D. et al. The molecular and phenotypic spectrum of IQSEC2-related epilepsy. Epilepsia 2016; 57 (11) 1858-1869
• 12 Wang J, Zhang Q, Chen Y, Yu S, Wu X, Bao X. Rett and Rett-like syndrome: Expanding the genetic spectrum to KIF1A and GRIN1 gene. Mol Genet Genomic Med 2019; 7 (11) e968
• 13 Olson HE, Tambunan D, LaCoursiere C. et al. Mutations in epilepsy and intellectual disability genes in patients with features of Rett syndrome. Am J Med Genet A 2015; 167A [phone]
• 14 Shoubridge C, Harvey RJ, Dudding-Byth T. IQSEC2 mutation update and review of the female-specific phenotype spectrum including intellectual disability and epilepsy. Hum Mutat 2019; 40 (01) 5-24
• 15 Lux AL, Edwards SW, Hancock E. et al. United Kingdom Infantile Spasms Study. The United Kingdom Infantile Spasms Study (UKISS) comparing hormone treatment with vigabatrin on developmental and epilepsy outcomes to age 14 months: a multicentre randomised trial. Lancet Neurol 2005; 4 (11) 712-717
• 16 Mytinger JR, Quigg M, Taft WC, Buck ML, Rust RS. Outcomes in treatment of infantile spasms with pulse methylprednisolone. J Child Neurol 2010; 25 (08) 948-953
• 17 Yeh HR, Kim MJ, Ko TS, Yum MS, You SJ. Short-term outcome of intravenous methylprednisolone pulse therapy in patients with infantile spasms. Pediatr Neurol 2017; 71: 50-55