Loss-of-function mutation in inositol monophosphatase 1 (IMPA1) results in abnormal synchrony in resting-state EEG

Author(s):Show less -

Walker, Christopher P. ^{[1, 2]} ; Pessoa, Andre L. S. ^[3] ; Figueiredo, Thalita ^[4] ; Rafferty, Megan ^[5] ; Melo, Uira S. ^[4] ; Nobrega, Paulo R. ^[6] ; Murphy, Nicholas ^[5] ; Kok, Fernando ^[4] ; Zatz, Mayana ^[4] ; Santos, Silvana ^[7] ; Cho, Raymond Y. ^[5]

Affiliation

^[1] Hosp Infantil Albert Sabin, Fortaleza, Ceara - Brazil

^[2] Univ Texas Hlth Sci Ctr Houston, Grad Sch Biomed Sci, Houston, TX 77030 - USA

^[3] Univ Estadual Ceara UECE, Fortaleza, Ceara - Brazil

^[4] Univ Sao Paulo, Inst Biociencias, Dept Genet & Evolutionary Biol, Human Genome & Stem Cell Res Ctr, BR-05508090 Sao Paulo, SP - Brazil

^[5] Baylor Coll Med, Dept Psychiat, Houston, TX 77030 - USA

^[6] Univ Fed Ceara, Fortaleza, Ceara - Brazil

^[7] State Univ Paraiba UEPB, Dept Biol, Campina Grande, PB - Brazil

• Document type: Journal article
• Source: ORPHANET JOURNAL OF RARE DISEASES; v. 14, JAN 7 2019.
• Web of Science Citations: 1

Abstract

BackgroundDysregulation of the inositol cycle is implicated in a wide variety of human diseases, including developmental defects and neurological diseases. A homozygous frameshift mutation in IMPA1, coding for the enzyme inositol monophosphatase 1 (IMPase), has recently been associated with severe intellectual disability (ID) in a geographically isolated consanguineous family in Northeastern Brazil (Figueredo et al., 2016). However, the neurophysiologic mechanisms that mediate the IMPA1 mutation and associated ID phenotype have not been characterized. To this end, resting EEG (eyes-open and eyes-closed) was collected from the Figueredo et al. pedigree. Quantitative EEG measures, including mean power, dominant frequency and dominant frequency variability, were investigated for allelic associations using multivariate family-based association test using generalized estimating equations.ResultsWe found that the IMPA1 mutation was associated with relative decreases in frontal theta band power as well as altered alpha-band variability with no regional specificity during the eyes-open condition. For the eyes-closed condition, there was altered dominant theta frequency variability in the central and parietal regions.ConclusionsThese findings represent the first human in vivo phenotypic assessment of brain function disturbances associated with a loss-of-function IMPA1 mutation, and thus an important first step towards an understanding the pathophysiologic mechanisms of intellectual disability associated with the mutation that affects this critical metabolic pathway. (AU)

• FAPESP's process: 16/09618-5 - What is the role of IMPA1 enzyme in Familial Intellectual Disability?
• Grantee: Thalita Cristina Figueiredo Cunha
• Support Opportunities: Scholarships in Brazil - Post-Doctoral