Loss-of-function mutation in inositol monophosphatase 1

• Published in: Orphanet journal of rare diseases Vol. 14; no. 1
• Main Authors: Walker, Christopher P, Pessoa, Andre L. S, Figueiredo, Thalita, Rafferty, Megan, Melo, Uirá S, Nóbrega, Paulo R, Murphy, Nicholas, Kok, Fernando, Zatz, Mayana, Santos, Silvana, Cho, Raymond Y
• Format: Journal Article
• Language: English
• Published: BioMed Central Ltd 07-01-2019
• Subjects: Analysis; Brain; Electroencephalography; Gene mutation; Inositol; Inositol phosphates; Nervous system diseases; Neurophysiology; Ontogeny
• ISSN: 1750-1172; 1750-1172
• DOI: 10.1186/s13023-018-0977-1

Dysregulation 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. We 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. These 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.