Graduate School of Biomedical Sciences, University of Texas Health Science Center at Houston, Houston, TX, USA.
Hospital Infantil Albert Sabin, Fortaleza, Brazil.
Orphanet J Rare Dis. 2019 Jan 7;14(1):3. 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.
肌醇循环失调与多种人类疾病有关，包括发育缺陷和神经疾病。最近，在巴西东北部一个地理上孤立的近亲家庭中，一种编码肌醇单磷酸酶 1（IMPase）的酶的 IMPA1 基因的纯合移码突变与严重的智力障碍（ID）有关（Figueredo 等人，2016 年）。然而，介导 IMPA1 突变和相关 ID 表型的神经生理机制尚未得到表征。为此，从 Figueredo 等人的家系中采集了静息 EEG（睁眼和闭眼）。使用广义估计方程的多变量基于家庭的关联测试，对定量 EEG 测量值（包括平均功率、优势频率和优势频率变异性）进行了等位基因关联研究。
我们发现，IMPAl 突变与额叶 theta 频段功率相对降低以及睁眼状态下 alpha 频段变异性改变有关，但无区域特异性。对于闭眼状态，中央和顶叶区域的主导 theta 频率变异性发生改变。
这些发现代表了首例与 IMPA1 功能丧失突变相关的脑功能障碍的人类体内表型评估，因此是理解影响该关键代谢途径的突变与智力障碍相关的病理生理机制的重要第一步。
