Eshaghi Khashayar, Rao Prima H, Shen Megan M, Lynch David R
Perelman School of Medicine, University of Pennsylvania, Philadelphia; and.
Division of Neurology, The Children's Hospital of Philadelphia, PA.
Neurol Genet. 2025 Jan 13;11(1):e200234. doi: 10.1212/NXG.0000000000200234. eCollection 2025 Feb.
Friedreich ataxia (FRDA) is an autosomal recessive disorder caused by gene mutations involving GAA trinucleotide repeat expansions. This study explores phenotypic heterogeneity between siblings, focusing on differences in age at onset (AAO) and shorter GAA repeat (GAA1) length to improve understanding of disease variability.
We analyzed AAO and genotype of siblings with FRDA. Linear regression examined AAO differences and genetic predictors (GAA1 length and S46N single nucleotide polymorphism), while logistic regression assessed discordant clinical manifestations and GAA1 heterogeneity.
This study included 150 siblings with FRDA from 70 families. GAA1 and AAO differences between siblings were not significant, although discordance between siblings in the diagnosis of hypertrophic cardiomyopathy and scoliosis was noted in approximately a quarter of the families. Differences in GAA1 length predicted a modest amount of AAO heterogeneity (R = 0.075). The S46N polymorphism in did not predict the differences in AAO.
Genetic and phenotypic variability between paired siblings with FRDA was moderate to small, with GAA1 differences explaining some of the variance in AAO. Other factors (genetic or environmental) or data collection bias may explain the remaining variance. These findings highlight the complexity of FRDA and reiterate the role of GAA1 length in disease severity.
弗里德赖希共济失调（FRDA）是一种常染色体隐性疾病，由涉及GAA三核苷酸重复序列扩增的基因突变引起。本研究探讨了同胞之间的表型异质性，重点关注发病年龄（AAO）差异和较短的GAA重复序列（GAA1）长度，以增进对疾病变异性的理解。
我们分析了患有FRDA的同胞的AAO和基因型。线性回归分析了AAO差异和遗传预测因素（GAA1长度和S46N单核苷酸多态性），而逻辑回归评估了不一致的临床表现和GAA1异质性。
本研究纳入了来自70个家庭的150名患有FRDA的同胞。同胞之间的GAA1和AAO差异不显著，尽管在大约四分之一的家庭中发现同胞在肥厚型心肌病和脊柱侧弯的诊断上存在不一致。GAA1长度的差异预测了适度的AAO异质性（R = 0.075）。 中的S46N多态性不能预测AAO的差异。
患有FRDA的配对同胞之间的遗传和表型变异性为中度至低度，GAA1差异解释了AAO中的部分变异。其他因素（遗传或环境）或数据收集偏差可能解释了其余的变异。这些发现突出了FRDA的复杂性，并重申了GAA1长度在疾病严重程度中的作用。
