Watanabe Kazuki, Ema Tatsuya, Shimizu Kenji, Yamada Kosuke, Nakashima Mitsuko, Saitsu Hirotomo
Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, Japan.
Department of Neurology, Hamamatsu University School of Medicine, Hamamatsu, Japan.
J Hum Genet. 2025 Aug 22. doi: 10.1038/s10038-025-01392-4.
UBQLN2 is located on Xp11.21 and encodes the ubiquilin 2 protein involved in protein homeostasis. Heterozygous or hemizygous missense variants in UBQLN2 cause amyotrophic lateral sclerosis (ALS). In addition, rare cases of primary lateral sclerosis (PLS) and spastic paraplegia (SPG) associated with UBQLN2 variants have also been reported. Here, we report four male patients in a family with SPG carrying a hemizygous missense UBQLN2 variant (NM_013444.4:c.1442G>T, p.(Gly481Val)). These patients showed childhood-onset lower limb spasticity, progressing to gait disturbance. The mean onset age (11 years) was earlier than that of previous ALS (49.6 years), SPG (29 years) and PLS (25.5 years) cases, and their progression was slower than in ALS or PLS. Literature review reveals Pro506 missense variants are associated with various motor neuron disease phenotypes, with some SPG patients progressing to ALS. Therefore, we consider that careful follow-up is warranted for UBQLN2-related SPG patients.
泛素连接酶2（UBQLN2）位于Xp11.21，编码参与蛋白质稳态的泛素连接酶2蛋白。UBQLN2中的杂合或半合子错义变异可导致肌萎缩侧索硬化症（ALS）。此外，也有罕见的与UBQLN2变异相关的原发性侧索硬化症（PLS）和痉挛性截瘫（SPG）病例的报道。在此，我们报告了一个患有SPG的家族中的四名男性患者，他们携带半合子错义UBQLN2变异（NM_013444.4:c.1442G>T，p.(Gly481Val)）。这些患者表现为儿童期起病的下肢痉挛，逐渐发展为步态障碍。平均起病年龄（11岁）早于先前报道的ALS（49.6岁）、SPG（29岁）和PLS（25.5岁）病例，且其病情进展比ALS或PLS更慢。文献综述显示，Pro506错义变异与多种运动神经元疾病表型相关，一些SPG患者会进展为ALS。因此，我们认为对于与UBQLN2相关的SPG患者有必要进行密切随访。
