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<p><i>UBQLN2</i> is located on Xp11.21 and encodes the ubiquilin 2 protein involved in protein homeostasis. Heterozygous or hemizygous missense variants in <i>UBQLN2</i> cause amyotrophic lateral sclerosis (ALS). In addition, rare cases of primary lateral sclerosis (PLS) and spastic paraplegia (SPG) associated with <i>UBQLN2</i> variants have also been reported. Here, we report four male patients in a family with SPG carrying a hemizygous missense <i>UBQLN2</i> variant (NM_013444.4:c.1442G&gt;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 <i>UBQLN2</i>-related SPG patients.</p>

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A Japanese familial spastic paraplegia associated with a missense UBQLN2 variant

  • 期刊论文

  • 发表日期：

    2025年8月22日

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  • Kazuki Watanabe,
  • Tatsuya Ema,
  • Kenji Shimizu,
  • Kosuke Yamada,
  • Mitsuko Nakashima,
  • Hirotomo Saitsu

摘要

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.