To establish molecular diagnosis for a family with a complicated form of autosomal recessive hereditary spastic paraplegia with intellectual disability, cognitive decline, psychosis, peripheral neuropathy, upward gaze palsy, and thin corpus callosum (TCC).

Physical examinations, laboratory tests, structural neuroimaging studies, and exome sequence analysis were carried out.

The 3 patients exhibited intellectual disability and progressive intellectual decline accompanied by psychiatric symptoms. Gait difficulty with spasticity and pyramidal weakness appeared at the ages of 20s–30s. Brain MRI revealed TCC with atrophic changes in the frontotemporal lobes, caudate nuclei, and cerebellum. Exome sequence analysis revealed a novel homozygous c.2654C>A (p. Ala885Asp) variant in the ATP13A2, a gene responsible for a complicated form of hereditary spastic paraplegia (SPG78), Kufor-Rakeb syndrome, and neuronal ceroid lipofuscinosis. The predominant clinical presentations of the patients include progressive intellectual disability and gait difficulty with spasticity and pyramidal weakness, consistent with the diagnosis of SPG78. Of note, prominent psychiatric symptoms and extrapyramidal signs including rigidity, dystonia, and involuntary movements preceded the spastic paraparesis.

Our study further broadens the clinical spectrum associated with ATP13A2 mutations.

为患有智力障碍、认知能力下降、精神病、周围神经病变、向上凝视麻痹和胼胝体薄 (TCC) 的复杂型常染色体隐性遗传性痉挛性截瘫家庭建立分子诊断。

进行了体格检查、实验室测试、结构神经影像学研究和外显子组序列分析。

3名患者出现智力障碍和进行性智力下降并伴有精神症状。痉挛和锥体无力的步态困难出现在 20 至 30 岁之间。脑部 MRI 显示 TCC 伴有额颞叶、尾状核和小脑的萎缩性变化。外显子组序列分析揭示了 ATP13A2 中的一个新的纯合 c.2654C>A (p. Ala885Asp) 变体，一种导致复杂形式的遗传性痉挛性截瘫 (SPG78)、Kufor-Rakeb 综合征和神经元蜡样脂褐质沉积症的基因。患者的主要临床表现包括进行性智力障碍和步态困难，伴有痉挛和锥体无力，与 SPG78 的诊断一致。值得注意的是，痉挛性截瘫之前有突出的精神症状和锥体外系体征，包括强直、肌张力障碍和不自主运动。

我们的研究进一步拓宽了与ATP13A2突变相关的临床范围。