Cerebral choline metabolism is crucial for normal brain function, and its homoeostasis depends on carrier-mediated transport. Here, we report on four individuals from three families with neurodegenerative disease and homozygous frameshift mutations (Asp517Metfs*19, Ser126Metfs*8, and Lys90Metfs*18) in the SLC44A1 gene encoding choline transporter-like protein 1. Clinical features included progressive ataxia, tremor, cognitive decline, dysphagia, optic atrophy, dysarthria, as well as urinary and bowel incontinence. Brain MRI demonstrated cerebellar atrophy and leukoencephalopathy. Moreover, low signal intensity in globus pallidus with hyperintensive streaking and low signal intensity in substantia nigra were seen in two individuals. The Asp517Metfs*19 and Ser126Metfs*8 fibroblasts were structurally and functionally indistinguishable. The most prominent ultrastructural changes of the mutant fibroblasts were reduced presence of free ribosomes, the appearance of elongated endoplasmic reticulum and strikingly increased number of mitochondria and small vesicles. When chronically treated with choline, those characteristics disappeared and mutant ultrastructure resembled healthy control cells. Functional analysis revealed diminished choline transport yet the membrane phosphatidylcholine content remained unchanged. As part of the mechanism to preserve choline and phosphatidylcholine, choline transporter deficiency was implicated in impaired membrane homeostasis of other phospholipids. Choline treatments could restore the membrane lipids, repair cellular organelles and protect mutant cells from acute iron overload. In conclusion, we describe a novel childhood-onset neurometabolic disease caused by choline transporter deficiency with autosomal recessive inheritance.

中文翻译：

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胆碱转运蛋白样缺陷1导致一种新型的儿童期神经退行性变性。

脑胆碱代谢对于正常的大脑功能至关重要，其同位依赖取决于载体介导的转运。在这里，我们报道了来自编码胆碱转运蛋白样蛋白1的SLC44A1基因的三个神经退行性疾病和纯合移码突变（Asp517Metfs * 19，Ser126Metfs * 8和Lys90Metfs * 18）的四个人。临床特征包括进行性共济失调，震颤，认知能力下降，吞咽困难，视神经萎缩，构音障碍以及小便和尿失禁。脑部MRI显示小脑萎缩和白质脑病。此外，在两个人中均发现苍白球的高信号强度低信号强度和黑质黑质信号强度低。Asp517Metfs * 19和Ser126Metfs * 8成纤维细胞在结构和功能上是无法区分的。突变的成纤维细胞最显着的超微结构变化是游离核糖体的减少，内质网的拉长以及线粒体和小囊泡的数量显着增加。当长期用胆碱治疗时，那些特征消失了，突变的超微结构类似于健康的对照细胞。功能分析表明胆碱运输减少，但膜磷脂酰胆碱含量保持不变。作为保护胆碱和磷脂酰胆碱的机制的一部分，胆碱转运蛋白缺乏与其他磷脂的膜稳态平衡有关。胆碱治疗可以恢复膜脂，修复细胞器并保护突变细胞免于急性铁超负荷。综上所述，