Childhood-onset neurodegeneration with ataxia, tremor, optic atrophy, and cognitive decline (CONATOC): An integrated clinical series with genetic analysis

CONATOC-Childhood-Onset Neurodegeneration with Ataxia, Tremor, Optic Atrophy, and Cognitive decline-is a newly identified neurodegenerative disorder linked to pathogenic variants in the SLC44A1 gene, which encodes the choline transporter-like protein CTL1. This transporter is essential for choline uptake in the nervous system, and its deficiency leads to a spectrum of neurological symptoms. We integrate clinical, neuroimaging, functional, and genetic data from four patients to refine the phenotype and variant classification. We present two newly identified cases and updated clinical and imaging data on two previously reported patients. All patients exhibited features such as tremors, ataxia, dysarthria, and cerebellar atrophy. Two siblings carried homozygous c.1549del (p.Asp517fs) variant (pathogenic). A third patient carried homozygous c.36+2T>C (splice-site) likely pathogenic variant. One patient harbored a single heterozygous c.1306A>G (p.Ile436Val) variant (VUS) with markedly reduced choline (−99.4%) and ethanolamine (−44.7%) uptake in fibroblasts. MRI consistently showed bilateral periventricular/deep white-matter T2/FLAIR hyperintensities with variable cerebellar atrophy and putaminal/substantia nigra susceptibility. Our series broadens the clinical–genetic spectrum of CONATOC and supports loss of CTL1 function as a convergent mechanism. Standardized iron-sensitive imaging and prospective outcome measures are needed to guide therapy development.