Abstract: Ufmylation is an ubiquitin-like post-translational modification characterized by the covalent binding of mature UFM1 to target proteins. Although the consequences of ufmylation on target proteins are not fully understood, its importance is evident from the disorders resulting from its dysfunction. Numerous case reports have established a link between biallelic loss-of-function and/or hypomorphic variants in ufmylation-related genes and a spectrum of pediatric neurodevelopmental disorders. These include developmental and epileptic encephalopathy (DEE44), autosomal r e c e s s i v e c e r e b e l l a r a t a x i a , c o n g e n i t a l neuropathy, hypomyelinating leukodystrophy, and neurodevelopmental disorder with spasticity and poor growth, each presenting with varying severity (Zhou et al., 2024). Children affected by these disorders often exhibit a range of symptoms, including intellectual disability, seizures, microcephaly, abnormal electroencephalogram, impaired motor function, dystonia, and/or global developmental delay, which result in premature death in severe cases. Variants in ufmylation genes have been shown to disrupt UFM1 activation and/or transthiolation, thereby impairing the ufmylation pathway (Pan et al., 2023; Zhou et al., 2024). These findings underline the importance of maintaining balanced ufmylation activity for optimal brain development and function.