Clinical-genetic features of the TBCE-related spectrum disorders: A focus on the childhood-onset neurodegenerative phenotype

Background: Tubulin-folding cofactor E (TBCE) plays a central role in tubulin heterodimer formation and disaggregation. Both TBCE biallelic and monoallelic pathogenic variants have been associated with human diseases involving endocrine and/or neurologic system. This study aimed to expand current knowledge on the neurodegenerative phenotype associated with TBCE variants, and to explore possible genotype-phenotype correlations. Methods: Subjects with a neurodegenerative syndrome caused by biallelic TBCE variants were recruited from three centers. Clinical, genetic, neuroimaging and neurophysiological data were collected retrospectively and, when available, longitudinally. A systematic literature review focusing on genotype-phenotype correlations was also performed. Results: Thirteen subjects, including eight newly reported and five previously published, were enrolled. Data from 322 additional patients were available from systematic literature review, for a total of 335 TBCE mono- and biallelic patients. Sanjad-Sakati syndrome was the most frequent form (85%), while the neurodegenerative phenotype accounted for a minority (5%) of cases. TBCE-related neurodegeneration ranged from progressive spastic-ataxic tetraparesis, optic atrophy and distal motor axonal neuropathy, consistent with already named PEAMO (progressive encephalopathy with amyotrophy and optic atrophy) to milder complex spastic paraparesis. Brain imaging often revealed progressive thinning of the corpus callosum, cerebro-cerebellar atrophy, white matter abnormalities and possible iron accumulation in deep grey matter structures. Additional relevant features included scoliosis, respiratory and gastrointestinal dysfunctions. Genotype-phenotype correlation and a distinct geographic distribution were identified across phenotypes. Conclusion: Pathogenic biallelic TBCE variants present phenotypic heterogeneity, with at least four different phenotypes, with genotype-phenotype correlation. TBCE-related neurodegeneration is a severe multisystem disorder that requires multidisciplinary management.