Phenotypic variability in progressive encephalopathy with brain atrophy and thin corpus callosum: insights from two families.

Abstract

The cytoskeleton, composed of microtubules, intermediate filaments and actin filaments is vital for various cellular functions, particularly within the nervous system, where microtubules play a key role in intracellular transport, cell morphology, and synaptic plasticity. Tubulin-specific chaperones, including tubulin folding cofactors (TBCA, TBCB, TBCC, TBCD, TBCE), assist in the proper formation of α/β-tubulin heterodimers, essential for microtubule stability. Pathogenic variants in these chaperone-encoding genes, especially TBCD, have been linked to Progressive Encephalopathy with Brain Atrophy and Thin Corpus Callosum (PEBAT, OMIM #604,649), a severe neurodevelopmental disorder. We report three cases from two consanguineous families with varying clinical presentations of PEBAT syndrome due to homozygous pathogenic variants in the TBCD. In Family 1, two siblings (F1C1 and F1C2) harboring the homozygous c.2314C > T, p.(Arg772Cys) variant exhibited severe neurodevelopmental regression, spastic tetraplegia, seizures, and brain atrophy. In contrast, Family 2, Case 3 (F2C3), with the homozygous c.230A > G, p.(His77Arg) variant, presented a milder phenotype, including absence seizures, slight developmental delay, and less pronounced neuroanatomical abnormalities. These findings contribute to the expanding phenotypic spectrum of PEBAT and suggesting that modifier genes or epigenetic factors may influence disease severity.