Aynekin Busra, Akbaş Sinan, Gulec Ayten, Gumus Ummu Gulsum Ozgul, Guner Abdullah Emre, Efthymiou Stephanie, Houlden Henry, Sayın Gözde Yesil, Per Huseyin
Department of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, London, WC1N 3BG, UK.
Department of Neuroscience, Physiology & Pharmacology, University College London, Gower Street, London, WC1E 6BT, UK.
Neurogenetics. 2025 Jan 24;26(1):23. doi: 10.1007/s10048-025-00799-7.
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.
细胞骨架由微管、中间丝和肌动蛋白丝组成，对各种细胞功能至关重要，特别是在神经系统中，微管在细胞内运输、细胞形态和突触可塑性中起关键作用。微管蛋白特异性伴侣蛋白，包括微管蛋白折叠辅助因子（TBCA、TBCB、TBCC、TBCD、TBCE），有助于α/β-微管蛋白异二聚体的正确形成，这对微管稳定性至关重要。这些伴侣蛋白编码基因中的致病性变异，尤其是TBCD，与伴有脑萎缩和胼胝体变薄的进行性脑病（PEBAT，OMIM #604,649）有关，这是一种严重的神经发育障碍。我们报告了来自两个近亲家庭的三例病例，由于TBCD中的纯合致病性变异，这些病例表现出不同的PEBAT综合征临床表现。在家族1中，两名携带纯合c.2314C>T，p.(Arg772Cys)变异的兄弟姐妹（F1C1和F1C2）表现出严重的神经发育倒退、痉挛性四肢瘫痪、癫痫发作和脑萎缩。相比之下，家族2的病例3（F2C3）携带纯合c.230A>G，p.(His77Arg)变异，表现出较轻的表型，包括失神发作、轻微发育迟缓以及不太明显的神经解剖学异常。这些发现有助于扩大PEBAT的表型谱，并表明修饰基因或表观遗传因素可能影响疾病严重程度。
