Developmental Regression and Epilepsy of Infancy with Migrating Focal Seizures Caused by TBCD Mutation: A Case Report and Review of the Literature

Abstract

Microtubule dynamics plays a crucial role in neuronal development and function. Variants in the tubulin cofactor D (TBCD) gene, which encodes one of the five co-chaperones required for assembly and disassembly of α/β-tubulin heterodimers, may lead to neurodevelopmental disorders. We aimed to study the clinical, electroencephalographic, and imaging features of a male patient with TBCD variants, and to provide a detailed review of the previously reported cases of TBCD-related neurological disorders. The patient presented with early-onset developmental regression, secondary microcephaly, epilepsy of infancy with migrating focal seizures, hypotonia, and brain atrophy with thin corpus callosum on brain magnetic resonance imaging. Genetic analyses of the family members revealed a compound heterozygous variant of c.230A > G (p.H77R) in the proband and deletion of exons 28 to 39 of TBCD, which has not been previously reported and was inherited from his carrier parents. Epilepsy of the patient was refractory to numerous antiepileptic drugs. The review of 33 previously reported patients revealed that the age at the onset was very early, and all the patients had presentations during the first year of life. This case report provides insight regarding the clinical features and genetic etiology of TBCD-related tubulinopathy. Identification of phenotypes and genotypes in patients may help in early diagnosis and appropriate genetic counseling.

Keywords

TBCD - developmental regression - epilepsy of infancy with migrating focal seizures - microcephaly

• References

• 1 Kapitein LC, Hoogenraad CC. Building the neuronal microtubule cytoskeleton. Neuron 2015; 87 (03) 492-506
• 2 Lewis SA, Tian G, Cowan NJ. The alpha- and beta-tubulin folding pathways. Trends Cell Biol 1997; 7 (12) 479-484
• 3 Tian G, Lewis SA, Feierbach B. , et al. Tubulin subunits exist in an activated conformational state generated and maintained by protein cofactors. J Cell Biol 1997; 138 (04) 821-832
• 4 Tian G, Thomas S, Cowan NJ. Effect of TBCD and its regulatory interactor Arl2 on tubulin and microtubule integrity. Cytoskeleton (Hoboken) 2010; 67 (11) 706-714
• 5 Flex E, Niceta M, Cecchetti S. , et al. Biallelic mutations in TBCD, encoding the tubulin folding cofactor D, perturb microtubule dynamics and cause early-onset encephalopathy. Am J Hum Genet 2016; 99 (04) 962-973
• 6 Miyake N, Fukai R, Ohba C. , et al. Biallelic TBCD mutations cause early-onset neurodegenerative encephalopathy. Am J Hum Genet 2016; 99 (04) 950-961
• 7 Edvardson S, Tian G, Cullen H. , et al. Infantile neurodegenerative disorder associated with mutations in TBCD, an essential gene in the tubulin heterodimer assembly pathway. Hum Mol Genet 2016; 25 (21) 4635-4648
• 8 Pode-Shakked B, Barash H, Ziv L. , et al. Microcephaly, intractable seizures and developmental delay caused by biallelic variants in TBCD: further delineation of a new chaperone-mediated tubulinopathy. Clin Genet 2017; 91 (05) 725-738
• 9 Ikeda T, Nakahara A, Nagano R. , et al. TBCD may be a causal gene in progressive neurodegenerative encephalopathy with atypical infantile spinal muscular atrophy. J Hum Genet 2017; 62 (04) 473-480
• 10 Grønborg S, Risom L, Ek J. , et al. A Faroese founder variant in TBCD causes early onset, progressive encephalopathy with a homogenous clinical course. Eur J Hum Genet 2018; 26 (10) 1512-1520
• 11 Stephen J, Nampoothiri S, Vinayan KP. , et al. Cortical atrophy and hypofibrinogenemia due to FGG and TBCD mutations in a single family: a case report. BMC Med Genet 2018; 19 (01) 80
• 12 Okumura M, Sakuma C, Miura M, Chihara T. Linking cell surface receptors to microtubules: tubulin folding cofactor D mediates Dscam functions during neuronal morphogenesis. J Neurosci 2015; 35 (05) 1979-1990
• 13 Bahi-Buisson N, Poirier K, Fourniol F. , et al; LIS-Tubulinopathies Consortium. The wide spectrum of tubulinopathies: what are the key features for the diagnosis?. Brain 2014; 137 (Pt 6): 1676-1700
• 14 Peron A, Baratang NV, Canevini MP, Campeau PM, Vignoli A. Hot water epilepsy and SYN1 variants. Epilepsia 2018; 59 (11) 2162-2163