Progressive Encephalopathy with Brain Atrophy and Thin corpus callosum is caused by a homozygous or compound heterozygous mutation in the TBCD gene on chromosome 17q25. The TBCD (Tubulin-specific chaperone D) gene encodes one of the five co-chaperones required for assembly and disassembly of the alpha/beta-tubulin heterodimer.
Edvardson et al (2016) described 4 children from 2 families with homozygous mutations in TBCD. These patients presented with severe developmental delay, dystonia, and intractable seizures. They developed acquired microcephaly and features of autism (regression in social skills and visual attention). Miyake et al (2016) described biallelic TBCD mutations in 8 individuals with early onset brain atrophy with regression, post-natal microcephaly, and weakness. Pode-Shakked et al (2017) described 5 patients who presented with microcephaly, delays, and intractable seizures.
On neuroimaging common findings to all cases include brain atrophy with ventricular enlargement, thin corpus callosum, and a decrease in white matter. Patients typically have acquired microcephaly. Patients may have a delay in myelination of the remaining white matter. Both severe and milder patterns, e.g. partial white matter delayed myelination and mild cortical atrophy, have been observed. Cerebellar atrophy has also been reported as a later finding in select cases (Edvardson et al 2016, Miyake 2016, Flex 2016). Partial callosal agenesis in addition to thinning has also been reported (Flex 2016, Pode-Shakked et al 2017). All cases show no signs of brain malformations such as cortical dysplasia or simplified gyral pattern. Predominant and progressive brain cortical and cerebellar atrophy appear to suggest a primary neuronal involvement driving secondary white matter hypomyelination and volume loss (Flex et al 2016).
References:
1. Edvardson S et al. Infantile neurodegenerative disorder associated with mutations in TBCD, an essential gene in the tubulin heterodimer assembly pathway, Human Molecular Genetics 2016: 25(21), 4635-4648
2. Flex E et al. Biallelic mutations in TBCD, encoding the tubulin folding cofactor D, perturb microtubule dynamics and cause early-onset encephalopathy, American Journal of Human Genetics 2016:99, 962-973
3. Miyake N et al. TBCD mutations cause early-onset neurodegenerative encephalopathy. American Journal of Human Genetics 2016: 99, 950-961
4. Pode-Shakked at al. Microcephaly, intractable seizures and developmental delay caused by biallelic variants in TBCD: further delineation of a new chaperone-mediated tubulinopathy. Clin Genet 2017:91,725-738
Dr. Ratika Srivastava, October 2019