Submission Details

Progressive encephalopathy with amyotrophy and optic atrophy was first linked to biallelic variants of TBCE in 2016 (PMID:27666369). Six probands from 4 unrelated Southern Italian families were described as having early onset slowly progressive distal motor neuropathy resembling spinal muscular atrophy with bilateral foot drop, spasticity, cerebellar ataxia and moderate to severe intellectual developmental disorder. Brain MRIs of these patients showed cerebellar atrophy; abnormal iron deposits were also recorded in the older patients. Other reports about a recurrent non-frameshift deletion responsible for the autosomal recessive Kenny-Caffey and Sanjad-Sakati syndromes are not included as they will be lumped in another curation. TBCE is required for the folding of a-tubulin, a/b-tubulin dimerization, and subsequent heterodimer polymerization into microtubules, which are major components of the cytoskeleton. Structurally contains a CAP-Gly domain which mediates protein binding to a-tubulin, nine tandemly arranged leucine-rich repeat (LRR) motifs which mediate protein-protein interaction, and a ubiquitin-like domain (UBL) which is implicated in a-tubulin degradation via the proteasome. The mechanism of pathogenicity is thus far associated with two recurrent variants; the homozygous p.Ile155Asn variant or the compound heterozygous c.924del:p.Leu309Ter variant. The gene-disease relationship is also supported by experimental evidence and specifically the mouse model pmn (PMID: 12446740), which is homozygous for the missense variant TBCE:p.Trp524Gly, and shares the same phenotypic features as those observed in affected individuals. In summary, TBCE is associated with autosomal recessive progressive encephalopathy with amyotrophy and optic atrophy, seen in 6 individuals. This was approved by the ClinGen Brain Malformation GCEP on 02/25/2025.