The TBC1D24 story. Mutations in TBC1D24 were found initially in two recessive families with different types of epilepsy in 2010. This was followed by the identification of mutations in another recessive epilepsy family in 2013, and then by the identification of 9 families with mutations and DOORS syndrome (Deafness, Onycho-Osteodystrophy, mental Retardation and Seizures). Surprisingly, TBC1D24 mutations were then also identified in families with autosomal dominant or recessive non-syndromic deafness without epilepsy.
TBC1D24 mutations can cause a wide range of phenotypes, including many that feature seizures. DOORS syndrome is characterized by profound sensorineural hearing loss, onychodystrophy (short or absent nails), osteodystrophy (short terminal phalanges), intellectual disability or developmental delay, and seizures (generalized tonic-clonic, myoclonic, partial, and absence seizures) which sometimes increase in severity over time. Familial infantile myoclonic epilepsy (FIME) is characterized by early-onset myoclonic seizures, focal epilepsy, dysarthria, and intellectual disability or developmental delay. Progressive myoclonus epilepsy (PME) is characterized by action myoclonus, tonic-clonic seizures, progressive neurologic decline, and ataxia. Early-infantile epileptic encephalopathy 16 (EIEE16) is characterized by epilepsy and epileptiform EEG abnormalities, which could contribute to progressive neurologic decline.
Hearing loss. The other predominant feature of TBC1D24 mutation phenotypes is hearing loss. Mutations in TBC1D24 can cause autosomal recessive nonsyndromic hearing loss (DFNB86) characterized by profound prelingual deafness. Autosomal dominant nonsyndromic hearing loss (DFNA65), also caused by a TBC1D24 mutation, is characterized by slowly progressive deafness affecting initially the high frequencies in the third decade.
The mutations causing these different phenotypes are all different. Some of the mutations are shown in the image above.
There is currently no way to predict the phenotype based on the genotype, apart from the fact that truncating mutations generally lead to the most severe phenotypes (EIEE16 and DOORS syndrome). Dominant deafness is caused by a missense mutation (p.(Ser178Leu)), and recessive deafness by a number of different missense mutations (including p.(Asp70Tyr), p,(Arg214His) and p.(Arg293Pro)).
TBC1D24 encodes a protein with two identifiable domains: a Tre2–Bub2–Cdc16 (TBC) domain similar to other RAB GTPase-activating proteins (RabGAPs), and a TLDc domain (TBC, LysM, Domain catalytic). The TBC/RabGAP domains interact with small GTPases, often helping to hydrolyze GTP and rendering the Rab proteins unable to interact with effectors, thus regulating the proper transport of intracellular vesicles. The function of the TLDc domain is not known but is thought to be involved in oxidative stress resistance. TBC1D24 has been demonstrated to interact with the ARF6 GTPase. In Drosophila, the ortholog Skywalker (Sky) facilitates endosomal trafficking in synaptic vesicles by facilitating GTP hydrolysis by Rab35, thus controlling synaptic vesicle rejuvenation and neurotransmitter release. Notably, mutating Sky caused synaptic vesicles to travel excessively to endosomes, so that older proteins are more efficiently degraded. These perturbations could affect proper regulation of neurotransmitter release and lead to epilepsy.
My patient has a mutation in TBC1D24 – what does this mean?
1 – Variant. A first step would be to determine how frequent the variant is in the general population. A useful tool for that is the ExAC browser. One can also see if the mutation has been identified previously in patients with TBC1D24-related disorders, either by consulting a locus-specific mutation database, ClinVar or the literature.
2 – Segregation. Although most phenotypes associates with TBC1D24 mutations are recessive, it is important to note that a few heterozygous carriers have presented mild epilepsies. If the patient has two rare mutations, it is important to verify if unaffected individuals (parents or siblings) carry one or both mutations. This will help determine if the variants are in trans and if they co-segregate with the disease.
3 – Phenotype. The phenotype of the patient should ideally overlap with the phenotypes previously described in the literature and summarized in this GeneReview, although since the data are quite recent, there might be some phenotypic expansion which will occur over the years.
Families with mutations in TBC1D24 can connect with other families using the links found here.