TBC1D24 – Familial Infantile Myoclonic Epilepsy

Familial infantile myoclonic epilepsy (FIME) is an autosomal-recessive early-onset epilepsy syndrome marked by isolated myoclonic seizures that may progress to generalized tonic-clonic seizures. The TBC1D24 gene TBC1D24 was mapped to chromosome 16p13.3 in a large consanguineous pedigree and two compound heterozygous missense mutations, c.439G>C (p.Asp147His) and c.1544C>T (p.Ala515Val), were identified as causal (PMID:20727515).

Independent case series in two additional families reinforce this association. An Italian family exhibited a homozygous c.457G>A (p.Glu153Lys) variant in two affected siblings with FIME (PMID:25769375), and a Chinese pedigree demonstrated a homozygous c.241_252del (p.Ile81_Lys84del) allele in three siblings followed over 20 years (PMID:35413638). In total, seven probands across three unrelated families show segregation of biallelic TBC1D24 variants, consistent with autosomal-recessive inheritance and multi-family segregation.

The variant spectrum in FIME includes missense substitutions within conserved TBC domains, in-frame deletions, and truncating mutations, all predicted to result in loss of TBC1D24 function. The recurrent c.439G>C (p.Asp147His) allele suggests a possible population-specific founder effect. One representative variant is c.439G>C (p.Asp147His).

Functional studies demonstrate that TBC1D24 binds ARF6 to regulate dendritic branching and spine formation; overexpression of wild-type TBC1D24 increases neurite length, whereas introduction of FIME-associated mutations reverses this phenotype (PMID:20727515). Structural modeling of the c.241_252del allele predicts disruption of protein folding and decreased activity (PMID:35413638).

On the basis of seven probands in three families, segregation data in multiple affected relatives, and concordant in vitro functional assays, the TBC1D24–FIME association achieves a Strong clinical validity classification according to ClinGen criteria. Genetic screening for biallelic TBC1D24 variants is recommended in infants presenting with early myoclonic seizures to support diagnosis and family counseling.

Key Take-home: Biallelic loss-of-function TBC1D24 variants are a well-validated cause of autosomal-recessive familial infantile myoclonic epilepsy, warranting inclusion in diagnostic gene panels.

References

• American journal of human genetics • 2010 • TBC1D24, an ARF6-interacting protein, is mutated in familial infantile myoclonic epilepsy. PMID:20727515
• Epilepsy research • 2015 • Homozygous TBC1D24 mutation in two siblings with familial infantile myoclonic epilepsy (FIME) and moderate intellectual disability. PMID:25769375
• Epilepsy research • 2022 • TBC1D24-related familial infantile multifocal myoclonus: Description of a new Chinese pedigree with a 20 year follow up. PMID:35413638

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