Clinical characteristics: TBC1D24-related disorders comprise a continuum of features that were originally described as distinct, recognized phenotypes:
DOORS syndrome (deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures). Profound sensorineural hearing loss, onychodystrophy, osteodystrophy, intellectual disability / developmental delay, and seizures
Familial infantile myoclonic epilepsy (FIME). Early-onset myoclonic seizures, focal epilepsy, dysarthria, and mild-to-moderate intellectual disability
Progressive myoclonus epilepsy (PME). Action myoclonus, tonic-clonic seizures, progressive neurologic decline, and ataxia
Early-infantile epileptic encephalopathy 16 (EIEE16). Epileptiform EEG abnormalities which themselves are believed to contribute to progressive disturbance in cerebral function
Autosomal recessive nonsyndromic hearing loss, DFNB86. Profound prelingual deafness
Autosomal dominant nonsyndromic hearing loss, DFNA65. Slowly progressive deafness with onset in the third decade, initially affecting the high frequencies
Diagnosis/testing: The diagnosis of a TBC1D24-related disorder is established in an individual with biallelic TBC1D24 pathogenic variants when the mode of inheritance is autosomal recessive (i.e., DOORS syndrome, FIME, PME, EIEE16, and DFNB86), and in an individual with a heterozygous TBC1D24 pathogenic variant when the mode of inheritance is autosomal dominant (DFNA65).
Management: Treatment of manifestations: Hearing aids or cochlear implants as needed for hearing loss; early educational intervention and physical, occupational, and speech therapy for developmental delay; symptomatic pharmacologic management for seizures; routine management of visual impairment and renal and cardiac anomalies.
Surveillance: Neurology evaluations with EEGs depending on seizure frequency and/or progression of clinical manifestations; yearly audiologic evaluation to assess for possible progression of hearing loss and/or the efficacy of hearing aids; yearly dental evaluation.
Agents/circumstances to avoid: Excessive ambient noise, which may exacerbate hearing loss in heterozygotes for a TBC1D24 pathogenic variant that causes DFNA65.
Evaluation of relatives at risk: Molecular genetic testing for the familial TBC1D24 pathogenic variant(s) in older and younger sibs of a proband in order to identify as early as possible those who would benefit from early treatment of seizures and/or hearing loss.
Genetic counseling: Most TBC1D24-related disorders are inherited in an autosomal recessive manner (DOORS syndrome, FIME, PME, EIEE16, and DFNB86). For autosomal recessive inheritance: at conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives requires prior identification of the TBC1D24 pathogenic variants in the family. Prenatal testing is possible for a pregnancy at increased risk if the TBC1D24 pathogenic variants have been identified in an affected family member.
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