Monday, October 12, 2015

TBC1D24-related disorders

Mucha BE, Hennekam RCM, Sisodiya S, Campeau PM. TBC1D24-Related Disorders .
2015 Feb 26. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH,
Bird TD, Dolan CR, Fong CT, Smith RJH, Stephens K, editors. GeneReviews®
[Internet]. Seattle (WA): University of Washington, Seattle; 1993-2015. Available



TBC1D24-related disorders comprise a continuum that includes the following 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.


The diagnosis of a TBC1D24-related disorder is established in an individual with two TBC1D24 pathogenic variants when the mode of inheritance is autosomal recessive (i.e., DOORS syndrome, FIME, PME, EIEE16, and DFNB86).


Treatment of manifestations: Hearing aids or cochlear implants as needed for hearing loss; early educational intervention, physical, occupational, and speech therapy for developmental delay; symptomatic pharmacologic management for seizures; routine management of 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.


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 pregnancies at increased risk if the TBC1D24 pathogenic variants have been identified in an affected family member.

Inspired by this diagnosis being established in a brother and sister at my institution.

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