TBC1D24 genotype–phenotype correlation

Abstract

Objective:To evaluate the phenotypic spectrum associated with mutations in TBC1D24.Methods:We acquired new clinical, EEG, and neuroimaging data of 11 previously unreported and 37 published patients. TBC1D24 mutations, identified through various sequencing methods, can be found online (http://lovd.nl/TBC1D24).Results:Forty-eight patients were included (28 men, 20 women, average age 21 years) from 30 independent families. Eighteen patients (38%) had myoclonic epilepsies. The other patients carried diagnoses of focal (25%), multifocal (2%), generalized (4%), and unclassified epilepsy (6%), and early-onset epileptic encephalopathy (25%). Most patients had drug-resistant epilepsy. We detail EEG, neuroimaging, developmental, and cognitive features, treatment responsiveness, and physical examination. In silico evaluation revealed 7 different highly conserved motifs, with the most common pathogenic mutation located in the first. Neuronal outgrowth assays showed that some TBC1D24 mutations, associated with the most severe TBC1D24-associated disorders, are not necessarily the most disruptive to this gene function.Conclusions:TBC1D24-related epilepsy syndromes show marked phenotypic pleiotropy, with multisystem involvement and severity spectrum ranging from isolated deafness (not studied here), benign myoclonic epilepsy restricted to childhood with complete seizure control and normal intellect, to early-onset epileptic encephalopathy with severe developmental delay and early death. There is no distinct correlation with mutation type or location yet, but patterns are emerging. Given the phenotypic breadth observed, TBC1D24 mutation screening is indicated in a wide variety of epilepsies. A TBC1D24 consortium was formed to develop further research on this gene and its associated phenotypes.

TBC1D24 Mutations in a Sibship with Multifocal Polymyoclonus

“…Overall, among disorders associated with TBC1D24 mutations, recurring phenotypes include seizures, myoclonus, neurodevelopmental impairment, sensorineural hearing impairment, visual impairment, and cerebral and/or cerebellar atrophy on brain imaging. Movement disorders including dystonia, choreoathetosis, and dyskinesia have also been reported 12,13. Our sibship shares a number of clinical features with previously reported TBC1D24 cases.…”

“…Ictal EEG not availableFocal migrating EEG discharges during seizuresInterictal EEG: disorganizedSlow background in EEGMultifocal or bilateral generalized multiple spikes and spike waves in EEG associated with myoclonias.Generalized spike-wave discharges with frontocentral predominance during seizuresNo clear EEG correlate for myoclonic jerksImaging findingsNormal 1 individual with nodular periventricular heterotopia 1 individual had MRI abnormalities in lentiform nuclei, ventricular dilatation and white matter changes post-cardiac arrest. An earlier MRI was normalSelective atrophy and signal abnormality in cerebellumCerebral cortical thickening most marked in cingulate regions and occipital polesGlobal cerebral atrophy sparing the posterior fossaThin corpus callosumDelayed myelinationDiffuse cerebral atrophy (asymmetrical for one patient)Cerebellar atrophyProminent frontotemporal atrophyClinical PhenotypeSpectrum of Epilepsy Phenotypes Including DOORS SyndromeDOORS Syndrome (OMIM 220500)Non-syndromic Deafness (DFNB86) (OMIM 614617)Non-syndromic Hearing Loss (DFNA65) (OMIM 616044)Migrating Paroxysmal Myoclonus and Cerebellar SignsReferencesBalastrini et al13Campeau et al18Rehman et al14, Bakhchane et al15Azaiez et al16, Zhang et al17Doummar et al22Reported mutations/genotypec.32A>G (p.Asp11Gly)c.58C>T (p.Gln20*)c.115G>C (p.Ala39Pro)c.118C>T (p.Arg40Cys)c.119G>T (p.Arg40Leu)c.277C>T (p.Pro93Ser)c.313T>C (p.Cys105Arg)c.328G>A (p.Gly110Ser)c.439G>C (p.Asp147His)c.457G>A (p.Glu153Lys)c.468C>A (p.Cys156*)c.533C>G (p.Ser178Trp)c.619C>T (p.Gln207*)c.679C>T (p.Arg227Trp)c.680G>A (p.Arg227Gln)c.686T>C (p.Phe229Ser)c.724C>T (p.Arg242Cys)c.731C>T (p.Ala244Val)c.751T>C (p.Phe251Leu)c.809G>A (p.Arg270His)c.845C>G (p.Pro282Arg)c.919A>G (p.Asn307Asp)c.957G>C (p.Lys319Asn)c.969_970delGT(p.Ser324Thrfs*3)c.999G>T (p.Leu333Phe)c.1008delT (p.His336Glnfs*12)c.1126G>C (p.Gly376Arg)c.1384del (p.Glu462Serfs*61)c.1460dup (p.His487Glnfs*71)c.1079G>T (p.Arg360Leu)c.1499C>T (p.Ala500Val)c.1544C>T (p.Ala515Val)c.1661_1667del (p.Gln554Leufs*12)c.724C>T (p.Arg24...…”

“…Using these criteria, two heterozygous variants confirmed by Sanger sequencing were identified in TBC1D24 (Supplementary Figure 1): 1) a previously reported missense change c.457G>A (p.Glu153Lys; rs376712059)6,13,15 and 2) a previously unreported frameshift mutation, c.545del (p.Thr182Serfs*6) predicted to cause nonsense-mediated RNA decay or result in a truncated protein. Both mutations showed appropriate familial segregation.…”

Coordination of synaptic vesicle trafficking and turnover by the Rab35 signaling network

“…These roles are essential for long-term neuronal health, as evidenced by the identification of human patients with neurologic and neurodegenerative conditions who have mutations in these genes. [17][18][19][20][21][22][23] In this review, we will discuss how the antagonistic and synergistic functions of molecules within the Rab35 signaling network are necessary for regulating SV protein trafficking, degradation, and neurotransmitter release, and conclude with a discussion of how dysfunction of this signaling network may induce neurologic and neurodegenerative diseases.…”

Case Report: Novel mutations in TBC1D24 are associated with autosomal dominant tonic-clonic and myoclonic epilepsy and recessive Parkinsonism, psychosis, and intellectual disability

“…Mutations in the TBC1D24 gene are the cause of multiple rare disorders whose phenotype consists of varying degrees of intellectual disability, deafness, cortical malformations, and/or epilepsy 1 . To date, the disorders caused by TBC1D24 dysfunction make up a continuum of six distinct phenotypes that include DOORS syndrome (Deafness, Onochydystrophy, Osteodystrophy, mental Retardation and Seizures; autosomal recessive; AR), familial infantile myoclonic epilepsy (FIME; AR), progressive myoclonus epilepsy (PME; AR), early-infantile epileptic encephalopathy (EIEE16; AR), autosomal recessive non-syndromic hearing loss (DFNB86; AR), and autosomal dominant non-syndromic hearing loss (DFNA65; AD).…”