Video 1
(A) Patient A1 at various ages. The video demonstrates orolingual and facial myoclonus.
(B) Patient A1 at various ages. The video demonstrates limb myoclonus, abdominal myoclonus and widespread polymyoclonus. Towards the end of the video distal choreoathetoid movements are also present in the upper limbs.
(C) Patient A2 at approximately 3 months of age. The video demonstrates myoclonus in the right arm and orolingual myoclonus.
Figure 1
Magnetic Resonance Imaging Features in Sibship with TBC1D24 Mutations. (A) MRI brain scan (Axial T2-weighted) of A1 age 19 months showing underdevelopment of the frontal and temporal lobes. (B) CT head scan of A1 20 months showing small non-specific foci of calcification within the basal ganglia. (C) MRI head scan (Coronal T2-weighted) of A2 at 3 years 10 months showing symmetrical signal abnormalities and atrophy of the lateral aspects of the cerebellar hemispheres.
Table 1
Phenotypes Associated with TBC1D24 Mutations
| Clinical Phenotype | Familial Infantile Myoclonic Epilepsy (OMIM 605021) | Focal Epilepsy with Cerebrocerebellar Malformation | MMPSI (OMIM 615338) | Progressive Myoclonic Epilepsy with Dystonia (OMIM 615338) | EOEE and Hearing Loss |
|---|---|---|---|---|---|
| References | Zara et al.3, de Falco et al.4, Falace et al.5, Poulat et al.6 | Corbett et al.7, Afawi et al.8 | Milh et al.9 | Duru et al.10, Guven and Tolun11 | Stražišar et al.12 |
| Reported mutations/genotype | c.439G>C (p.Asp147His) c.1526C>T (p.Ala509Val) c.457G>A (p.Glu157Lys) | c.751C>T (p.Phe251Leu) | c.468C>A (p.Cys156*) c.686T>A (p.Phe229Ser) | c.969_970delGT (p.Ser324Thrfs*3) | c.32A>G (p.Asp11Gly) c.1008delT (p.His336GInfs*12) |
| Inheritance | AR | AR | AR | AR | AR |
| Clinical features | Seizures Normal psychomotor development and neurological examination to moderate intellectual and psychomotor impairment Bulbous nose and flat nasal root | Seizures Myoclonus Moderate intellectual disability Ataxic with cerebellar signs Dystonia Dysarthria | Seizures Psychomotor regression Axial hypotonia Loss of visual contact | Seizures Post-ictal hemiparesis Dystonic episodes Myoclonus with startle responses to auditory and tactile stimuli Axial hypotonia Pyramidal signs Severe neurodevelopmental impairment Vulnerability to infection Bilateral optic atrophy, macular degeneration and visual impairment in one individual | Seizures Profound sensorineural deafness Myoclonic jerks Acquired microcephaly Dyskinetic movements Axial hypotonia Poor visual contact |
| Types of seizures | GTC Myoclonic: trigger sensitive | Focal seizures with auras Tonic–clonic Myoclonic | Focal prolonged migrating clonic seizures | Focal/unilateral Clonic seizures Myoclonic Tonic | Clonic seizures Tonic seizures |
| EEG/EMG findings | Preserved background. 1 individual with slow background activity in occipital region. Interictal multiple diffuse spikes and slow waves. Ictal EEG with low amplitude spikes at vertex Jerk-locked back averaging confirmed cortical myoclonus | Slow background rhythms. No epileptiform discharges. Ictal EEG not available | Focal migrating EEG discharges during seizures Interictal EEG: disorganized | Slow background in EEG Multifocal or bilateral generalized multiple spikes and spike waves in EEG associated with myoclonias. | Generalized spike-wave discharges with frontocentral predominance during seizures No clear EEG correlate for myoclonic jerks |
| Imaging findings | Normal 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 normal | Selective atrophy and signal abnormality in cerebellum Cerebral cortical thickening most marked in cingulate regions and occipital poles | Global cerebral atrophy sparing the posterior fossa | Thin corpus callosum Delayed myelination Diffuse cerebral atrophy (asymmetrical for one patient) Cerebellar atrophy | Prominent frontotemporal atrophy |
| Clinical Phenotype | Spectrum of Epilepsy Phenotypes Including DOORS Syndrome | DOORS Syndrome (OMIM 220500) | Non-syndromic Deafness (DFNB86) (OMIM 614617) | Non-syndromic Hearing Loss (DFNA65) (OMIM 616044) | Migrating Paroxysmal Myoclonus and Cerebellar Signs |
|---|---|---|---|---|---|
| References | Balastrini et al.13 | Campeau et al.18 | Rehman et al.14, Bakhchane et al.15 | Azaiez et al.16, Zhang et al.17 | Doummar et al.22 |
| Reported mutations/genotype | c.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.Arg242Cys) c.118C>T (p.Arg40Cys) c.119G>T (p.Arg40Leu) c.1008delT (p.His336GInfs*12) c.1206+5G>A (Splice site) c.58C>G (p.Gln20Glu) c.328G>A (p.Gly110Ser) c.999G>T (p.Leu333Phe) | c.208G>T (p.Asp70Tyr) c.878G>C (p.Arg293Pro) c.641G>A (p.Arg214His) c.1316insG (p.Val439Valfs*32) c.457G>A (p.Glu153Lys) c.798G>T (p.Lys266Asn) | c.533C>T (p.Ser178Leu) | c.809G>A (p.Arg270His) |
| Inheritance | AR | AR | AR | AD | AR |
| Clinical features | Seizures In some Axial hypotonia Acquired microcephaly Poor visual contact, cortical blindness, bilateral optic atrophy, macular degeneration Sensorineural deafness Dysmorphia including bulbous nose with flat nasal root, thin or prominent philtrum, synophrys, up or down slanting palpebral fissures Acral abnormalities: hypoplastic terminal phalanges, brachydactyly Skeletal abnormalities tibial torsion, scoliosis, etc. Movement disorders: dystonic episodes, tremor, dyskinesia Ataxia Feeding difficulties Heart defects Autism spectrum disorder Psychosis Hyperactivity Peripheral neuropathy Renal anomalies | Seizures Sensorineural deafness Small or absent nails Hypoplastic terminal phalanges 2-Oxoglutaric aciduria Neurodevelopmental Impairment Bulbous nose with flat nasal root In some individuals: Microcephaly in one-third Occasional craniosynostosis Autistic spectrum disorder Eyes: colobomas, visual impairment Heart defects (ASD/VSD), double outlet right ventricle) Kidneys, adrenal glands, and genitalia malformations | Non-syndromic sensorineural deafness Of 15 affected individuals assessed for epilepsy in Rehman et al.16, 1 individual had a history of seizures: attributed to coincidence Family history of epilepsy | Non-syndromic hearing loss with onset in the third decade | Paroxysmal migrating myoclonus with preserved awareness Ataxia Progressive cognitive decline |
| Clinical Phenotype | Spectrum of Epilepsy Phenotypes Including DOORS Syndrome | DOORS Syndrome (OMIM 220500) | Non-syndromic Deafness (DFNB86) (OMIM 614617) | Non-syndromic Hearing Loss (DFNA65) (OMIM 616044) | Migrating Paroxysmal Myoclonus and Cerebellar Signs |
|---|---|---|---|---|---|
| Types of seizures | Infantile spasms Febrile seizures Myoclonic Tonic seizures Clonic seizures Tonic–clonic with/without focal onset Focal seizures | GTC Myoclonic Infantile spasms Absence seizures Focal seizures | Not mentioned | NA | NIL |
| EEG/EMG findings | Focal epileptiform discharges: frontocentral, temporal, occipital Multifocal discharges Migrating focal discharges Generalized spike-waves | Not mentioned | Normal | Not done | Interictal EEG: slow waves in occipital region |
| Imaging findings | Cerebellar atrophy Global cerebral atrophy Cerebral atrophy sparing the posterior fossa Hippocampal atrophy Basal ganglia atrophy Hippocampal sclerosis Delayed myelination Thin corpus callosum Hyperintensity of basal ganglia Hyperintensity in cerebellar cortex and white matter | Thin corpus callosum Corpus callosum agenesis Dandy walker malformation Cerebellar atrophy Hyperintense T2 in cerebellar hemispheres Cortical atrophy Delayed myeliniation Increased T2 signal in frontal region Increased flair in occipital horn | Normal | Not mentioned | Progressive hemispheric cerebellar atrophy with hypersignal of the cerebellar cortex and white matter on T2 and fluid-attenuated inversion recovery sequences |
[i] Abbreviations: AD, Autosomal Dominant; AR, Autosomal Recessive; ASD, Atrial Septal Defect; EEG, Electroencephalogram; EOEE, Early-onset Epileptic Encephalopathy; GTC, Generalized Tonic Clonic; MMPSI, Malignant Migrating Partial Seizures of Infancy; NA, Not Available; VSD, Ventricular Septal Defect.