TBC1D24 Research Articles

A TBC1D24 gene variant coincides with STRC compound heterozygosity in a family with hearing loss: a case report

BackgroundHearing loss is a common inborn neurosensory condition. Hearing loss is very heterogeneous, and while screening programs exist for children, adolescents and adults with late-onset hearing loss often do not get referrals to geneticists.ObjectiveTo diagnose the cause of hearing impairment in two related late-onset hearing loss patients—father and son—on a molecular level. Both underwent audiological examinations, and both had moderate hearing loss.Case presentation.We used massive parallel sequencing, Sanger sequencing, MLPA, and standard audiological methods. We identified an inherited autosomal dominant likely causative variant in the TBC1D24 gene of both patients. They did not show any other TBC1D24 spectrum-related symptoms. Furthermore, the younger patient was found to be compound heterozygous for two variants in STRC gene.ConclusionsOnly a few dozen TBC1D24 hearing loss patients have been reported. On the contrary, STRC is a common hearing loss cause. We speculate that in the younger patient, the phenotype is caused by a combination of effects of both genes. The older patient’s phenotype is more likely caused only by the TBC1D24 variant. We believe that more attention should be paid to adolescent and adult-onset hearing loss patients, and more frequent referrals to geneticists are warranted.

Investigation of a novel TBC1D24 variation causing autosomal dominant non-syndromic hearing loss.

Hearing loss is considered one of the most common sensory neurological defects, with approximately 60% of cases attributed to genetic factors. Human pathogenic variants in the TBC1D24 gene are associated with various clinical phenotypes, including dominant nonsyndromic hearing loss DFNA65, characterized by progressive hearing loss after the development of language. This study provides an in-depth analysis of the causative gene and mutations in a family with hereditary deafness. We recruited a three-generation family with autosomal dominant nonsyndromic hearing loss (ADNSHL) and conducted detailed medical histories and relevant examinations. Next-generation sequencing (NGS) was used to identify genetic variants in the proband, which were then validated using Sanger sequencing. Multiple computational software tools were employed to predict the impact of the variant on the function and structure of the TBC1D24 protein. A series of bioinformatics tools were applied to determine the conservation characteristics of the sequence, establish a three-dimensional structural model, and investigate changes in molecular dynamics. A detailed genotype and phenotype analysis were carried out. The family exhibited autosomal dominant, progressive, postlingual, and nonsyndromic sensorineural hearing loss. A novel heterozygous variant, c.1459C>T (p.His487Tyr), in the TBC1D24 gene was identified and confirmed to be associated with the hearing loss phenotype in this family. Conservation analysis revealed high conservation of the amino acid affected by this variant across different species. The mutant protein showed alterations in thermodynamic stability, elasticity, and conformational dynamics. Molecular dynamics simulations indicated changes in RMSD, RMSF, Rg, and SASA of the mutant structure. We computed the onset age of non-syndromic hearing loss associated with mutations in the TBC1D24 gene and identified variations in the hearing progression time and annual threshold deterioration across different frequencies. The identification of a new variant associated with rare autosomal dominant nonsyndromic hereditary hearing loss in this family broadens the range of mutations in the TBC1D24 gene. This variant has the potential to influence the interaction between the TLDc domain and TBC domain, thereby affecting the protein's biological function.

The mutation of TBC1D24 associated with epilepsy: About 3 cases

Purpose : The aim of our work is to study the clinical, electrical, imaging and evolutionary profile of epilepsy caused by mutation of the TBC1D24 gene in our patients and to emphasize the interest of genetic counseling.
 Methodology : This is a qualitative observational study about 3 cases, highlighting the clinical, electrical, and evolutionary characteristics of the disease.
 Findings : In this study we report the clinical history of three patients from two families, hospitalized at the Mohamed V hospital in Tangier, during the year 2022, having in common a first degree consanguinity, a severe epilepsy, pharmaco-resistant, with a very early onset during the first months of life, with several hospitalizations for epileptic seizures, the repercussion on psychomotor development, and schooling was noted with the three children, the genetic study confirmed the presence of mutation of the TBC1D24 gene.
 Unique contribution to theory, practice and policy: The cases reported in the literature are not numerous (1) (2) (3). Balestrini et al (1), reported 48 cases, followed for epilepsy related to the mutation of this gene, with a great clinical heterogeneity, and an age of onset in early childhood.
 The correlation between the TBC1D24 gene and epilepsy was known for the first time in 2010,it represents a great clinical heterogeneity, ranging from simple epileptic seizure with good cognitive and intellectual development and complete control of the disease, to severe epileptic encephalopathy, so the mutation of this gene can be associated with brain malformations and can be found in several syndromes including DOORS syndrome (which associates deafness, intellectual disability, seizures, onycho-dystrophy, osteo-dystrophy).
 This mutation is also described in non-syndromic deafness and in people suffering from various forms of epilepsy, including familial infantile myoclonic epilepsy, progressive myoclonic epilepsy, focal migrating epilepsy and writer's stress-induced paroxysmal rolandic-dystonic epilepsy syndrome.
 A panel of genes were searched in particular clinical situations when there are severe epilepsies, consanguinity, or similar family cases, with or without other associated damaged organ, thus the screening of the TBC1D24 mutation is indicated in a wide variety of epilepsies.

Investigation of the Genetic Etiology in Idiopathic Generalized Epileptic Disorders by Targeted Next-generation Sequencing Technique

Idiopathic generalized epilepsy is the most common group of epilepsy disorders in children and adolescents. Various types of genetic abnormality were identified among the hereditary factors that explain epilepsy. To determine the variations in the etiopathogenesis, treatment protocol planning, and prognosis of idiopathic generalized epilepsy using the next-generation sequencing method. A cross-sectional study. This study included 32 patients with idiopathic generalized epilepsy. Genomic DNA was obtained from peripheral venous blood samples taken from the patients. A total of 18 genes encoding ion channel subunits that are involved in monogenic disorders and are associated with idiopathic generalized epilepsy were included. The targeted custom next-generation sequencing panel was designed to cover all coding exons and all exon/intron splice site regions of 18 genes. We detected 9 (28%) variations, including 1 likely pathogenic (a variant in the SCN1A gene) and 8 of unknown clinical significance (2 in the CLCN2 genes, GABBR2, SCN1B, SLC2A1, SLC4A10 genes, and 2 in the TBC1D24 gene). Study results should be supported by functional advanced studies, with increased existing knowledge in the relevant variations.

The epilepsy and intellectual disability-associated protein TBC1D24 regulates the maintenance of excitatory synapses and animal behaviors.

Perturbation of synapse development underlies many inherited neurodevelopmental disorders including intellectual disability (ID). Diverse mutations on the human TBC1D24 gene are strongly associated with epilepsy and ID. However, the physiological function of TBC1D24 in the brain is not well understood, and there is a lack of genetic mouse model that mimics TBC1D24 loss-of-function for the study of animal behaviors. Here we report that TBC1D24 is present at the postsynaptic sites of excitatory synapses, where it is required for the maintenance of dendritic spines through inhibition of the small GTPase ARF6. Mice subjected to viral-mediated knockdown of TBC1D24 in the adult hippocampus display dendritic spine loss, deficits in contextual fear memory, as well as abnormal behaviors including hyperactivity and increased anxiety. Interestingly, we show that the protein stability of TBC1D24 is diminished by the disease-associated missense mutation that leads to F251L amino acid substitution. We further generate the F251L knock-in mice, and the homozygous mutants show increased neuronal excitability, spontaneous seizure and pre-mature death. Moreover, the heterozygous F251L knock-in mice survive into adulthood but display dendritic spine defects and impaired memory. Our findings therefore uncover a previously uncharacterized postsynaptic function of TBC1D24, and suggest that impaired dendritic spine maintenance contributes to the pathophysiology of individuals harboring TBC1D24 gene mutations. The F251L knock-in mice represent a useful animal model for investigation of the mechanistic link between TBC1D24 loss-of-function and neurodevelopmental disorders.

Early infantile epileptic encephalopathy type 16: the new clinical and genetic variant of TBC1D24 gene mutation

Objective: to analyse the clinical and neurophysiological data from a case of early infantile epileptic encephalopathy type 16 in a child with homozygous mutation in TBC1D24 gene. Material and methods . Female child M. aged 1 year and 2 months, with identified mutations in TBC1D24 gene was examined. The whole exome sequencing was performed (Next Generation Sequencing with the Illumina HiSeq 1500 platform, USA). Dynamic video-EEG monitoring was conducted with a “Encephalan-Video” RM-19/26 instrument (“Medicom MTD”, Russia). Results . According to the patient history, on the 22nd day of life, the child developed vocalisms with tonic tension of the limbs. At her 2 months of life, focal myoclonia and myoclono-clonies were noted; at her 4 months – return of tonic seizures with vocalisms followed by eyelid myoclonus, perioral myoclonus, ophthalmoclonia, alternating hemiconvulsions and tonic-clonic seizures. The family history of epilepsy was negative; the parents denied any consanguinity, but admitted a chance of being distant relatives. Neurological examination revealed hypotonic-astatic syndrome and psycho-motor retardation. A video EEG monitoring test detected multiple EEG negative multifocal myoclonic episodes in combination with dystonic hyperkinesia and motor automatism. Although typical epileptiform spike-wave discharges were rare, a focus of low-index spike-wave complexes was identified in the left temporal zone. Therapy with valproates, barbiturates and levetiracetam did not produce any significant effect but benzodiazepines (clonazepam) caused a moderate improvement; a switch to clobazam therapy was then recommended. This case of inherited developmental and epileptic encephalopathy was defined as early infantile epileptic encephalopathy type 16 (OMIM#615338) with autosomal recessive inheritance associated with a previously not described homozygous mutation of the TBC1D24 gene, chr:16:2546775 A>C that caused Tyr209Ser amino acid substitution. Pre-conception testing of the TBC1D24 gene under the IVF condition is recommended to the parents. Discussion . Since 2010, a few variants of early infantile epileptic encephalopathy type 16 caused by homozygous mutation of the TBC1D24 gene have been described in the literature. This clinical case is closer to progressive myoclonic epilepsy with dystonia (PMED), which indicates the nosological autonomy of this form of epilepsy. С onclusion . Children with pharmacoresistant epilepsy and epileptic encephalopathies, as well as those with unusual course of these diseases need genetic assessment with the new generation exom sequencing techniques – such as the “hereditary epilepsy” panel, as well as clinical and full-exom sequencing. All authors contributed equally to this publication.

Pathogenic gene variants and clinical phenotype features of 26 children with progressive myoclonic epilepsy

Objective: To identify the pathogenic gene variants and clinical phenotype features of 26 children with progressive myoclonic epilepsy (PME). Methods: In this cross-sectional study, 26 PME children (11 boys and 15 girls) sent to neurological outpatient clinics and admitted to wards of the Department of Pediatrics, Peking University First Hospital were enrolled prospectively from January 2014 to October 2018. The pathogenic gene variants of PME children and their parents were identified by Sanger sequencing, next generation sequencing panels of epilepsy or trio-based whole exome sequencing and so on. The genotypes and phenotypes of the PME children were anaylzed. Results: The clinical features of 26 children include myoclonus, multiple types of seizures and progressive neurological regression. Their onset ages ranged from 3 months to 15 years. Several pathogenic gene variants were identified in the 15 patients, including TPP1 gene variantions in 3 patients; NEU1, GBA, TBC1D24 and KCNC1 gene variantions in 2 patients respectively; CLN6, MFSD8, ASAH1 and ATN1 gene variantions in 1 patient respectively. Several variants of uncertain significance were identified in 4 patients, including GOSR2 gene compound heterozygous variants in 2 patients, KCTD7 gene compound heterozygous variants in 1 patient, and compound heterozygous variants of an unreported TARS gene in 1 patient. No pathogenic gene variant was identified in 7 patients. In 15 children with the identified pathogenic gene variants, 5 patients were diagnosed with neuronal ceroid lipofuscinoses (NCL), 2 patients with sialidosis, 2 patients with neuronopathic Gaucher disease, 1 patient with dentatorubral-pallidoluysian atrophy (DRPLA), and 1 patient with spinal muscular atrophy-progressive myoclonic epilepsy (SMA-PME). Conclusions: PME include a group of diseases with genetic heterogeneity. Identification of the pathogenic gene variants of PME could help to predict the prognosis and guide the genetic counseling.

Clinical phenotypes of TBC1D24 gene related epilepsy

Objective: To summarize the clinical features of TBC1D24 gene mutations associated with epilepsy. Methods: All the patients with TBC1D24 gene compound heterozygous mutations were retrospectively collected at the Pediatric Department of Peking University First Hospital from March 2015 to July 2017, and the features of clinical manifestations, electroencephalogram, and neuroimaging were analyzed. Results: Eighteen cases with TBC1D24 gene compound heterozygous mutations were included. The age of seizure onset was 1 day to 8 months, and the median age was 90 days. Seizure types included generalized tonic-clonic seizures (GTCS) in 3 cases, focal seizures in 18 cases, myoclonus in 18 cases, and 17 cases had focal myoclonus and myoclonus status. The focal myoclonus involving one or multiple muscle groups, sometimes migrating and alternating, lasting up to minutes to several days, and could be terminated by sleep or sedation drugs. In 11 cases, myoclonus was exacerbated by fever or infections, and 2 cases developed into myoclonic status during infection, in a severe case with the loss of consciousness. The magnetic resonance imaging (MRI) of seven patients was abnormal, including cerebral atrophy or cerebellar atrophy with abnormal signals. Segment myoclonus was captured in 10 patients, but without correlated epileptiform discharges. There were ten cases had varying degrees of developmental delay, 7 were normal, and one patient died of status epilepticus at the age of 4 months. Three cases had hearing disorders. In the 18 patients, the clinical phenotype of 4 cases consisted of epilepsy of infancy with migrating focal seizures, 2 with progressive myoclonus epilepsies, 1 with Dravet syndrome, 1 with DOORS syndrome, and 3 with unclassified epileptic encephalopathy. Conclusions: The clinical feature of TBC1D24 gene mutation related epilepsy was focal myoclonus, and tended to develop into myoclonic status epilepticus, and could be aggravated by infections, and terminated by sleep or sedation drugs. Mental retardation involved or not, neuroimaging could present with cerebral atrophy or cerebellar atrophy with abnormal signals.

Clinical features and gene analysis of TBC1D24 gene mutation related early-onset focal myoclonic epilepsy

Objective: To investigate the clinical features and genetic characteristics of patients with TBC1D24 gene mutation related early-onset focal myoclonic epilepsy. Methods: Clinical data of 3 patients with TBC1D24 gene mutation related early-onset focal myoclonic epilepsy of Xuanwu Hospital from November 2016 to June 2017 was collected and analyzed.Candidate gene mutations were screened by second generation sequencing. Results: Among the 3 patients, 1 was male and 2 were females.Seizure onset age was 4 months, 3 years and 5 years after birth respectively. Two patients had family history of epilepsy.They all had prolonged episodes of focal myoclonus. Two patients had mental retardation.Scalp electroencephalograms (EEG) was recorded in all 3 cases and myoclonic seizures were captured.The ictal EEGs were normal in all cases. In one patient, the ictal EEG of generalized seizure showed alpha rhythm originating from left fronto-central region. Brain magnetic resonance imaging (MRI) was normal in 2 patients. Abnormal signal was found bilaterally in cerebellum in 1 patient. The gene screening showed that two patients carried compound heterozygous mutation of TBC1D24 gene and one carried homozygous mutation, all of which were de novo mutations.All the patients were treated with multiple antiepileptic drugs (AEDs) and seizures were uncontrolled in 2 patients. One patient was followed up for 10 months without recurrence. Conclusions: TBC1D24 gene related early-onset focal myoclonic epilepsy is clinically characterized by early onset, prolonged focal myoclonus which relieved with sleep, mental retardation and poor response to AEDs.The interictal and ictal EEG usually show normal. Genetic analysis can assist in diagnosis and genetic counseling.

Study on the causative genes and analysis of genotypes and phenotypes of Dravet syndrome

Objective To identify the rare causative genes of Dravet syndrome(DS) in patients who do not have SCN1A mutation and to analyze genotypes and phenotypes of DS patients with different rare causative genes. Methods DS patients were collected from the Pediatric Department of Peking University First Hospital from February 2005 to August 2016.SCN1A and PCDH19 gene mutations were screened by Sanger sequencing and multiple ligation-dependant probe amplification (MLPA). Next generation sequencing (NGS) for epilepsy-related gene-panel was applied to SCN1A and PCDH19 mutation-negative patients.The phenotypes of DS patients with different rare causative genes were analyzed. Results Six hundred and seventy patients with DS were collected and 556 patients (83.0%) carried SCN1A mutations and 6 patients with PCDH19 mutations.Epilepsy-related gene-panel was applied to remain 108 patients without SCN1A or PCDH19 mutation, and among them 12 patients were detected with 6 rare causative genes, with heterozygous mutations in GABRA1 mutations in 3, GABRG2 in 2 cases, GABRB2 mutations in 2 cases and SCN2A mutation in 1 case, complex heterozygous mutations in TBC1D24 in 2 cases and ALDH7A1 in 2 cases.The clinical phenotypes of 6 patients with PCDH19 mutations were featured by clustering of repeated seizures with short periods of times, only 1 case had an episode of status epilepticus.Patients with GABRB2 mutations had a relatively better outcome of seizure control.Many episodes of myoclonic status were emerging as hallmark features in patients with TBC1D24 mutations.Vitamin B had a dramatic therapeutic effect in patients with ALDH7A1 mutations.The clinical phenotypes of DS patients with GABRG2, SCN2A and GABRA1 had no obvious specificity. Conclusions The rare causative genes in DS patients include PCDH19, GABRG2, SCN2A, GABRA1, GABRB2, TBC1D24 and ALDH7A1.The finding of causative genes GABRB2 and TBC1D24 may enrich the gene spectrum of DS.Patients with PCDH19 mutations are featured by clustering of repeated seizures with short periods of time and rare status epilepticus.Patients with GABRB2 mutations have a relatively better outcome of seizure control.Many episodes of myoclonic status are emerging as hallmark features in patients with TBC1D24 mutations. Key words: Dravet syndrome; Gene mutation; Genotypes; Phenotypes

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

Mutations disrupting presynaptic protein TBC1D24 are associated with a variable neurological phenotype, including DOORS syndrome, myoclonic epilepsy, early-infantile epileptic encephalopathy, and non-syndromic hearing loss. In this report, we describe a family segregating autosomal dominant epilepsy, and a 37-year-old Caucasian female with a severe neurological phenotype including epilepsy, Parkinsonism, psychosis, visual and auditory hallucinations, gait ataxia and intellectual disability. Whole exome sequencing revealed two missense mutations in the TBC1D24 gene segregating within this family (c.1078C>T; p.Arg360Cys and c.404C>T; p.Pro135Leu). The female proband who presents with a severe neurological phenotype carries both of these mutations in a compound heterozygous state. The p.Pro135Leu variant, however, is present in the proband's mother and sibling as well, and is consistent with an autosomal dominant pattern linked to tonic-clonic and myoclonic epilepsy. In conclusion, we describe a single family in which TBC1D24 mutations cause expanded dominant and recessive phenotypes. In addition, we discuss and highlight that some variants in TBC1D24 might cause a dominant susceptibility to epilepsy.

<i>TBC1D24</i> Mutations in a Sibship with Multifocal Polymyoclonus

<i>TBC1D24</i> Mutations in a Sibship with Multifocal Polymyoclonus

Alternating Hemiplegia and Epilepsia Partialis Continua: A new phenotype for a novel compound TBC1D24 mutation

Mutations in the TBC1D24 gene (MIM 613577) cause familial infantile myoclonic epilepsy (FIME; 605021) and early infantile epileptic encephalopathy-16 (EIEE16; 615338), both inherited with an autosomal recessive trait. The TBC1D24 gene encodes a member of the TBC family domain proteins, involved in cell signaling and oxidative stress resistance. We studied, by a Next Generation Sequencing (NGS) target re-sequencing gene approach, the DNA of a 5 year-old girl, affected by recurrent attacks of Alternating Hemiplegia (AH) and by recurrent episodes of Epilepsia Partialis Continua (EPC). The NGS study showed the presence of two different heterozygous, probably pathogenic variants in the TBC1D24 gene, inherited in trans from her parents: the c.116C>T (p.Ala39Val) and the c.457G>A (p.Glu153Lys). This study describes for the first time the association between TBC1D24 variants and AH expanding the phenotypic spectrum of TBC1D24-related diseases and suggesting that TBC1D24 molecular analysis should be considered in the diagnostic work up of AH patients. An additional peculiar feature is the association of AH and EPC.

Clinical features and gene mutations in epilepsy of infancy with migrating focal seizures

Objective: To summarize the clinical features and gene mutations of epilepsy of infancy with migrating focal seizures (EIMFS). Method: Clinical features and electroencephalograms(EEG)of 9 patients with EIMFS of Peking University First Hospital from May 2015 to January 2016 were analyzed. Candidate gene mutations were screened by next generation sequencing. Result: Among the 9 patients, 3 were males and 6 were females. Two patients had family history. Seizure onset age was 2 days to 3 months after birth (median age 35 days). Migrating focal seizure was presented. Seizures manifested as eyes and(or)head deviation, involuntary blinking, swallowing, trembling or stiffness of limbs, hand clenching, flushing and cyanosis of lips, etc. Four patients had a history of status epilepticus. All 9 patients had psychomotor delay. EEG of all patients presented relatively slow background; during interictal phase, there were multi-focal epileptic discharges, which dominated one hemisphere or brain region; seizures were recorded in all 9 cases, which manifested eyes or(and)head deviation, stiffening or trembling of limbs, lip smacking, etc. Corresponding EEG showed low-medium-amplitude fast waves that originated from some brain regions and migrated to other regions. Cranial magnetic resonance imaging (MRI) was abnormal in 4 cases, which predominantly showed white matter dysplasia and enlargement of subarachnoid spaces. Two cases carried heterozygous missense mutations of SCN1A gene, while 3 cases carried heterozygous missense mutations of KCNT1 gene, all of which were de novo. One case carried compound heterozygous mutation of TBC1D24 gene(p.Gln207*, p. Ala289Va). Gene mutation was not found in 3 cases. All patients used multiple antiepileptic drugs (AED) and their seizures were not controlled. Follow-up ranged from 2 months to 5 years and 8 months, during which 4 were found dead. Two were lost to follow-up. Conclusion: EIMFS is clinically characterized by early onset, which is usually within 3 months after birth, migrating focal seizures, psychomotor delay, bad response to AED and high death rate. The interictal EEG showed multi-focal discharges, while ictal EEG shows migrating multifocal discharges. Genetic analysis can assist in diagnosis and genetic counseling.

Clinical intrafamilial variability in lethal familial neonatal seizure disorder caused by TBC1D24 mutations.

TBC1D24-related disorders include a wide phenotypic ranging from mild to lethal seizure disorders, non-syndromic deafness, and composite syndromes such as DOORS (deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures). The TBC1D24 gene has a role in cerebral cortex development and in presynaptic neurotransmission. Here, we present a familial case of a lethal early-onset epileptic encephalopathy, associated with two novel compound heterozygous missense variants on the TBC1D24 gene, which were detected by exome sequencing. The detailed clinical data of the three siblings is summarized in order to support the variability of the phenotype, severity, and progression of this disorder among these family members. Functional studies demonstrated that the identified novel missense mutations result in a loss of expression of the protein, suggesting a correlation between residual expression, and the disease severity. This indicates that protein expression analysis is important for interpreting genetic results when novel variants are found, as well as for complementing clinical assessment by predicting the functional impact. Further analysis is necessary to delineate the clinical presentation of individuals with TBC1D24 pathogenic variants, as well as to develop markers for diagnosis, prognosis, and potential targeted treatments. © 2016 Wiley Periodicals, Inc.

Recessive TBC1D24 Mutations Are Frequent in Moroccan Non-Syndromic Hearing Loss Pedigrees.

Mutations in the TBC1D24 gene are responsible for four neurological presentations: infantile epileptic encephalopathy, infantile myoclonic epilepsy, DOORS (deafness, onychodystrophy, osteodystrophy, mental retardation and seizures) and NSHL (non-syndromic hearing loss). For the latter, two recessive (DFNB86) and one dominant (DFNA65) mutations have so far been identified in consanguineous Pakistani and European/Chinese families, respectively. Here we report the results of a genetic study performed on a large Moroccan cohort of deaf patients that identified three families with compound heterozygote mutations in TBC1D24. Four novel mutations were identified, among which, one c.641G>A (p.Arg214His) was present in the three families, and has a frequency of 2% in control Moroccan population with normal hearing, suggesting that it acts as an hypomorphic variant leading to restricted deafness when combined with another recessive severe mutation. Altogether, our results show that mutations in TBC1D24 gene are a frequent cause (>2%) of NSHL in Morocco, and that due to its possible compound heterozygote recessive transmission, this gene should be further considered and screened in other deaf cohorts.

Homozygous TBC1D24 mutation in two siblings with familial infantile myoclonic epilepsy (FIME) and moderate intellectual disability

Mutations in the TBC1D24 gene were first reported in an Italian family with a unique epileptic phenotype consisting of drug-responsive, early-onset idiopathic myoclonic seizures. Patients presented with isolated bilateral or focal myoclonia, which could evolve to long-lasting attacks without loss of consciousness, with a peculiar reflex component, and were associated with generalized tonic-clonic seizures. This entity was named "familial infantile myoclonic epilepsy" (FIME). More recently, TBC1D24 mutations have been shown to cause a variable range of disorders, including epilepsy of various seizure types and severity, non-syndromic deafness, and DOORS syndrome. We report on the electro-clinical features of two brothers, born to first-cousin parents, affected with infantile-onset myoclonic epilepsy. The peculiar epileptic presentation prompted us to perform direct sequencing of the TBC1D24 gene. The patients had very early onset of focal myoclonic fits with variable topography, lasting a few minutes to several hours, without loss of consciousness, which frequently evolved to generalized myoclonus or myoclonic status. Reflex myoclonia were noticed in one patient. Neurological outcome was marked by moderate intellectual disability. Despite the high frequency of seizures, repeated EEG recordings showed normal background rhythm and rare interictal spikes and waves. We found a homozygous missense mutation, c.457G>A/p.Glu153Lys, in the two affected brothers. This observation combined with recent data from the literature, suggest that mutations in TBCD24 cause a pathological continuum, with FIME at the "benign" end and severe drug-refractory epileptic encephalopathy on the severe end. Early-onset myoclonic epilepsy with focal and generalized myoclonic seizures is a common characteristic of this continuum.

Early-onset epileptic encephalopathy with hearing loss in two siblings with TBC1D24 recessive mutations

BackgroundRecent studies have shown that recessive mutations in the TBC1D24 gene cause a variety of epilepsy syndromes, DOORS syndrome and nonsyndromic deafness. Methods/ResultsWe report on two siblings with hypotonia, early-onset epileptic encephalopathy, and severe developmental delay. The patients presented with clonic and myoclonic jerks within 1 h after birth. The seizures were resistant to treatment. Audiologic examination showed bilateral sensorineural hearing loss in both siblings. Genetic analysis revealed compound heterozygous mutations in the TBC1D24 gene: a novel missense mutation c.32A > G (p.Asp11Gly) in exon 2 and a frameshift mutation c.1008delT (p.His336Glnfs*12) in exon 4. ConclusionThis report supports previous observations that mutations in TBC1D24 cause diverse phenotypes. In fact, early-onset epileptic encephalopathy with sensorineural hearing loss is an additional phenotype observed in patients with recessive TBC1D24 mutations.

TBC1D24 truncating mutation resulting in severe neurodegeneration

BackgroundRecessive TBC1D24 gene mutations have been described in two families: an Italian family afflicted with familial infantile myoclonic epilepsy, and an Arab family with focal epilepsy and intellectual disability syndrome....