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

Stražišar, Barbara Gnidovec; Neubauer, David; Panjan, Darja Paro; Writzl, Karin

doi:10.1016/j.ejpn.2014.12.011

Cited by 25 publications

(36 citation statements)

References 13 publications

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“…The electro-clinical presentation of the two affected sisters from the second family was consistent with the diagnosis of malignant migrating partial seizures of infancy (Milh et al, 2013). In the third family, the epileptic phenotype was very similar to the patients reported here despite very severe neurological outcome, with early lethality in one patient (Stražišar et al, 2014).…”

Section: Discussionsupporting

confidence: 74%

“…Several patients had a more severe neurological presentation (Corbett et al, 2010;Milh et al, 2013;Duru et al, 2010;Stražišar et al, 2014). Corbett et al reported a large consanguineous family with seven affected individuals, who were described as having focal seizures with prominent eye blinking, as well as facial and limb jerking, which started at two months of age and persisted throughout life (Corbett et al, 2010;Afawi et al, 2013).…”

Section: Discussionmentioning

confidence: 96%

“…EEG data were not reported. Other mutations in TBC1D24 have been found in three families with devastating infantile epileptic encephalopathy (Milh et al, 2013;Duru et al, 2010;Stražišar et al, 2014). In the first one, the patients had long-lasting myoclonic seizures that were exacerbated by common infections and that did not respond to medication, with neurological deterioration (Duru et al, 2010).…”

Section: Discussionmentioning

confidence: 98%

“…This may suggest that missense mutations of TBC1D24 may have different functional consequences according their location on the protein sequence. It is also possible that truncating mutations may cause a more severe course of disease, with high mortality rate (Guven and Tolun, 2010;Stražišar et al, 2014).…”

Section: Discussionmentioning

confidence: 98%

“…The detailed electroclinical presentation, reported ten years earlier, has long remained an isolated description (de Falco et al, 2001). In the past year, thanks to the use of whole-exome sequencing, additional mutations in TBC1D24 have been reported in an increasing range of developmental disorders, including epilepsy of various severity, non-syndromic deafness and DOORS syndrome (OMIM 220500) that gets its name from the acronym of the main features: deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures (Corbett et al, 2010;Milh et al, 2013;Guven and Tolun, 2010;Rehman et al, 2014;Campeau et al, 2014;Stražišar et al, 2014).…”

Section: Introductionmentioning

confidence: 97%

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

Poulat¹,

Ville²,

Bellescize³

et al. 2015

Epilepsy Research

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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.

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Section: Discussionsupporting

confidence: 74%

Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 97%

See 3 more Smart Citations

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

Poulat¹,

Ville²,

Bellescize³

et al. 2015

Epilepsy Research

View full text Add to dashboard Cite

show abstract

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

Lozano

Herman

Rothfuss

et al. 2016

American J of Med Genetics Pt A

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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.

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A case of early‐onset epileptic encephalopathy with a homozygous TBC1D24 variant caused by uniparental isodisomy

Nakashima

Negishi

Hori

et al. 2019

American J of Med Genetics Pt A

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TBC1D24‐related disorders are rare neurodevelopmental disorders that show a broad range of neuropsychiatric deficits and are mostly inherited in an autosomal recessive manner. Here we describe a case with early‐onset epileptic encephalopathy, in whom exome sequencing detected a novel pathogenic homozygous c.442G>A, p.(Glu148Lys) variant in TBC1D24. She showed severe developmental delay, congenital sensorineural hearing loss and seizures, but the combination of a high dose phenobarbital and potassium bromide was very effective for the seizures. Sanger sequencing revealed that her mother was a heterozygous carrier of the TBC1D24 variant, but her father showed only wild‐type alleles. Homozygosity mapping analysis using exome data showed loss of the heterozygosity region at 16p13.3–p13.13 encompassing TBC1D24. Genotyping analysis using rare variants within loss of the heterozygosity region indicated that the patient has a homozygous haplotype inherited from her mother, indicating maternal segmental uniparental isodisomy (UPiD). These data clearly show that exome sequencing is a powerful tool to perform comprehensive genetic analysis.

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

Cited by 25 publications

References 13 publications

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

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

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

A case of early‐onset epileptic encephalopathy with a homozygous TBC1D24 variant caused by uniparental isodisomy

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