TBC1D24 Mutations in a Sibship with Multifocal Polymyoclonus

Ngoh, Adeline; Brás, José; Guerreiro, Rita; McTague, Amy; Ng, Joanne; Meyer, Esther; Chong, W.K.; Boyd, Stewart; MacLellan, Linda; Kirkpatrick, Martin; Kurian, Manju A.

doi:10.7916/d8q52vbv

Cited by 5 publications

(2 citation statements)

References 22 publications

(35 reference statements)

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“…Research on patients with TBC1D24 gene mutations has shown a correlation between the severity of axon formation defects and disease severity 26 . Literature reports describe two siblings with multifocal myoclonus and developmental delay, where compound heterozygous mutations were identified, including missense and frameshift mutations within TBC1D24 34 . The protein product of the TBC1D24 gene acts as an ADP-ribosylation factor 6 (ARF6) binding partner, exerting its function by regulating the activity of ARF6.…”

Section: Discussionmentioning

confidence: 99%

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

Lei,

Zhu,

Dong

2024

Sci Rep

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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.

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Section: Discussionmentioning

confidence: 99%

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

Lei,

Zhu,

Dong

2024

Sci Rep

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“…In the study of Balestrini (1), one third of the patients with the TBC1D24 mutation had an abnormal MRI, in particular, hippocampal sclerosis, vermian hypoplasia, delayed myelination, cerebellar atrophy and cerebellar signal hyperintensity, for the case reported by Qilin Zhou (3), the MRI came back without abnormality, but he suggested that if further exploration, by a post-processing MRI procedure and by a combination of multimodality neuroimaging, restricted cerebral structural abnormalities, potentially epileptogenic can be found , for this patient the post-processing MRI procedure has objectified a slight gray-white blur in the left medial parietal region, Several studies have found cerebellar atrophy or cerebellar atrophy with abnormal MRI signals in patients with TBC1D24 mutations (7,8,9), in the study of Zing et al (2), MRI abnormalities were found in eight patients, including cerebellar atrophy, cerebral atrophy and abnormal signals in the cerebellum. Two patients had cerebellar atrophy with abnormal signals after prolonged myoclonus induced by infection and fever, in our patients the EEG was abnormal in only one patient showing a diffuse encephalopathy, the MRI came back normal for only one patient, for the second one it showed a diffuse parenchymal atrophy and for the third one it came back in favor of an enlargement of the sub-arachnoid spaces.…”

Section: Discussionmentioning

confidence: 99%

The mutation of TBC1D24 associated with epilepsy: About 3 cases

Mehdaoui,

Khabbache,

Bousgheiri

et al. 2023

IJHS

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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.

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Infantile-Onset Paroxysmal Movement Disorder and Episodic Ataxia Associated with a TBC1D24 Mutation

et al. 2019

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Mutations that disrupt the TBC1D24 presynaptic protein have been implicated in various neurological disorders including epilepsy, chronic encephalopathy, DOORS (deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures) syndrome, nonsyndromic hearing loss, and myoclonus. We present the case of a 22-month-old male with infantile-onset paroxysmal episodes of facial and limb myoclonus. The episodes were linked to biallelic variants in exon 2 of the TBC1D24 gene that lead to amino acid changes (c.304C >T/p.Pro102Ser and c.410T > C/p.Val137Ala), each variant being inherited from a parent. Follow-up imaging in adolescence revealed widened right cerebellar sulci. We discuss the evolving landscape of TBC1D24 associated phenotypes; this case adds to a growing body of evidence linking this gene to movement disorders in children.

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TBC1D24 Mutations in a Sibship with Multifocal Polymyoclonus

Cited by 5 publications

References 22 publications

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

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

The mutation of TBC1D24 associated with epilepsy: About 3 cases

Infantile-Onset Paroxysmal Movement Disorder and Episodic Ataxia Associated with a TBC1D24 Mutation

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