TBC1D24-Related Disorders

Balestrini S, Campeau PM, Mei D, et al.

Publication Details

Estimated reading time: 46 minutes

Summary

Clinical characteristics.

TBC1D24-related disorders comprise a continuum of features that were originally described as distinct, recognized phenotypes: DOORS syndrome (deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures), with profound sensorineural hearing loss, onychodystrophy, osteodystrophy, intellectual disability / developmental delay, and seizures; familial infantile myoclonic epilepsy (FIME), with early-onset myoclonic seizures, focal epilepsy, dysarthria, and mild-to-moderate intellectual disability; progressive myoclonus epilepsy (PME), with action myoclonus, tonic-clonic seizures, ataxia, and progressive neurologic decline; rolandic epilepsy with paroxysmal exercise-induced dystonia and writer's cramp (EPRPDC); developmental and epileptic encephalopathy (DEE), including epilepsy of infancy with migrating focal seizures (EIMFS); autosomal recessive nonsyndromic hearing loss (DFNB); and autosomal dominant nonsyndromic hearing loss (DFNA).

Diagnosis/testing.

The diagnosis of a TBC1D24-related disorder is established in an individual with suggestive findings biallelic TBC1D24 pathogenic variants when the mode of inheritance is autosomal recessive (i.e., DOORS syndrome, FIME, PME, EPRPDC, DEE, and DFNB), and in an individual with suggestive findings and a heterozygous TBC1D24 pathogenic variant when the mode of inheritance is autosomal dominant (DFNA).

Management.

Treatment of manifestations: Hearing aids or cochlear implants as needed for hearing loss; early educational intervention and physical, occupational, and speech therapy for developmental delay; symptomatic pharmacologic management for seizures; standard treatment for tremors, dystonic attacks, or other neurologic manifestations; routine management of visual impairment and renal, cardiac, dental, orthopedic, and endocrine issues.

Surveillance: Neurologic evaluations with EEGs depending on seizure frequency and/or progression; annual audiologic evaluations to assess for possible progression of hearing loss and/or the efficacy of hearing aids; annual dental evaluations; annual endocrine evaluations.

Agents/circumstances to avoid: Excessive ambient noise, which may exacerbate hearing loss in individuals with a heterozygous TBC1D24 pathogenic variant that causes autosomal dominant hearing loss (DFNA).

Evaluation of relatives at risk: Molecular genetic testing for the familial TBC1D24 pathogenic variant(s) in older and younger sibs of a proband is appropriate in order to identify as early as possible those who would benefit from early treatment of seizures and/or hearing loss.

Genetic counseling.

Most TBC1D24-related disorders are inherited in an autosomal recessive manner (DOORS syndrome, FIME, PME, EPRPDC, and DEE [including EIMFS]). TBC1D24-related nonsyndromic hearing loss can be inherited in an autosomal recessive (DFNB) or autosomal dominant (DFNA) manner.

Autosomal recessive inheritance: If both parents are known to be heterozygous for a TBC1D24 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial TBC1D24 pathogenic variants. Heterozygotes (carriers) are typically asymptomatic. Carrier testing for at-risk relatives requires prior identification of the TBC1D24 pathogenic variants in the family.

Once the TBC1D24 pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

GeneReview Scope

Table Icon

Table

TBC1D24-Related Disorders: Included Phenotypes 1

Diagnosis

TBC1D24-related disorders comprise a continuum of distinct phenotypes:

  • DOORS syndrome (deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures)
  • Familial infantile myoclonic epilepsy (FIME)
  • Progressive myoclonic epilepsy (PME)
  • Rolandic epilepsy with paroxysmal exercise-induced dystonia and writer's cramp (EPRPDC)
  • Developmental and epileptic encephalopathy (DEE), including epilepsy of infancy with migrating focal seizures (EIMFS)
  • Autosomal recessive nonsyndromic hearing loss (DFNB)
  • Autosomal dominant nonsyndromic hearing loss (DFNA)

Suggestive Findings

A TBC1D24-related disorder should be suspected in individuals with the following clinical features, which have been reported in several phenotypes that comprise a phenotypic continuum (information on additional features is provided in Clinical Characteristics).

  • Deafness, including profound sensorineural hearing loss
  • Seizures
    • Variable in severity; can be mild to severe, including early-onset and intractable epilepsy
    • Different seizure types including myoclonic, generalized tonic-clonic, focal including hemifacial, with or without autonomic changes
    • Variable EEG findings including centrotemporal sharp waves and spikes
  • Other neurologic features including:
    • Ataxia
    • Exercise-induced dystonia
    • Writer's cramp, difficulties with fine motor skills
  • Neurodevelopmental features, including intellectual disability / developmental delays; can vary in severity from mild to severe delays with progressive neurologic decline
  • Nail and digital features including:
    • Onychodystrophy (short/absent nails)
    • Osteodystrophy (short phalanges)

Establishing the Diagnosis

The diagnosis of a TBC1D24-related disorder is established in a proband with suggestive findings and one of the following identified by molecular genetic testing (see Table 1):

  • Biallelic TBC1D24 pathogenic variants when the mode of inheritance is autosomal recessive (i.e., DOORS syndrome, FIME, EIFMS, PME, EPRPDC, DEE, and DFNB)
  • A heterozygous TBC1D24 pathogenic variant when the mode of inheritance is autosomal dominant (DFNA)

Notes: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) The identification of variant(s) of uncertain significance cannot be used to confirm or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of a TBC1D24-related disorder has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Option 1

Single-gene testing. Sequence analysis of TBC1D24 is performed first to detect missense, nonsense, and splice site variants as well as small intragenic deletions/insertions. Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications.

Note: (1) The molecular diagnostic yield appears to be highest in individuals who have all five typical features of DOORS syndrome [Campeau et al 2014]. (2) The proportion of epilepsy caused by pathogenic variants in TBC1D24 is unknown but appears to be small [Symonds et al 2019].

A multigene panel that includes TBC1D24 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including TBC1D24) that cannot be detected by sequence analysis. Some laboratories use low-pass whole-genome sequencing (LP-WGS) instead of CMA for genome-wide CNV detection.

For an introduction to CMA click here. More detailed information for clinicians ordering genetic tests can be found here.

Option 2

When the diagnosis of a TBC1D24-related disorder has not been considered because an individual has atypical phenotypic features, comprehensive genomic testing does not require the clinician to determine which gene is likely involved. Exome sequencing is most commonly used; genome sequencing is also possible. To date, the majority of TBC1D24 pathogenic variants reported (e.g., missense, nonsense) are within the coding region and are likely to be identified on exome sequencing.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table Icon

Table 1.

Molecular Genetic Testing Used in TBC1D24-Related Disorders

Clinical Characteristics

Clinical Description

Pathogenic variants in TBC1D24 are associated with a spectrum of epilepsy and hearing loss phenotypes, including DOORS syndrome (deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures), familial infantile myoclonic epilepsy (FIME), progressive myoclonic epilepsy (PME), rolandic epilepsy with paroxysmal exercise-induced dystonia and writer's cramp (EPRPDC), developmental and epileptic encephalopathy (DEE) including epilepsy of infancy with migrating focal seizures (EIMFS), autosomal recessive nonsyndromic hearing loss (DFNB), and autosomal dominant nonsyndromic hearing loss (DFNA).

The contribution of TBC1D24 variants to these phenotypes is shown in Table 3.

Table Icon

Table 2.

Epilepsy/Deafness Phenotypes in TBC1D24-Related Disorders

To date, at least 200 individuals have been identified with pathogenic variant(s) in TBC1D24 [Corbett et al 2010, Falace et al 2010, Afawi et al 2013, Guven & Tolun 2013, Milh et al 2013, Azaiez et al 2014, Campeau et al 2014, Rehman et al 2014, Zhang et al 2014, Bakhchane et al 2015, Muona et al 2015, Poulat et al 2015, Appavu et al 2016, Balestrini et al 2016, de Kovel et al 2016, Lozano et al 2016, Hamdan et al 2017, Atli et al 2018, Danial-Farran et al 2018, Burgess et al 2019, Lüthy et al 2019, Nakashima et al 2019, Wang et al 2019, Zhang et al 2019, Boucher et al 2020, Hong et al 2020, Parzefall et al 2020, Safka Brozkova et al 2020, Salemi et al 2020, Steel et al 2020, Tona et al 2020, Uzunhan & Uyanik 2020, Xiang et al 2020, Chen et al 2021, Fang et al 2021, Oziębło et al 2021, Panjan et al 2021, Lee et al 2022, Quaio et al 2022, Reis et al 2022, Shao et al 2022, Zhao et al 2022, Hosseinpour et al 2023, Jiang et al 2023, Lei et al 2024]. The following description of the phenotypic features associated with this condition is based on these reports.

Table Icon

Table 3.

TBC1D24-Related Disorders: Frequency of Select Features

DOORS Syndrome

The five major features of DOORS syndrome are profound sensorineural hearing loss, onychodystrophy, osteodystrophy, intellectual disability / developmental delay, and seizures [James et al 2007, Campeau et al 2014].

Sensorineural hearing loss is often profound and prelingual. Some individuals have benefited from cochlear implants.

Onychoosteodystrophy affects the hands and feet equally. Small or absent nails (onychodystrophy) and hypoplastic terminal phalanges (osteodystrophy) are noted in most individuals. A triphalangeal thumb is present in one third of affected individuals.

Intellectual disability can vary significantly in degree but is often severe [Balestrini et al 2016, Atli et al 2018]. When such details were available, motor and language skills were most delayed [Nomura et al 2009, Girish et al 2011]. One child had autism spectrum disorder [Nomura et al 2009].

Seizures, present in most individuals with DOORS syndrome, usually start in the first year of life. The seizures are more often generalized tonic-clonic, but myoclonic, partial, and absence seizures also occur. Occasionally their frequency or severity increases. In several instances, seizures have been difficult to control even with multiple anti-seizure medications and have led to status epilepticus and death.

On brain MRI, hyperintense T2-weighted signal anomalies may be observed in the cerebellar hemispheres and the frontal regions [Campeau et al 2014].

Nonspecific dysmorphic features. A wide nasal base and a bulbous nose are the most common facial dysmorphisms. Other findings in a minority of individuals include narrow forehead, narrow or high-arched palate, broad alveolar ridge, short frenulum, and nevus simplex on the glabella and nose.

Other features. In individuals with DOORS syndrome, several additional anomalies may be noted, including the following [Campeau et al 2014]:

  • Microcephaly (estimated to occur in one third of individuals)
  • Other cranial anomalies (sagittal craniosynostosis, frontal bossing, trigonocephaly, or brachycephaly in several other affected individuals)
  • Dental anomalies (delayed eruption, wide spacing, and abnormal shape, size, and number)
  • Congenital heart defects (e.g., double outlet right ventricle, atrial septal defect, third-degree atrioventricular block)
  • Skeletal anomalies (e.g., calcaneal deformities)
  • Hypothyroidism
  • Renal and urinary tract anomalies (e.g., hydronephrosis, nephrocalcinosis)
  • Elevated levels of urinary 2-oxoglutaric acid, which can fluctuate between normal and elevated over time [Patton et al 1987, van Bever et al 2007, Campeau et al 2014]
  • Visual impairment [Balestrini et al 2016]
  • Peripheral neuropathy (in 1 individual with confirmed TBC1D24 pathogenic variants [Balestrini et la 2016] and 3 individuals who either did not undergo genetic testing or in whom no TBC1D24 pathogenic variant was identified)
  • Hypochromic microcytic anemia (reported in at least 1 individual with confirmed TBC1D24 pathogenic variants [Atli et al 2018])

Familial Infantile Myoclonic Epilepsy (FIME)

TBC1D24-related FIME is characterized by early-onset myoclonic seizures. Findings include focal epilepsy, dysarthria, mild-to-moderate intellectual disability, and cerebellar abnormalities including symmetrical and bilateral selective atrophy and signal abnormality (including decreased T1 signal and increased FLAIR and T2 signal with blurring of the gray-white boundary in the ansiform lobule on brain MRI) [Corbett et al 2010, Afawi et al 2013].

Intellect may be normal; all seven members of an Italian family with FIME and biallelic TBC1D24 pathogenic variants had normal intelligence. Six had normal brain imaging and one had periventricular nodular heterotopia [Zara et al 2000, de Falco et al 2001, Falace et al 2010].

Progressive Myoclonic Epilepsy (PME)

TBC1D24-related PME is characterized by action myoclonus, tonic-clonic seizures, ataxia, and progressive neurologic decline. In one child with PME and biallelic pathogenic variants in TBC1D24, tonic seizures started 36 hours after birth. Developmental delay and later regression were reported. Myoclonus started at age eight months and tonic-clonic seizures at age 3.5 years. Ataxia, spasticity, supranuclear gaze palsy, and visual function decline were also noted. Although the initial clinical diagnosis was epileptic encephalopathy, a florid PME pattern became apparent by age nine years [Muona et al 2015]. There were no digital anomalies or deafness [S Berkovic, personal observation]. Two additional sporadic individuals have been reported with PME caused by biallelic TBC1D24 variants. The clinical manifestations included prominent myoclonus, cerebellar ataxia, and developmental delay. Seizure onset was at ages three and seven months, respectively. Both individuals had cerebellar atrophy with hyperintense T2 signals; one also had global cerebral atrophy [Zhang et al 2019]. In one of the affected individuals, hearing was assessed to be normal before age 9 years. However, bilateral profound sensorineural deafness became apparent on subsequent auditory testing.

Rolandic Epilepsy with Paroxysmal Exercise-Induced Dystonia and Writer's Cramp (EPRPDC)

TBC1D24-related EPRPDC is a syndrome with onset in infancy, featuring focal motor seizures, often hemifacial, centrotemporal EEG abnormalities, and paroxysmal dystonia precipitated by sustained exercise or emotional stress. Exercise-induced dystonia includes forearm dystonia that causes writing to progressively become scribbled and then impossible after a few minutes. Data on long-term follow up show that focal motor seizures, manifesting infrequently after infancy, respond to carbamazepine or oxcarbazepine treatment, with no relapse in adulthood. Exercise-induced dystonia can still be present, although attacks are less frequent in adulthood, with affected individuals reported to have learned how to limit fatigue or physical exercise by modulating their activities.

Adult individuals can still exhibit mild nystagmus and postural tremor of the hands. Trihexyphenidyl can be effective as an anti-tremor drug. Treatment with carbidopa/levodopa, lamotrigine, and benzodiazepines can be effective for treatment of dystonic attacks or seizures. Acetazolamide, flunarizine, valproate, and levetiracetam have been reported as ineffective. Treatment with ubidecarenone was tentatively started at age 30 years in one individual who reported no overall benefits and ceased medication after two months, as seizures had long been under remission and exercise-induced dystonia episodes were rare at the time [Guerrini et al 1999, Lüthy et al 2019].

Brain MRI is typically normal including in adulthood in most individuals [Lüthy et al 2019, Hosseinpour et al 2023]. Mild nonprogressive pontocerebellar hypoplasia was reported in one individual [Steel et al 2020].

Developmental and Epileptic Encephalopathy (DEE)

Clinical manifestations in individuals with TBC1D24-related DEE include myoclonic epilepsy with episodic dystonia, hemiparesis, autonomic signs, and lethargy evolving to chronic dystonia, progressive diffuse cerebral atrophy, and early death. Several families [Guven & Tolun 2013, Milh et al 2013, Lozano et al 2016, Panjan et al 2021, Lee et al 2022] and 21 additional unrelated individuals have been reported [Appavu et al 2016, de Kovel et al 2016, Hamdan et al 2017, Nakashima et al 2019, Zhang et al 2019, Hong et al 2020, Salemi et al 2020, Uzunhan & Uyanik 2020, Chen et al 2021, Zhao et al 2022, Jiang et al 2023].

Epilepsy of infancy with migrating focal seizures (EIMFS). Epilepsy of infancy with migrating focal seizures (EIMFS) is a type of DEE characterized by seizure migration between cerebral hemispheres and profound developmental impairment often with regression. Seizure onset occurs in the first six months of life, with seizures that often increase in frequency over the first few months and are refractory to anti-seizure medications. This phenotype has been reported in French sibs [Milh et al 2013]. Several additional unrelated individuals have also been reported [Appavu et al 2016, Burgess et al 2019, Zhang et al 2019, Fang et al 2021].

Autosomal Recessive Nonsyndromic Hearing Loss (DFNB)

Clinical findings in individuals with TBC1D24-related DFNB include profound prelingual deafness with hearing thresholds above 90 dB for all test frequencies (in 2 consanguineous Pakistani families; one affected family member and one individual with a heterozygous TBC1D24 pathogenic variant also had seizures [Rehman et al 2014]).

Additional compound heterozygous pathogenic variants have been reported in three Moroccan families [Bakhchane et al 2015], one consaguineous family of the Arab population of northern Israel [Danial-Farran et al 2018], one non-consaguineous Pakistani family [Tona et al 2020], and several unrelated individuals of Czech [Safka Brozkova et al 2020], Chinese [Xiang et al 2020], Portuguese [Reis et al 2022], and Brazilian ancestry [Quaio et al 2022].

Autosomal Dominant Nonsyndromic Hearing Loss (DFNA)

Clinical findings in individuals with TBC1D24-related DFNA include slowly progressive deafness with onset in the third decade, initially affecting high frequencies (in a Chinese family [Zhang et al 2014] and in a family of European descent [Azaiez et al 2014]). Additional heterozygous pathogenic variants in TBC1D24 have been reported in two northern European, two Polish, one Brazilian, and one Chinese family with autosomal dominant nonsyndromic late-onset hearing loss [Parzefall et al 2020, Oziębło et al 2021, Quaio et al 2022, Lei et al 2024] and in one French individual [Boucher et al 2020].

Other Phenotypes

Other phenotypes seen in individuals with biallelic TBC1D24 pathogenic variants include parkinsonism [Banuelos et al 2017], ataxia, dysarthria, axial hypotonia, hearing loss, visual impairment, mild dysmorphic facial features, developmental delay or intellectual disability, microcephaly [Balestrini et al 2016], alternating hemiplegia of childhood [Ragona et al 2017, Cordani et al 2022], non-convulsive status epilepticus (NCSE), cerebellar ataxia and ophthalmoplegia [Li et al 2018], epilepsia partialis continua [Zhou et al 2018], infantile-onset paroxysmal movement disorder and episodic ataxia [Zimmern et al 2019], and multifocal polymyoclonus with or without neurodevelopmental delay [Ngoh et al 2017, Murofushi et al 2023, Sarıgecılı & Anlas 2023].

Heterozygotes

Several clinical features have been observed in individuals who have heterozygous pathogenic TBC1D24 variants in the context of autosomal recessive disease.

Two unrelated individuals with generalized tonic-clonic seizures and biallelic pathogenic TBC1D24 variants had a family history of hearing loss, but the relatives with hearing loss were not tested for a heterozygous TBC1D24 pathogenic variant. In one family the affected individual's brother had hearing loss, and in the other family the affected individual's maternal grandmother had hearing loss [Balestrini et al 2016].

In a family with autosomal recessive hearing loss, an individual with a heterozygous TBC1D24 pathogenic variant (c.208G>T [p.Asp70Tyr]) developed seizures starting at age three years [Rehman et al 2014].

A family history of seizures was also reported in two families with DOORS syndrome, including a mother who was heterozygous for the TBC1D24 pathogenic variant c.1008delT [p.His336GlnfsTer12] and had absence seizures in childhood [Campeau et al 2014] and a heterozygous father [Balestrini et al 2016 (supplemental material)].

In a family with an atypical neurologic phenotype in the proband, the affected individual's mother and her brother had seizures in childhood and adolescence, respectively. Both were confirmed to have a heterozygous pathogenic TBC1D24 variant (c.404C>T [p.Pro135Leu]) [Banuelos et al 2017].

Genotype-Phenotype Correlations

TBC1D24 pathogenic variants are located throughout the gene.

  • In general, loss-of-function (LOF) variants (frameshift, nonsense, or splice site variants) are associated with more severe epilepsy phenotypes with resistance to anti-seizure medications (ASM) and early death, except when the LOF variant is in the last exon.
  • TBC1D24 (TBC1 domain family member 24; protein encoded by TBC1D24) has two functional domains: a proximal TBC domain and a distal TLDc domain. Pathogenic missense variants in or before the TBC domain are associated with a higher risk of mortality [Balestrini et al 2016].
  • To date, all known pathogenic variants of TBC1D24 associated with autosomal dominant inherited deafness have been missense variants [Lei et al 2024].

Interfamilial clinical heterogeneity. Some pathogenic variants causing one phenotype have been demonstrated to cause other phenotypes in different families. Examples include:

  • The p.Ala500Val heterozygous variant, which has been identified in compound heterozygous individuals with EIMFS (n=3), infantile myoclonic epilepsy (n=1), and nonconvulsive status epilepticus (NCSE), cerebellar ataxia, and ophthalmoplegia (n=1);
  • The c.1008delT frameshift variant, which has been identified in compound heterozygous individuals with DOORS syndrome (n=2) and one sib pair with DEE and early death (n=2);
  • The p.Ala39Val pathogenic variant, which has been identified in compound heterozygous individuals with EIMFS (n=1) and alternating hemiplegia of childhood and epilepsia partialis continua (n=1);
  • The p.Gln207Term pathogenic variant, which has been identified in compound heterozygous individuals with EIMFS (n=1), infantile myoclonic epilepsy (n=1), and generalised epilepsy, DOORS syndrome, and parkinsonism (n=1).

Intrafamilial clinical heterogeneity. The c.965+1G>A pathogenic splice site variant has been identified in trans with the c.641G>A (p.Arg214His) pathogenic missense variant in a Pakistani family in whom affected individuals exhibited either a deafness-seizure syndrome or nonsyndromic deafness.

Penetrance

Penetrance of TBC1D24-related disorders appears to be high, at least for the conditions known to be inherited in an autosomal recessive pattern, but variable expressivity, even within the same phenotype, has been described. Penetrance is not different between males and females. DFNA usually manifests in the third decade of life.

Nomenclature

The acronym "DOOR syndrome" was coined in 1975 [Cantwell 1975]. Subsequently, Qazi & Nangia [1984] suggested adding an "S" (DOORS syndrome) because of the seizures present in most individuals. Other terms used for this condition include digito-reno-cerebral syndrome [Eronen et al 1985] and Eronen syndrome [Le Merrer et al 1992].

Developmental and epileptic encephalopathies (DEE) are defined by the International League Against Epilepsy (ILAE) as conditions in which epileptiform EEG abnormalities themselves are believed to contribute to progressive disturbance in cerebral function [Scheffer et al 2017, Scheffer et al 2024].

Epilepsy of infancy with migrating focal seizures (EIMFS) – a type of DEE – was initially referred to as migrating partial seizures of infancy (MMPSI) [Coppola et al 1995, Milh et al 2013].

Prevalence

The prevalence of TBC1D24-related disorders is very low. To date, fewer than 50 families with DOORS syndrome are known. TBC1D24 pathogenic variants have been identified in individuals from different populations, including Moroccan, Pakistani, Czech, Chinese, Brazilian, Polish, and northern European.

Differential Diagnosis

DOORS Syndrome

Table Icon

Table 4.

Genetic Disorders in the Differential Diagnosis of DOORS Syndrome

Fetal anticonvulsant syndrome, also associated with intellectual disability, developmental delay, and nail hypoplasia, can be considered in the differential diagnosis of DOORS syndrome. However, fetal anticonvulsant syndrome is not associated with hearing loss or seizures and is further characterized by dental abnormalities with delayed eruption, talipes equinovarus, and otitis media with effusion.

Familial Infantile Myoclonic Epilepsy (FIME) and Progressive Myoclonus Epilepsy (PME)

Table Icon

Table 5.

Disorders to Consider in the Differential Diagnosis of FIME and PME

Developmental and Epileptic Encephalopathy (DEE)

DEE is genetically heterogeneous. More than 100 genes are known to be associated with DEE. See OMIM Phenotypic Series: Developmental and epileptic encephalopathy to view genes associated with this phenotype in OMIM.

Hereditary Hearing Loss and Deafness

See Genetic Hearing Loss Overview.

Management

No clinical practice guidelines for TBC1D24-related disorders have been published.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with a TBC1D24-related disorder, the evaluations summarized in Table 6 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table Icon

Table 6.

TBC1D24-Related Disorders: Recommended Evaluations Following Initial Diagnosis

Treatment of Manifestations

There is no cure for TBC1D24-related disorders. Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 7).

Table Icon

Table 7.

TBC1D24-Related Disorders: Treatment of Manifestations

Developmental Delay / Intellectual Disability Management Issues

The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.

Ages 0-3 years. Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy as well as infant mental health services, special educators, and sensory impairment specialists. In the US, early intervention is a federally funded program available in all states that provides in-home services to target individual therapy needs.

Ages 3-5 years. In the US, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed for those who qualify based on established motor, language, social, or cognitive delay. The early intervention program typically assists with this transition. Developmental preschool is center based; for children too medically unstable to attend, home-based services are provided.

All ages. Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies (US) and to support parents in maximizing quality of life. Some issues to consider:

  • IEP services:
    • An IEP provides specially designed instruction and related services to children who qualify.
    • IEP services will be reviewed annually to determine whether any changes are needed.
    • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
    • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
    • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
    • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
  • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
  • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
  • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.

Motor Dysfunction

Gross motor dysfunction

  • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
  • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).

Fine motor dysfunction. Occupational therapy is recommended for difficulty with fine motor skills that affect adaptive function such as feeding, grooming, dressing, and writing.

Communication issues. Consider evaluation for alternative means of communication (e.g., augmentative and alternative communication [AAC]) for individuals who have expressive language difficulties. An AAC evaluation can be completed by a speech-language pathologist who has expertise in the area. The evaluation will consider cognitive abilities and sensory impairments to determine the most appropriate form of communication. AAC devices can range from low-tech, such as picture exchange communication, to high-tech, such as voice-generating devices. Contrary to popular belief, AAC devices do not hinder verbal development of speech, but rather support optimal speech and language development.

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 8 are recommended.

Table Icon

Table 8.

TBC1D24-Related Disorders: Recommended Surveillance

Agents/Circumstances to Avoid

Individuals with a heterozygous TBC1D24 pathogenic variant causing autosomal dominant deafness (DFNA) should avoid excessive ambient noise, as it may exacerbate hearing loss.

Evaluation of Relatives at Risk

It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk sibs of an affected individual to identify as early as possible those who would benefit from early treatment of seizures and/or hearing loss.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

In general, no information on specific prenatal presentations is available.

Polyhydramnios is often noted when a fetus has DOORS syndrome [James et al 2007]. A subsequent affected pregnancy in one family with DOORS syndrome was terminated due to an increased nuchal translucency of 5.1 mm at 12 weeks' estimated gestational age [Balestrini et al 2016].

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members; it is not meant to address all personal, cultural, or ethical issues that may arise or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Most TBC1D24-related disorders are inherited in an autosomal recessive manner, including DOORS syndrome, familial infantile myoclonic epilepsy (FIME), progressive myoclonic epilepsy (PME), rolandic epilepsy with paroxysmal exercise-induced dystonia and writer's cramp (EPRPDC), and developmental and epileptic encephalopathy (DEE), including epilepsy of infancy with migrating focal seizures (EIMFS).

TBC1D24-related nonsyndromic hearing loss can be inherited in an autosomal recessive (DFNB) or an autosomal dominant (DFNA) manner. For a review of genetic counseling issues associated with nonsyndromic hearing loss, see Genetic Hearing Loss Overview, Genetic Counseling.

Risk to Family Members (Autosomal Recessive Inheritance)

Parents of a proband

  • The parents of an affected child are presumed to be heterozygous for a TBC1D24 pathogenic variant.
  • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a TBC1D24 pathogenic variant and to allow reliable recurrence risk assessment.
  • If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
    • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
    • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
  • Heterozygotes (carriers) are typically asymptomatic. It is possible that certain TBC1D24 pathogenic variants may be associated with an increased susceptibility to seizures in heterozygotes, but genotype-phenotype correlation is lacking and no risk estimates are available (see Clinical Description, Heterozygotes).

Sibs of a proband

  • If both parents are known to be heterozygous for a TBC1D24 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial TBC1D24 pathogenic variants.
  • Sibs who inherit biallelic pathogenic variants are likely to have clinical manifestations similar to those in the proband.
  • Heterozygotes (carriers) are typically asymptomatic. It is possible that certain TBC1D24 pathogenic variants may be associated with an elevated susceptibility to seizures in heterozygotes, but genotype-phenotype correlation is lacking and no risk estimates are available (see Clinical Description, Heterozygotes).

Offspring of a proband

  • To date, individuals with DOORS syndrome, TBC1D24-related PME, and TBC1D24-related DEE are not known to reproduce.
  • The offspring of an individual with TBC1D24-related FIME or TBC1D24-related DFNB are obligate heterozygotes (carriers) for a pathogenic variant in TBC1D24.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a TBC1D24 pathogenic variant.

Heterozygote detection. Carrier testing for at-risk relatives requires prior identification of the TBC1D24 pathogenic variants in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

The following points are noteworthy:

  • Clear communication between individuals with hearing loss, families, and health care providers is key. D/deaf and hard of hearing (DHH) persons may use a variety of communication methods including spoken language, sign language, lip reading, and written notes. For DHH individuals and families who use sign language, a certified sign language interpreter must be used. Communication aids such as visual aids and verbal cues when changing topics can be helpful.
  • It is important to ascertain and address the questions and concerns of the family/individual. DHH persons may be interested in obtaining information about the cause of their hearing loss, including information on medical, educational, and social services. Others may seek information about the chance of having children with hearing loss and information for family planning decisions.
  • The use of neutral or balanced terminology can enhance the provision of services; for example: use of the term "chance" instead of "risk"; "deaf" or "hearing" instead of "affected" or "unaffected"; and "deaf" or "hard of hearing" instead of "hearing impaired." Members of the Deaf community may view deafness as a distinguishing characteristic and not as a handicap, impairment, or medical condition requiring a "treatment" or "cure," or to be "prevented." Terms such as "handicap" should be avoided.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

Prenatal Testing and Preimplantation Genetic Testing

Once the TBC1D24 pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • American Epilepsy Society
  • American Society for Deaf Children
    Phone: 800-942-2732 (ASDC)
    Email: info@deafchildren.org
  • Canadian Epilepsy Alliance
    Canada
    Phone: 1-866-EPILEPSY (1-866-374-5377)
  • Epilepsy Foundation
    Phone: 800-332-1000; 866-748-8008
  • National Association of the Deaf
    Phone: 301-587-1788 (Purple/ZVRS); 301-328-1443 (Sorenson); 301-338-6380 (Convo)
    Fax: 301-587-1791
    Email: nad.info@nad.org
  • National Institute of Neurological Disorders and Stroke (NINDS)
    Phone: 800-352-9424

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table Icon

Table A.

TBC1D24-Related Disorders: Genes and Databases

Table Icon

Table B.

OMIM Entries for TBC1D24-Related Disorders (View All in OMIM)

Molecular Pathogenesis

TBC1D24 encodes TBC1 domain family member 24 (TBC1D24), a Tre2-Bub2-Cdc16 (TBC) domain-containing RAB GTPase-activating protein, which catalyzes the hydrolysis of GTP by small GTPases, thus regulating the proper transport of intracellular vesicles. TBC1D24 is the only TBC/RabGAP protein with a TLDc domain (TBC, LysM, Domain catalytic); it is of unknown function but is thought to be involved in oxidative stress resistance and may have some enzymatic activity. TBC1D24 has been demonstrated to interact with ARF6 when both proteins are overexpressed in cell culture [Falace et al 2010, Falace et al 2014]. In C elegans, C31H2.1 (a TBC1D24 ortholog) was implicated in synaptic function by an RNAi screen [Sieburth et al 2005]. In Drosophila, the ortholog Skywalker (Sky) facilitates endosomal trafficking in synaptic vesicles by facilitating GTP hydrolysis by Rab35, thus controlling synaptic vesicle rejuvenation and neurotransmitter release [Uytterhoeven et al 2011]. Analysis of the crystal structure of Sky identified a cationic pocket that is preserved in human TBC1D24. This pocket is necessary for binding to the lipid membrane via phosphoinositides phosphorylated at the 4 and 5 positions [Fischer et al 2016]. TBC1D24 facilitates the formation of tubular recycling endosomes that are a hallmark of the clathrin-independent endocytosis cargo trafficking pathway in HeLa cells. Overexpression of TBC1D24 in HeLa cells dramatically increased tubular recycling endosomes loaded with clathrin-independent endocytosis cargo proteins, while deletion of TBC1D24 impaired tubular recycling endosome formation and delayed the recycling of clathrin-independent endocytosis cargo proteins back to the plasma membrane. TBC1D24 binds to Rab22A, through which TBC1D24 regulates TRE-mediated clathrin-independent cargo recycling [Kim Nguyen et al 2020].

TBC1D24-related disorders inherited in an autosomal recessive manner are thought to be the result of reduced function or loss of function. Abrogation of the cationic pocket by introducing two human pathogenic variants, p.Arg40 and p.Arg242, led to impaired synaptic vesicle trafficking and seizures in Drosophila [Fischer et al 2016]. The functional consequences of a strong and a weak TLDc variant (Gly501Arg and Arg360His, respectively) have been investigated in Drosophila, where TBC1D24/Skywalker regulates synaptic vesicle trafficking. In a Drosophila model neuronally expressing human TBC1D24, the Gly501Arg variant caused activity-induced locomotion and synaptic vesicle trafficking defects, while the Arg360His was benign. The neuronal phenotypes of the Gly501Arg variant were consistent with exacerbated oxidative stress sensitivity, which was rescued by treating animals with mutated Gly501Arg with antioxidants as indicated by restored synaptic vesicle trafficking levels and sustained behavioral activity. The humanized Gly501Arg fly model exhibited sustained activity and vesicle transport defects [Lüthy et al 2019].

Cellular studies have revealed that disease-causing variants that disrupt either of the conserved protein domains in TBC1D24 are implicated in neuronal development and survival and are likely acting as loss-of-function alleles. Genetic disruption of Tbc1d24 expression in mice leads to impaired endocytosis and enlarged endosomal compartment in neurons with a decrease in spontaneous neurotransmission, demonstrating that TBC1D24 is also crucial for normal presynaptic function [Finelli et al 2019]. A knock-in mouse model of the p.Phe251Leu variant [Corbett et al 2010] showed increased neuronal excitability, spontaneous seizures, and premature death. The heterozygous p.Phe251Leu knock-in mice survive into adulthood but display dendritic spine defects and impaired memory [Lin et al 2020]. Mouse models of DFNB (p.Asp70Tyr) and DFNA (p.Ser178Leu) as well as of syndromic forms of deafness (p.His336GlnfsTer12) have been generated. No auditory dysfunction was detected in Tbc1d24 mutated mice, although homozygosity for some of the variants caused seizures or early lethality [Tona et al 2020].

Mechanism of disease causation

  • Autosomal recessive disorders (DOORS syndrome, FIME, EIMFS, PME, EPRPDC, DEE, and DFNB): loss of function
  • Autosomal dominant disorders (DFNA): unknown
Table Icon

Table 9.

TBC1D24 Pathogenic Variants Referenced in This GeneReview

Chapter Notes

Author Notes

The authors would like to thank the patients and family members who take part in the TBC1D24 Foundation and have contributed hugely to our understanding of this disorder.

Acknowledgments

This work was supported by Current Research 2023 of the Italian Ministry of Health (to RG, SB), Ministry of University and Research (MIUR), National Recovery and Resilience Plan (NRRP), project MNESYS (PE0000006) (to RG, SB), Brain Optical Mapping by Fondazione CARIFI (to RG), and DECODEE, Call Health 2018 of the Tuscany Region (to RG).

Author History

Simona Balestrini, MD, PhD (2024-present)
Philippe M Campeau, MD (2015-present)
Renzo Guerrini, MD, FRCP (2024-present)
Raoul CM Hennekam, MD, PhD; University of Amsterdam (2015-2024)
Davide Mei, MSc (2024-present)
Bettina E Mucha, MD; Sainte-Justine Hospital (2015-2024)
Sanjay Sisodiya, MD, PhD (2015-present)

Revision History

  • 24 October 2024 (gm) Comprehensive update posted live
  • 7 December 2017 (ma) Comprehensive update posted live
  • 26 February 2015 (me) Review posted live
  • 31 July 2014 (pmc) Original submission

References

Literature Cited

  • Afawi Z, Mandelstam S, Korczyn AD, Kivity S, Walid S, Shalata A, Oliver KL, Corbett M, Gecz J, Berkovic SF, Jackson GD. TBC1D24 mutation associated with focal epilepsy, cognitive impairment and a distinctive cerebro-cerebellar malformation. Epilepsy Res. 2013;105:240-4. [PubMed: 23517570]

  • Appavu B, Guido-Estrada N, Lindstrom K, Grebe T, Kerrigan JF, Troester M. Electroclinical phenotypes and outcomes in TBC1D24-related epilepsy. Epileptic Disord. 2016;18:324-8. [PubMed: 27502353]

  • Atli E, Gurkan H, Ulusal S, Karal Y, Atli EI, Tozkir H. Identification of a novel homozygous TBC1D24 mutation in a Turkish family with DOORS syndrome. Clin Dysmorphol. 2018;27:1-3. [PubMed: 29176366]

  • Azaiez H, Booth KT, Bu F, Huygen P, Shibata SB, Shearer AE, Kolbe D, Meyer N, Black-Ziegelbein EA, Smith RJ. TBC1D24 mutation causes autosomal-dominant nonsyndromic hearing loss. Hum Mutat. 2014;35:819-23. [PMC free article: PMC4267685] [PubMed: 24729539]

  • Bakhchane A, Charif M, Salime S, Boulouiz R, Nahili H, Roky R, Lenaers G, Barakat A. Recessive TBC1D24 mutations are frequent in Moroccan non-syndromic hearing loss pedigrees. PLoS One. 2015;10:e0138072 [PMC free article: PMC4570774] [PubMed: 26371875]

  • Balestrini S, Milh M, Castiglioni C, Lüthy K, Finelli MJ, Verstreken P, Cardon A, Stražišar BG, Holder JL, Lesca G, Mancardi MM. TBC1D24 genotype–phenotype correlation: epilepsies and other neurologic features. Neurology 2016; 87:77-85. [PMC free article: PMC4932231] [PubMed: 27281533]

  • Banuelos E, Ramsey K, Belnap N, Krishnan M, Balak C, Szelinger S, Siniard AL, Russell M, Richholt R, De Both M, Piras I. Case report: novel mutations in TBC1D24 are associated with autosomal dominant tonic-clonic and myoclonic epilepsy and recessive Parkinsonism, psychosis, and intellectual disability. F1000Res. 2017; 6:553. [PMC free article: PMC5473401] [PubMed: 28663785]

  • Boucher S, Tai FWJ, Delmaghani S, Lelli A, Singh-Estivalet A, Dupont T, Niasme-Grare M, Michel V, Wolff N, Bahloul A, Bouyacoub Y, Bouccara D, Fraysse B, Deguine O, Collet L, Thai-Van H, Ionescu E, Kemeny JL, Giraudet F, Lavieille JP, Devèze A, Roudevitch-Pujol AL, Vincent C, Renard C, Franco-Vidal V, Thibult-Apt C, Darrouzet V, Bizaguet E, Coez A, Aschard H, Michalski N, Lefevre GM, Aubois A, Avan P, Bonnet C, Petit C. Ultrarare heterozygous pathogenic variants of genes causing dominant forms of early-onset deafness underlie severe presbycusis. Proc Natl Acad Sci U S A. 2020;117:31278-89. [PMC free article: PMC7733833] [PubMed: 33229591]

  • Burgess R, Wang S, McTague A, Boysen KE, Yang X, Zeng Q, Myers KA, Rochtus A, Trivisano M, Gill D; EIMFS Consortium; Sadleir LG, Specchio N, Guerrini R, Marini C, Zhang YH, Mefford HC, Kurian MA, Poduri AH, Scheffer IE. The genetic landscape of epilepsy of infancy with migrating focal seizures. Ann Neurol. 2019;86:821-31. [PMC free article: PMC7423163] [PubMed: 31618474]

  • Campeau PM, Kasperaviciute D, Lu JT, Burrage LC, Kim C, Hori M, Powell BR, Stewart F, Félix TM, van den Ende J, Wisniewska M, Kayserili H, Rump P, Nampoothiri S, Aftimos S, Mey A, Nair LD, Begleiter ML, De Bie I, Meenakshi G, Murray ML, Repetto GM, Golabi M, Blair E, Male A, Giuliano F, Kariminejad A, Newman WG, Bhaskar SS, Dickerson JE, Kerr B, Banka S, Giltay JC, Wieczorek D, Tostevin A, Wiszniewska J, Cheung SW, Hennekam RC, Gibbs RA, Lee BH, Sisodiya SM. The genetic basis of DOORS syndrome: an exome-sequencing study. Lancet Neurol. 2014;13:44-58. [PMC free article: PMC3895324] [PubMed: 24291220]

  • Cantwell RJ. Congenital sensori-neural deafness associated with onycho-osteo dystrophy and mental retardation (D.O.O.R. syndrome). Humangenetik. 1975;26:261-5. [PubMed: 1132883]

  • Chen W, Qin J, Shen Y, Liang J, Cui Y, Zhang Y. Next generation sequencing in children with unexplained epilepsy: a retrospective cohort study. Brain Dev. 2021;43:1004-12. [PubMed: 34120799]

  • Coppola G, Plouin P, Chiron C, Robain O, Dulac O. Migrating partial seizures in infancy: a malignant disorder with developmental arrest. Epilepsia 1995;36:1017–24. [PubMed: 7555952]

  • Corbett MA, Bahlo M, Jolly L, Afawi Z, Gardner AE, Oliver KL, Tan S, Coffey A, Mulley JC, Dibbens LM, Simri W, Shalata A, Kivity S, Jackson GD, Berkovic SF, Gecz J. A focal epilepsy and intellectual disability syndrome is due to a mutation in TBC1D24. Am J Hum Genet. 2010;87:371-5. [PMC free article: PMC2933342] [PubMed: 20797691]

  • Cordani R, Pisciotta L, Mancardi MM, Stagnaro M, Prato G, Giacomini T, Morana G, Walsh P, Ghia T, Nobili L, De Grandis E. Alternating hemiplegia of childhood in a child harboring a novel TBC1D24 mutation: case report and literature review. Neuropediatrics. 2022;53:69-74. [PubMed: 34852372]

  • Danial-Farran N, Brownstein Z, Gulsuner S, Tammer L, Khayat M, Aleme O, Chervinsky E, Zoubi OA, Walsh T, Ast G, King MC, Avraham KB, Shalev SA. Genetics of hearing loss in the Arab population of northern Israel. Eur J Hum Genet. 2018;26:1840-7. [PMC free article: PMC6244407] [PubMed: 30139988]

  • de Falco FA, Majello L, Santangelo R, Stabile M, Bricarelli FD, Zara F. Familial infantile myoclonic epilepsy: clinical features in a large kindred with autosomal recessive inheritance. Epilepsia. 2001;42:1541-8. [PubMed: 11879364]

  • de Kovel CG, Brilstra EH, Kempen MJ, Slot R, Nijman IJ, Afawi Z, De Jonghe P, Djémié T, Guerrini R, Hardies K, Helbig I. Targeted sequencing of 351 candidate genes for epileptic encephalopathy in a large cohort of patients. Mol Genet Genomic Med. 2016;4:568-80. [PMC free article: PMC5023942] [PubMed: 27652284]

  • Eronen M, Somer M, Gustafsson B, Holmberg C, Fraser FC, Preus M. New syndrome: a digito-reno-cerebral syndrome. Am J Med Genet. 1985;22:281-5. [PubMed: 4050858]

  • Falace A, Buhler E, Fadda M, Watrin F, Lippiello P, Pallesi-Pocachard E, Baldelli P, Benfenati F, Zara F, Represa A, Fassio A, Cardoso C. TBC1D24 regulates neuronal migration and maturation through modulation of the ARF6-dependent pathway. Proc Natl Acad Sci U S A. 2014;111:2337-42. [PMC free article: PMC3926028] [PubMed: 24469796]

  • Falace A, Filipello F, La Padula V, Vanni N, Madia F, De Pietri Tonelli D, de Falco FA, Striano P, Dagna Bricarelli F, Minetti C, Benfenati F, Fassio A, Zara F. TBC1D24, an ARF6-interacting protein, is mutated in familial infantile myoclonic epilepsy. Am J Hum Genet. 2010;87:365-70. [PMC free article: PMC2933335] [PubMed: 20727515]

  • Fang ZX, Xie LL, Yan LS, Lin H, Pan YN, Liu BK, Jiang Y, Cheng M, Li XJ, Jiang L. Clinical and genetic characteristics of epilepsy of infancy with migrating focal seizures in Chinese children. Epilepsy Res. 2021;174:106669. [PubMed: 34020146]

  • Finelli MJ, Aprile D, Castroflorio E, Jeans A, Moschetta M, Chessum L, Degiacomi MT, Grasegger J, Lupien-Meilleur A, Bassett A, Rossignol E, Campeau PM, Bowl MR, Benfenati F, Fassio A, Oliver PL. The epilepsy-associated protein TBC1D24 is required for normal development, survival and vesicle trafficking in mammalian neurons. Hum Mol Genet. 2019;28:584-97. [PMC free article: PMC6360273] [PubMed: 30335140]

  • Fischer B, Lüthy K, Paesmans J, De Koninck C, Maes I, Swerts J, Kuenen S, Uytterhoeven V, Verstreken P, Versées W. Skywalker-TBC1D24 has a lipid-binding pocket mutated in epilepsy and required for synaptic function. Nat Struct Mol Biol. 2016; 23:965-73. [PubMed: 27669036]

  • Girish M, Mujawar N, Salodkar A. DOOR syndrome. Indian Pediatr. 2011;48:479-81. [PubMed: 21743113]

  • Guerrini R, Bonanni P, Nardocci N, Parmeggiani L, Piccirilli M, De Fusco M, Aridon P, Ballabio A, Carrozzo R, Casari G. Autosomal recessive rolandic epilepsy with paroxysmal exercise-induced dystonia and writer's cramp: delineation of the syndrome and gene mapping to chromosome 16p12-11.2. Ann Neurol. 1999;45:344-52. [PubMed: 10072049]

  • Guven A, Tolun A. TBC1D24 truncating mutation resulting in severe neurodegeneration. J Med Genet. 2013;50:199-202. [PubMed: 23343562]

  • Hamdan FF, Myers CT, Cossette P, Lemay P, Spiegelman D, Laporte AD, Nassif C, Diallo O, Monlong J, Cadieux-Dion M, Dobrzeniecka S, Meloche C, Retterer K, Cho MT, Rosenfeld JA, Bi W, Massicotte C, Miguet M, Brunga L, Regan BM, Mo K, Tam C, Schneider A, Hollingsworth G; Deciphering Developmental Disorders Study; FitzPatrick DR, Donaldson A, Canham N, Blair E, Kerr B, Fry AE, Thomas RH, Shelagh J, Hurst JA, Brittain H, Blyth M, Lebel RR, Gerkes EH, Davis-Keppen L, Stein Q, Chung WK, Dorison SJ, Benke PJ, Fassi E, Corsten-Janssen N, Kamsteeg EJ, Mau-Them FT, Bruel AL, Verloes A, Õunap K, Wojcik MH, Albert DVF, Venkateswaran S, Ware T, Jones D, Liu YC, Mohammad SS, Bizargity P, Bacino CA, Leuzzi V, Martinelli S, Dallapiccola B, Tartaglia M, Blumkin L, Wierenga KJ, Purcarin G, O'Byrne JJ, Stockler S, Lehman A, Keren B, Nougues MC, Mignot C, Auvin S, Nava C, Hiatt SM, Bebin M, Shao Y, Scaglia F, Lalani SR, Frye RE, Jarjour IT, Jacques S, Boucher RM, Riou E, Srour M, Carmant L, Lortie A, Major P, Diadori P, Dubeau F, D'Anjou G, Bourque G, Berkovic SF, Sadleir LG, Campeau PM, Kibar Z, Lafrenière RG, Girard SL, Mercimek-Mahmutoglu S, Boelman C, Rouleau GA, Scheffer IE, Mefford HC, Andrade DM, Rossignol E, Minassian BA, Michaud JL. High rate of recurrent de novo mutations in developmental and epileptic encephalopathies. Am J Hum Genet. 2017;101:664-85. [PMC free article: PMC5673604] [PubMed: 29100083]

  • Hong SY, Yang JJ, Li SY, Lee IC. A wide spectrum of genetic disorders causing severe childhood epilepsy in Taiwan: a case series of ultrarare genetic cause and novel mutation analysis in a pilot study. J Pers Med. 2020;10:281. [PMC free article: PMC7765181] [PubMed: 33333793]

  • Hosseinpour S, Tavasoli AR, Rohani M, Emamikhah M. Rolandic epilepsy with paroxysmal exercise-induced dystonia and writer's cramp: a case report. Neurol Sci. 2023;44:381-4. [PubMed: 36087149]

  • James AW, Miranda SG, Culver K, Hall BD, Golabi M. DOOR syndrome: clinical report, literature review and discussion of natural history. Am J Med Genet A. 2007;143A:2821-31. [PubMed: 17994565]

  • Jiang L, Bi S, Lin L, He F, Deng F. Phenotypic and genetic characteristics of 24 cases of early infantile epileptic encephalopathy in East China, including a rare case of biallelic UGDH mutations. Mol Genet Genomic Med. 2023;11:e2269. [PMC free article: PMC10724516] [PubMed: 37593999]

  • Jónsson H, Sulem P, Kehr B, Kristmundsdottir S, Zink F, Hjartarson E, Hardarson MT, Hjorleifsson KE, Eggertsson HP, Gudjonsson SA, Ward LD, Arnadottir GA, Helgason EA, Helgason H, Gylfason A, Jonasdottir A, Jonasdottir A, Rafnar T, Frigge M, Stacey SN, Th Magnusson O, Thorsteinsdottir U, Masson G, Kong A, Halldorsson BV, Helgason A, Gudbjartsson DF, Stefansson K. Parental influence on human germline de novo mutations in 1,548 trios from Iceland. Nature. 2017;549:519-22. [PubMed: 28959963]

  • Kim Nguyen NT, Ohbayashi N, Kanaho Y, Funakoshi Y. TBC1D24 regulates recycling of clathrin-independent cargo proteins mediated by tubular recycling endosomes. Biochem Biophys Res Commun. 2020;528:220-6. [PubMed: 32475639]

  • Lee HF, Chi CS, Tsai CR. Intrafamilial phenotypic variability in TBC1D24-TLDc homozygous pathogenic variant-related developmental and epileptic encephalopathy. Clin Neurol Neurosurg. 2022;214:107142. [PubMed: 35149262]

  • Lei P, Zhu Q, Dong W. Investigation of a novel TBC1D24 variation causing autosomal dominant non-syndromic hearing loss. Sci Rep. 2024;14:4734. [PMC free article: PMC10899226] [PubMed: 38413761]

  • Le Merrer M, David A, Goutieres F, Briard ML. Digito-reno-cerebral syndrome: confirmation of Eronen syndrome. Clin Genet. 1992;42:196-8. [PubMed: 1424243]

  • Li J, Liu R, Feng H, Zhang J, Wang D, Wang Y, Zeng J, Fan Y. Novel TBC1D24 mutations in a case of nonconvulsive status epilepticus. Front Neurol. 2018;9:623. [PMC free article: PMC6079244] [PubMed: 30108545]

  • Lin L, Lyu Q, Kwan PY, Zhao J, Fan R, Chai A, Lai CSW, Chan YS, Shen X, Lai KO. The epilepsy and intellectual disability-associated protein TBC1D24 regulates the maintenance of excitatory synapses and animal behaviors. PLoS Genet. 2020;16:e1008587. [PMC free article: PMC7015432] [PubMed: 32004315]

  • Lozano R, Herman K, Rothfuss M, Rieger H, Bayrak-Toydemir P, Aprile D, Fruscione F, Zara F, Fassio A. Clinical intrafamilial variability in lethal familial neonatal seizure disorder caused by TBC1D24 mutations. Am J Med Genet A. 2016;170:3207-14. [PubMed: 27541164]

  • Lüthy K, Mei D, Fischer B, De Fusco M, Swerts J, Paesmans J, Parrini E, Lubarr N, Meijer IA, Mackenzie KM, Lee WT, Cittaro D, Aridon P, Schoovaerts N, Versées W, Verstreken P, Casari G, Guerrini R. TBC1D24-TLDc-related epilepsy exercise-induced dystonia: rescue by antioxidants in a disease model. Brain. 2019;142:2319-35. [PubMed: 31257402]

  • Milh M, Falace A, Villeneuve N, Vanni N, Cacciagli P, Assereto S, Nabbout R, Benfenati F, Zara F, Chabrol B, Villard L, Fassio A. Novel compound heterozygous mutations in TBC1D24 cause familial malignant migrating partial seizures of infancy. Hum Mutat. 2013;34:869-72. [PubMed: 23526554]

  • Mucha BE, Banka S, Ajeawung NF, Molidperee S, Chen GG, Koenig MK, Adejumo RB, Till M, Harbord M, Perrier R, Lemyre E, Boucher RM, Skotko BG, Waxler JL, Thomas MA, Hodge JC, Gecz J, Nicholl J, McGregor L, Linden T, Sisodiya SM, Sanlaville D, Cheung SW, Ernst C, Campeau PM. A new microdeletion syndrome involving TBC1D24, ATP6V0C, and PDPK1 causes epilepsy, microcephaly, and developmental delay. Genet Med. 2019;21:1058-64. [PubMed: 30245510]

  • Muona M, Berkovic SF, Dibbens LM, Oliver KL, Maljevic S, Bayly MA, Joensuu T, Canafoglia L, Franceschetti S, Michelucci R, Markkinen S, Heron SE, Hildebrand MS, Andermann E, Andermann F, Gambardella A, Tinuper P, Licchetta L, Scheffer IE, Criscuolo C, Filla A, Ferlazzo E, Ahmad J, Ahmad A, Baykan B, Said E, Topcu M, Riguzzi P, King MD, Ozkara C, Andrade DM, Engelsen BA, Crespel A, Lindenau M, Lohmann E, Saletti V, Massano J, Privitera M, Espay AJ, Kauffmann B, Duchowny M, Møller RS, Straussberg R, Afawi Z, Ben-Zeev B, Samocha KE, Daly MJ, Petrou S, Lerche H, Palotie A, Lehesjoki AE. A recurrent de novo mutation in KCNC1 causes progressive myoclonus epilepsy. Nat Genet. 2015;47:39-46. [PMC free article: PMC4281260] [PubMed: 25401298]

  • Murofushi Y, Hayakawa I, Kawai M, Abe Y, Kosaki R, Suzuki H, Takenouchi T, Kubota M. Oral baclofen therapy for multifocal spinal myoclonus with TBC1D24 variant. Mov Disord Clin Pract. 2023;10:719-21. [PMC free article: PMC10105102] [PubMed: 37070046]

  • Nakashima M, Negishi Y, Hori I, Hattori A, Saitoh S, Saitsu H. A case of early-onset epileptic encephalopathy with a homozygous TBC1D24 variant caused by uniparental isodisomy. Am J Med Genet A. 2019;179:645-9. [PubMed: 30680869]

  • Ngoh A, Bras J, Guerreiro R, McTague A, Ng J, Meyer E, Chong WK, Boyd S, MacLellan L, Kirkpatrick M, Kurian MA. TBC1D24 Mutations in a Sibship with Multifocal Polymyoclonus. Tremor Other Hyperkinet Mov (N Y). 2017;7:452. [PMC free article: PMC5395678] [PubMed: 28428906]

  • Nomura T, Koyama N, Yokoyama M, Awaya A, Yokochi K. DOOR syndrome concomitant with non-convulsive status epilepticus and hyperintense cerebellar cortex on T2-weighted imaging. Brain Dev. 2009;31:75-8. [PubMed: 18440741]

  • Oziębło D, Leja ML, Lazniewski M, Sarosiak A, Tacikowska G, Kochanek K, Plewczynski D, Skarżyński H, Ołdak M. TBC1D24 emerges as an important contributor to progressive postlingual dominant hearing loss. Sci Rep. 2021;11:10300. [PMC free article: PMC8119487] [PubMed: 33986365]

  • Panjan M, Paro-Panjan D, Salamon AS. Genetic-cellular epilepsy: Clues to diagnosing newborns with neonatal seizures. Seizure. 2021;92:68-75. [PubMed: 34474328]

  • Parzefall T, Frohne A, Koenighofer M, Neesen J, Laccone F, Eckl-Dorna J, Waters JJ, Schreiner M, Amr SS, Ashton E, Schoefer C, Gstœttner W, Frei K, Lucas T. A novel variant in the TBC1D24 lipid-binding pocket causes autosomal dominant hearing loss: evidence for a genotype-phenotype correlation. Front Cell Neurosci. 2020;14:585669. [PMC free article: PMC7689082] [PubMed: 33281559]

  • Patton MA, Krywawych S, Winter RM, Brenton DP, Baraitser M. DOOR syndrome (deafness, onycho-osteodystrophy, and mental retardation): elevated plasma and urinary 2-oxoglutarate in three unrelated patients. Am J Med Genet. 1987;26:207-15. [PubMed: 3812564]

  • Poulat AL, Ville D, de Bellescize J, André-Obadia N, Cacciagli P, Milh M, Villard L, Lesca G. Homozygous TBC1D24 mutation in two siblings with familial infantile myoclonic epilepsy (FIME) and moderate intellectual disability. Epilepsy Res. 2015;111:72-7. [PubMed: 25769375]

  • Qazi QH, Nangia BS. Abnormal distal phalanges and nails, deafness, mental retardation, and seizure disorder: a new familial syndrome. J Pediatr. 1984;104:391-4. [PubMed: 6707793]

  • Quaio CRAC, Coelho AVC, Moura LMS, Guedes RLM, Chen K, Ceroni JRM, Minillo RM, Caraciolo MP, Reis RS, de Azevedo BMC, Nobrega MS, Teixeira ACB, Martinelli Lima M, da Mota TR, da Matta MC, Colichio GBC, Roncalho AL, Ferreira AFM, Campilongo GP, Perrone E, Virmond LDA, Moreno CA, Prota JRM, de França M, Cervato MC, de Almeida TF, de Oliveira Filho JB. Genomic study of nonsyndromic hearing loss in unaffected individuals: Frequency of pathogenic and likely pathogenic variants in a Brazilian cohort of 2,097 genomes. Front Genet. 2022;13:921324. [PMC free article: PMC9486813] [PubMed: 36147510]

  • Ragona F, Castellotti B, Salis B, Magri S, DiFrancesco JC, Nardocci N, Franceschetti S, Gellera C, Granata T. Alternating hemiplegia and epilepsia partialis continua: a new phenotype for a novel compound TBC1D24 mutation. Seizure. 2017;47:71-3. [PubMed: 28292732]

  • Rehman AU, Santos-Cortez RL, Morell RJ, Drummond MC, Ito T, Lee K, Khan AA, Basra MA, Wasif N, Ayub M, Ali RA, Raza S; University of Washington Center for Mendelian Genomics, Nickerson DA, Shendure J, Bamshad M, Riazuddin S, Billington N, Khan SN, Friedman PL, Griffith AJ, Ahmad W, Riazuddin S, Leal SM, Friedman TB. Mutations in TBC1D24, a gene associated with epilepsy, also cause nonsyndromic deafness DFNB86. Am J Hum Genet. 2014;94:144-52. [PMC free article: PMC3882911] [PubMed: 24387994]

  • Reis CS, Quental S, Fernandes S, Castedo S, Moura CP. Whole-exome sequencing targeting a gene panel for sensorineural hearing loss: the first Portuguese cohort study. Cytogenet Genome Res. 2022;162:1-9. [PubMed: 35580552]

  • Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405-24. [PMC free article: PMC4544753] [PubMed: 25741868]

  • Safka Brozkova D, Poisson Marková S, Mészárosová AU, Jenčík J, Čejnová V, Čada Z, Laštůvková J, Rašková D, Seeman P. Spectrum and frequencies of non GJB2 gene mutations in Czech patients with early non-syndromic hearing loss detected by gene panel NGS and whole-exome sequencing. Clin Genet. 2020;98:548-54. [PubMed: 32860223]

  • Salemi M, Cali' F, Giambirtone M, Elia M, Romano C. TBC1D24 gene mRNA expression in a boy with early infantile epileptic encephalopathy-16. Acta Neurol Belg. 2020;120:381-3. [PubMed: 28726039]

  • Sarıgecılı E, Anlas O. A rare cause of paroxysmal movement disorder associated with TBC1D24 gene mutation in two siblings. Ann Indian Acad Neurol. 2023;26:290-3. [PMC free article: PMC10394464] [PubMed: 37538433]

  • Shao Q, Shi X, Ma B, Zeng J, Zheng A, Xie W. TBC1D24-related familial infantile multifocal myoclonus: description of a new Chinese pedigree with a 20 year follow up. Epilepsy Res. 2022;182:106923. [PubMed: 35413638]

  • Scheffer IE, Berkovic S, Capovilla G, Connolly MB, French J, Guilhoto L, Hirsch E, Jain S, Mathern GW, Moshé SL, Nordli DR, Perucca E, Tomson T, Wiebe S, Zhang YH, Zuberi SM. ILAE classification of the epilepsies: position paper of the ILAE Commission for Classification and Terminology. Epilepsia. 2017;58:512-21. [PMC free article: PMC5386840] [PubMed: 28276062]

  • Scheffer IE, Zuberi S, Mefford HC, Guerrini R, McTague A. Developmental and epileptic encephalopathies. Nat Rev Dis Primers. 2024;10:61. [PubMed: 39237642]

  • Sieburth D, Ch'ng Q, Dybbs M, Tavazoie M, Kennedy S, Wang D, Dupuy D, Rual JF, Hill DE, Vidal M, Ruvkun G, Kaplan JM. Systematic analysis of genes required for synapse structure and function. Nature. 2005;436:510-7. [PubMed: 16049479]

  • Steel D, Heim J, Kruer MC, Sanchis-Juan A, Raymond LF, Eunson P, Kurian MA. Biallelic mutations of TBC1D24 in exercise-induced paroxysmal dystonia. Mov Disord. 2020;35:372-3. [PubMed: 31922275]

  • Stenson PD, Mort M, Ball EV, Chapman M, Evans K, Azevedo L, Hayden M, Heywood S, Millar DS, Phillips AD, Cooper DN. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting. Hum Genet. 2020;139:1197-207. [PMC free article: PMC7497289] [PubMed: 32596782]

  • Stražišar, B.G., Neubauer, D., Panjan, D.P. and Writzl, K. Early-onset epileptic encephalopathy with hearing loss in two siblings with TBC1D24 recessive mutations. Eur J Paediatr Neurol. 2015;19:251-6. [PubMed: 25557349]

  • Symonds JD, Zuberi SM, Stewart K, McLellan A, O'Regan M, MacLeod S, Jollands A, Joss S, Kirkpatrick M, Brunklaus A, Pilz DT, Shetty J, Dorris L, Abu-Arafeh I, Andrew J, Brink P, Callaghan M, Cruden J, Diver LA, Findlay C, Gardiner S, Grattan R, Lang B, MacDonnell J, McKnight J, Morrison CA, Nairn L, Slean MM, Stephen E, Webb A, Vincent A, Wilson M. Incidence and phenotypes of childhood-onset genetic epilepsies: a prospective population-based national cohort. Brain. 2019;142:2303-18. [PMC free article: PMC6658850] [PubMed: 31302675]

  • Tona R, Lopez IA, Fenollar-Ferrer C, Faridi R, Anselmi C, Khan AA, Shahzad M, Morell RJ, Gu S, Hoa M, Dong L, Ishiyama A, Belyantseva IA, Riazuddin S, Friedman TB. Mouse models of human pathogenic variants of TBC1D24 associated with non-syndromic deafness DFNB86 and DFNA65 and syndromes involving deafness. Genes (Basel). 2020;11:1122. [PMC free article: PMC7598720] [PubMed: 32987832]

  • Uytterhoeven V, Kuenen S, Kasprowicz J, Miskiewicz K, Verstreken P. Loss of Skywalker reveals synaptic endosomes as sorting stations for synaptic vesicle proteins. Cell. 2011;145:117-32. [PubMed: 21458671]

  • Uzunhan TA, Uyanik B. Disrupted oxidative stress resistance: a homozygous mutation in the catalytic (TLDc) domain of TBC1D24 gene associated with epileptic encephalopathy. Clin Neurol Neurosurg. 2020;196:106080. [PubMed: 32663648]

  • van Bever Y, Balemans W, Duval EL, Jespers A, Eyskens F, van Hul W, Courtens W. Exclusion of OGDH and BMP4 as candidate genes in two siblings with autosomal recessive DOOR syndrome. Am J Med Genet A. 2007;143A:763-7. [PubMed: 17343268]

  • Wang J, Wen Y, Zhang Q, Yu S, Chen Y, Wu X, Zhang Y, Bao X. Gene mutational analysis in a cohort of Chinese children with unexplained epilepsy: identification of a new KCND3 phenotype and novel genes causing Dravet syndrome. Seizure. 2019;66:26-30. [PubMed: 30776697]

  • Xiang YB, Xu CY, Xu YZ, Li HZ, Zhou LL, Xu XQ, Chen ZH, Tang SH. Next-generation sequencing identifies rare pathogenic and novel candidate variants in a cohort of Chinese patients with syndromic or nonsyndromic hearing loss. Mol Genet Genomic Med. 2020;8:e1539. [PMC free article: PMC7767562] [PubMed: 33095980]

  • Zara F, Gennaro E, Stabile M, Carbone I, Malacarne M, Majello L, Santangelo R, de Falco FA, Bricarelli FD. Mapping of a locus for a familial autosomal recessive idiopathic myoclonic epilepsy of infancy to chromosome 16p13. Am J Hum Genet. 2000;66:1552-7. [PMC free article: PMC1378007] [PubMed: 10741954]

  • Zhang J, Chen J, Zeng Q, Zhang L, Tian X, Yang X, Yang Z, Wu Y, Wu X, Zhang Y. Infantile epilepsy with multifocal myoclonus caused by TBC1D24 mutations. Seizure. 2019;69:228-34. [PubMed: 31112829]

  • Zhang L, Hu L, Chai Y, Pang X, Yang T, Wu H. A dominant mutation in the stereocilia-expressing gene TBC1D24 is a probable cause for nonsyndromic hearing impairment. Hum Mutat. 2014;35:814-8. [PubMed: 24729547]

  • Zhao X, Ning H, Wang Y, Zhao G, Mei S, Liu N, Wang C, Cai A, Wei E, Kong X. Genetic analysis and identification of novel variations in Chinese patients with pediatric epilepsy by whole-exome sequencing. Neurol Sci. 2022;43:4439-51. [PubMed: 35217970]

  • Zhou Q, Lin Y, Ye J, Li L, Hu N, Wang D, Wang Y. Homozygous TBC1D24 mutation in a case of epilepsia partialis continua. Front Neurol. 2018;8:750. [PMC free article: PMC5787533] [PubMed: 29416524]

  • Zimmern V, Riant F, Roze E, Ranza E, Lehmann-Horn F, de Bellescize J, Ville D, Lesca G, Korff CM. Infantile-onset paroxysmal movement disorder and episodic ataxia associated with a TBC1D24 mutation. Neuropediatrics. 2019;50:308-12. [PubMed: 31226716]