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.

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).

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.

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.

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.

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)

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.

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.

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).

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.

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.

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.

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

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

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