Clinical Description
While initial reports suggested specific phenotypes associated with pathogenic variants in TBC1D24, several recent publications suggest that the features represent a phenotypic spectrum ranging from a mild form of familial infantile myoclonic epilepsy (FIME) to a combination of epilepsy with variable other features, to DOORS syndrome [Balestrini et al 2016]. Features seen in individuals with biallelic TBC1D24 pathogenic variants who do not have DOORS syndrome include parkinsonism [Banuelos et al 2017], ataxia, dysarthria, axial hypotonia, hearing loss, visual impairment, mild dysmorphic facial features, developmental delay or intellectual disability, and microcephaly [Balestrini et al 2016].
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].
The sensorineural hearing loss is often profound and prelingual. Some have benefited from cochlear implants.
The 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.
The intellectual disability (previously referred to as mental retardation) can vary significantly in degree but is often severe [Balestrini et al 2016]. The motor and language skills were most delayed in two children where such details are available [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, the seizures have been difficult to control even with multiple antiepileptic medications, and have led to status epilepticus and death.
On MRI hyperintense T2-weighted signal anomalies may be observed in the cerebellar hemispheres and the frontal region [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. In individuals with DOORS syndrome the additional anomalies noted are the following:
Microcephaly in one third of individuals
Other cranial anomalies (sagittal craniosynostosis in 1 individual; 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 (double outlet right ventricle)
Skeletal anomalies (e.g., calcaneal deformities)
Hypothyroidism
Renal and urinary tract anomalies (e.g., hydronephrosis, nephrocalcinosis) [
Campeau et al 2014]
Peripheral neuropathy in one individual with confirmed
TBC1D24 pathogenic variants [
Balestrini et la 2016] and three individuals who either did not undergo genetic testing or in whom no
TBC1D24 pathogenic variant was identified
Familial Infantile Myoclonic Epilepsy (FIME)
FIME is characterized by early-onset myoclonic seizures.
Findings include focal epilepsy, dysarthria, mild-to-moderate intellectual disability, and cortical thickening and cerebellar atrophy with high T2-weighted and FLAIR on MRI (in 4 sibs of an Israeli Arab family [Corbett et al 2010, Afawi et al 2013]).
Intellect may be normal: all seven members of an Italian family who had FIME and biallelic TBC1D24 pathogenic variants also had normal intelligence. Six had normal brain MRI and one had periventricular nodular heterotopia [Zara et al 2000, de Falco et al 2001, Falace et al 2010].
Progressive Myoclonus Epilepsy (PME)
PME is characterized by action myoclonus, tonic-clonic seizures, progressive neurologic decline, and ataxia.
For the child described with PME caused by biallelic pathogenic variants in TBC1D24, tonic seizures started at age 36 hours. Developmental delay with later regression was then noted. Myoclonus started at age eight months and tonic-clonic seizures at age 3.5 years. Ataxia, spasticity, supranuclear gaze palsy, and visual decline were also noted. Although the initial clinical diagnosis was of an epileptic encephalopathy, a florid PME pattern was apparent by age nine years [Muona et al 2015]. There were no digital anomalies or deafness [Sam Berkovic, MD, personal communication].
Early-Infantile Epileptic Encephalopathy 16 (EIEE16)
Epileptic encephalopathies 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 [Engel 2001, Berg et al 2010].
Findings may include:
Myoclonic epilepsy with episodic dystonia, hemiparesis, autonomic signs, and lethargy evolving to chronic dystonia, progressive diffuse cerebral atrophy, and early death (in 5 Turkish families [
Duru et al 2010,
Guven & Tolun 2013]);
Malignant migrating partial seizures in infancy with progressive diffuse cerebral atrophy of the gray matter (sparing the posterior fossa) and early death (in 2 French sibs [
Milh et al 2013]).
Autosomal Dominant Nonsyndromic Hearing Loss, DFNA65
Findings include slowly progressive deafness with onset in the third decade, initially affecting the high frequencies (in 1 Chinese family [Zhang et al 2014] and in a family of European descent [Azaiez et al 2014]) (see Deafness and Hereditary Hearing Loss Overview).
Heterozygotes, in the context of autosomal recessive disease. Two unrelated individuals with generalized tonic-clonic seizures and biallelic pathogenic TBC1D24 variants both 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].
Increasing evidence points to an elevated susceptibility to seizure disorders in apparently unaffected individuals who have a heterozygous TBC1D24 pathogenic variant (i.e., a "carrier") as compared to the population frequency estimated at seven per 1,000 individuals.
Family history was positive in an additional five families with
TBC1D24 pathogenic variants; family members were unavailable for sequencing [
Stražišar et al 2015,
Balestrini et al 2016, supplemental material].
Genotype-Phenotype Correlations
The TBC1D24 pathogenic variants that cause DOORS syndrome, FIME, EIEE16, DFNB86, and DFNA65 are located throughout the gene; no pattern has emerged to date. Most pathogenic variants causing one phenotype have not been demonstrated to cause the others, either within the same family or in different families. However, a heterozygous frameshift variant (c.1008delT) coupled with another pathogenic variant affecting the other TBC1D24 allele was identified in four affected individuals, two with DOORS and one sib pair with EIEE16 and early death.
In general, loss-of-function variants (frameshift, nonsense, or splice site) are associated with a more severe epilepsy phenotype with drug resistance and early death, except when the loss-of-function variant is located in the last exon. Pathogenic missense variants in or before the TBC domain are also associated with a higher risk of lethality.
The diagnosis of DOORS does not allow for a prediction of the epilepsy type [Balestrini et al 2016]. The location of new pathogenic variants cannot yet be used to predict a phenotype. This may change as more pathogenic variants are identified.
