TBC1D24-related disorders are a group of rare genetic conditions caused by changes (variants) in the TBC1D24 gene. This gene plays an important role in the normal function of nerve cells, particularly in processes involved in communication between neurons. Changes in TBC1D24 can affect the brain and nervous system in different ways, resulting in a broad spectrum of neurological features.
What are TBC1D24-related disorders?
TBC1D24-related disorders encompass several clinical presentations, ranging from severe early-onset neurological disease to milder conditions that primarily affect movement or peripheral nerves. The most commonly recognised features include epilepsy, developmental delay, intellectual disability, movement disorders and hearing loss.
One important feature of TBC1D24-related disease is its variability. Some children develop seizures during infancy and experience significant developmental difficulties, while others may have relatively mild epilepsy or a predominantly neurological or neuromuscular presentation.
TBC1D24 variants have been associated with conditions including developmental and epileptic encephalopathy, familial infantile myoclonic epilepsy, DOORS syndrome, and Charcot-Marie-Tooth disease. DOORS syndrome is characterised by deafness, onychodystrophy (abnormalities of the nails), osteodystrophy (abnormalities of the bones), intellectual disability and seizures.
Seizures and epilepsy
Epilepsy is one of the most prominent features of many TBC1D24-related disorders. Seizures can begin in infancy or childhood and may include different seizure types, including myoclonic, focal and generalised seizures.
In more severe forms, seizures may be difficult to control and can occur alongside developmental regression or significant developmental delay. However, not everyone with a TBC1D24 variant will develop epilepsy, and the severity can vary considerably even between individuals with variants in the same gene.
Development and neurological features
Children with TBC1D24-related disorders may experience developmental delay, particularly affecting motor skills, speech and language, or learning. Some individuals develop ataxia, meaning difficulties with coordination and balance, while others may have tremor, dystonia or other movement abnormalities.
Some TBC1D24 variants can also affect the peripheral nerves, resulting in a form of Charcot-Marie-Tooth disease. This may cause muscle weakness, reduced reflexes, sensory changes and difficulties with walking.
Hearing loss is another recognised feature and may occur as part of DOORS syndrome or in other TBC1D24-related presentations.
How is TBC1D24-related disease inherited?
Inheritance depends on the particular TBC1D24-related disorder and the specific genetic variants involved. Some conditions are inherited in an autosomal recessive manner, meaning an affected individual usually has two disease-causing variants, one inherited from each parent. Other TBC1D24-associated conditions can result from a single variant acting in a dominant manner.
Genetic counselling is therefore particularly important when a TBC1D24 variant is identified. Testing parents and, where appropriate, other family members can help clarify inheritance and provide information about the chance of the condition occurring in future pregnancies.
How is it diagnosed?
Diagnosis usually involves a combination of clinical assessment, neurological investigations and genetic testing. A multigene epilepsy or neurological gene panel, exome sequencing or genome sequencing may identify a TBC1D24 variant.
Interpreting the genetic result requires care. Not every variant found in TBC1D24 causes disease, and the significance of a variant depends on factors including its type, inheritance pattern and the individual’s clinical features.
Living with a TBC1D24-related disorder
There is currently no cure that specifically targets the underlying genetic cause of TBC1D24-related disorders. Management focuses on the individual’s symptoms and may involve neurologists, geneticists, audiologists, physiotherapists, occupational therapists, speech pathologists and other specialists.
Because TBC1D24-related disorders can affect people in very different ways, individualised care and genetic counselling are important parts of management.
At Rosalind Genetics, genetic counselling can help families understand what a TBC1D24 genetic result means, how it may relate to a person’s symptoms, what it could mean for other family members, and what genetic testing options may be appropriate.
