Timothy syndrome is a rare autosomal-dominant disorder characterized by physical malformations, as well as neurological and developmental defects, including heart QT-prolongation, heart arrhythmias, structural heart defects, syndactyly (webbing of fingers and toes), and autism spectrum disorders. Timothy syndrome represents one clinical manifestation of a range of disorders associated with mutations in CACNA1C, the gene encoding the calcium channel Ca<sub>v</sub>1.2 α subunit.
Signs and symptoms
The most striking sign of Timothy syndrome type 1 is the co-occurrence of both syndactyly (about 0.03% of births) and long QT syndrome (1% per year) in a single patient. Other common symptoms include cardiac arrhythmia (94%), heart malformations (59%), and autism or an autism spectrum disorder (80% who survive long enough for evaluation). Facial dysmorphologies such as flattened noses also occur in about half of patients. Children with this disorder have small teeth, which is due to poor enamel coating, are prone to dental cavities and often require removal. The average age of death due to complications of these symptoms is 2.5 years, although there have been multiple reports of patients living in to their mid- or late-twenties.
Timothy syndrome type 2 has largely the same symptoms as the classical form. Differences in the type 2 form are the lack of syndactyly, the presence of musculoskeletal problems (particularly hyperflexible joints), and often hip dysplasia. Patients with Timothy syndrome type 2 also have more facial deformities, including protruding foreheads and tongues.
Children with Timothy syndrome tend to be born via caesarean section due to fetal distress. Single cell studies identified that CaMKII autophosphorylation reduced the peak sodium current, thus causing the slowing of conduction.