Timothy syndrome represents one clinical manifestation of a range of disorders associated with mutations in CACNA1C,[1] the gene encoding the calcium channel Cav1.2 α subunit.

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,[2][3][4] although there have been multiple reports of patients living in to their mid- or late-twenties.

Differences in the type 2 form are the lack of syndactyly, the presence of musculoskeletal problems (particularly hyperflexible joints), and often hip dysplasia.

Timothy syndrome mutations in CACNA1C cause delayed channel closing, also known as voltage-dependent inactivation, thus increased cellular excitability.

A second mutation resulting in G402S, located a few amino acids upstream, was originally also given the name of type 2, but it is now recognized as a variant that causes non-syndromic LQT8.

[6] The lack of proper voltage-dependent inactivation in these mutants causes prolonged inward current and depolarization during cardiac action potentials.

[5] A pig model of the disease, carrying the same mutation as the one found in patients, allowed to identify that the calcium overload state leads the development of a substrate for functional reentry characterised by slowing of cardiac impulse propagation.

[7] Single cell studies identified that CaMKII autophosphorylation reduced the peak sodium current, thus causing the slowing of conduction.