to be vital for proper voltage-dependent inactivation, as the mutant is lacking in this respect. Timothy syndrome type 2 mutations are similar, being the identical G406R mutation in the other splice form. 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. The effect of the G406R mutations on channel function is identical in the two forms of Timothy syndrome. The lack of proper voltage-dependent inactivation in these mutants causes prolonged inward current and depolarization during cardiac action potentials. This leads to long QT syndrome and resultant arrhythmia. Because exon 8 has greater expression in the heart versus exon 8a, patients with Timothy syndrome type 2 have worsened cardiac defects compared to those with the classical form. Diagnosis Syndactyly and other deformities are typically observed and diagnosed at birth. Long QT syndrome sometimes presents itself as a complication due to surgery to correct syndactyly. Other times, children collapse spontaneously while playing. In all cases, it is confirmed with ECG measurements. Sequencing of the CACNA1C gene further confirms the diagnosis. Treatment Surgery is typically used to correct structural heart defects and syndactyly. Propranolol or other beta-adrenergic blockers are often prescribed, as well as insertion of a pacemaker to maintain proper heart rhythm. With the characterization of Timothy syndrome mutations indicating that they cause defects in calcium currents, calcium channel blockers may be effective as a therapeutic agent. Prognosis The prognosis for patients diagnosed with Timothy syndrome is very poor. Of 17 children analyzed in one study, 10 died at an average age of 2.5 years. Of those that did survive, three were diagnosed with autism, one with an autism spectrum disorder, and the last had severe delays in language development. One patient with the G402S mutation was largely normal with the exception of heart arrhythmia. Likewise, the mother of two Timothy syndrome patients also carried the mutation, but lacked any obvious phenotype. In both of these cases, however, the lack of severity of the disorder was due to mosaicism. History Some of the abnormalities observed in Timothy syndrome were described in the 1990s. However, it was linked with calcium channel abnormalities in 2004, and the disorder was thence named "Timothy syndrome" in honor of Katherine W. Timothy, who was among the first to identify a case and performed