Timothy syndrome is a rare autosomal dominant genetic disorder. Fewer than 20 cases have been reported worldwide. Symptoms are manifested early on in life and affected individuals tend to die during early childhood at about 3 years of age. The disorder was recognized only recently, being identified in 2004 by researchers at Children’s Hospital Boston, Howard Hughes Medical Institute, University of Utah, and the University of Pavia in Italy.
Timothy syndrome affects many parts of the body. Common symptoms include congenital heart defects, immune deficiencies, webbed fingers (100% of affected children)and neurodevelopmental defects. At physical examination the face may show a flat nasal bridge (seen in roughly half of patients), low-set ears and a thin upper lip. Neuropsychiatric manifestations, for those who survive long enough to be tested, include a global neurodevelopmental delay (e.g. walking, running) and autistic symptoms. A case report of a rare patient that survived childhood reported an association to Bipolar Disorder (Gershon et al., 2014).
Despite the wide variety of manifestation, the condition is caused by a single mutation in the CACNA1C gene, located in chromosome 12, that encodes a calcium channel subunit. The mutation is spontaneous (called de novo) and not inherited from one of the parents. In this regard there is no apparent need to evaluate relatives at risk. The end effect of this abnormality is the hyperexcitability of cells throughout the body that are overwhelmed by the continuous influx of calcium. In the case of heart, cells that contract have a difficult time in returning to their resting state. In the case of the brain, hyperexcitability is manifested as intractable seizures. Cells of the brain fire uncontrollably and loose their ability to shut down.
There is no cure for the disorder, rather treatment is symptomatic. Some patients may need surgery to correct their cardiac abnormalities; however, anesthesia is a recognized trigger for arrhythmias in Timothy syndrome and may require cardiac monitoring. Other interventions may include speech pathology and physical therapy. Prophylactic treatment (e.g. beta-blockers) has been recommended to prevent heart arrhythmias.
Whole genome studies of autistic individuals suggest its association to various channel defects (Schmunk and Gargus, 2013). Children with Timothy Syndrome are severely delayed in language, are intensely shy, lack common sense, prefer spending time alone, and suffer from mild mental retardation. Given the small series of reported patients it is difficult to make estimates as to comorbidities, including autism. It is fair to say that , “most people with the Timothy syndrome mutation have autism as a symptom” (News Medical 2015). At present a mouse model of Timothy Syndrome exhibits the characteristic behavioral manifestations of autism (Bett, et al., 2012).
Bett GCL, Lis A, Wersinger SR, et al. A mouse model of Timothy Syndrome: a complex autistic disorder resulting from a point mutation in Cav1.2 N Am J Med Sci 5(3):135-140, 2012.
Gershon ES, Grennman K, Busnello J, et al. A rare mutation of CACNA1C in a patient with Bipolar disorder, and decreased gene expression associated with a Bipolar-associated common SNP of CACNA1C in brain. Mol Psychiatry 19(8):890-894, 2014.
News Medical. Most people wth Timothy syndrome mutation have autistic symptoms. http://www.news-medical.net/news/20111128/Most-people-with-Timothy-syndrome-mutation-have-autistic-symptoms.aspx
Schmunk G, Gargus JJ. Channelopathy pathogenesis in autism spectrum disorders. Front Genet 4:222, 2013.