Timothy syndrome

Last updated
Timothy syndrome
Specialty Neurology   OOjs UI icon edit-ltr-progressive.svg

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, [1] the gene encoding the calcium channel Cav1.2 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, [2] [3] [4] although there have been multiple reports of patients living in to their mid- or late-twenties. [5]

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. [6]

Children with Timothy syndrome tend to be born via caesarean section due to fetal distress. [2] [3]


Timothy syndrome has an autosomal-dominant pattern of inheritance. Autosomal dominant - en.svg
Timothy syndrome has an autosomal-dominant pattern of inheritance.

There are two recognized types of Timothy syndrome, classical (type-1) and a second type (type-2). They are both caused by mutations in CACNA1C, the gene encoding the calcium channel Cav1.2 α subunit. Timothy syndrome mutations in CACNA1C cause delayed channel closing, also known as voltage-dependent inactivation, thus increased cellular excitability. [5]

Both types of Timothy syndromes are caused by mutations in CACNA1C. These mutations are in exon 8 (type 2) and exon 8a (classical form, type 1). Exons 8 and 8A are mutually exclusive exons. Exon 8a is highly expressed in the heart, brain, gastrointestinal system, lungs, immune system, and smooth muscle. Exon 8 is also expressed in these regions and its level is roughly five-fold higher than exon 8a expression. [5]

One mutation is found in patients with classical Timothy syndrome, G406R, located just past the sixth membrane-spanning segment of domain 1 (D1S6). The conserved glycine at this position seems to be vital for proper voltage-dependent inactivation, as the mutant is lacking in this respect. [4] 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. [6] 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. [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 [7] .


Syndactyly in a
.mw-parser-output .sfrac{white-space:nowrap}.mw-parser-output .sfrac.tion,.mw-parser-output .sfrac .tion{display:inline-block;vertical-align:-0.5em;font-size:85%;text-align:center}.mw-parser-output .sfrac .num,.mw-parser-output .sfrac .den{display:block;line-height:1em;margin:0 0.1em}.mw-parser-output .sfrac .den{border-top:1px solid}.mw-parser-output .sr-only{border:0;clip:rect(0,0,0,0);height:1px;margin:-1px;overflow:hidden;padding:0;position:absolute;width:1px}
2+1/2-year old girl with Timothy syndrome PMC5336871 Ergul 2015 Timothy syndrome syndactyly.jpg
Syndactyly in a 2+1/2-year old girl with Timothy syndrome

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. [5]


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. [6]


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. [4] One patient with the G402S mutation was largely normal with the exception of heart arrhythmia. [6] 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. [6] [4]


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 much of the phenotypic analysis that revealed other abnormalities. [4]

See also

Related Research Articles

<span class="mw-page-title-main">Brugada syndrome</span> Heart conduction disease

Brugada syndrome (BrS) is a genetic disorder in which the electrical activity of the heart is abnormal due to channelopathy. It increases the risk of abnormal heart rhythms and sudden cardiac death. Those affected may have episodes of syncope. The abnormal heart rhythms seen in those with Brugada syndrome often occur at rest. They may be triggered by a fever.

<span class="mw-page-title-main">Long QT syndrome</span> Medical condition

Long QT syndrome (LQTS) is a condition affecting repolarization (relaxing) of the heart after a heartbeat, giving rise to an abnormally lengthy QT interval. It results in an increased risk of an irregular heartbeat which can result in fainting, drowning, seizures, or sudden death. These episodes can be triggered by exercise or stress. Some rare forms of LQTS are associated with other symptoms and signs including deafness and periods of muscle weakness.

<span class="mw-page-title-main">Short QT syndrome</span> Medical condition

Short QT syndrome (SQT) is a very rare genetic disease of the electrical system of the heart, and is associated with an increased risk of abnormal heart rhythms and sudden cardiac death. The syndrome gets its name from a characteristic feature seen on an electrocardiogram (ECG) – a shortening of the QT interval. It is caused by mutations in genes encoding ion channels that shorten the cardiac action potential, and appears to be inherited in an autosomal dominant pattern. The condition is diagnosed using a 12-lead ECG. Short QT syndrome can be treated using an implantable cardioverter-defibrillator or medications including quinidine. Short QT syndrome was first described in 2000, and the first genetic mutation associated with the condition was identified in 2004.

<span class="mw-page-title-main">Torsades de pointes</span> Type of abnormal heart rhythm

Torsades de pointes, torsade de pointes or torsades des pointes is a specific type of abnormal heart rhythm that can lead to sudden cardiac death. It is a polymorphic ventricular tachycardia that exhibits distinct characteristics on the electrocardiogram (ECG). It was described by French physician François Dessertenne in 1966. Prolongation of the QT interval can increase a person's risk of developing this abnormal heart rhythm, occurring in between 1% and 10% of patients who receive QT-prolonging antiarrhythmic drugs.

<span class="mw-page-title-main">Jervell and Lange-Nielsen syndrome</span> Medical condition

Jervell and Lange-Nielsen syndrome (JLNS) is a rare type of long QT syndrome associated with severe, bilateral sensorineural hearing loss. Those with JLNS are at risk of abnormal heart rhythms called arrhythmias, which can lead to fainting, seizures, or sudden death. JLNS, like other forms of long QT syndrome, causes the cardiac muscle to take longer than usual to recharge between beats. It is caused by genetic variants responsible for producing ion channels that carry transport potassium out of cells. The condition is usually diagnosed using an electrocardiogram, but genetic testing can also be used. Treatment includes lifestyle measures, beta blockers, and implantation of a defibrillator in some cases. It was first described by Anton Jervell and Fred Lange-Nielsen in 1957.

<span class="mw-page-title-main">Romano–Ward syndrome</span> Medical condition

Romano–Ward syndrome is the most common form of congenital Long QT syndrome (LQTS), a genetic heart condition that affects the electrical properties of heart muscle cells. Those affected are at risk of abnormal heart rhythms which can lead to fainting, seizures, or sudden death. Romano–Ward syndrome can be distinguished clinically from other forms of inherited LQTS as it affects only the electrical properties of the heart, while other forms of LQTS can also affect other parts of the body.

<span class="mw-page-title-main">Andersen–Tawil syndrome</span> Rare autosomal dominant genetic disorder

Andersen–Tawil syndrome, also called Andersen syndrome and long QT syndrome 7, is a rare genetic disorder affecting several parts of the body. The three predominant features of Andersen–Tawil syndrome include disturbances of the electrical function of the heart characterised by an abnormality seen on an electrocardiogram and a tendency to abnormal heart rhythms, physical characteristics including low-set ears and a small lower jaw, and intermittent periods of muscle weakness known as hypokalaemic periodic paralysis.

Voltage-gated calcium channels (VGCCs), also known as voltage-dependent calcium channels (VDCCs), are a group of voltage-gated ion channels found in the membrane of excitable cells (e.g., muscle, glial cells, neurons, etc.) with a permeability to the calcium ion Ca2+. These channels are slightly permeable to sodium ions, so they are also called Ca2+–Na+ channels, but their permeability to calcium is about 1000-fold greater than to sodium under normal physiological conditions.

hERG Mammalian protein found in humans

hERG is a gene that codes for a protein known as Kv11.1, the alpha subunit of a potassium ion channel. This ion channel is best known for its contribution to the electrical activity of the heart: the hERG channel mediates the repolarizing IKr current in the cardiac action potential, which helps coordinate the heart's beating.

<span class="mw-page-title-main">Gitelman syndrome</span> Medical condition

Gitelman syndrome (GS) is an autosomal recessive kidney tubule disorder characterized by low blood levels of potassium and magnesium, decreased excretion of calcium in the urine, and elevated blood pH. It is the most frequent hereditary salt-losing tubulopathy. Gitelman syndrome is caused by disease-causing variants on both alleles of the SLC12A3 gene. The SLC12A3 gene encodes the thiazide-sensitive sodium-chloride cotransporter, which can be found in the distal convoluted tubule of the kidney.

<span class="mw-page-title-main">Larsen syndrome</span> Medical condition

Larsen syndrome (LS) is a congenital disorder discovered in 1950 by Larsen and associates when they observed dislocation of the large joints and face anomalies in six of their patients. Patients with Larsen syndrome normally present with a variety of symptoms, including congenital anterior dislocation of the knees, dislocation of the hips and elbows, flattened facial appearance, prominent foreheads, and depressed nasal bridges. Larsen syndrome can also cause a variety of cardiovascular and orthopedic abnormalities. This rare disorder is caused by a genetic defect in the gene encoding filamin B, a cytoplasmic protein that is important in regulating the structure and activity of the cytoskeleton. The gene that influences the emergence of Larsen syndrome is found in chromosome region, 3p21.1-14.1, a region containing human type VII collagen gene. Larsen syndrome has recently been described as a mesenchyme disorder that affects the connective tissue of an individual. Autosomal dominant and recessive forms of the disorder have been reported, although most cases are autosomal dominant. Reports have found that in Western societies, Larsen syndrome can be found in one in every 100,000 births, but this is most likely an underestimate because the disorder is frequently unrecognized or misdiagnosed.

SCN5A Protein-coding gene in the species Homo sapiens

Sodium channel protein type 5 subunit alpha, also known as NaV1.5 is an integral membrane protein and tetrodotoxin-resistant voltage-gated sodium channel subunit. NaV1.5 is found primarily in cardiac muscle, where it mediates the fast influx of Na+-ions (INa) across the cell membrane, resulting in the fast depolarization phase of the cardiac action potential. As such, it plays a major role in impulse propagation through the heart. A vast number of cardiac diseases is associated with mutations in NaV1.5 (see paragraph genetics). SCN5A is the gene that encodes the cardiac sodium channel NaV1.5.

Ca<sub>v</sub>1.2 Protein-coding gene in humans

Calcium channel, voltage-dependent, L type, alpha 1C subunit is a protein that in humans is encoded by the CACNA1C gene. Cav1.2 is a subunit of L-type voltage-dependent calcium channel.

<span class="mw-page-title-main">Catecholaminergic polymorphic ventricular tachycardia</span> Medical condition

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited genetic disorder that predisposes those affected to potentially life-threatening abnormal heart rhythms or arrhythmias. The arrhythmias seen in CPVT typically occur during exercise or at times of emotional stress, and classically take the form of bidirectional ventricular tachycardia or ventricular fibrillation. Those affected may be asymptomatic, but they may also experience blackouts or even sudden cardiac death.

<span class="mw-page-title-main">KCNE2</span> Protein-coding gene in the species Homo sapiens

Potassium voltage-gated channel subfamily E member 2 (KCNE2), also known as MinK-related peptide 1 (MiRP1), is a protein that in humans is encoded by the KCNE2 gene on chromosome 21. MiRP1 is a voltage-gated potassium channel accessory subunit associated with Long QT syndrome. It is ubiquitously expressed in many tissues and cell types. Because of this and its ability to regulate multiple different ion channels, KCNE2 exerts considerable influence on a number of cell types and tissues. Human KCNE2 is a member of the five-strong family of human KCNE genes. KCNE proteins contain a single membrane-spanning region, extracellular N-terminal and intracellular C-terminal. KCNE proteins have been widely studied for their roles in the heart and in genetic predisposition to inherited cardiac arrhythmias. The KCNE2 gene also contains one of 27 SNPs associated with increased risk of coronary artery disease. More recently, roles for KCNE proteins in a variety of non-cardiac tissues have also been explored.

<span class="mw-page-title-main">Calmodulin 1</span> Protein-coding gene in the species Homo sapiens

Calmodulin 1 is a protein in humans that is encoded by the CALM1 gene.

<span class="mw-page-title-main">Ankyrin-2</span> Protein-coding gene in the species Homo sapiens

Ankyrin-2, also known as Ankyrin-B, and Brain ankyrin, is a protein which in humans is encoded by the ANK2 gene. Ankyrin-2 is ubiquitously expressed, but shows high expression in cardiac muscle. Ankyrin-2 plays an essential role in the localization and membrane stabilization of ion transporters and ion channels in cardiomyocytes, as well as in costamere structures. Mutations in ANK2 cause a dominantly-inherited, cardiac arrhythmia syndrome known as long QT syndrome 4 as well as sick sinus syndrome; mutations have also been associated to a lesser degree with hypertrophic cardiomyopathy. Alterations in ankyrin-2 expression levels are observed in human heart failure.

<span class="mw-page-title-main">KCNE5</span> Protein-coding gene in the species Homo sapiens

KCNE1-like also known as KCNE1L is a protein that in humans is encoded by the KCNE1L gene.

<span class="mw-page-title-main">Celivarone</span> Experimental drug being tested for use in pharmacological antiarrhythmic therapy

Celivarone is an experimental drug being tested for use in pharmacological antiarrhythmic therapy. Cardiac arrhythmia is any abnormality in the electrical activity of the heart. Arrhythmias range from mild to severe, sometimes causing symptoms like palpitations, dizziness, fainting, and even death. They can manifest as slow (bradycardia) or fast (tachycardia) heart rate, and may have a regular or irregular rhythm.

CACNA1C-related disorders are a group of rare diseases caused by variants in the CACNA1C gene, which encodes a subunit of the L-type voltage-dependent calcium channel. Genomic sequencing has linked a number of heterogenous phenotypes to pathogenic variants in the CACNA1C gene:


  1. Napolitano, Carlo; Timothy, Katherine W.; Bloise, Raffaella; Priori, Silvia G. (Feb 11, 2021) [1993]. "CACNA1C-Related Disorders". In Adam, Margaret P.; Feldman, Jerry; Mirzaa, Ghayda; Pagon, Roberta A.; Wallace, Stephanie E.; Bean, Laura J.H.; Gripp, Karen W.; Amemiya, Anne (eds.). GeneReviews. Seattle (WA): University of Washington, Seattle. PMID   20301577.
  2. 1 2 Marks ML, Whisler SL, Clericuzio C, Keating M (January 1995). "A new form of long QT syndrome associated with syndactyly". Journal of the American College of Cardiology. 25 (1): 59–64. doi:10.1016/0735-1097(94)00318-K. PMID   7798527.
  3. 1 2 Marks ML, Trippel DL, Keating MT (October 1995). "Long QT syndrome associated with syndactyly identified in females". The American Journal of Cardiology. 76 (10): 744–745. doi:10.1016/S0002-9149(99)80216-1. PMID   7572644.
  4. 1 2 3 4 5 Splawski I, Timothy KW, Sharpe LM, Decher N, Kumar P, Bloise R, et al. (October 2004). "Ca(V)1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism". Cell. 119 (1): 19–31. doi: 10.1016/j.cell.2004.09.011 . PMID   15454078. S2CID   15325633.
  5. 1 2 3 4 5 Bauer R, Timothy KW, Golden A (2021). "Update on the Molecular Genetics of Timothy Syndrome". Frontiers in Pediatrics. 9: 668546. doi: 10.3389/fped.2021.668546 . PMC   8165229 . PMID   34079780.
  6. 1 2 3 4 5 Splawski I, Timothy KW, Decher N, Kumar P, Sachse FB, Beggs AH, et al. (June 2005). "Severe arrhythmia disorder caused by cardiac L-type calcium channel mutations". Proceedings of the National Academy of Sciences of the United States of America. 102 (23): 8089–8096. Bibcode:2005PNAS..102.8089S. doi: 10.1073/pnas.0502506102 . PMC   1149428 . PMID   15863612.
  7. 1 2 Porta-Sánchez, Andreu; Mazzanti, Andrea; Tarifa, Carmen; Kukavica, Deni; Trancuccio, Alessandro; Mohsin, Muhammad; Zanfrini, Elisa; Perota, Andrea; Duchi, Roberto; Hernandez-Lopez, Kevin; Jáuregui-Abularach, Miguel Eduardo; Pergola, Valerio; Fernandez, Eugenio; Bongianino, Rossana; Tavazzani, Elisa (2023-12-11). "Unexpected impairment of INa current underpins reentrant arrhythmias in a knock-in swine model of Timothy syndrome". Nature Cardiovascular Research. 2 (12): 1291–1309. doi:10.1038/s44161-023-00393-w. ISSN   2731-0590.