#ShareForRare: Timothy Syndrome
What is Timothy Syndrome?
Timothy Syndrome (TS) is an ultra-rare genetic disorder that affects multiple organs and systems in the body. It is characterized by cardiac arrhythmias, webbing of fingers and toes (syndactyly), developmental delays, intellectual disability, and features of autism spectrum disorder.
Timothy syndrome often manifests during the neonatal period. However, in many cases, it is diagnosed later, between the ages of 2–4 years old. As a result of the serious cardiac issues related to Timothy syndrome, some patients live only into childhood, with the leading case of death being ventricular tachycardia in around 80% of the cases. Currently, there are three clinical subtypes recognized: the classical types present with a prolonged QT interval and either with (Type 1) or without (Type 2) cutaneous syndactyly of fingers and toes; and the atypical form (ATS) causes multi-system health concerns but not necessarily with prolonged QT.
Timothy syndrome is caused by mutations in the CACNA1C gene, which codes for a calcium channel called Cav1.2. This protein plays a crucial role in regulating the flow of calcium ions into cells, including cardiac cells and neurons. Genetic variants in this gene disrupt the normal functioning of the calcium channel, leading to the various symptoms and multi-system features associated with Timothy Syndrome, as well as other CACNA1C-related arrhythmic syndromes, including Brugada Syndrome, short QT, and LongQT Syndrome 8.
Unlike other CACNA1C-related disorders, Timothy Syndrome is extremely rare, with less than 100 cases reported in the literature worldwide. Since causal variants for this disease are not usually inherited, no higher prevalence was documented for any specific population.
Molecular aspects of Timothy syndrome
The CACNA1C gene is located in 12p13.33 and it encodes the α1C subunit of the Cav1.2 voltage-gated calcium channel, which is expressed in many tissues of the body, including heart muscle and brain. This protein product bonds with an intracellular β subunit and an extracellular α2δ subunit to form the fully functional channel complex.
The majority of mutations in CACNA1C associated with Timothy Syndrome are de novo mutations. However, in some cases, TS has been identified as an inherited autosomal dominant trait resulting from parental germline mosaicism. Regardless of the inheritance, all causal variants result in a missense effect with gain-of-function, delaying the closing of the Cav1.2 calcium channel, thus leading to an excessive influx of calcium ions into cells. This increase in cellular excitability disrupts normal cellular processes and can result in the characteristic features of Timothy syndrome.
The CACNA1C gene spans an estimated 150 kb of the human genome and is composed of 44 invariant and 6 alternative exons. In particular, exons 8 (GRCh38/hg38, chr12: 2504436–2504539) and 8A (GRCh38/hg38, chr12: 2504842–2504945) are alternatively spliced, but both encode for a glycin in amino acid 406, which is the most commonly mutated residue in Timothy Syndrome. The most frequent causal variant (for both transcripts) is Gly406Arg, but there have been some other missense mutations reported in patients with TS, such as Gly402Ser. According to this study, the variants usually disrupt the 6th transmembrane helix in some intracellular domain of the α1C subunit, resulting in a gain-of-function phenotype.
Interestingly, the location of the missense mutation on the alternatively-spliced exons correlates with the different clinical subtypes.
- Timothy Syndrome type 1 (TS1) is caused by the G406R change in exon 8A of the CACNA1C gene. Apart from suffering from syndactly, children with this variant are usually less-severely affected than children with the same missense variant in exon 8, which likely is due to the fact that this transcript has been shown to have a 4-times lower expression in the most affected tissues.
- Timothy Syndrome type 2 (TS2) is caused by the G406R change in exon 8 of the CACNA1C gene. Because this transcript is highly expressed in the heart and brain, patients with this variant suffer from severe cardiac and cognitive defects.
- Atypical Timothy Syndrome (ATS) is caused by other missense variants in the CACNA1C gene, located in exon 8 or other regions. This variation of the Syndrome is also called CACNA1C-related disorder.
As of April 2023, according to Franklin, at least 51 pathogenic SNPs have been identified in the CACNA1C gene, causing Short QT Syndrome, Brugada Syndrome, Timothy Syndrome, and other CACNA1C-related diseases. While 38 of these pathogenic variants have a missense effect, most missense variants are currently classified as VUS (Variant of Uncertain Significance).
Clinical features and diagnostics
Timothy Syndrome patients present a wide range of clinical features that can vary in severity among affected individuals.
The most common and characteristic feature is cardiac arrhythmias, which can include prolonged QT intervals, ventricular tachycardia, and other abnormalities in heart rhythm. These cardiac issues can be life-threatening and may require medical intervention. Other common features of Timothy syndrome include abnormal heart structure, syndactyly (in TS1), hip dysplasia (in TS2), facial anomalies, skeletal/smooth muscle anomalies, immunodeficiencies, gastrointestinal issues, developmental delays, and features of autism spectrum disorder such as impaired social interaction and communication skills.
Some patients with TS can also suffer from significant episodes of hypoglycemia, seizures, and hypothermia, as well as some other systemic phenotypic features. A complete list of phenotypes, with their respective occassionallity, can be found here.
Diagnosis of Timothy Syndrome is typically based on clinical evaluation and genetic testing. Genetic testing of the whole CACNA1C gene can identify variants that are associated with Timothy syndrome.
Since not all CACNA1C missense variants cause this disease, it is recommended that TS is diagnosed when both of these conditions are met:
- the identification of a specific variant change in the CACNA1C gene
- the presentation of multisystem health issues, congenital heart defects, and/or developmental concerns
In addition, electrocardiograms and other tests may also be performed to assess the heart rhythm and identify any cardiac abnormalities. As for antenatal diagnosis, echocardiography can often identify fetal distress secondary to the cardiac findings of 2:1 AV Block or bradycardia. When the pathogenic CACNA1C variant has been identified in a family member, prenatal genetic testing is possible for at-risk pregnancies, although TS is usually caused by de novo variants.
Treatment and clinical trials
There is currently no cure for Timothy Syndrome, and management is focused on treating the symptoms and associated health issues. Treatment may involve medication to manage cardiac arrhythmias, physical and occupational therapy to address developmental delays and motor skills issues, and behavioral interventions for features of autism spectrum disorder.
The main objective of the treatments is to prevent ventricular fibrillation and possible sudden death. Regular monitoring of cardiac function is important, and individuals with Timothy syndrome may require lifelong cardiac management and follow-up care. Interventions should be considered as early as possible and include the combination of left cardiac sympathetic denervation (LCSD) with an implantable cardioverter-defibrillator (ICD). A pacemaker can be placed during the first days of life to control 2:1 AV block and resultant bradycardia. Beta-blockers and/or other antiarrhythmic drugs can be administered to maintain QT interval and prevent ventricular tachyarrhythmias.
Other symptoms, such as additional congenital heart defects, respiratory infections, hypoglycemia, epilepsy, hypoglycemic episodes, and muscle anomalies should be managed according to standard protocols.
To date and to the best of our knowledge, there are no clinical trials studying therapeutic strategies for Timothy Syndrome.
Resources and initiatives
There are interesting resources for patients and caregivers, such as the NIH’s Genomic and Rare Disease (GARD) and MedlinePlus. Furthermore, the Timothy Syndrome Foundation, founded by Katherine Timothy, for whom the condition was named after her years of TS research, offers educational materials for families and individuals.
For doctors and other help professionals, the website Orphanet and the NIH’s Genetic Testing Registry offer information to help with diagnosis and testing.
Regarding advocacy, several NGOs are especially dedicated for the connect families affected by the disease, such as the Timothy Syndrome Alliance (TSA). In addition, the NORD (National Organization for Rare Disorders) offers programs of education, advocacy, research, and patient services for many rare diseases, and has resources for patients, caregivers, clinicians, and researchers.
One particularly noteworthy initiative driven by the TSA is the creation of a CACNA1C Community Registry: a voluntary, patient-driven global registry of individuals with variants in the CACNA1C gene. With this repository, they aim to collect patients’ data so that their real-world experience with the condition is documented in a way that can be used to scientifically study the condition, improve the disorder’s diagnosis and management, and develop new treatments. We encourage the genetic’s community to participate in this important data-sharing initiative.
What’s #ShareForRare?
In line with Franklin’s commitment to advancing the field of rare disease diagnosis and treatment, this initiative aims to raise awareness of uncommon disorders in the Franklin Community and encourage collaboration among community members.
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