Timothy Syndrome

Cause

Timothy Syndrome (TS) is a rare, genetic condition caused by changes to a gene called CACNA1C.

Genes are made from DNA sequences found in our chromosomes. Changes to DNA sequences are called variants. Variants that alter the function of a gene and consequently affect health and/or development are called pathogenic variants.

Specific pathogenic variants of the CACNA1C gene have been found to cause different types of Timothy Syndrome.

Most of the time, CACNA1C pathogenic variants appear randomly in a child and are not identified in either parent. This is known as de novo.

Occasionally a parent can pass on the CACNA1C pathogenic variant to their child if it exists in an egg or sperm cell, or in a few of their body’s cells. This is known as mosaicism.

As far as we are aware, parents with a mosaic CACNA1C pathogenic variant are unaffected, since the variant only exists in a few specific cells.

Everyone has DNA sequence variants. They happen by chance but we only notice them when they alter the function of important genes and our health, physical appearance or behaviour are affected. They are not caused by anything we did or didn’t do, they are just a part of a natural biological process.

Symptoms

Most children with Timothy Syndrome have:

  • abnormal heart function
  • irregular heart beat
  • abnormal heart structure
  • neuronal developmental delays
  • immunodeficiencies
  • endocrinological dysfunction
  • gastrointestinal concerns
  • effects on smooth muscle
  • effects on skeletal muscle
  • facial anomalies
  • syndactyly (joined fingers or toes)
  • mild dental, skin, eye and hair anomalies

Some children with Timothy Syndrome have:

  • significant episodes of low blood sugar levels (hypoglycemia)
  • seizures
  • an unusually low body temperature (hypothermia)

Diagnosis

Timothy Syndrome is diagnosed when both of these conditions are met:

  • a mutational change to gene CACNA1C is identified
  • the patient has multisystem health, congenital heart defects or developmental concerns

A CACNA1C mutational change that results in a single condition should not be diagnosed as TS.

Any child suspected of having TS should have their CACNA1C gene fully sequenced.

Treatment

Currently, there is no cure for Timothy Syndrome.

There are, however, various treatments that can help with specific symptoms of the condition. These include:

  • heart medication
  • blood sugar monitoring (and management)
  • speech and physical therapy
  • gastrointestinal medication

Types of Timothy Syndrome

There are 3 types of Timothy Syndrome.

These diagnoses are often suspected at birth and confirmed by sequencing of the CACNA1C gene shortly thereafter.

TS1

TS1 is diagnosed when a genetic test identifies an amino acid* change of G406R** in exon 8A of CACNA1C.

Infants present with serious cardiac concerns and syndactyly.

TS2

TS2 is diagnosed when a genetic test identifies an amino acid* change of G406R** in exon 8 (not 8A).

Infants present with very serious cardiac concerns in association with hypotonia and/or congenital hip dysplasia, however, without syndactyly.

ATS

ATS (Atypical Timothy Syndrome) is diagnosed when a genetic test identifies a pathogenic variant of the CACNA1C gene different to those that cause TS1 and TS2.

Infants present with a multisystem health concern, which often includes cardiac, muscular and other physical anomalies.

* Amino acids are the “building blocks” of proteins (in the context of an amino acid change, the function of the protein channel may be disrupted).

** The amino acid Glycine is substituted by a different amino acid (Arginine) in G406R, affecting the functionality of the L-type Ca2+ Channel.

Background

Timothy Syndrome is named after Katherine Timothy who first described the condition.

While conducting a study on Long QT Syndrome, Katherine identified a very small subset of infants who had extremely prolonged QT intervals and always presented at birth with syndactyly or conjoined fingers and toes.

The DNA of these children was collected and entered into every possible genetic study for almost 20 years. In 2004, the discovery was finally made.

Each child shared an identical genetic change in the L-type Calcium Channel gene, CACNA1C. This condition came to be known as Timothy Syndrome.

This website contains general information about CACNA1C-related disorders. The information is not advice, and should not be treated as such. You must not rely on the information on this website as an alternative to medical advice from your relevant medical professional. TSA does not promote or recommend any treatment, therapy, institution or health care plan.

The information contained in this site is intended for your general education and information only. Any treatment plan for any given patient must be carried out on an individual basis, after a thorough discussion with the patient’s medical professional(s).

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