Timothy Syndrome

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

Cause

When children are conceived, genetic material is copied in the egg and sperm. The biological copying method is not perfect, and occasionally random changes occur in the genetic code of children that are not seen in the DNA of their parents.

This happens naturally and is not due to any lifestyle, dietary or environmental factors. No-one is to blame when these changes occur, and no-one is at fault.

In most children diagnosed with Timothy Syndrome, the change in the CACNA1C gene occurred by chance and was not found in their parents. This is known as a de novo variant (new).

In some cases, however, parents have been found to carry a pathogenic CACNA1C gene variant in some of their cells. Parents are often unaffected by the variant and show no symptoms.

This is known as mosaicism, which means the variant can be passed on from parent to child.

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

Children with Timothy Syndrome should be under the care of a multidisciplinary team, including a cardiac specialist.

Care for the type of anesthesia should be considered during a surgery. Cardiac and glucose monitoring is highly recommended throughout surgery and recovery periods.

Early intervention with physical and speech therapies as well as social integration is often beneficial.

Increased magnesium intake may be helpful for bowel movements and also for migraine headaches.

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.

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 2003, 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.

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