CACNA1C

CACNA1C-related Disorders (CRD) including Timothy Syndrome (TS) and Non-syndromic Long QT Syndrome 8 (LQT8).

Cause

Timothy Syndrome (TS) is a rare, genetic condition caused by specific 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.

Some variants are unique and it is uncertain if they are harmful; these variants are called “variants of uncertain significance” and should not be assumed to be pathogenic.

Specific pathogenic variants of the CACNA1C gene have been found to cause two 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 a few but not all of their body’s cells, when it is present in an egg or sperm. 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:

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:

• the identification of a specific mutational change in the CACNA1C gene
• the patient has multisystem health concerns, congenital heart defects and/or developmental concerns

A CACNA1C mutational change that results in a single condition or symptom should not be assumed to be TS. Not all variants in the CACNA1C gene cause Timothy Syndrome.

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 2 types of Timothy Syndrome.

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

* 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.

Non-syndromic Long QT Syndrome 8 (LQT8)

Non-syndromic LQT8 overlaps with Timothy Syndrome in that the affected individual has LQT (a prolonged QT interval on an ECG).

There are many variants throughout the CACNA1C gene that appear to cause non-syndromic LQT8. All individuals with such a diagnosis should seek advice from a cardiologist and electrophysiologist.

Atypical Timothy Syndrome (ATS)

ATS is an old label that we are trying to redefine. We are now referring to individuals bearing a novel variant in the CACNA1C gene, who have some, but not all, symptoms typical of Timothy Syndrome, as potentially having a CACNA1C-related disorder.

Some affected individuals may present with multisystem health concerns that overlap entirely with Timothy Syndrome. Such individuals should seek further medical attention to determine if they have a novel variant that causes a syndrome indistinguishable from Timothy Syndrome.

CACNA1C-related Disorder

Symptoms

The protein coded by the CACNA1C gene functions in many different tissues and organs in our bodies. It is possible that some disorders that have an overlapping symptom with Timothy Syndrome are caused by novel variants in the CACNA1C gene.

Diagnosis

Genetic testing may reveal a novel variant in the CACNA1C gene. In most cases, this new variant may be labelled as a “variant of uncertain significance”. It will take further medical evaluations and research to determine if this variant is causative of an individual’s symptoms. If shown to cause particular symptoms, this variant may then be labelled as “pathogenic” for a CACNA1C-related disorder.

LoF variants

Timothy Syndrome is characterised by Gain of Function (GoF) variants in the CACNA1C gene, however, there are also individuals with CACNA1C-related disorders who have Loss of Function (LoF) variants.

In a Gain of Function variant, the calcium channels open and stay open for a long time. As a result, calcium ion influx is increased, causing increased neuronal excitability.

In a Loss of Function variant, the opposite occurs; there is improper channel opening, resulting in less calcium entering the cells and decreased neuronal firing.

Loss of Function CACNA1C variants can lead to Short QT (SQT), a highly lethal heart rhythm disturbance that is the mirror image of Long QT (prolonged QT interval), one of the hallmark features of Timothy Syndrome.

To date, only a few individuals with Loss of Function CACNA1C variants have been found. These individuals show a combined phenotype (symptoms) of a short QT interval and a Brugada pattern. Brugada Syndrome is another rare, genetic heart disease.

In at least one individual, there is an overlap with Timothy Syndrome. This one patient does not – as has been reported for the other loss-of-function CACNA1C patients – have an isolated cardiac phenotype, but multiple symptoms:

• short QT Syndrome (in this case without Brugada pattern)
• autism
• poor dental enamel
• a minor effect on the immune system
• hypoglycaemia
• severe affective disorder (depression).

Short QT can be treated with hydroquinidine (which prolongs the QT interval). Sudden cardiac death can be prevented by implanting an implantable cardioverter-defibrillator (ICD).

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.