What’s It All About?
Making sense of the Science
THE LATEST RESEARCH EFFORT TRIES TO BETTER UNDERSTAND WHAT CAUSES LOW BLOOD SUGAR LEVELS IN SOME CHILDREN WITH TIMOTHY SYNDROME
What Do We Know Already?
We know that children and young people with Timothy syndrome (TS) have a rare genetic abnormality (a mutation) in a gene (CACNA1C) that affects a protein which serves as a tiny channel to enable calcium molecules to move into and out of various cells in the body. The normal movement of calcium through these so-called calcium channels is important for healthy growth and development, and for maintaining normal tissue function and structure.
Although every cell in the body may have the TS hallmark in its DNA, the biological effects of the mutation on tissue and organ function are complex, still not well understood and may vary between different cell types and different children. In some organs and tissues, for example, the TS genetics lead to ‘gain-of-function’ effects involving the calcium channels whereas in other tissues the TS gene seems to cause problems due to a loss of normal calcium channel functioning.
We also know that TS children can have a variety of symptoms and difficulties ranging from the well-known cardiac effects (Long-QT) and neuro-developmental challenges (autism spectrum disorders) to other features involving bones, immunity, metabolism and the brain. The extent to which different CACNA1C gene abnormalities affect different tissues and organs, and different children, is still being uncovered by scientists and clinicians around the world, but more information is emerging about this multisystem disorder.
Transient reductions in blood glucose levels (‘hypos’)
Lately, it has been highlighted that children with TS can suffer from spontaneous and intermittent episodes of low blood sugar (glucose) levels, also known as hypoglycemia (‘hypos’ for short). A hypo is usually defined as a blood glucose level below 70mg/dl (or 3.5mmol/L) but detecting transient reductions in blood glucose levels can be very difficult – it depends upon recognizing the symptoms and/or a finger-prick blood test.
Nevertheless, from clinical observations it would seem that hypos of varying severity and frequency are an under-recognized problem for many TS children. We don’t know exactly how common it is, but in some observational studies as many as one-third of children were affected.
The symptoms of hypoglycemia can include floppiness, shakiness or tremor, poor feeding, drowsiness, confusion, increased sweating, intense hunger and a rapid heart rate. Because the brain is reliant on a continuous supply of glucose to function normally (other organs can switch to utilizing alternative fuels, e.g fats or proteins, if sugar levels fall), severe hypoglycemia can cause loss of consciousness, seizures and other life-threatening complications, including heart rhythm abnormalities.
If a hypo is suspected, and the child is sufficiently alert to swallow safely, the best treatment is to give some glucose orally, e.g concentrated fruit juice or something similar that is sweet.
This usually restores glucose levels quite quickly (within 1-2 minutes) and resolves the symptoms. We also know from young people with type 1 diabetes that they can learn to recognize the early symptoms of a hypo, e.g after exercise, and take prompt action themselves.
How are blood glucose levels normally controlled?
We know that glucose levels in the blood are normally maintained within a fairly narrow range. Insulin is a key hormone which helps us to lower blood glucose levels, e.g after a meal, by stimulating glucose uptake into liver, muscle and fat. Insulin is released into the bloodstream by specialized cells (known as beta-cells) which are located within the pancreas (a gland in the upper part of the abdomen) and can sense the concentration of glucose in the bloodstream at any given moment.
Beta-cell secretion of insulin occurs typically after a meal and the beta cells will automatically switch off insulin release during periods of fasting, e.g overnight, thus helping to keep blood glucose levels and the supply of glucose to the brain remarkably constant.
Interestingly, it has been known for some time that release of insulin from pancreatic beta-cells is triggered by an influx of calcium through the same type of calcium channels that are involved in TS, but the mechanisms that cause some TS children to suffer from intermittent hypos remain unclear.
The latest research (Kummer S et al; https://doi.org/10.3390/ijms23158097)
On this background, a group of scientists from Germany and the USA have recently published a report which provides some new insights. In particular, they studied similarities and differences between TS-associated hypoglycemia and a rare condition called congenital hyperinsulinism (CHI)
CHI affects approximately 1 in 20,000 children. It usually presents soon after birth and is characterized by episodes of intermittent, sometimes severe hypoglycemia. Children with CHI, for some reason, produce inappropriate and excessive amounts of insulin from their pancreas, which in turn causes blood glucose levels to fall, often suddenly.
Kummer S and colleagues studied a 17-year old girl who first presented with seizures due to severe hypos at the age of 8 months. The hypos were attributed to episodes of inappropriately high circulating insulin levels, often triggered by an overnight fast. Her ECG showed borderline QT-prolongation but there was no history of cardiac problems and she was considered low probability for having Long-QT syndrome.
Although various other genetic abnormalities have been reported in patients with CHI, Kummer et al identified a novel mutation in the CACNA1C gene in this patient. CACNA1C-associated cases of CHI have not previously been reported, but this discovery provides strong evidence that the CACNA1C (TS) gene influences beta-cell secretion of insulin and the overall regulation of glucose levels.
Furthermore, in experiments using isolated cells Kummer et al were able to demonstrate the functional consequences of this new CACNA1C mutation. The researchers were also able to analyze the medical records of five TS patients / families who had reported suffering from hypos. The information was inconclusive, in particular with regard to whether or not circulating insulin levels were elevated at the time of the hypos.
What Does All This Mean For Families Like Mine?
Firstly, we all need to be aware that TS children and young people might be prone to symptomatic hypos, e.g after fasting overnight or missing a meal or after strenuous exercise. Symptoms may be mild and transient (e.g sweating, tremor, blurred vision) or more severe (drowsiness, confusion, disorientation) and prolonged.
Preventative treatments are mainly dietary, e.g taking regular small meals and consuming some carbohydrate after exercise, so consulting a dietician can be very helpful. For families and carers of TS children, being alert to, and able to recognize hypo symptoms, along with everyday circumstances that could trigger a hypo, are important messages.
TS-associated hypos are probably under-recognized and under-reported. This research provides the first evidence that CACNA1C gene variants may affect the function of insulin producing beta-cells in the pancreas and disturb normal glucose regulation. Further research will no doubt focus on studying glucose regulation in TS children, and comparing the genetic and metabolic features of CHI with those of TS.
Richard Donnelly *
*The author is a physician and parent of a young person with TS
Full Reference
Kummer S et al: https://doi.org/10.3390/ijms23158097
