Familial hyperinsulinism (ABCC8-related) is a rare genetic disorder characterized by dysregulation of insulin secretion from the pancreas, leading to abnormally high insulin levels in the blood. This condition results in hypoglycemia (low blood sugar), which can be severe and potentially life-threatening.
Familial hyperinsulinism genetic testing is included in Diagnostiki Athinon Monogenic Diseases Genetic Testing along with approximately 100 other inherited diseases, including cystic fibrosis (71 mutations) and hereditary breast cancer (genes BRCA1 415 mutations & BRCA2 419 mutations).
Critical features of familial hyperinsulinism (ABCC8-related) include:
- Recurrent Hypoglycemia: Individuals with this disorder experience recurrent episodes of hypoglycemia, which can lead to symptoms such as seizures, lethargy, and unconsciousness.
- Early Onset: Symptoms often manifest in infancy or early childhood.
- Autosomal Recessive Inheritance: Familial hyperinsulinism is typically inherited in an autosomal recessive manner, meaning that affected individuals inherit two copies of the mutated gene (one from each parent). The most common genes associated with this condition are ABCC8 and KCNJ11.
- Response to Glucose Load: The hypoglycemia in familial hyperinsulinism is often unresponsive to standard measures that increase blood sugar, such as giving glucose orally.
- Increased Insulin Secretion: The underlying cause is an abnormal regulation of insulin secretion by the pancreatic beta cells, resulting in excessive insulin release.
The ABCC8 and KCNJ11 genes provide instructions for making proteins part of the beta cell's potassium channel, a crucial component in regulating insulin secretion. Mutations in these genes can disrupt the normal functioning of the potassium channel, leading to excessive insulin release even without appropriate triggers.
Diagnosis of familial hyperinsulinism involves clinical evaluation, blood tests to measure insulin and glucose levels during fasting and after a glucose load, and genetic testing to identify mutations in the ABCC8 or KCNJ11 genes.
Management of familial hyperinsulinism often involves carefully monitoring blood glucose levels, frequent feedings to prevent hypoglycemia, and medications to help regulate insulin secretion. In severe cases that do not respond to medical management, surgical options such as partial or near-total pancreatectomy may be considered.
Genetic counseling is essential for families affected by familial hyperinsulinism to understand the inheritance pattern, assess the risk of passing the condition to future generations, and explore family planning options.
Early diagnosis and appropriate management are crucial for preventing complications associated with hypoglycemia and optimizing the long-term health of individuals with familial hyperinsulinism. A multidisciplinary approach involving endocrinologists, geneticists, and other specialists is often necessary for comprehensive care.
More Information
In most cases, hyperinsulinism is of genetic origin, and, to date, 12 genes involved in its development have been described. Between 50% and 60% of patients with hyperinsulinism have pathogenic variants in the ABCC8 gene, which codes for the ABC transporter family protein. The ABCC8 protein acts as a regulator of ATP-dependent potassium channels involved in insulin release in beta-pancreatic cells. The type of inheritance is mainly autosomal recessive. However, some variants follow a dominant mode of inheritance, implying that carriers of a single copy of a pathogenic variant in ABCC8 may manifest symptoms.
It has been observed that there are individuals who may be asymptomatic carriers of a pathogenic variant in ABCC8 with autosomal dominant inheritance and that there are others with a single copy of the variant who may develop hyperinsulinism in childhood or develop a milder form of diabetes that appears in adulthood.
The most frequent variants in ABCC8 are c.4160_4162del and c.3989-9G>A. They are present in 45% of cases of congenital hyperinsulinism and follow an autosomal recessive mode of inheritance. The pathogenic variant c.4160_4162del results in the deletion of three nucleotides and a protein that does not function properly. On the other hand, the variant c.3989-9G>A affects one nucleotide of an alternative splicing site.
Some variants are specific to certain populations, such as c.3989-9G>A, which is especially prevalent in the Ashkenazi Jewish population and the variants c.4516G>A and c.560T>A which are more frequent in the Finnish population than in other populations. c.4516G>A follows an autosomal dominant mode of inheritance, and c.560T>A is autosomal recessive.
Familial hyperinsulinism genetic testing analyzes the 13 most frequent pathogenic mutation of ABCC8 gene.
With the technique used for genetic testing, only the gene's specific mutations, which are the most important and frequent in the literature, are analyzed. However, it should be noted that there are likely other gene or chromosomal mutations in the gene to be tested, which cannot be identified with this method. Different analysis techniques can be used for these cases, such as e.g. next-generation sequencing (NGS).
