Permanent neonatal diabetes mellitus

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

Permanent neonatal diabetes mellitus is a type of diabetes that typically appears within the first 6 months after birth (the neonatal period) and continues throughout life. Diabetes is characterized by high levels of glucose in the blood, also called blood sugar. In infants with permanent neonatal diabetes mellitus, diabetes results from a shortage or absence of the hormone insulin. Insulin is produced by the pancreas. It helps move glucose from the blood into cells, where glucose is converted into energy.

The signs and symptoms of permanent neonatal diabetes mellitus can vary among affected individuals. Infants with this condition typically have abnormally high levels of glucose in the blood, glucose in the urine, severe fluid loss (dehydration), and a history of slow growth before birth (intrauterine growth retardation). After birth, affected infants may also have difficulty gaining weight and growing at the expected rate (faltering weight).

A small number of individuals with permanent neonatal diabetes mellitus have an underdeveloped pancreas. Because the pancreas produces digestive enzymes in addition to insulin, affected individuals may also experience digestive problems, such as fatty stools and an inability to absorb fat-soluble vitamins.

The long-term complications of permanent neonatal diabetes mellitus can include kidney disease and retinopathy, which is damage to the small blood vessels in the specialized light-sensitive tissue that lines the back of the eye (retina). The risk of long-term complications is reduced with proper diabetes management.

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

Variants (also called mutations) in one of several genes can cause permanent neonatal diabetes mellitus. The signs and symptoms of the condition, the severity of the condition, and the treatment options can vary depending on the particular gene involved. Variants in the KCNJ11, ABCC8, and INS genes are responsible for most cases of permanent neonatal diabetes mellitus.

About 25 percent of individuals with permanent neonatal diabetes mellitus have a variant in the KCNJ11 gene. Variants in the ABCC8 gene cause an additional 10 to 15 percent of cases. These genes provide instructions for making parts (subunits) of the ATP-sensitive potassium (KATP) channels that are found in specialized pancreas cells called beta cells. Each of these KATP channels consists of four subunits that are produced from the KCNJ11 gene and four subunits that are produced from the ABCC8 gene.

These KATP channels span the cell membranes of the beta cells and open and close in response to the amount of glucose in the bloodstream. The KATP channels close when blood glucose levels increase, which triggers the release of insulin from the beta cells into the bloodstream. In this way, the KATP channels help regulate insulin secretion and control blood glucose levels.

The variants in the KCNJ11 or ABCC8 gene that are associated with permanent neonatal diabetes mellitus cause cells to produce proteins that do not function properly. As a result, KATP channels do not close when they should, leading to reduced insulin secretion from the beta cells and impaired blood glucose control.

Variants in the INS gene, which provides instructions for making insulin, have been found in approximately 20 to 25 percent of individuals with permanent neonatal diabetes mellitus. The precursor to insulin is called proinsulin, which consists of a single chain of protein building blocks (amino acids). The proinsulin chain is cut (cleaved) to form individual pieces called A and B chains, which are joined together to form insulin. Variants in the INS gene disrupt the cleavage of proinsulin or the binding of the A and B chains, which reduces the amount of available insulin and leads to impaired blood glucose control.

Gene variants have not been found in all people with permanent neonatal diabetes mellitus. Researchers suspect that other genes may be involved in the development of this condition.

Permanent neonatal diabetes mellitus can also be part of a syndrome that affects multiple parts of the body. When the condition is part of a syndrome, it is caused by variants in the gene associated with that syndrome.

Inheritance and family implications

From: MedlinePlus Genetics, National Library of Medicine

Permanent neonatal diabetes mellitus can have different inheritance patterns depending on the gene involved.

This condition can be inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. Many of these cases result from a new (de novo) variant in the gene that occurs during the formation of reproductive cells (eggs or sperm) in an affected individual's parent or during early embryonic development. These affected individuals have no history of the disorder in their family.

Permanent neonatal diabetes mellitus can also be inherited in an autosomal recessive pattern, which means both copies of the gene in each cell must have a variant to cause the disorder. The parents of an individual with an autosomal recessive condition each carry one copy of the altered gene, but they typically do not show signs and symptoms of the condition.

When permanent neonatal diabetes mellitus is part of a syndrome, it follows the inheritance pattern of that syndrome.

How common is it?

From: MedlinePlus Genetics, National Library of Medicine

Approximately 1 in 90,000 to 260,000 infants receive a diagnosis of neonatal diabetes mellitus each year. About half of these babies have permanent neonatal diabetes mellitus.

Which doctor should you see?

The suggested department for discussing Permanent neonatal diabetes mellitus is Diabetology, with a endocrinologist / diabetologist as the relevant type of clinician. General physician / Family Medicine; paediatrician for children. Referral depends on symptoms.

Additional services that may be relevant, depending on the findings, include: Clinical Genetics.

This is an editorial referral starting point. The appropriate clinic depends on the person’s age, symptoms, previous diagnosis and local services. The first clinician can decide whether another specialty or a team is needed; a department label does not confirm the diagnosis.

How to prepare for an assessment

Bring a short timeline of the main symptoms: when they first appeared, whether they are constant or episodic, what seems to change them, and how they affect daily activities. Include previous reports, discharge summaries, current medicines and supplements, allergies, and any relevant family history. A dated record is more useful than trying to match every feature in an online article.

Ask the clinician what is already established and what remains uncertain. If a test is suggested, ask what question it answers, what its limitations are and how the result would change the next step. The information here is not an instruction to arrange every possible test. In children, bring growth, developmental and school information if it is relevant to the concern.

• What type of glucose problem has been confirmed?
• What are the individual monitoring and follow-up goals?
• If treatment can cause low glucose, what response plan should be taught?

Treatment discussions and follow-up

The material gathered for this draft does not provide a complete condition-specific treatment pathway for Permanent neonatal diabetes mellitus. That gap does not mean that treatment is unavailable. A clinician needs to establish the diagnosis and review current guidance before recommending medicines, procedures, rehabilitation or other support.

Before leaving the appointment, clarify the next review date, who will communicate results, and whom to contact if the situation changes. Discuss difficulties with sleep, work, school, mobility, eating or emotional wellbeing when these are relevant. Practical support may require coordination between the treating clinician and other services.

The collected references do not establish a complete prevention or long-term outlook section for this entry. Missing information should not be interpreted as proof that prevention is impossible or that a particular outcome is inevitable. Ask what is known for the exact subtype, stage and personal circumstances, and which uncertainties remain.

When to seek emergency help

Severe breathing difficulty, collapse, new stroke-like symptoms, a seizure that is prolonged or repeated without recovery, uncontrolled major bleeding, or an immediate risk of self-harm require emergency help. In India, call 112 or reach the nearest emergency department. This is a general, non-exhaustive warning list; it is not a condition-specific triage tool.