Hyper IgD syndrome is the less severe form of a metabolic disorder known as mevalonate kinase deficiency. It is considered an auto-inflammatory disease, with recurrent episodic or chronic unexplained inflammation, characterized by periodic episodes of fever, and other symptoms such as joint pain, swollen lymph nodes, skin rash, headaches, and abdominal pain. Most episodes last several days and occur periodically throughout life. The frequency of episodes and their severity vary greatly from person to person. These attacks can occur spontaneously or be triggered by vaccinations, infections, and/or emotional or physical stress. Growth and development is usually not affected.

Hyper IgD syndrome is caused by mutations in the MVK gene which provides instructions for making the mevalonate kinase enzyme. The mutations result in the partial deficiency of the enzyme. A more severe form of maevalonate kinase deficiency is known as mevalonic aciduria. It is inherited in an autosomal recessive manner.

Treatment is with anakinra, and other medications, but not all patients show a complete response. In most cases, the frequency of the disease's episodes decreases over time.

Hyper IgD syndrome is caused by mutations in the gene MVK whichencodes the enzyme mevalonate kinase. The mutations lead to a partial deficiency of the enzyme mevalonate kinase. This enzyme converts a substance called mevalonic acid into mevalonate-5-phosphate. This conversion is the second step in a pathway that makes cholesterol. The cholesterol is later converted into steroid hormones and bile acids. Steroid hormones are needed for normal development and reproduction, and bile acids are used to digest fats. The enzyme also helps to produce other substances that are necessary for certain cellular functions, such as cell growth, cell maturation (differentiation), formation of the cell's structural framework (the cytoskeleton), gene activity (expression), and protein production and modification. A role for this pathway in inflammation is still not completely understood, but it is known that the mevalonate pathway produces cholesterol, and also some compounds which are necessary for the proper interaction and function of these proteins.

Normal Function

The MVK gene provides instructions for making the mevalonate kinase enzyme. This enzyme converts a substance called mevalonic acid into mevalonate-5-phosphate. This conversion is the second step in a pathway that produces cholesterol. The cholesterol is later converted into steroid hormones and bile acids. Steroid hormones are needed for normal development and reproduction, and bile acids are used to digest fats. Mevalonate kinase also helps to produce other substances that are necessary for certain cellular functions, such as cell growth, cell maturation (differentiation), formation of the cell's structural framework (the cytoskeleton), gene activity (expression), and protein production and modification.

Health Conditions Related to Genetic Changes

Mevalonate kinase deficiency

At least 80 mutations in the MVK gene have been found to cause mevalonate kinase deficiency. There are two types of mevalonate kinase deficiency, which are differentiated by the severity of the signs and symptoms. The less severe of the two types is called hyperimmunoglobulinemia D syndrome (HIDS) and the more severe type is called mevalonic aciduria (MVA). Most of the MVK gene mutations that cause mevalonate kinase deficiency lead to changes in single protein building blocks (amino acids) in the mevalonate kinase enzyme. One mutation that replaces the amino acid valine with the amino acid isoleucine at position 337 in the enzyme (written as Val337Ile or V337I) is found in approximately 80 percent of people with HIDS. The V337I mutation has never been found in people with MVA.

Most MVK gene mutations lead to the production of a mevalonate kinase enzyme that is unstable and folded into an incorrect 3-dimensional shape, leading to a reduction of mevalonate kinase enzyme activity. The severity of the enzyme shortage (deficiency) determines the severity of the condition. People who have approximately 1 to 20 percent of normal mevalonate kinase activity typically develop HIDS. Individuals who have less than 1 percent of normal enzyme activity usually develop MVA. Despite this shortage of mevalonate kinase activity, people with mevalonate kinase deficiency typically have normal production of cholesterol, steroid hormones, and bile acids.

Some researchers believe the features may be due to a buildup of mevalonic acid, the substance that mevalonate kinase normally acts on. Other researchers think that a shortage of the substances produced from mevalonic acid, such as those substances necessary for certain cellular functions, causes the fever episodes and other features of this condition. The exact mechanism that causes inflammatory reactions such as fevers, skin rashes, elevated immune system proteins, and many other features of mevalonate kinase deficiency is unclear.

Other Names for This Gene

• KIME_HUMAN
• LH receptor mRNA-binding protein
• LRBP
• mevalonate kinase 1
• MK
• MVLK

Genomic Location

Hyper IgD syndrome is characterized by periodic high fevers that may be associated with other symptoms including:

• Cold chills
• Swollen lymph nodes (lymphadenopathy)
• Abdominal pain
• Diarrhea
• Headache
• Joints pain
• Increased size of the liver (hepatomegaly) and/or increased size of the spleen (splenomegaly)
• Skin lesions
• Canker sores (aphthous ulcers)

Most episodes last several days and occur periodically throughout life. The frequency of episodes and their severity vary greatly from person to person. The first attack usually takes place during infancy. Patients may have no symptoms between attacks. However, in some patients, the attacks may be so frequent that the symptoms persist. The attacks can occur spontaneously or be triggered by vaccinations, infections, and/or emotional or physical stress. Growth and development is usually not affected. Disease complications sometimes seen in adults include amyloidosis, abdominal adhesions, and very rarely joint contractures.

Some people seem to have an intermediate form that is more severe than hyper IgD syndrome but less severe than classic mevalonate aciduria. These people suffer from a neurological illness with or without periodic fever.

The mainstay of the treatment of hyper IgD is anakinra, but not all patients show a complete response. Usually five to seven daily injections are sufficient to prevent an early relapse. Anakinra can also be used to prevent vaccine-induced attacks in patients that need immunizations.In 2015, a group of experts from different countries proposed recommendations for the management of several anti-inflammatory diseases including hyper IgD syndrome. Recommendations include:

• NSAIDs may provide symptom relief during inflammatory attacks
• Short-term glucocorticoids, with or without NSAIDs, may be effective for alleviating inflammatory attacks
• Short-term IL-1 blocking agents (anakinra or canakinumab) may be effective for ending inflammatory attacks and should be considered to limit or prevent steroid side effects or as a maintenance therapy
• If one IL-1-blocking agent at an adequate dose is ineffective or not well tolerated, a switch to another IL-1-blocking agent or another biological agent (including TNF-α blockers (etanercept (Enbrel), rituximab, o infliximab) or IL-6 blockade (tocilizumab) should be considered.
• If TNF-α blocker is ineffective or intolerable, a switch to another biological agent (including an IL-1- or IL-6-blocking agent) should be considered.

In selected cases with severe disease that does not improve, and poor quality of life, referral to a specialist center for consideration of allogeneic hematopoietic stem cell transplantation is recommended.

Consultations with the following specialists may be helpful: dermatologist, rheumatologist, and infectious disease specialist (to evaluate periodic fever).

Life expectancy is not shortened except for in rare cases where severe infections or kidney amyloidosis occur. Between fever attacks, patients are generally free of symptoms. Attacks do continue throughout the lifetime, although there may be a slight decrease following adolescence.

A long-term follow-up study showed that the frequency of the attacks decreases over time, but about half of the patients more than 20 years of age still experience six or more attacks per year, with quite an impact on quality of life.