NLRP12

Causes

NLRP12-associated periodic fever is a genetic disorder. The responsible gene is NLRP3. Mutations in the gene lead to increased activity of the protein, resulting in elevated inflammatory responses. These increased inflammatory responses are responsible for the clinical manifestations seen in the disease.

NLRP12-associated periodic fever is an autosomal dominant disease. This means that the disease is passed on by one of the parents who also has an abnormal copy of the NLRP12 gene. Because we have two copies of each gene, the risk of an affected parent passing on a mutated copy to the child, and thus passing on the disease, is 50%. New mutations also occur. This means that neither of the parents has the disease and that the NLRP12 gene has spontaneously mutated in the child. In that case, the chances of the next child in the family developing NLRP12-associated periodic fever are extremely low. NLRP12-associated periodic fever syndromes show a wide clinical spectrum. This means that people who have the mutated gene don’t all suffer from it to the same extent. Occasionally, the disorder may even be that mild that there are no symptoms at all.

The disease is caused by a gene mutation. Usually the mutated gene is passed on by one of the parents, who is the carrier. This carrier may also have symptoms of the disease, but not necessarily. The disease cannot be prevented.

NLRP12-associated periodic fever is not contagious.

Symptoms

The main symptom is fever. The fever lasts about 5-10 days and recurs at irregular intervals. The fever episodes are accompanied by a variety of symptoms. Examples are headaches, joint pain, joint swelling and muscle pain. A notable symptom is the rash. These are raised bumps and spots that look like hives but are usually not itchy. The severity of the rash varies from patient to patient and can also vary over time. The flare-ups are often triggered by exposure to cold temperatures. Symptoms begin 1 to 2 hours after exposure to low temperatures or after significant changes in the temperature. To what extent van NLRP12-associated periodic fever affects the quality of life depends on the frequency and intensity of the disease symptoms. Complications later in life, such as deafness, have been described. Amyloidosis, a harmful deposit of inflammatory proteins in organs such as the kidneys, has not (yet) been described for NLRP12-associated periodic fever.

The severity of symptoms varies greatly between different patients. Even in the same patient, the duration and intensity of the different episodes can vary considerably.

As children get older, the fever attacks tend to be less frequent and less severe. Still, most adults continue to be affected by the disease. Sometimes adults develop a hearing impairment.

Diagnosis

The diagnosis NLRP12-associated periodic fever is based on the clinical symptoms, the medical history of the patient and the family history. The diagnosis can only be confirmed by genetic testing. Distinguishing between NLRP12-associated periodic fever and other inflammatory diseases (CAPS) may be difficult because of the overlapping symptoms. Ophthalmologic evaluation (in particular fundoscopy), cerebrospinal fluid examination (lumbar puncture) and X-rays can help distinguish between these related diseases, but in but in the end, genetic testing is the deciding factor.

Tests:

●      Blood tests: Genetic testing is necessary to make the diagnosis. Tests such as the sedimentation rate (“sedimentation”, BSE), CRP, serum Amyloid-A protein (SAA), complete blood count and fibrinogen can establish the degree of inflammation during an episode. These are repeated when the symptoms have passed to check if the inflammation has completely subsided.

●      Urine test: the urine is tested for the presence of protein and red blood cells. Although amyloidosis has not yet been described for NLRP12-associated periodic fever, the physician will be alert to this possible complication. Amyloidosis can be identified by an elevated level of protein in the urine.

Treatment

NLRP12-associated periodic fever cannot be cured, as it is a genetic disorder. There is no proven method to prevent episodes. The symptoms can be suppressed with painkillers and anti-inflammatory drugs. However, thanks to advances in understanding the cause of this disorder, new promising treatments are under investigation.

Therapies for NLRP12-associated periodic fever include nonsteroidal anti-inflammatory drugs (NSAIDs), such as diclofenac and indometacin; corticosteroids, such as prednisolone. Blocking the inflammatory protein Interleukin-1 (IL-1) may be effective. The best known medicine that blocks IL-1 is anakinra (Kineret ®). Anakinra is given daily, via injections under the skin. Skin irritation at the site of the injections often occurs. None of these treatments have been proven to be effective, but there are some patients who certainly benefit from them.

The side effects of the treatment depend on which medication is used. NSAIDs can cause headaches, stomach ulcers, and kidney damage. Corticosteroids and recombinant proteins increase the susceptibility to infections. In addition, corticosteroids can cause a variety of side effects.

It is uncertain how long the treatment should be continued. Normally, the disease tends to improve as patients get older. For this reason, it is probably a good idea to try to discontinue medication if a patient does not have any symptoms anymore.

There are no published studies on effective alternative or complementary treatments.

Children who have active disease symptoms or are being treated with medication should have their blood and urine checked at least twice a year.

Prognosis

It is a lifelong disease, although over the years the symptoms may decrease.

The long-term prognosis (predicted course and outcome) of the disease is that NLRP12-associated periodic fever is a lifelong disease, although the symptoms may decrease as the patient gets older. Very rarely, patients may develop organ damage, particularly hearing loss. Because NLRP12-associated periodic fever is very rare and has only recently been discovered, the long-term prognosis is not well known.