Muckle-Wells syndrome is a hereditary disease from the group of cryopyrin—associated periodic syndromes (CAPS), which occurs due to a mutation of the NLRP3 gene. Pathology is manifested by recurrent fever, skin rashes, progressive hearing disorders. Eye damage and joint inflammation are also often observed. Biochemical and immunological blood tests, genetic testing, instrumental methods (ophthalmoscopy, X-ray examination of joints, audiometry) are used for diagnosis. Pathogenetic treatment involves taking interleukin-1 blockers to control symptoms.
E85.0 Hereditary familial amyloidosis without neuropathy
The disease got its name in honor of scientists from the UK Thomas Muckle and Michael Wells, who in 1962 described the typical symptoms in 9 members of the same family. In 1969, a neurologist from the USA, Joseph Black, supplemented the clinical picture of the disease, and the genetic basis of pathology was established in 2001. The prevalence of Muckle-Wells syndrome is 1 case per 1 million population. There were no gender and racial differences in morbidity. The high relevance of genetic pathology is due to the complexity of its diagnosis, the need for expensive treatment.
Like other cryopyrin-associated periodic diseases, Muckle-Wells disease is caused by a defect in the NLRP3 gene (CIAS1) located on the 1st chromosome. According to research, the most common are missense mutations (63.4%), nonsensical substitutions (26.41%), nonsense defects (5.75%). In modern genetics, mutations c.3088dupG (9 exon), c.2759G>A (7 exon), c.2582A>G (6 exon) are mainly associated with the development of Muckle-Wells syndrome.
The disease is inherited by an autosomal dominant type. For its appearance, the presence of a mutant gene allele in one of the parents is sufficient. In such a situation, the risk of having a sick child is 50%, regardless of gender. Cases of sporadic disease formation in the absence of family predisposition, which is possible with spontaneous gene mutation, are also described.
All variants of CAPS are caused by a genetic defect, as a result of which the increased production of the cryopyrin protein begins. It is responsible for the activation of cellular nonspecific immunity, with the help of a cytoplasmic protein complex it stimulates the work of monocytes, macrophages. In the case of Muckle-Wells syndrome, there is a violation of the structure of the NLRP3-inflamassome, its uncontrolled activation, which causes the severity of clinical signs.
Activated cryopyrin triggers excessive synthesis of the pro-inflammatory agent interleukin, which occurs in two stages. At the first stage, ligands of Toll-like receptors (lipopolysaccharides) stimulate the production of an inactive precursor of pro-IL-1. Then, when the balance of intracellular redox reactions changes or under the action of exogenous adenositriphosphate, the inert form turns into active interleukin-1.
A similar mechanism of development is observed in any cryopyrin-associated periodic disease. The difference is usually in the severity. Muckle-Wells syndrome is accompanied by moderate clinical symptoms, being an intermediate variant between the milder familial autoinflammatory cold syndrome (FCAS) and extremely severe chronic infantile neurological cutaneous articular syndrome (CINCA).
Muckle-Wells syndrome is characterized by a large age range of clinical manifestations. According to clinical observations, the average age of development of symptoms is 6 years (ranging from 6 months to 45 years), at the same time, diagnosis is significantly delayed and is performed on average at 31.5 years. In children, it takes about 3 years from the appearance of signs to the confirmation of pathology, in adults — more than 33 years.
In Muckle-Wells disease, a pathognomonic triad is described, including urticaria, deafness, reactive amyloidosis. However, the full range of symptoms is extremely rare, more often the patient has 1 or 2 signs. A prolonged increase in body temperature is detected in 50% of children and 33% of adults, so the disease is often attributed to periodic fever syndromes.
For the disease, recurring episodes of spotty-papular rash are typical, which occur under the influence of cold, as well as other provoking factors that have not yet been established. Many patients face recurrent conjunctivitis and uveitis, manifested by redness of the eyes, photophobia, lacrimation. Up to 40% of patients suffer from joint pain, restrictions on the volume of active movements.
A pathognomonic complication of Muckle-Wells syndrome is sensorineural hearing loss, which is noted in approximately 70% of patients. Hearing disorders begin in adolescence or at a young age, gradually progress, ending in deafness. In 25% of cases, hearing loss occurs in middle-aged or elderly patients, which is more typical for a mild, low-symptomatic course of pathology.
In 20-40% of cases, with the long-term existence of the disease, secondary AA-amyloidosis develops, which is the result of a violation of protein metabolism under the influence of chronic systemic inflammation. It is characterized by hypersecretion of alpha-globulin protein, deposition of amyloid in tissues. With AA-amyloidosis, internal organs are affected: liver, kidneys, spleen, lymph nodes. The death of patients occurs from multiple organ failure.
Timely diagnosis of Muckle-Wells syndrome presents difficulties due to the nonspecificity and polymorphism of the clinical picture, the lack of clear diagnostic criteria. Such patients may undergo an initial examination by a family doctor, ophthalmologist, rheumatologist. At the same time, a detailed diagnostic plan is assigned, which includes the following methods:
- Ophthalmological examination. Due to frequent complaints of eye inflammation, ophthalmoscopy of the fundus and biomicroscopy are necessarily performed to detect precipitates, synechiae, and cellular reactions. Standard visometry and perimetry are also performed, pupillary reactions are examined.
- Radiography of joints. When detecting local inflammatory changes in the articular joints, a standard radiograph or a more informative computed tomography is recommended. Those suffering from Muckle-Wells syndrome do not show destructive processes in the pictures, which makes it possible to exclude rheumatic diseases.
- Audiometry. First, the audibility of whispered and spoken speech is assessed, after which they proceed to in-depth research methods: tonal audiometry, tuning fork tests (Weber, Rinne), registration of auditory potentials. According to the indications, a CT scan of the temporal bones is performed.
- Laboratory tests. In the hemogram, leukocytosis, an increase in ESR is determined, in the blood test — a sharp increase in the level of C-reactive protein, an increase in other acute-phase indicators. With an extended immunogram, an increase in immunoglobulins A, M, G is often detected.
- Genetic analysis. Exon sequencing in order to detect pathognomonic mutations is the main way to 100% confirm the diagnosis. The study is carried out not only to the patient, but also to his family members in order to confirm or refute the hereditary nature of the disease, to conduct medical and genetic counseling.
Like many other genetic diseases, Muckle-Wells pathology cannot be completely cured, but there is an effective pathogenetic therapy. It is aimed at relieving the inflammatory process, preventing episodes of fever and rash, and preventing complications. Drug treatment includes several groups of drugs:
- Interleukin-1 blockers. Modern medications (recombinant antagonists, monoclonal antibodies) reduce the level of pro-inflammatory proteins in the blood, stabilize the patient’s condition.
- Glucocorticoids. They are prescribed as symptomatic therapy for exacerbation of pathology. They contribute to the rapid regression of fever, reducing the reaction of the joints.
- Nonsteroidal anti-inflammatory drugs. To eliminate joint pain, traditional NSAIDs help well, which have fewer adverse reactions than hormones, can be recommended at any age.
When the disease is complicated by hearing loss, physiotherapy techniques (electrostimulation, acupuncture, phonophoresis), neurometabolic drugs, histamine-like drugs are used. With a severe degree of impairment, the issue of hearing prosthetics, cochlear implantation is considered. For the pathogenetic therapy of amyloidosis, drugs of the 4-aminoquinoline series, cytostatics, hormones are used.
Prognosis and prevention
When using IL-1 inhibitors, it is possible to achieve complete remission of the disease and improve the quality of life of patients. A less favorable prognosis is for patients with late-diagnosed Muckle-Wells syndrome, who often die from multiple organ disorders associated with amyloidosis. Prevention of the disease involves consulting a geneticist before planning conception, if one of the parents has a burdened family history of CAPS.