Muckle Wells Syndrome

What is Muckle wells syndrome?

Muckle wells syndrome is a genetic auto-inflammatory disorder. The identified abnormal genetic mutation involved  CIAS1/NLRP3 gene. Muckle wells syndrome causes a periodic fever with other associated symptoms. It is classified under cryopyrin associated periodic syndromes (CAPS). Muckle wells syndrome has many more major organ complications in advance stage. At the initial stage, the sign of Muckle wells syndrome is easy to get cold attack in exposure to a cold weather. ^(1,2)

Sign and Symptoms

The sign and symptoms of Muckle wells syndrome are quite similar as Familial cold autoinflammatory syndrome. The affected individual has the following signs:

1. Undersized physique,
2. Distinct forehead,
3. Nasal bridge devastation and  inflammation of the optic disc in the eye (papilloedema)
4. The symptoms of the Muckle wells syndrome arise during the childhood itself and the progression of the symptoms and complication severity increases with day by day. The following symptoms are associated with the Muckle wells syndrome.
5. The affected infants get chronic urtercaria. The characteristic features included non itchy, onset is frequent and cause distress, as it is spread over a whole body.
6. Episodic fever with moderate to minor body temperature increment. Infants get affected in cold weather and even in random situations. Swelling of eyes, rashes, pains in joints and headache are the symptoms associated with fever. The onset of fever does not follow any rule, may it occur every day or gap between the episodes.
7. Joint pain and inflammation is a common symptom, but the deformity of bones and cartilages are rare.
8. Eye inflammation or conjunctivitis is another common symptom
9. Hearing loss at the early adolescence. It is considered as a complication of the Muckle wells syndrome. This may not be completely prevented, but early diagnosis and proper treatment can minimize the severity.
10. Muckle wells syndrome  is associated with amyloidosis or increase level of amyloid protein and cause general inflammation. This can provide fetal consequences, as Generalized Amyloidosis of the AA type develops. ^(1,2,3)

Genetics/Causes

Muckle wells syndrome is developed due to prevailing mutation alteration occurs in the NLRP3 (1q44) gene. This genetic deformity increase the functionality of cryopyrin that eventually direct to the increased secretion of the pro-inflammatory cytokine interleukin (IL)-1 beta and uncontrolled inflammation. The hyper-functionality of impairment of cryopyrin also causes impairment of the body defense and cause episodic fever and inflammation.

Analogues genetic mutation is involved in similar phenotypes which include, familial cold urticaria (FCAS) and CINCA syndrome. The distinct clinical features of these sub types are due to sequence of identical amino acids. Environmental modifying factors are great role in abnormal genetic sequences. In some cases, patients do not provide positive correlation with conventional genetic testing.  Even in some cases, NLRP3 mutation may not be involved. ⁽⁴⁾

Diagnosis

The clinical feature of Muckle-Wells syndrome is a classic indication during physical examination of the patient.

In maximum cases, a finding of a positive family history of cryopyrin-associated periodic syndrome (CAPS) is also a considerable identification factor of Muckle wells syndrome.

Muckle-Wells syndrome should be considered on the typical clinical features, even in the absence of a positive family history of cryopyrin-associated periodic syndrome (CAPS). But this finding may missing in some cases.

Following blood test results also indicate abnormality during an acute attack:

• Higher level of ESR (erythrocyte sedimentation rate), CRP (C-reactive protein) and SAA (serum amyloid A)
• Decrease level of Hemoglobin (chronic anemic condition)
• Increase white blood cell count (leukocytosis) including neutrophils and eosinophils without any evidence of infection.
• High pressure of cerebrospinal fluid (CSF)

Apart from above mentioned hematological abnormality, the following tests are additionally performed to detect complications

Audiogram in which high frequency waves are transferred to detect the hearing loss  and findings supports initial hearing loss which is progressive to bilateral sensorineural.

Urine analysis detects amyloidosis, as protein present in the urine without RBCs and WBCs in the initial stage. Renal biopsy provides confirmation of the deposition of amyloid proteins in the kidney. Genetic testing performs for aNLRP3 gene mutation in exon 3. ⁽²⁾

Treatment

Rilonacept and Canakinumab are the FDA approved drugs for treating the patients have Muckle-Wells syndrome.

These drugs act as interleukin-1 antagonists and require prolonged therapy. Anakinra is first identified to control inflammation in the year 2003 and after that it is successfully used to treat Muckle-Wells syndrome. This drug acts as an interleukin 1 receptor antagonist. Some study reports also claim that Anakinra also effective for preventing hearing loss and improvement of the deafness for early commencement of the treatment. But to get confirmatory result prolonged duration follow-up requires. Anakinra also effective in reversing the deposition of amyloid.

Some included side effects of Anakinra are pain at injection site, fatigue, weight gain etc. Anakinra is approved medicine for rheumatoid arthritis, and yet not get approval for treating Muckle-Wells syndrome.

Improved quality of life can be obtained by early commencement of anti-interleukin-1 treatment for patients with Muckle-Wells syndrome. The treatment can be continued for lifelong treatment for reduction of the deafness and amyloidosis. ^(1,2)