Introduction
A rare genetic autoinflammatory illness called Nakajo-Nishimura syndrome (NNS) is primarily prevalent in a small region of Japan. The relevant gene for joint contractures, muscular atrophy (muscle wasting), microcytic anemia, and panniculitis-associated lipodystrophy (JMP) syndrome, as well as chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome, was discovered to be PSMB8 Recently, it was shown that other genetic abnormalities connected to the proteasome (protein complexes that use proteolysis, a chemical process that disrupts peptide links, to break down unwanted or damaged proteins) exhibit the same phenotype as PSMB8-related illnesses. PSMB8 genes for the immune proteasome's 5i subunit. NNS is no longer an endemic disease, and these conditions are now known as proteasome-associated autoinflammatory syndromes (PRAASs). The other names for this syndrome are:
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ALDD.
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Autoinflammation, lipodystrophy, and dermatosis syndrome.
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Japanese autoinflammatory syndrome with lipodystrophy.
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JASL.
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Nakajo syndrome.
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NKJO.
How Is Nakajo Syndrome Caused?
PSMB8 gene mutations are the cause of Nakajo-Nishimura syndrome. This gene codes for a particular subunit (part) of immunoproteasomes, specialized cell structures typically present in immune system cells. Immunoproteasomes are crucial in controlling how the immune system reacts to invading pathogens like viruses and bacteria. Immunoproteasomes play a key role in the immune system's ability to discriminate between proteins produced by the body and those produced by foreign invaders, allowing the immune system to react to infections most effectively.
Mutations bring immune system dysfunction in the PSMB8 gene, drastically lowering the quantity of protein produced from the PSMB8 gene and interfering with immunoproteasome assembly normally. As a result, Nakajo syndrome is categorized as an autoinflammatory condition. This is because it is thought that, for unknown reasons, the immune system's dysfunction causes abnormal inflammation that may harm the body's own tissues and organs.
Many Nakajo-Nishimura syndrome symptoms, such as nodular erythema (characterized by symmetrical, tender, red pimples that are generally located on the shins), recurring fevers, joint discomfort, and hepatosplenomegaly (enlarged liver and spleen), are likely caused by abnormal inflammation. Little is known about how mutations in the PSMB8 gene cause lipodystrophy and muscular atrophy. According to studies, the PSMB8 gene protein may have a unique role in the maturation of fat cells (adipocytes). A deficiency in this protein may prevent these cells from developing and functioning normally.
What Is the Inheritance Pattern of Nakajo Syndrome?
The autosomal recessive inheritance for this disease results in mutations in both copies of the gene in every cell. Each parent of a person with an autosomal recessive disorder carries one copy of the defective gene, although usually, neither parent exhibits the disease's signs and symptoms. An autosomal gene can be found on any chromosome other than the X or Y (sex chromosomes). Like chromosomes, genes often exist in pairs. Recessive means that for a person to develop a disorder, both copies of the disease-causing gene (pathogenic variation) must possess the disease-causing alteration. Pathogenic variations have historically been referred to as mutations, an older term. A gene with a harmful mutation is inherited from each parent by a child with an autosomal recessive disorder. Each parent is a carrier of the pathogenic variation of the gene since each has one copy of it. Usually, carriers of autosomal recessive diseases don't exhibit any disease symptoms. The probability of having a kid with an autosomal recessive disease increases by 25 % when two carriers are pregnant (1 in 4).
What Are the Symptoms of Nakajo Syndrome?
Affected people experience the following symptoms:
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Red, swollen lumps (nodular erythema) on their skin in infancy or early childhood. Recurring fevers.
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Lengthened fingers and toes with broadened and rounded tips (clubbing).
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Later in childhood, those impacted experience joint pain and contractures, which are abnormalities of the joints that restrict motion, especially in the hands, wrists, and elbows.
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Losing fat tissue (lipodystrophy), primarily in the upper torso, they also have muscle weakness and atrophy. During this time, muscle and fat loss intensifies, giving the face, chest, and arms an excessively thin (emaciated) appearance.
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A lack of red blood cells (anemia).
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A decrease in platelets (thrombocytopenia).
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An enlarged liver and spleen (hepatosplenomegaly).
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Unusual calcium deposits (calcification) in the brain's basal ganglia.
Several affected people have reportedly been diagnosed with intellectual impairment.
How Is Nakajo Syndrome Diagnosed?
The diagnostic criteria for Nakajo syndrome are:
1. Clinical presentation of the illness:
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Pernio-like (small patches on the inflamed skin) rash on hands and feet (develops in winter from infancy).
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Recurrent remittent fever or periodic fever (not always present).
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Nodular erythema with strong infiltration appears and disappears (sometimes annular).
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Progressive localized lipomuscular dystrophy or emaciation (dominant in the face and upper limbs).
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Elongated clubbed fingers or joint contracture.
2. Laboratory Findings:
- Hypergammaglobulinemia (excessive synthesis of several immunoglobulin classes by plasma cells).
- Persistently increased C-reactive protein (CRP) levels.
- As the illness worsens, some people's autoantibody titers increase, whereas they don't exist in others.
3. Histopathology - Shows vasculopathy (impacts the blood arteries that eliminate waste from the tissues and transport oxygen and nutrients throughout the body) and localized mononuclear cell infiltration.
4. Molecular Genetics: To detect the disease-causing change in the gene.
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Computed Tomography (CT): To detect hepatosplenomegaly and basal ganglia calcification (calcium buildup in the brain).
How Is Nakajo Syndrome Managed?
Although systemic corticosteroid therapy is typically utilized (daily prednisolone equivalent dose of 1-2 mg per 2.2 pounds for children, 0.4-1 mg per 2.2 pounds for adults, maintained prednisolone dose at 5-10 mg per day in adults), there are no gold-standard treatment procedures for NNS and other PRAASs. Ineffective for lipomuscular dystrophy but effective for fever and skin rash. Even though Methotrexate, calcineurin inhibitors, and Tocilizumab (anti-IL-6 receptor antibody) have been utilized, their efficacies were only partially effective in treating the disease when the amount of corticosteroids is reduced.
What Other Conditions Resemble Nakajo Syndrome?
The Nakajo-Nishimura syndrome shares symptoms with two other diseases: chronic atypical neutrophilic dermatosis with lipodystrophy and increased temperature (CANDLE) syndrome and joint contractures, muscular atrophy, microcytic anemia, and panniculitis-induced lipodystrophy (JMP) syndrome. All three diseases share lipodystrophy and skin abnormalities. Although they are frequently regarded as distinct ailments, they are both caused by mutations in the same gene. As a result, some experts think they are different manifestations of the same disease.
Conclusion:
Each patient's prognosis for PRAASs, including NNS, is unique. Many children live to adulthood, whereas some infants pass away. In many adult cases, significant lipodystrophy develops. Patients' ability to carry out daily activities reduces as the condition progresses owing to muscle atrophy and joint rigidity, and many pass away around the age of 60. However, the disease is exceedingly severe in certain cases, and people pass away abruptly in their 30s.
