Myositis with sarcoplasmic inclusions in Nakajo–Nishimura syndrome: a genetic inflammatory myopathy

Abstract

(2020) Neuropathology and Applied Neurobiology 46, 579-587 Myositis with sarcoplasmic inclusions in Nakajo-Nishimura syndrome: a genetic inflammatory myopathy Aims: Nakajo-Nishimura syndrome (NNS) is an autosomal recessive disease caused by biallelic mutations in the PSMB8 gene that encodes the immunoproteasome subunit b5i. There have been only a limited number of reports on the clinicopathological features of the disease in genetically confirmed cases. Methods: We studied clinical and pathological features of three NNS patients who all carry the homozygous p.G201V mutations in PSMB8. Patients' muscle specimens were analysed with histology and immunohistochemistry. Results: All patients had episodes of typical periodic fever and skin rash, and later developed progressive muscle weakness and atrophy, similar to previous reports. Oral corticosteroid was used for treatment but showed no obvious efficacy. On muscle pathology, lymphocytes were present in the endomysium surrounding non-necrotic fibres, as well as in the perimysium perivascular area. Nearly all fibres strongly expressed MHC-I in the sarcolemma. In the eldest patient, there were abnormal protein aggregates in the sarcoplasm, immunoreactive to p62, TDP-43 and ubiquitin antibodies. Conclusions: These results suggest that inflammation, inclusion pathology and aggregation of abnormal proteins underlie the progressive clinical course of the NNS pathomechanism.

The 2021 European Alliance of Associations for Rheumatology/American College of Rheumatology points to consider for diagnosis and management of autoinflammatory type I interferonopathies: CANDLE/PRAAS, SAVI and AGS

“…However, this increasingly outdated ‘gene by gene’ approach ultimately may result in diagnostic delay and may not be cost-effective 32. In addition to the known disease-causing genes1 2 5 7 12 18 31 33–39 (table 1), screening should be considered for diseases that can mimic one of these disorders; their genetic causes8 12 40–45 are listed in table 2. Allelic, monogenic or digenic, double heterozygous mutations in genes encoding proteasome or immunoproteasome subunits are the cause for CANDLE/PRAAS, with biallelic pathogenic PSMB8 variants being the most common cause.…”

The role of interferons type I, II and III in myositis: A review

“…NNS is clinically characterised by a pernio‐like skin rash, periodic fever and myositis (121). Interestingly, myopathological analysis of small case series of NNS shows sarcolemmal MHC‐I expression, CD4 + and CD8 + T cell infiltrations, p62 and TDP43 aggregations and rimmed vacuoles in myofibres (122) similar to certain pathological features of sIBM muscle. Myeloid cell lines derived from pluripotent stem cell of NNS patients show dysfunction of proteasome activity and overproduction of inflammatory cytokines and chemokines such as IL‐6, CCL2 and CXCL10 with upregulation of reactive oxygen species under IFNγ and TNFα stimulation (123).…”

Pluripotent stem cell-based screening identifies CUDC-907 as an effective compound for restoring the in vitro phenotype of Nakajo-Nishimura syndrome

“…34,35 Therefore, we hypothesized that suppression of the overproduction could alleviate the autoinflammatory symptoms of NNS. However, NNS patients are known to suffer from lipomuscular atrophy in addition to inflammatory symptoms 6,9 ; whether the suppression of MCP-1 and IP-10 also alleviates these atrophic symptoms is unknown. New lipomuscular models of NNS would help in this regard.…”

“…The administration of systemic corticosteroids is partially effective against symptoms such as the rash and fever, but not the other symptoms. Furthermore, because the constitutive administration of steroids causes severe side effects, the prognosis of NNS patients relatively remains poor 6‐9 …”

“…Furthermore, because the constitutive administration of steroids causes severe side effects, the prognosis of NNS patients relatively remains poor. [6][7][8][9] The proteasome is a highly efficient enzyme complex and essential for the degradation of damaged or unnecessary proteins. 10 Such proteins are mainly degraded by a constitutively expressed proteasome to maintain cellular homeostasis or elude cell stress.…”