Nakajo–Nishimura syndrome and related proteasome-associated autoinflammatory syndromes

Figures & data

Table 1 Frequency of clinical characteristics in Nakajo–Nishimura syndrome

	Pt # assessed	Pt # positive	Frequency (%)
Symptom
Pernio	19	19	100
Erythema nodosum	28	28	100
Elongated clubbed finger	27	27	100
Lipodystrophy	26	26	100
Muscle dystrophy	16	14	88
Periodic fever	20	17	85
Joint contracture	18	14	78
Lymphadenopathy	12	8	67
Mental retardation	22	8	36
Clinical examination
ESR elevation	26	26	100
Basal ganglia calcification	16	14	88
Hypergammaglobulinemia	25	21	84
ANA positive	17	12	71
Hepatosplenomegaly	20	14	70
CPK elevation	16	6	38
Osteoperiostosis	20	3	15
Consanguineous marriage	27	19	70

Abbreviation: ESR, erythrocyte sedimentation rate.

Figure 1 Illustration of proteasome structure and assembly.

Notes: (A) Proteasome is formed by the assembly of a 20S core particle (CP) and two 19S regulatory particles (RP), and is called 26S constitutive or standard proteasome. 20S CP consists of two α-rings (light green) and β-rings (purple); each α-ring has seven subunits (α1-7) and each β-ring seven subunits (β1-7). When the cells are stimulated with IFNγ, β1i, β2i, and β5i are incorporated into the β-rings by replacing β1, β2, and β5, which forms immunoproteasome. G201V mutation in β5i subunit leads to proteasome dysfunction, causing Nakajo–Nishimura syndrome. (B) Assembly of 20S proteasome. Proteasome assembling chaperone 1 (PAC1)–PAC2 heterodimers and PAC3–PAC4 heterodimers assist α-ring formation. Ubiquitin-mediated proteolysis 1 (UMP1) assists β-ring formation sequentially from β2 subunit, and during and after assembly of all the other β subunits, all the PACs and UMP1 chaperones degrade and active 20S proteasome CP is formed.

Box 1 Diagnostic criteria of Nakajo–Nishimura Syndrome (NNS)

1. Autosomal Recessive heritability (consanguineous marriage or patients with family history)

2. Pernio-like rash on hands and feet (develops in winter from infancy)

3. Recurrent remittent fever or periodic fever (not always present)

4. Nodular erythema with strong infiltration appear and disappear (sometimes annular)

5. Progressive localized lipomuscular dystrophy or emaciation (dominant in face and upper limbs)

6. Elongated clubbed fingers or joint contracture

7. Hepatosplenomegaly

8. Calcification in the basal ganglia

Notes: Patients with five or more of the eight clinical characteristics are diagnosed with NNS. When homozygous PSMB8 mutations are detected, NNS is considered definite regardless of the number of clinical characteristics. In patients with five or more of the eight clinical characteristics but with no mutations in PSMB8 gene, a diagnosis of probable NNS is made.

Table 2 Comparison of clinical characteristics among three PSMB8-related diseases

Characteristics	NNS	JMP	CANDLE
Fever	+	–	+
Pernio-like rash	+	−	+
Erythema nodosum	+	+	+
Elongated clubbed finger	+	+	+
Lipomuscular dystrophy	+	++	+
Hepatosplenomegaly	±	+	+
Basal ganglia calcification	±	+	±
Seizure	−	+	−
Joint contracture	+	+++	−
Anemia	±	++	+

Abbreivations: NNS, Nakajo–Nishimura syndrome; JMP, joint contractures, muscular atrophy, microcytic anemia, and panniculitis-associated lipodystrophy; CANDLE, chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature.