高ＩｇＤ症候群

AIM: To compare macular microvascular and microstructural exploratory imaging findings in patients with childhood-onset mevalonate kinase deficiency (MKD) and healthy controls, and to assess associations with disease activity. METHODS: This cross-sectional case-control study included patients with childhood-onset, genetically confirmed MKD and healthy controls. Disease activity was assessed using the autoinflammatory disease activity index (AIDAI) score and C-reactive protein (CRP) levels. Choroidal images were obtained to measure subfoveal choroidal thickness (SFCT) and to calculate the total choroidal area (TCA), luminal area (LA), stromal area (SA), and the choroidal vascularity index (CVI). Macular optical coherence tomography (OCT) and optical coherence tomography-angiography (OCT-A) parameters were compared between groups, and associations with systemic disease activity were examined. RESULTS: The study included 17 patients with childhood-onset MKD and 30 healthy controls. The MKD group showed higher LA and CVI than in controls (p = 0.042 and p = 0.014, respectively), whereas TCA and SA were comparable between groups (p = 0.124 and p = 0.669, respectively). Mean central macular thickness was lower in the MKD group (p = 0.030), while SFCT was comparable between groups (p = 0.325). No significant differences were observed in macular microvascular parameters. CONCLUSION: Patients with childhood-onset MKD showed higher CVI, whereas macular microvascular parameters were comparable to those of controls. These findings may suggest subtle alterations in choroidal vascular composition, potentially related to the underlying inflammatory milieu; however, given that all patients were receiving canakinumab treatment, they should be interpreted cautiously as exploratory associations requiring confirmation in longitudinal studies.

OBJECTIVES: Statins (HMG-CoA reductase inhibitors) are associated with myopathy, yet the precise in vivo mechanisms underlying this association remain unclear. Emerging evidence implicates a deficiency of geranylgeranyl pyrophosphate (GGPP), a key downstream isoprenoid metabolite of the mevalonate pathway. We employed novel muscle-specific genetic mouse models to elucidate the roles of GGPP and Rab geranylgeranyl transferase β (RabGGT-β) in the development of myopathy. METHODS: Using doxycycline-inducible Cre-LoxP technology, we generated three skeletal muscle-specific knockout (KO) models: Hmgcr-DimKO, Rabggtb-DimKO, and combined Hmgcr/Rabggtb-DimKO mice. The severity of myopathy was evaluated based on serum creatine kinase levels and histological examination. Mitochondrial mass and function were rigorously quantified. Prenylation deficit in Rabggtb-DimKO mice was confirmed via subcellular fractionation. To validate GGPP's involvement, rescue experiments were conducted using its precursor, geranylgeraniol (GGOH). RESULTS: Hmgcr KO resulted in pronounced myopathy, marked by an early reduction in mitochondria-rich myosin heavy chain (MyHC) type I and IIa muscle fibers, followed by a later reduction in mitochondria-poor glycolytic MyHC type IIb muscle fibers, and these changes were reversed by GGOH administration. Rabggtb-DimKO mice developed myopathy later than Hmgcr-DimKO mice; however, in Hmgcr/Rabggtb-DimKO mice, myopathy was dramatically accelerated and more severe. Across all models, mitochondrial dysfunction emerged early-preceding clinical signs of myopathy-consistent with a causal relationship. CONCLUSIONS: Our findings demonstrate that myopathy induced by HMGCR deficiency is primarily driven by GGPP depletion in a mouse model. Furthermore, impaired RabGGT-β-mediated protein geranylgeranylation represents a critical downstream mechanism that aggravates the myopathic phenotype. Early mitochondrial abnormalities may contribute to the pathogenesis of myopathy due to disruption of the mevalonate pathway.

Mevalonate kinase deficiency (MKD) is a rare autosomal recessive autoinflammatory disorder with a broad clinical spectrum. Neonatal presentation is uncommon and may mimic severe infection, leading to diagnostic delay. We report a preterm female infant who presented with non-immune hydrops fetalis and persistent systemic inflammation from the first week of life, despite repeated negative blood and CSF cultures and multiple courses of broad-spectrum antibiotics. The infant subsequently developed progressive cholestasis with pale stools, and biliary atresia was confirmed by hepatobiliary imaging and intraoperative cholangiography, followed by portoenterostomy. Extensive metabolic, immunologic, and infectious evaluations were unrevealing. Whole-exome sequencing identified compound heterozygous pathogenic variants in the MVK gene, confirming the diagnosis of MKD. Perinatal-onset MKD is exceptionally rare and often presents with non-specific systemic inflammation that can mimic neonatal sepsis, resulting in delayed diagnosis and significant diagnostic and therapeutic challenges. The infant was treated with supportive care, corticosteroids, and the IL-1 receptor antagonist anakinra, but the clinical course was complicated by progressive multiorgan failure, and she died at 3.5 months of age. This case highlights the diagnostic challenges of neonatal-onset MKD and suggests a possible association between MKD, hydrops fetalis, and biliary atresia that requires further investigation. Early consideration of autoinflammatory disorders and timely genetic testing may facilitate diagnosis and guide management in neonates with unexplained systemic inflammation.

BACKGROUND: Mevalonate kinase deficiency (MKD) is a rare autosomal recessive autoinflammatory disease. Chronic nonbacterial osteomyelitis (CNO) represents another autoinflammatory disorder characterized by sterile bone inflammation. Although musculoskeletal pain is common in MKD, CNO-like bone lesions have rarely been described. Tocilizumab has been used separately in MKD / hyper-IgD syndrome (HIDS) and in CNO; however, pediatric cases showing both conditions together and responding completely to IL-6 blockade have not been previously reported. CASE PRESENTATION: We present a 16-year-old boy born to consanguineous parents who experienced early-onset recurrent fever episodes with abdominal pain, maculopapular rash, oral ulcers, and conjunctival injection. He was initially misdiagnosed with FMF and IgA vasculitis and treated with colchicine with partial improvement. Persistent systemic inflammation prompted referral to our tertiary center at age 9. A periodic fever gene panel revealed a homozygous MVK p.V377I mutation, confirming MKD. Anakinra therapy was initiated. Although no attacks occurred during the first month, flares characterized by fever, abdominal pain, rash, and elevated acute-phase reactants recurred in the second and third months, reflecting a partial response. Consequently, treatment was switched to canakinumab. Toward the end of the second year of IL-1 blockade, attack frequency increased to once every three months, and at age 12 he developed diffuse musculoskeletal pain. Whole-body magnetic resonance imaging demonstrated multifocal metaphyseal bone marrow edema compatible with CNO-like lesions. Sulfasalazine was added but discontinued after drug-induced pancreatitis. Given persistent systemic inflammation and inadequate response to IL-1 inhibitors, canakinumab was replaced with weekly subcutaneous tocilizumab, resulting in rapid improvement in bone pain and systemic inflammation. Since the third month of tocilizumab therapy, he has remained clinically stable with normalized inflammatory markers and only a single mild flare over the last year. CONCLUSION: This case highlights the potential role of IL-6 inhibition in complicated MKD presenting with autoinflammatory bone disease refractory to standard therapies.

Mevalonate kinase deficiency (MKD) is a rare autosomal recessive autoinflammatory disorder with marked clinical heterogeneity, frequently leading to delayed diagnosis. We describe a 71-year-old woman with lifelong episodic inflammatory symptoms beginning in infancy, including recurrent fevers, lymphadenopathy, and gastrointestinal and mucocutaneous manifestations, later evolving into intermittent arthralgia, myalgia, and fatigue. A unifying diagnosis was established when genetic testing identified two missense pathogenic MVK variants consistent with compound heterozygous MKD, supported by elevated serum IgD levels and a characteristic clinical phenotype. This case illustrates the essential role of molecular genetic testing in resolving prolonged diagnostic odyssey, in guiding surveillance for complications such as AA amyloidosis, and enabling targeted therapeutic strategies.