Multiple Cranial Neuropathies and Pachymeningitis in a Patient With a Pathogenic Nucleotide-Binding Oligomerization Domain 2 Polymorphism.

ABSTRACT: An 11-year-old boy presented with 2 weeks of intermittent headache, right orbital pain, and constant diplopia. Brain MRI showed dural thickening and enhancement of the right lateral cavernous sinus, right orbital apex, and tentorium. Initial cerebral spinal fluid analysis showed only mild pleocytosis, and serum diagnostics were unrevealing. The working diagnosis was Tolosa-Hunt syndrome. His pain and sixth nerve palsy resolved with corticosteroids. Five months after initial presentation, he developed new numbness of the right cheek, complete right ophthalmoplegia, and weakness and numbness of his right hand and leg, all of which were responsive to steroids. Fifteen months later, he returned to the emergency department with 2 weeks of left-sided headaches and acute diplopia. On examination, he had a left cranial nerve 6 palsy. Dural biopsy showed diffuse mononuclear inflammatory cell reaction consisting mostly of lymphocytes with no signs of granuloma formation, nor any epithelioid or giant cells. His clinical course was consistent with an autoinflammatory condition of unknown etiology. Genetic testing with an immunodeficiency panel showed a risk allele in NOD2 (nucleotide-binding oligomerization domain 2) c.3019dup (p.Leu1007Prof*2) that is associated with an increased risk for Crohn disease. His clinical condition had similarities to central nervous system sarcoidosis. Because of the similarities between our patient's clinical, imaging, and genetic findings and neurosarcoidosis, he was switched to a more targeted therapy-infliximab. His condition has since been stable for nearly 2 years. In conclusion, genetic testing should be considered in patients with suspected occult autoimmunity.

Neurocan is a New Substrate for the ADAMTS12 Metalloprotease: Potential Implications in Neuropathies.

BACKGROUND/AIMS: The composition of the extracellular matrix (ECM) in the central nervous system (CNS) has several features that make it unique. For instance, it is remarkable for the presence of proteoglycans such as versican, brevican, and neurocan, some of which have been identified as substrates of different members of the ADAMTS family of secreted metalloproteases. Previous studies have associated ADAMTSs with the repair of the CNS, including recovery following degradation of glial scar tissue and the stimulation of axonal growth after brain injury. However, the involvement of ADAMTSs in diseases of the CNS is complex and not understood fully, and a current challenge is unraveling the precise roles of these metalloproteases in the brain. METHODS: ADAMTS12 and neurocan gene expression was examined by quantitative PCR. Western blot analysis was employed to detect ADAMTS12 and neurocan protein expression in cell lines, and immunostaining techniques were used to detect neurocan in mouse brain tissues. Neurocan cleavage using recombinant ADAMTS1, ADAMTS4, ADAMTS5, and ADAMTS12 metalloproteases was evaluated by western blotting. Cell adhesion and migration were assessed using uncoated culture dishes or dishes coated with Matrigel or ECM components. RESULTS: We identified neurocan as a novel component of brain ECM that can be cleaved by ADAMTS12. In addition, we showed that neurocan cleavage by ADAMTS12 altered the adhesive properties of the human neuroglioma H4 cell line. Moreover, immunohistochemical analysis of Adamts12-deficient mice revealed the significant accumulation of neurocan in the brain of neonatal mice. CONCLUSION: Overall, our results suggest that ADAMTS12 could be involved in the repair of the CNS through its ability to degrade neurocan. Moreover, it can be inferred that alterations in neurocan degradation processes could be associated with the pathogenesis of neurological disorders.

MAPKs and NF-κB-mediated acrylamide-induced neuropathy in rat striatum and human neuroblastoma cells SY5Y.

Acrylamide (ACR) is a potent neurotoxin that can be produced during high-temperature food processing, but the underlying toxicological mechanism remains unclear. In this study, the detrimental effects of ACR on the striatal dopaminergic neurons and the roles of mitogen-activated protein kinases (MAPKs) and nuclear factor κB (NF-κB) in ACR-induced neuronal apoptosis were investigated. Acute ACR exposure caused dopaminergic neurons loss and apoptosis as revealed by decreased tyrosine hydroxylase (TH)-positive cells and TH protein level and increased terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL)-positive cells in the striatum. ACR-decreased glutathione content, increased levels of malondialdehyde, proinflammatory cytokines tumor necrosis factor α, and interleukin 6. In addition, nuclear NF-κB and MAPKs signaling pathway with c-Jun N-terminal kinase (JNK) and p38 were activated by ACR. Specific inhibitors were used to explore the roles of MAPKs and NF-κB pathways in ACR-induced apoptosis in SH-SY5Y cells. Pretreatment with JNK-specific inhibitors SP600125 markedly upregulated the reduced B-cell lymphoma 2 (Bcl-2) content and downregulated the increased Bcl-2-associated X protein (Bax) level and thereby eventually reduced the proportions of early and late apoptotic cells induced by ACR, while p38 suppression by SB202190 only reversed the decrease in Bcl-2 expression. Inhibition of NF-κB by BAY 11-7082 markedly upregulated Bax level and decreased Bcl-2 expression, and eventually increasing the proportions of neuronal apoptosis compared with that in ACR alone. These results suggested that JNK contributed to ACR-induced apoptosis, while NF-κB acted as a protective regulator in response to ACR-induced neuropathy. This study helps to offer a deeper insight into the mechanism of ACR-induced neuropathy.

RUNX1-RUNX1T1-positive acute myeloid leukaemia presenting as bilateral proptosis and multiple cranial nerve palsy.

We describe a unique presentation of acute myeloid leukaemia (AML) with myeloid sarcoma (MS), manifested as proptosis with multiple cranial nerve palsies in a 9-year-old boy. MRI of the brain revealed multiple enhancing lesions and bilateral mastoiditis, in addition to sagittal sinus thrombosis. Peripheral blood smear demonstrated blasts showing Auer rods. Bone marrow examination confirmed the diagnosis of AML. PCR was positive for RUNX1-RUNX1T1. Neurological deficits improved with induction chemotherapy for AML. Extramedullary MS can present simultaneously with or antedate AML. Common genetic aberrations include t(8;21) and inv(16). Therapy is akin to AML. An effect of MS on survival outcomes is variable.

Familial Idiopathic Cranial Neuropathy in a Chinese Family.

Cranial neuropathy is usually idiopathic and familial cases are uncommon. We describe a family with 5 members with cranial neuropathy over 3 generations. All affected patients were women, indicating an X-linked dominant or an autosomal dominant mode of inheritance. Our cases and a review of the literature suggest that familial idiopathic cranial neuropathy is a rare condition which may be related to autosomal dominant vascular disorders (e.g. vascular tortuosity, sclerosis, elongation or extension), small posterior cranial fossas, anatomical variations of the posterior circulation, hypersensitivity of cranial nerves and other abnormalities. Moreover, microvascular decompression is the treatment of choice because vascular compression is the main factor in the pathogenesis. To the best of our knowledge, this is the first report of familial cranial neuropathy in China.

Blau syndrome: cross-sectional data from a multicentre study of clinical, radiological and functional outcomes.

OBJECTIVE: To report baseline articular, functional and ocular findings of the first international prospective cohort study of Blau syndrome (BS). METHODS: Three-year, multicentre, observational study on articular, functional (HAQ, Childhood HAQ and VAS global and pain), ophthalmological, therapeutic and radiological data in BS patients. RESULTS: Baseline data on the first 31 recruited patients (12 females and 19 males) from 18 centres in 11 countries are presented. Of the 31 patients, 11 carried the p.R334W NOD2 mutation, 9 the p.R334Q and 11 various other NOD2 missense mutations; 20 patients were sporadic and 11 from five BS pedigrees. Median disease duration was 12.8 years (1.1-57). Arthritis, documented in all but one patient, was oligoarticular in 7, polyarticular in 23. The median active joint count was 21. Functional capacity was normal in 41%, mildly impaired in 31% and moderate-severe in 28% of patients. The most frequently involved joints at presentation were wrists, ankles, knees and PIPs. On radiographs, a symmetrical non-erosive arthropathy was shown. Previously unknown dysplastic bony changes were found in two-thirds of patients. Ocular disease was documented in 25 of 31 patients, with vitreous inflammation in 64% and moderate-severe visual loss in 33%. Expanded manifestations (visceral, vascular) beyond the classic clinical triad were seen in 52%. CONCLUSION: BS is associated with severe ocular and articular morbidity. Visceral involvement is common and may be life-threatening. Bone dysplastic changes may show diagnostic value and suggest a previously unknown role of NOD2 in bone morphogenesis. BS is resistant to current drugs, suggesting the need for novel targeted therapies.

Insights into the molecular basis of the NOD2 signalling pathway.

The cytosolic pattern recognition receptor NOD2 is activated by the peptidoglycan fragment muramyl dipeptide to generate a proinflammatory immune response. Downstream effects include the secretion of cytokines such as interleukin 8, the upregulation of pro-interleukin 1ß, the induction of autophagy, the production of antimicrobial peptides and defensins, and contributions to the maintenance of the composition of the intestinal microbiota. Polymorphisms in NOD2 are the cause of the inflammatory disorder Blau syndrome and act as susceptibility factors for the inflammatory bowel condition Crohn's disease. The complexity of NOD2 signalling is highlighted by the observation that over 30 cellular proteins interact with NOD2 directly and influence or regulate its functional activity. Previously, the majority of reviews on NOD2 function have focused upon the role of NOD2 in inflammatory disease or in its interaction with and response to microbes. However, the functionality of NOD2 is underpinned by its biochemical interactions. Consequently, in this review, we have taken the opportunity to address the more 'basic' elements of NOD2 signalling. In particular, we have focused upon the core interactions of NOD2 with protein factors that influence and modulate the signal transduction pathways involved in NOD2 signalling. Further, where information exists, such as in relation to the role of RIP2, we have drawn comparison with the closely related, but functionally discrete, pattern recognition receptor NOD1. Overall, we provide a comprehensive resource targeted at understanding the complexities of NOD2 signalling.

Caveats and truths in genetic, clinical, autoimmune and autoinflammatory issues in Blau syndrome and early onset sarcoidosis.

Blau syndrome (BS) and early onset sarcoidosis (EOS) are, respectively, the familial and sporadic forms of the pediatric granulomatous autoinflammatory disease, which belong to the group of monogenic autoinflammatory syndromes. Both of these conditions are caused by mutations in the NOD2 gene, which encodes the cytosolic NOD2 protein, one of the pivotal molecules in the regulation of innate immunity, primarily expressed in the antigen-presenting cells. Clinical onset of BS and EOS is usually in the first years of life with noncaseating epithelioid granulomas mainly affecting joints, skin, and uveal tract, variably associated with heterogeneous systemic features. The dividing line between autoinflammatory and autoimmune mechanisms is probably not so clear-cut, and the relationship existing between BS or EOS and autoimmune phenomena remains unclear. There is no established therapy for the management of BS and EOS, and the main treatment aim is to prevent ocular manifestations entailing the risk of potential blindness and to avoid joint deformities. Nonsteroidal anti-inflammatory drugs, corticosteroids and immunosuppressive drugs, such as methotrexate or azathioprine, may be helpful; when patients are unresponsive to the combination of corticosteroids and immunosuppressant agents, the tumor necrosis factor-α inhibitor infliximab should be considered. Data on anti-interleukin-1 inhibition with anakinra and canakinumab is still limited and further corroboration is required. The aim of this paper is to describe BS and EOS, focusing on their genetic, clinical, and therapeutic issues, with the ultimate goal of increasing clinicians' awareness of both of these rare but serious disorders.

Blau syndrome, the prototypic auto-inflammatory granulomatous disease.

Blau syndrome is a monogenic disease resulting from mutations in the pattern recognition receptor NOD2, and is phenotypically characterized by the triad of granulomatous polyarthritis, dermatitis and uveitis. This paper reviews briefly the classical clinical features of the disease, as well as more recently described extra-triad symptoms. From an ongoing prospective multicenter study, we provide new data on the natural history of Blau syndrome, focusing on functional status and visual outcome. We also present an update of the range of different NOD2 mutations found in Blau syndrome as well as recent data on morphologic and immunohistochemical characteristics of the Blau granuloma. Finally, emerging insights into pathogenic mechanisms including activation of NOD2 signal transduction, and potential biomarkers of disease activity are discussed.

Ultrasonographic assessment reveals detailed distribution of synovial inflammation in Blau syndrome.

INTRODUCTION: Arthritis is the most frequent manifestation of Blau syndrome, an autoinflammatory disorder caused by the genetic mutation of NOD2. However, detailed information on arthritis in Blau syndrome on which the therapeutic strategy should be based on is lacking. This multi-center study aimed to accurately characterize the articular manifestation of Blau syndrome and also to demonstrate the utility of musculoskeletal ultrasound in Blau syndrome. METHODS: Patients who had been diagnosed with Blau syndrome by genetic analysis of NOD2 were recruited. A total of 102 synovial sites in 40 joints were assessed semiquantitatively by ultrasound for gray-scale synovitis and synovial power Doppler (PD) signal. RESULTS: In total, 10 patients whose age ranged from 10 months to 37 years enrolled in this study. Although only 4 joints (0.8%) were tender on physical examination, 81 joints (16.9%) were clinically swollen. Moreover, 240 (50.0%), and 124 (25.8%) joints showed gray-scale (GS) synovitis and synovial PD signal on ultrasound, respectively. Importantly, GS synovitis was present in 168 out of 399 non-swollen joints, in which 61 also exhibited synovial PD signal. Among 40 joint regions, the ankle, the wrist, and the proximal interphalangeal joints were the most frequently and severely affected joints. Comparisons between different synovial tissues demonstrated a significantly higher proportion of the joints with tenosynovitis as compared with that with intra-articular synovitis (41.5% versus 27.9%, P < 0.0001). In respect of age and treatment, synovial PD signals were minimal in the youngest patient and in the oldest two patients, and were relatively mild in patients receiving treatment with methotrexate plus TNF antagonists. In two patients who underwent the second ultrasound examination, total PD scores markedly decreased after initiating the treatment with a tumor necrosis factor (TNF) antagonist. CONCLUSIONS: The detailed information on synovial inflammation obtained by ultrasound confirms the dissociation between pain and inflammation and the frequently involved joint regions and synovial tissue in the arthritis of Blau syndrome. Our data also demonstrate that ultrasonography can be a potent tool in monitoring the activity of synovial inflammation and in investigating the pathophysiology of arthritis in this rare but archetypical autoinflammatory condition.

Blau syndrome-associated uveitis and the NOD2 gene.

Blau syndrome (BS), a rare autosomal dominant autoinflammatory syndrome, is an example of a monogenic disease. It was first described as a classic triad of uveitis, arthritis, and exanthema, typically seen in patients less than four years of age. Since that time, the phenotype has been expanded to include fever, cranial neuropathies, cardiovascular abnormalities, and granulomas of the liver and kidney. The ocular inflammation is often a panuveitis that occurs later in the disease course and typically carries the greatest morbidity in BS. BS has been mapped to the chromosomal region 16q12-21, also known as the NOD2 gene (formerly CARD15/NOD2). The disease is secondary to a single amino acid mutation NOD2 that leads to peptidoglycan-independent activity of nuclear factor (NF)-κB. Clinical and genetic aspects of BS will be discussed, as well as recent advances in treatment protocols.

[The present and the prospect of study on Blau syndrome/early-onset sarcoidosis].

Blau syndrome (BS) and early-onset sarcoidosis (EOS) are both systemic granulomatous disease evoked by the mutated NOD2. It occurs in children younger than 4 years of age and is characterized by a distinct triad of skin, joint, and eye disorders without apparent pulmonary involvement. NOD2 encodes an intracellular receptor for muramyl dipeptide (MDP), the common component of bacterial cell wall peptidoglycan, and is expressed in cytoplasm of monocytic cells and epithelial cells. While its loss-of-function mutations are recognized in Crohn's disease, the mutations observed in BS/EOS are gain-of-function, and induced MDP-independent basal NF-kappaB activation. But we still do not know the precious molecular mechanism how the activation of NOD2 induces granuloma formation in the skin, joints and eyes.

Nucleotide-binding oligomerization domain containing 2: structure, function, and diseases.

OBJECTIVES: To systematically review literature about the structure and function of nucleotide-binding oligomerization domain containing 2 (NOD2) and its disease association. METHODS: The English literature was searched using keywords "NOD2" and "disease". Relevant original and review articles were reviewed. RESULTS: NOD2 is an intracellular protein and shares similar molecular structure with NOD1, pyrin, and cryopyrin. There are more than 100 NOD2 gene mutations, some of which have been linked to diseases such as Crohn disease, Blau syndrome, and NOD2-associated autoinflammatory disease (NAID). The NOD2 variants located in the leucine-rich repeat (LRR) region are susceptible to Crohn disease, and the variants in the nucleotide-binding domain (NBD) and in between the NBD and LRR are associated with Blau syndrome and NAID, respectively. No disease association with the gene variants has been found in rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, psoriasis/psoriatic arthritis, adult sarcoidosis, granulomatous polyangiitis, or multiple sclerosis. The potential association of the NOD2 variants with graft-versus-host-disease remains controversial. NOD2 functions mainly through RICK or RIP2 to activate p38 mitogen-activated protein kinases and NF-κB, resulting in inflammatory response, and enhanced autophagic activity. Biologic therapy may be beneficial for NOD2-associated diseases, and new drug development may be realized based upon the signaling pathways. CONCLUSIONS: NOD2 gene mutations are associated with several diseases, and some of the mutations are of diagnostic value in Blau disease and NAID. To understand the NOD2 function, disease association, and its pathogenesis is important given the ever increasing clinical significance of NOD2.

A case of infantile Takayasu arteritis with a p.D382E NOD2 mutation: an unusual phenotype of Blau syndrome/early-onset sarcoidosis?

Blau syndrome/early-onset sarcoidosis (Blau/EOS) is an autoinflammatory disease characterized by granulomatous arthritis, uveitis, and skin rash. It has been shown that gain-of-function NOD2 mutations cause Blau/EOS. In this paper, we describe a patient with a gain-of-function NOD2 mutation who developed infantile Takayasu arteritis, which is rare in Blau/EOS, but who has not yet had significant granulomatous changes in joints, eyes, or skin. We suspect that this case is an unusual phenotype of Blau/EOS.

Clinical and transcriptional response to the long-acting interleukin-1 blocker canakinumab in Blau syndrome-related uveitis.

OBJECTIVE: To report on the clinical response to canakinumab in a patient with sporadic nucleotide-binding oligomerization domain-containing protein 2 (NOD-2)-associated pediatric granulomatous arthritis (Blau syndrome) and severe resistant panuveitis, and to describe gene expression profile changes throughout such treatment. METHODS: A 4-year-old boy was diagnosed as having Blau syndrome on the basis of typical clinical features, histologic evidence of noncaseating granulomas, and a NOD2 mutation. Ocular involvement was initially controlled by topical and oral corticosteroids, but over the years visual impairment and complications, such as macular edema and retinal detachment, progressed. Ocular disease remained persistently active despite treatment with multiple different immunosuppressants; therefore, canakinumab treatment was started. Before and during the first 6 months of treatment, the gene expression profile was determined each month. RESULTS: Canakinumab treatment was well tolerated and led to rapid quiescence of uveitis, which had been continuously active before this treatment. Gene expression profiling analysis of the patient's blood prior to initiation of interleukin-1 (IL-1) blockade revealed differential expression of 1,993 transcripts when compared to healthy controls, and among the up-regulated transcripts, pathway analysis showed that the predominant network consisted of innate immunity-related transcripts. The transcriptional signature of the patient overlapped with the transcriptional signature of patients with systemic-onset juvenile idiopathic arthritis, and canakinumab treatment led to the normalization of most of these transcriptional changes. CONCLUSION: The pathogenesis of Blau syndrome may be mediated by IL-1, and canakinumab may be useful when this disorder is unresponsive to more conventional treatments.

Blau syndrome, clinical and genetic aspects.

Blau syndrome (BS) is a rare autosomal dominant, autoinflammatory syndrome characterized by the clinical triad of granulomatous recurrent uveitis, dermatitis and symmetric arthritis. The gene responsible for BS has been identified in the caspase recruitment domain gene CARD15/NOD2. In the majority of patients, the disease is characterized by early onset, usually before 3-4years of age. The manifestations at disease onset are usually represented by articular and cutaneous involvement signs, generally followed later by ocular manifestations which are often the most relevant morbidity of BS. In some cases the presence of fever is also observed; atypical cases of BS have been reported with cardiovascular, neurological, renal, intestinal and other organ involvement. The rarity and the variations in the severity and evolution of its expressions do not permit sufficient data about optimal treatment for patients with BS. The first step of therapy is represented by the use of corticosteroids and successively, in case of unsatisfactory response, by additional treatment with immunosuppressive agents. The results with biologic anti-cytokine agents, such as anti-TNFα and anti-IL1ß, are different, particularly with regard to ocular morbidity. Clinical and genetic aspects of the familial and the sporadic form of BS will be discussed and focused on. A description of a case study of an Italian family is also included.

[Autoinflammatory syndromes in dermatology]. / Syndromes auto-inflammatoires en dermatologie.

Hereditary periodic fever syndromes, also called autoinflammatory syndromes, are characterized by relapsing fever and additional manifestations such as skin rashes, mucosal manifestations, or arthralgias. Some of these disorders present without fever but with the associated systemic manifestations. The responsible mutated genes have been identified for most of these disorders, which lead to the induction of the uncontrolled and excessive production of interleukin-1beta (IL-1beta). The inhibition of IL-1beta through IL-1 receptor antagonist or monoclonal antibody against IL-1beta is used with success in most of these diseases. In case of TNF-receptor associated periodic syndrome (TRAPS) and paediatric granulomatous arthritis (PGA), TNF-antagonists may also be used; in familial Mediterranean fever (FMF) colchicine remains the first choice.

Morphologic and immunohistochemical characterization of granulomas in the nucleotide oligomerization domain 2-related disorders Blau syndrome and Crohn disease.

BACKGROUND: Blau syndrome (BS) and Crohn disease (CD) are both characterized by granulomatous inflammation and related to nucleotide oligomerization domain 2 (NOD2) mutations. OBJECTIVE: This study aimed to define the morphologic and immunohistochemical characteristics of granulomas in patients with NOD2-related BS and CD. METHODS: Granuloma-containing biopsy specimens from 6 patients with BS and 7 pediatric patients with CD carrying NOD2 mutations or single nucleotide polymorphisms were studied for morphology, cellular composition, and cytokine expression by using hematoxylin and eosin staining and immunohistochemistry. RESULTS: Biopsy specimens from patients with BS typically showed polycyclic granulomas with large lymphocytic coronas, extensive emperipolesis of lymphocytes within multinucleated giant cells (MGCs), MGC death, and fibrinoid necrosis and fibrosis. In contrast, biopsy specimens from patients with CD showed simple granulomas with subtle/absent lymphocytic coronas, sclerosis of the surrounding tissue, and polymorphonuclear cells. Findings found to be similar in all granulomas were as follows: CD68 and HLA-DR expression by epithelioid cells, monocyte-macrophage lineage cells and MGCs, increased lymphocytic HLA-DR expression, increased CD4(+)/CD8(+) T-cell ratio, and CD20(+) B lymphocytes evenly distributed within and around granulomas. In both patient groups prominent IFN-γ expression was found in and around granulomas, and TNF-α and IL-23 receptor expression was moderate. IL-6, IL-17, and TGF-ß expression was prominent in granulomas from patients with BS but sporadic in granulomas from patients with CD. IL-10 expression was absent. CONCLUSION: Granulomas from patients with BS and granulomas from patients with NOD2-associated CD show distinct morphologic features and cytokine expression patterns, suggesting that the T(H)17 axis might be involved in the pathogenesis of BS, whereas T(H)1 is important in both patients with BS and patients with CD.