Long-Term Visual Outcome of Patients with Blau Syndrome.

PURPOSE: To document the long-term visual outcomes in patients with Blau syndrome. METHODS: A retrospective institutional cohort study was conducted, and 13 patients with genetically confirmed Blau syndrome were included. Demographic and clinical data were collected from standardised medical charts. Baseline was defined as the first detected uveitis and data were recorded onwards at intervals of 1, 3, 5, 10, 15 and 20 years. RESULTS: Anterior uveitis was the most common classification at baseline (57.1%). Among patients with documented uveitis lasting 10 years or more, all of them developed panuveitis. Median logMAR visual acuity at baseline was 0 (range -0.5; 0.7), 0.19 (range 0; 1.5) at year 5, and 0.7 (range 0.1 - no perception of light) at year 20, as recorded in 13, 16, and 10 eyes, respectively. All patients received treatment with topical and oral steroids, and multiple systemic immunosuppressants including biologics. Disease control, defined as having cells <1+ in both eyes and using topical steroid eye drops less than twice daily, was achieved in 14.3% to 37.5% of patients at the different time points. Cataract surgery was performed in 12 eyes of 8 patients, 3 eyes of 3 patients necessitated glaucoma surgery, and 4 eyes of 4 patients required surgery for retinal detachment. CONCLUSION: Uveitis associated with Blau syndrome commonly leads to severe, chronic panuveitis, requiring long-term systemic immunosuppression. Early diagnosis and timely initiation of biologics may prevent significant visual impairment.

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.

Spatiotemporal control of mitochondrial network dynamics in astroglial cells.

Mitochondria are increasingly recognized for playing important roles in regulating the evolving metabolic state of mammalian cells. This is particularly true for nerve cells, as dysregulation of mitochondrial dynamics is invariably associated with a number of neuropathies. Accumulating evidence now reveals that changes in mitochondrial dynamics and structure may play equally important roles also in the cell biology of astroglial cells. Astroglial cells display significant heterogeneity in their morphology and specialized functions across different brain regions, however besides fundamental differences they seem to share a surprisingly complex meshwork of mitochondria, which is highly suggestive of tightly regulated mechanisms that contribute to maintain this unique architecture. Here, we summarize recent work performed in astrocytes in situ indicating that this may indeed be the case, with astrocytic mitochondrial networks shown to experience rapid dynamic changes in response to defined external cues. Although the mechanisms underlying this degree of mitochondrial re-shaping are far from being understood, recent data suggest that they may contribute to demarcate astrocyte territories undergoing key signalling and metabolic functions.

Human aminoacyl-tRNA synthetases in diseases of the nervous system.

Aminoacyl-tRNA synthetases (AaRSs) are ubiquitously expressed enzymes that ensure accurate translation of the genetic information into functional proteins. These enzymes also execute a variety of non-canonical functions that are significant for regulation of diverse cellular processes and that reside outside the realm of protein synthesis. Associations between faults in AaRS-mediated processes and human diseases have been long recognized. Most recent research findings strongly argue that 10 cytosolic and 14 mitochondrial AaRSs are implicated in some form of pathology of the human nervous system. The advent of modern whole-exome sequencing makes it all but certain that similar associations between the remaining 15 ARS genes and neurologic illnesses will be defined in future. It is not surprising that an intense scientific debate about the role of translational machinery, in general, and AaRSs, in particular, in the development and maintenance of the healthy human neural cell types and the brain is sparked. Herein, we summarize the current knowledge about causative links between mutations in human AaRSs and diseases of the nervous system and briefly discuss future directions.

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.

Gastrointestinal and feeding difficulties in CHARGE syndrome: A review from head-to-toe.

CHARGE syndrome is an autosomal dominant genetic condition that is primarily diagnosed based on clinical features, with genetic testing available for confirmation. The CHARGE mnemonic stands for some of the common characteristics: coloboma, heart defects, atresia/stenosis of the choanae, retardation of growth/development, genitourinary anomalies, and ear abnormalities (CHARGE). However, many of the common clinical features are not captured by this mnemonic, including cranial nerve dysfunction, considered by some to be one of the major diagnostic criteria. Over 90% of individuals experience feeding and gastrointestinal dysfunction, which carries great morbidity and mortality. The aim of this review is to examine the nature of gastrointestinal (GI) symptoms and feeding difficulties in CHARGE syndrome, focusing on their underlying pathology, associated investigations, and available treatment options. We also provide information on available tools (for parents, clinicians, and researchers) that are important additions to the lifelong healthcare management of every individual with CHARGE syndrome. We review how cranial nerve dysfunction is one of the most important characteristics underlying the pervasive GI and feeding dysfunction, and discuss the need for future research on gut innervation and motility in this genetic disorder.

A girl with developmental delay, ataxia, cranial nerve palsies, severe respiratory problems in infancy-Expanding NDST1 syndrome.

NDST1 encodes an enzyme involved in the first steps in the synthesis of heparan sulfate chains, proteoglycans that are regulators found on the cell surface and in the extracellular matrix. Eight individuals homozygous for one of four family-specific missense mutations in the sulfotransferase domain of the enzyme have been described. They have intellectual disability. Some additionally had hypotonia, ataxia. seizures, and/or short stature, but none had history of respiratory problems. No humans with homozygous null mutations are known. ndst1b (orthologous to NDST1) morpholino knockdown in zebrafish (Danio rerio) causes delayed development, craniofacial cartilage abnormalities, shortened body and pectoral fin length. Ndst1 homozygous null mice have craniofacial abnormalities and die within the first 10 h of life of respiratory failure. We report a girl upon whom deep phenotyping, extensive genetic and biochemical investigations, and exome sequencing were performed. She had cranial nerves dysfunction, gastroesophageal reflux, history of a seizure, ataxia, developmental delays, head sparing failure to thrive, and minor malformations including distinctive facial features and a bifid uvula. Compound heterozygous mutations in NDST1 were identified, in the heparan sulfate N deacetylatase domain of one allele and the sulfotransferase domain of the other allele. This report expands the phenotypic spectrum of Ndst1 deficiency in humans. © 2017 Wiley Periodicals, Inc.

SBF1 mutations associated with autosomal recessive axonal neuropathy with cranial nerve involvement.

Biallelic mutations in the SBF1 gene have been identified in one family with demyelinating Charcot-Marie-Tooth disease (CMT4B3) and two families with axonal neuropathy and additional neurological and skeletal features. Here we describe novel sequence variants in SBF1 (c.1168C>G and c.2209_2210del) as the potential causative mutations in two siblings with severe axonal neuropathy, hearing loss, facial weakness and bulbar features. Pathogenicity of these variants is supported by co-segregation and in silico analyses and evolutionary conservation. Our findings suggest that SBF1 mutations may cause a syndromic form of autosomal recessive axonal neuropathy (AR-CMT2) in addition to CMT4B3.

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.

The congenital cranial dysinnervation disorders.

Congenital cranial dysinnervation disorders (CCDD) encompass a number of related conditions and includes Duane syndrome, congenital fibrosis of the external ocular muscles, Möbius syndrome, congenital ptosis and hereditary congenital facial paresis. These are congenital disorders where the primary findings are non-progressive and are caused by developmental abnormalities of cranial nerves/nuclei with primary or secondary dysinnervation. Several CCDD genes have been found, which enhance our understanding of the mechanisms involved in brain stem development and axonal guidance.

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 polymorphisms in NOD2 identify nucleotide hydrolysis and helical domain 1 as signalling regulators.

Understanding how single nucleotide polymorphisms (SNPs) lead to disease at a molecular level provides a starting point for improved therapeutic intervention. SNPs in the innate immune receptor nucleotide oligomerisation domain 2 (NOD2) can cause the inflammatory disorders Blau Syndrome (BS) and early onset sarcoidosis (EOS) through receptor hyperactivation. Here, we show that these polymorphisms cluster into two primary locations: the ATP/Mg(2+)-binding site and helical domain 1. Polymorphisms in these two locations may consequently dysregulate ATP hydrolysis and NOD2 autoinhibition, respectively. Complementary mutations in NOD1 did not mirror the NOD2 phenotype, which indicates that NOD1 and NOD2 are activated and regulated by distinct methods.