Case report: Mutations in DNAJC30 causing autosomal recessive Leber Hereditary Optic Neuropathy are common amongst Eastern European individuals.

Background: Leber Hereditary Optic Neuropathy (LHON) is the most common inherited mitochondrial disease characterised by bilateral, painless, subacute visual loss with a peak age of onset in the second to third decade. Historically, LHON was thought to be exclusively maternally inherited due to mutations in mitochondrial DNA (mtDNA) however, recent studies have identified an autosomal recessive form of LHON (arLHON) caused by point mutations in the nuclear gene, DNAJC30.Case Presentations: Here we report the cases of three Eastern European individuals presenting with bilateral painless visual loss, one of whom was also exhibiting motor symptoms. After a several year-long diagnostic journey, all three patients were found to carry the homozygous c.152A>G (p.Tyr51Cys) mutation in DNAJC30. This has been identified as the most common arLHON pathogenic variant and has been shown to exhibit a significant founder effect amongst Eastern European individuals.This finding adds to the growing cohort of patients with arLHON and demonstrates the importance of DNAJC30 screening in patients with molecularly undiagnosed LHON, particularly in Eastern European individuals. It is of heightened translational significance as patients diagnosed with arLHON exhibit a better prognosis and response to therapeutic treatment with the co-enzyme Q10 analogue idebenone.R.H. is a Wellcome Trust Investigator (109915/Z/15/Z), who receives support from the Medical Research Council (UK) (MR/V009346/1), the Addenbrookes Charitable Trust (G100142), the Evelyn Trust, the Stoneygate Trust, the Lily Foundation, Action for AT and an MRC strategic award to establish an International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD) MR/ S005021/1. This research was supported by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. RH is part of the PROSPAX consortium under the frame of EJP RD, the European Joint Programme on Rare Diseases, under the EJP RD COFUND-EJP N°825575

The Urine Proteome Profile Is Different in Neuromyelitis Optica Compared to Multiple Sclerosis: A Clinical Proteome Study.

Inflammatory demyelinating diseases of the CNS comprise a broad spectrum of diseases like neuromyelitis optica (NMO), NMO spectrum disorders (NMO-SD) and multiple sclerosis (MS). Despite clear classification criteria, differentiation can be difficult. We hypothesized that the urine proteome may differentiate NMO from MS.The proteins in urine samples from anti-aquaporin 4 (AQP4) seropositive NMO/NMO-SD patients (n = 32), patients with MS (n = 46) and healthy subjects (HS, n = 31) were examined by quantitative liquid chromatography-tandem mass spectrometry (LC-MS/MS) after trypsin digestion and iTRAQ labelling. Immunoglobulins (Ig) in the urine were validated by nephelometry in an independent cohort (n = 9-10 pr. groups).The analysis identified a total of 1112 different proteins of which 333 were shared by all 109 subjects. Cluster analysis revealed differences in the urine proteome of NMO/NMO-SD compared to HS and MS. Principal component analysis also suggested that the NMO/NMO-SD proteome profile was useful for classification. Multivariate regression analysis revealed a 3-protein profile for the NMO/NMO-SD versus HS discrimination, a 6-protein profile for NMO/NMO-SD versus MS discrimination and an 11-protein profile for MS versus HS discrimination. All protein panels yielded highly significant ROC curves (AUC in all cases >0.85, p≤0.0002). Nephelometry confirmed the presence of increased Ig-light chains in the urine of patients with NMO/NMO-SD.The urine proteome profile of patients with NMO/NMO-SD is different from MS and HS. This may reflect differences in the pathogenesis of NMO/NMO-SD versus MS and suggests that urine may be a potential source of biomarkers differentiating NMO/NMO-SD from MS

Case report: Mutations in DNAJC30 causing autosomal recessive Leber hereditary optic neuropathy are common amongst Eastern European individuals

Peer reviewed: TrueAcknowledgements: This research was made possible through access to data in the National Genomic Research Library, which is managed by Genomics England Limited (a wholly-owned company of the Department of Health and Social Care). The National Genomic Research Library holds data provided by patients and collected by the NHS as part of their care and data collected as part of their participation in research.Background: Leber Hereditary Optic Neuropathy (LHON) is the most common inherited mitochondrial disease characterized by bilateral, painless, subacute visual loss with a peak age of onset in the second to third decade. Historically, LHON was thought to be exclusively maternally inherited due to mutations in mitochondrial DNA (mtDNA); however, recent studies have identified an autosomal recessive form of LHON (arLHON) caused by point mutations in the nuclear gene, DNAJC30. Case Presentations: In this study, we report the cases of three Eastern European individuals presenting with bilateral painless visual loss, one of whom was also exhibiting motor symptoms. After a several-year-long diagnostic journey, all three patients were found to carry the homozygous c.152A>G (p.Tyr51Cys) mutation in DNAJC30. This has been identified as the most common arLHON pathogenic variant and has been shown to exhibit a significant founder effect amongst Eastern European individuals. Conclusion: This finding adds to the growing cohort of patients with arLHON and demonstrates the importance of DNAJC30 screening in patients with molecularly undiagnosed LHON, particularly in Eastern European individuals. It is of heightened translational significance as patients diagnosed with arLHON exhibit a better prognosis and response to therapeutic treatment with the co-enzyme Q10 analog idebenone

Change in autoantibody and cytokine responses during the evolution of neuromyelitis optica in patients with systemic lupus erythematosus : A preliminary study

Background: Neuromyelitis optica (NMO)-systemic lupus erythematosus (SLE) association is a rare condition characterized by multiple autoantibodies. Objective: To examine if, during the evolution of NMO, anti-AQP4 responses are part of polyclonal B cell activation, and if T cell responses contribute. Methods: In 19 samples of six patients who developed NMO during SLE, we examined the correlation of AQP4-IgG1 and IgM with (i) anti-MOG IgG and IgM, (ii) anti-nuclear, anti-nucleosome and anti-dsDNA IgG antibodies, (iii) cytokines and chemokines in the serum and (iv) longitudinal relation to NMO relapses/remission. Results: AQP4-IgG1 was present 1-2-5 years before the first NMO relapse. During relapse, AQP4-IgG1, ANA, anti-dsDNA and anti-nucleosome antibodies were elevated. Anti-MOG IgG/IgM and AQP4-IgM antibodies were not detected. AQP4-IgG1 antibodies correlated with concentration of anti-nucleosome, IFN-γ,interferon-gamma-induced CCL10/IP-10 and CCL17/TARC (

Cluster analysis of detected proteins in the urine comparing patients with NMO/NMO-SD, MS and healthy subjects.

<p>(A) Out of the 1112 proteins detected in the urine, 333 proteins were found in all samples. (B) PCA of all 333 proteins differentiated NMO/NMO-SD from HS samples. (C) MS samples could not be differentiated from HS by PCA. (D) NMO/NMO-SD samples could not be differentiated from MS samples by PCA. (E) PCA of proteins, which were differentially expressed (<i>p</i><0.05) compared to HS and present in at least 80% of the samples enabled differentiation of the NMO/NMO-SD samples from HS. (F) PCA of proteins, which were differentially expressed (<i>p</i><0.05) compared to HS and present in at least 80% of the samples enabled separation of the MS samples from HS. (G) PCA of proteins, which were differentially expressed (<i>p</i><0.05) compared to HS and present in at least 80% of the samples enabled separation of the NMO/NMO-SD samples from MS. <i>PCA</i>, <i>principal component analysis; NMO/NMO-SD</i>, <i>neuromyelitis optica/neuromyelitis optica spectrum disorder; MS</i>, <i>multiple sclerosis; HS</i>, <i>healthy subjects</i>.</p

Risk scores by logistic regression.

<p>Risk scores and ROC curves for the discriminating profiles are shown. (A) A 3- protein profile based on the 333 proteins detected in all 109 was the optimal model (ROC AUC = 0.93, <i>p</i><0.0001) for NMO/NMO-SD versus HS discrimination. (B) An 11-protein profile based on either proteins present in at least 80% of the samples in each group (520 proteins), or proteins present in at least 2 samples in each group (1021 proteins) was optimal for MS versus HS. (C) For NMO/NMO-SD versus MS discrimination, the best model was a 4-protein profile based on proteins present in at least 80% of the samples in each group (520 proteins).</p

False Discovery Rate Adjustment identifies 4 proteins significant for NMO/NMO-SD and MS discrimination in the urine.

<p>A) Heat maps comparing NMO/NMO-SD and MS samples by false discovery rate adjustment with <i>q</i>-values less than 0.05 are shown. The analysis identified 4 proteins that discriminated NMO/NMO-SD from MS. (B) Only the protein Ig-G3 chain were found to be upregulated in NMO/NMO-SD compared to MS. <i>Magenta</i>, <i>upregulated compared to HS; Green</i>, <i>downregulated compared to HS; NMO/NMO-SD</i>, <i>neuromyelitis optica/neuromyelitis optica spectrum disorder; MS</i>, <i>multiple sclerosis; HS</i>, <i>healthy subjects; Ig-G3</i>, <i>immunoglobulin 3 chain; ICAM–2</i>, <i>Intercellular adhesion molecule</i>.</p

Clinical and therapeutic predictors of disease outcomes in AQP4-IgG+ neuromyelitis optica spectrum disorder

Aquaporin-4-IgG positive (AQP4-IgG+) Neuromyelitis Optica Spectrum Disorder (NMOSD) is an uncommon central nervous system autoimmune disorder. Disease outcomes in AQP4-IgG+NMOSD are typically measured by relapse rate and disability. Using the MSBase, a multi-centre international registry, we aimed to examine the impact immunosuppressive therapies and patient characteristics as predictors of disease outcome measures in AQP4-IgG+NMOSD