CLN8 is a ubiquitously expressed membrane-spanning protein that localizes primarily in the ER, with partial localization in the ER-Golgi intermediate compartment. Mutations in CLN8 cause late-infantile neuronal ceroid lipofuscinosis (LINCL). We describe a female pediatric patient with LINCL. She exhibited a typical phenotype associated with LINCL, except she did not present spontaneous myoclonus, her symptoms occurrence was slower and developed focal sensory visual seizures. In addition, whole-exome sequencing identified a novel homozygous variant in CLN8, c.531G>T, resulting in p.Trp177Cys. Ultrastructural examination featured abundant lipofuscin deposits within mucosal cells, macrophages, and monocytes. We report a novel CLN8 mutation as a cause for NCL8 in a girl with developmental delay and epilepsy, cerebellar syndrome, visual loss, and progressive cognitive and motor regression. This case, together with an analysis of the available literature, emphasizes the existence of a continuous spectrum of CLN8-associated phenotypes rather than a sharp distinction between them.

Cognitive impairment is a significant clinical problem both in multiple sclerosis (MS) and systemic lupus erythematosus (SLE) patients. In MS cognitive dysfunction has been associated with brain atrophy and total demyelinating lesion volume. In SLE cognitive impairment is much less understood, and its link to structural brain damage remains to be established. The aim of this study was to identify the relationship between subcortical gray matter volume and cognitive impairment in MS and SLE. We recruited 37 MS and 38 SLE patients matched by age, disease duration and educational level. Patients underwent magnetic resonance imaging (MRI) and a battery of psychometric tests. Severity of cognitive impairment was similar in both cohorts despite larger white matter lesion load in MS patients. Psychometric scores were associated with global and subcortical gray matter atrophy measures and lesion load in MS, but not in SLE. In SLE, the lack of a relationship between cognitive impairment and structural damage, defined either as atrophy or white matter lesions, indicates a different causal mechanism of cognitive deficit.

While interferon beta-1b (IFN-β-1b) is still a commonly used disease-modifying drug in the treatment of multiple sclerosis (MS), therapeutic possibilities are expanding, and treatment failure should be identified early. Markers to predict response to IFN-β-1b, either clinical or biochemical, are therefore urgently needed. Interferon-induced proteins, including viperin, suppressor of cytokine signaling 3 (SOCS3), ubiquitin specific peptidase-18 (USP18), and myxovirus resistance protein A (MxA), are possible markers of IFN-β-1b bioavailability and treatment response. To evaluate viperin, SOCS3, USP18 and MxA as markers of treatment response in Polish IFN-β-1btreated patients with MS. In 45 IFN-β-1b-treated Polish patients with MS, serum concentrations of viperin, SOCS3, USP18, and MxA were assessed before and after 24 months of IFN-β-1b treatment. The patients were followed clinically and with magnetic resonance imaging (MRI) for a median of 6.8 years. Low viperin, USP18 and MxA at baseline and 24 months and high SOCS3 at 24 months correlated with higher disease activity up to the 6th year of observation, but only baseline MxA and USP18 were independently related to outcome, with higher concentrations predicting less disease activity in the first 3 years and after the 1st year, respectively. We confirm the predictive value of MxA and propose USP18 as a possible new prognostic biomarker in IFN-β-1btreated MS patients.

Aim of the study. To determine the prevalence of anti-interferon-β binding (BAb) and neutralising antibodies (NAb), and to investigate whether NAb measured by luciferase-based cell assay can predict treatment response in multiple sclerosis (MS) patients treated with interferon-β-1b (IFNβ-1b). Clinical rationale for the study. A subgroup of IFNβ-treated MS patients develop NAb directed against the drug. The clinical significance remains controversial, which could be explained to some extent by technical difficulties in NAb detection and quantification. A simple, specific and reproducible test for NAb might help elucidate these uncertainties. Materials and methods. Sera from 101 consecutive MS patients initiating treatment with IFNβ-1b were collected at baseline and during the first two years, and assessed for BAbNAb with a novel luciferase-based cell assay. Median clinical follow-up lasted 5.1 years. Results. BAb were present in 97% and NAb in 88% of the study cohort. Unexpectedly, 92% of patients tested positive for BAb and 12.5% for NAb at baseline, before drug exposure. Patients with baseline NAb positivity were more likely to remain free of disease activity in the first three years of treatment. When baseline-positive cases were grouped together with those who remained NAb-negative, and the resulting group was compared to those who became positive after drug exposure, NAb positivity was associated with a higher risk of disease activity during the entire follow-up. Direct comparison of BAb/Nab-positive and BAb/Nab-negative patients only revealed an association of BAb positivity with more active disease after four years of treatment, while NAb failed to predict the outcome. Conclusions and clinical implications. Antibodies developed after treatment initiation are associated with a worse outcome. Naturally-occurring antibodies appear to predict more benign disease. Their prevalence and specificity require further investigation. Aim of the study. To determine the prevalence of anti-interferon-β binding (BAb) and neutralising antibodies (NAb), and to investigate whether NAb measured by luciferase-based cell assay can predict treatment response in multiple sclerosis (MS) patients treated with interferon-β-1b (IFNβ-1b). Clinical rationale for the study. A subgroup of IFNβ-treated MS patients develop NAb directed against the drug. The clinical significance remains controversial, which could be explained to some extent by technical difficulties in NAb detection and quantification. A simple, specific and reproducible test for NAb might help elucidate these uncertainties. Materials and methods. Sera from 101 consecutive MS patients initiating treatment with IFNβ-1b were collected at baseline and during the first two years, and assessed for BAbNAb with a novel luciferase-based cell assay. Median clinical follow-up lasted 5.1 years. Results. BAb were present in 97% and NAb in 88% of the study cohort. Unexpectedly, 92% of patients tested positive for BAb and 12.5% for NAb at baseline, before drug exposure. Patients with baseline NAb positivity were more likely to remain free of disease activity in the first three years of treatment. When baseline-positive cases were grouped together with those who remained NAb-negative, and the resulting group was compared to those who became positive after drug exposure, NAb positivity was associated with a higher risk of disease activity during the entire follow-up. Direct comparison of BAb/Nab-positive and BAb/Nab-negative patients only revealed an association of BAb positivity with more active disease after four years of treatment, while NAb failed to predict the outcome. Conclusions and clinical implications. Antibodies developed after treatment initiation are associated with a worse outcome. Naturally-occurring antibodies appear to predict more benign disease. Their prevalence and specificity require further investigation.

Introduction. Prompt successful control of disease activity in multiple sclerosis (MS) patients improves outcomes. Therefore, tools to aid drug selection and detect non-responders are urgently needed. Although several biochemical markers for predicting response to treatment have been proposed, clinical markers involving relapses, imaging activity and disability progression in the initial years of therapy remain competitive and appear cost-effective in a real-life setting. The aim of this study was to evaluate the prognostic value of select clinical scores in interferon beta-lb (IFN beta-1b) treated MS patients. Materials and methods. Eighty-eight relapsing-remitting MS (RRMS) patients initiating treatment with IFN beta-1b in a Polish outpatient clinic were followed for a median of 5.5 years. Rio, modified Rio and BREMSO scores, as well as two-year no evidence of disease activity (NEDA), were assessed as predictors of disease activity during the observation. Results. A Rio score of 1 had a Positive Predictive Value (PPV) of 83.3% and a Negative Predictive Value (NPV) of 71.4% for the occurrence of relapses in the first five years. A Rio and modified Rio score of 1 was associated with MRI activity after year 3. A loss of NEDA within the first two years was associated with a failure to maintain NEDA in the next three years. The BREMSO score was higher in patients with early relapse activity. Only baseline EDSS and total number of pre-treatment relapses were significantly associated with disability progression. Conclusions. Rio, modified Rio, early NEDA on treatment and BREMSO score are relatively specific, but insensitive, predictors of relapse activity in the first years of IFN beta-1b treatment. Higher pre-treatment EDSS and relapse activity is associated with disability progression, but not overall NEDA, in subsequent observation. While none of the markers is sufficiently sensitive or specific to make a certain prognosis, they may aid treatment decisions in patients with continued early disease activity.