Lifestyle and medical conditions in relation to ALS risk and progression-an introduction to the Swedish ALSrisc Study.

BACKGROUND: This study was an introduction to the Swedish ALSrisc Study and explored the association of lifestyle and medical conditions, with risk and progression of amyotrophic lateral sclerosis (ALS). METHODS: We included 265 newly diagnosed ALS patients during 2016-2022 in Stockholm and 207 ALS-free siblings and partners of the patients as controls. Information on body mass index (BMI), smoking, and history of head injuries, diabetes mellitus, hypercholesterolemia, and hypertension was obtained through the Euro-MOTOR questionnaire at recruitment. Patients were followed from diagnosis until death, invasive ventilation, or November 30, 2022. RESULTS: Higher BMI at recruitment was associated with lower risk for ALS (OR 0.89, 95%CI 0.83-0.95), especially among those diagnosed after 65 years. One unit increase in the average BMI during the 3 decades before diagnosis was associated with a lower risk for ALS (OR 0.94, 95%CI 0.89-0.99). Diabetes was associated with lower risk of ALS (OR 0.38, 95%CI 0.16-0.90), while hypercholesterolemia was associated with higher risk of ALS (OR 2.10, 95%CI 1.13-3.90). Higher BMI at diagnosis was associated with lower risk of death (HR 0.91, 95%CI 0.84-0.98), while the highest level of smoking exposure (in pack-years) (HR 1.90, 95%CI 1.20-3.00), hypercholesterolemia (HR 1.84, 95%CI 1.06-3.19), and hypertension (HR 1.76, 95%CI 1.03-3.01) were associated with higher risk of death, following ALS diagnosis. CONCLUSIONS: Higher BMI and diabetes were associated with lower risk of ALS. Higher BMI was associated with lower risk of death, whereas smoking (especially in high pack-years), hypercholesterolemia, and hypertension were associated with higher risk of death after ALS diagnosis.

Neurodegenerative biomarkers outperform neuroinflammatory biomarkers in amyotrophic lateral sclerosis.

OBJECTIVE: To describe the diagnostic and prognostic performance, and longitudinal trajectories, of potential biomarkers of neuroaxonal degeneration and neuroinflammation in amyotrophic lateral sclerosis (ALS). METHODS: This case-control study included 192 incident ALS patients, 42 ALS mimics, 114 neurological controls, and 117 healthy controls from Stockholm, Sweden. Forty-four ALS patients provided repeated measurements. We assessed biomarkers of (1)neuroaxonal degeneration: neurofilament light (NfL) and phosphorylated neurofilament heavy (pNfH) in cerebrospinal fluid (CSF) and NfL in serum, and (2)neuroinflammation: chitotriosidase-1 (CHIT1) and monocyte chemoattractant protein 1 (MCP-1) in CSF. To evaluate diagnostic performance, we calculated the area under the curve (AUC). To estimate prognostic performance, we applied quantile regression and Cox regression. We used linear regression models with robust standard errors to assess temporal changes over time. RESULTS: Neurofilaments performed better at differentiating ALS patients from mimics (AUC: pNfH 0.92, CSF NfL 0.86, serum NfL 0.91) than neuroinflammatory biomarkers (AUC: CHIT1 0.71, MCP-1 0.56). Combining biomarkers did not improve diagnostic performance. Similarly, neurofilaments performed better than neuroinflammatory biomarkers at predicting functional decline and survival. The stratified analysis revealed differences according to the site of onset: in bulbar patients, neurofilaments and CHIT1 performed worse at predicting survival and correlations were lower between biomarkers. Finally, in bulbar patients, neurofilaments and CHIT1 increased longitudinally but were stable in spinal patients. CONCLUSIONS: Biomarkers of neuroaxonal degeneration displayed better diagnostic and prognostic value compared with neuroinflammatory biomarkers. However, in contrast to spinal patients, in bulbar patients neurofilaments and CHIT1 performed worse at predicting survival and seemed to increase over time.

Validation of elevated levels of interleukin-8 in the cerebrospinal fluid, and discovery of new biomarkers in patients with GBS and CIDP using a proximity extension assay.

Background: Biomarkers for diagnosis of inflammatory neuropathies, assessment of prognosis, and treatment response are lacking. Methods: CSF and EDTA plasma from patients with Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP), healthy controls (HC) and disease controls were analyzed with Olink multiplex proximity extension assay (PEA) from two independent cohorts. Levels of interleukin-8 (IL8) were further analyzed with ELISA in patients with GBS, CIDP, paraproteinemia-related demyelinating polyneuropathy (PDN), multifocal motor neuropathy (MMN), HC and disease controls. ROC analysis was performed. Outcome was measured with the GBS-disability score (GBS-ds) or Inflammatory Neuropathy Cause and Treatment (INCAT) score. Results: In CSF, multiplex PEA analysis revealed up-regulation of IL8 in GBS compared to CIDP and HC respectively, and CIDP compared to HC. In addition, levels of IL2RA were upregulated in GBS compared to both HC and CIDP, SELE in GBS compared to HC, and ITGAM, IL6, and NRP1 in GBS compared to CIDP. In plasma, levels of MMP3, THBD and ITGAM were upregulated in CIDP compared to HC. Validation of multiplex IL8 results using ELISA, revealed increased levels of IL8 in CSF in patients with GBS and CIDP versus HC and non-inflammatory polyneuropathies (NIP) respectively, as well as in PDN versus NIP and HC. Levels of IL8 in CSF correlated with impairment in the acute phase of GBS as well as outcome at 6-months follow up. Conclusion: IL8 in CSF is validated as a diagnostic biomarker in GBS and CIDP, and a prognostic biomarker in GBS. Multiplex PEA hereby identifies several potential biomarkers in GBS and CIDP.

The path to diagnosis in ALS: delay, referrals, alternate diagnoses, and clinical progression.

Objective: To provide a detailed and differentiated description of the path to receiving the correct amyotrophic lateral sclerosis (ALS) diagnosis, including delay times, referrals, alternate diagnoses, and clinical progression.Methods: Medical records until the date of ALS diagnosis were reviewed and linked to the Swedish Motor Neuron Disease Quality Registry.Results: The study included 353 Stockholm ALS patients diagnosed in 2016-2021. Patients were divided into four groups: 117 (33.1%) with lower extremity (LE), 85 (24.1%) with upper extremity (UE), 136 (38.5%) with bulbar, and 15 (4.2%) with respiratory onset. The time from onset to diagnosis was 16.0 (9.4-27.5) months in LE, 12.9 (8.8-17.8) months in UE, 11.7 (7.4-16.0) months in bulbar, and 8.3 (4.7-15.6) months in respiratory onset. Patients with UE or LE onset were often referred to orthopedics or a spinal/hand surgery clinic (29.3% for LE and 41.8% for UE), while bulbar patients were more frequently referred to ENT (66.3%). For those with LE or UE onset, the most common alternate diagnosis was spinal/foraminal stenosis whereas myasthenia gravis and stroke were more common for bulbar onset patients. For the respiratory group, cardiopulmonary diagnoses predominated. The proportion of all patients in King's stage 3 or 4 increased from 11.3% to 46.1% from the initial health care visit to diagnosis.Conclusions: There was great variation in the path to ALS diagnosis according to the onset clinical phenotype. In all groups, the diagnostic delay and clinical progression was substantial. We identified subgroups where the delay was the longest and might be reduced.

Dying from ALS in Sweden: clinical status, setting, and symptoms.

OBJECTIVES: This retrospective cohort study aims to provide a comprehensive account of death in Swedish patients with ALS, including clinical status preceding death, the death setting, as well as symptoms. METHODS: The study presents detailed information on a cohort of patients with ALS from Stockholm, Sweden, deceased in 2018-2020. In addition, selected information is presented on a larger complementary cohort of ALS patients from all regions of Sweden deceased in 2011-2020. Data were obtained from patient medical records, the Swedish Motor Neuron Disease Quality Registry, and the Swedish Quality Registry of Palliative Care. RESULTS: Ninety-three patients were included in the main cohort and 2224 patients in the complementary cohort. In the main cohort, there was a slow decline in weight and motor function during the 12 months preceding death. Most (93.4%) anticipated/prolonged deaths occurred in a palliative care unit, at home, or in an assisted living facility while 44.8% of precipitous deaths occurred in a hospital ward. Next of kin or health care staff were present at death for most patients (78.7%). In the final week of life, 41.1% experienced at least one symptom (either pain, anxiety, confusion, or dyspnea) that was only partially relieved or not at all. CONCLUSION: The majority of patients died in their own homes or at a palliative unit in the presence of next of kin and most symptoms were adequately managed. This paper might be used in educating patients, next of kin as well as health professionals, decreasing uncertainty surrounding the end of life.

T cell responses at diagnosis of amyotrophic lateral sclerosis predict disease progression.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, involving neuroinflammation and T cell infiltration in the central nervous system. However, the contribution of T cell responses to the pathology of the disease is not fully understood. Here we show, by flow cytometric analysis of blood and cerebrospinal fluid (CSF) samples of a cohort of 89 newly diagnosed ALS patients in Stockholm, Sweden, that T cell phenotypes at the time of diagnosis are good predictors of disease outcome. High frequency of CD4+FOXP3- effector T cells in blood and CSF is associated with poor survival, whereas high frequency of activated regulatory T (Treg) cells and high ratio between activated and resting Treg cells in blood are associated with better survival. Besides survival, phenotypic profiling of T cells could also predict disease progression rate. Single cell transcriptomics analysis of CSF samples shows clonally expanded CD4+ and CD8+ T cells in CSF, with characteristic gene expression patterns. In summary, T cell responses associate with and likely contribute to disease progression in ALS, supporting modulation of adaptive immunity as a viable therapeutic option.

Efficacy and Safety of Rituximab for New-Onset Generalized Myasthenia Gravis: The RINOMAX Randomized Clinical Trial.

Importance: Rituximab is a third-line option for refractory generalized myasthenia gravis (MG) based on empirical evidence, but its effect in new-onset disease is unknown. Objective: To investigate the efficacy and safety of rituximab compared with placebo as an add-on to standard of care for MG. Design, Setting, and Participants: This randomized, double-blind, placebo-controlled study took place throughout 48 weeks at 7 regional clinics in Sweden. Key inclusion criteria were age older than 18 years, onset of generalized symptoms within 12 months or less, and a Quantitative Myasthenia Gravis (QMG) score of 6 or more. Patients were screened from October 20, 2016, to March 2, 2020. Key exclusion criteria included pure ocular MG, suspected thymoma, previous thymectomy, and prior noncorticosteroid immunosuppressants or high doses of corticosteroids. Interventions: Participants were randomized 1:1 without stratification to a single intravenous infusion of 500 mg of rituximab or matching placebo. Main Outcomes and Measures: Minimal disease manifestations at 16 weeks defined as a QMG score of 4 or less with prednisolone, 10 mg or less daily, and no rescue treatment. Results: Of 87 potentially eligible patients, 25 were randomized to rituximab (mean [SD] age, 67.4 [13.4] years; 7 [28%] female) and 22 to placebo (mean [SD] age, 58 [18.6] years; 7 [32%] female). Compared with placebo, a greater proportion with rituximab met the primary end point; 71% (17 of 24) in the rituximab group vs 29% (6 of 21) in the placebo group (Fisher exact test P = .007; probability ratio, 2.48 [95% CI, 1.20-5.11]). Secondary end points, comparing changes in Myasthenia Gravis Activities of Daily Living and Myasthenia Gravis Quality of Life at 16 weeks with QMG at 24 weeks did not differ between groups with censoring for rescue treatment (per-protocol analysis) but were in favor of active treatment when rescue treatment was taken into account by worst rank imputation (post hoc analysis). Rescue treatments were also more frequent in the placebo arm (rituximab: 1 [4%]; placebo, 8 [36%]). One patient in the placebo arm had a myocardial infarction with cardiac arrest and 1 patient in the active arm experienced a fatal cardiac event. Conclusions and Relevance: A single dose of 500 mg of rituximab was associated with greater probability of minimal MG manifestations and reduced need of rescue medications compared with placebo. Further studies are needed to address long-term benefit-risk balance with this treatment. Trial Registration: ClinicalTrials.gov Identifier: NCT02950155.

Neurofilament light chain and total tau in the differential diagnosis and prognostic evaluation of acute and chronic inflammatory polyneuropathies.

BACKGROUND AND PURPOSE: To investigate the diagnostic and prognostic value of axonal injury biomarkers in patients with inflammatory polyneuropathies. METHODS: Neurofilament light chain (NfL) and total tau (T-tau) were measured in the cerebrospinal fluid (CSF) and plasma in 41 patients with Guillain-Barré syndrome (GBS), 32 patients with chronic inflammatory demyelinating polyneuropathy (CIDP), 10 with paraproteinemia-related demyelinating polyneuropathy (PDN), and 8 with multifocal motor neuropathy (MMN), in comparison with 39 disease-free controls and 59 other controls. Outcome was measured with the GBS-disability score (GBS-ds) or Inflammatory Neuropathy Cause and Treatment (INCAT) disability score. RESULTS: Neurofilament light chain levels in CSF and plasma were higher in GBS, CIDP, and PDN vs. disease-free controls. Patients with MMN had higher NfL levels in plasma vs. disease-free controls, but lower levels in CSF and plasma vs. patients with amyotrophic lateral sclerosis (ALS). T-tau levels in plasma were higher in GBS, CIDP, PDN, and MMN vs. all control groups. Neurofilament light chain levels in CSF and plasma in patients with GBS correlated with GBS-ds, as higher levels were associated with inability to run after 6 and 12 months. NfL levels in CSF and plasma in CIDP did not correlate significantly with outcome. CONCLUSIONS: Acute and chronic inflammatory neuropathies are associated with an increase in levels of NfL in CSF and plasma, but NfL is validated as a prognostic biomarker only in GBS. NfL could be used in differentiating patients with MMN from ALS. T-tau in plasma is a novel biomarker that could be used in a diagnostic assessment of patients with acute and chronic inflammatory polyneuropathies.

Hereditary transthyretin amyloidosis in Sweden: Comparisons between a non-endemic and an endemic region.

INTRODUCTION: Hereditary transthyretin amyloidosis (ATTRv) is endemic in northern Sweden (Västerbotten). The awareness of ATTRv amyloidosis is lower in Stockholm, a non-endemic region in Sweden. The aim of this study was to compare the possible differences in diagnostic delay, disease phenotypes, treatment and survival between a non-endemic and an endemic region in Sweden. METHODS: The in- and outpatient diagnosis registry at the Department of Neurology at Karolinska University Hospital and the Amyloidosis Centre at University Hospital of Umeå were used to identify patients between January 2006 and November 2017. RESULTS: In total, 21 patients in Stockholm and 134 patients in Västerbotten were included. The time between symptom onset to time-point of diagnosis was significantly longer in Stockholm vs Västerbotten. This corresponded to a longer median time between first visit at amyloidosis centre to time-point of diagnosis in Stockholm vs in Västerbotten. The most common reason for a diagnostic delay was negative tissue biopsies. CONCLUSION: There was a diagnostic-, but no patient-delay in non-endemic Stockholm vs endemic Västerbotten. Despite a more severe neuropathic phenotype in Stockholm at the onset, the systemic affection over the course of disease and of survival seems not to be influenced by the diagnosis delay in Stockholm.

Cardiac troponin T is elevated and increases longitudinally in ALS patients.

Objective: To test whether high-sensitivity cardiac troponin T (hs-cTnT) could act as a diagnostic or prognostic biomarker in ALS, comparing hs-cTnT to neurofilament light (NfL). Methods: We performed a case-control study, including 150 ALS patients, 28 ALS mimics, and 108 healthy controls, and a follow-up study of the ALS patients, during 2014-2020 in Stockholm, Sweden. We compared concentrations of hs-cTnT in plasma and NfL in the cerebrospinal fluid between cases and controls. To evaluate the diagnostic performance, we calculated the area under the curve (AUC). Hazard ratios (HRs) were estimated from Cox models to assess associations between hs-cTnT and NfL at ALS diagnosis and risk of death. The longitudinal analysis measured changes of hs-cTnT and NfL since ALS diagnosis. Results: We noted higher levels of hs-cTnT in ALS patients (median: 16.5 ng/L) than in ALS mimics (11 ng/L) and healthy controls (6 ng/L). Both hs-cTnT and NfL could distinguish ALS patients from ALS mimics, with higher AUC noted for NfL (AUC 0.88; 95%CI 0.79-0.97). Disease progression correlated weakly with hs-cTnT (Pearson's r = 0.18, p = 0.04) and moderately with NfL (Pearson's r = 0.41, p < 0.001). Shorter survival was associated with higher levels of NfL at diagnosis (HR 1.08, 95%CI 1.04-1.11), but not hs-cTnT. hs-cTnT increased (12.61 ng/L per year, 95%CI 7.14-18.06) whereas NfL decreased longitudinally since ALS diagnosis. Conclusions: NfL is a stronger diagnostic and prognostic biomarker than hs-cTnT for ALS. However, hs-cTnT might constitute a disease progression biomarker as it increases longitudinally. The underlying causes for this increase need to be investigated.

Novel Mutation m.10372A>G in MT-ND3 Causing Sensorimotor Axonal Polyneuropathy.

OBJECTIVE: To investigate the pathogenicity of a novel MT-ND3 mutation identified in a patient with adult-onset sensorimotor axonal polyneuropathy and report the clinical, morphologic, and biochemical findings. METHODS: Clinical assessments and morphologic and biochemical investigations of skeletal muscle and cultured myoblasts from the patient were performed. Whole-genome sequencing (WGS) of DNA from skeletal muscle and Sanger sequencing of mitochondrial DNA (mtDNA) from both skeletal muscle and cultured myoblasts were performed. Heteroplasmic levels of mutated mtDNA in different tissues were quantified by last-cycle hot PCR. RESULTS: Muscle showed ragged red fibers, paracrystalline inclusions, a significant reduction in complex I (CI) respiratory chain (RC) activity, and decreased adenosine triphosphate (ATP) production for all substrates used by CI. Sanger sequencing of DNA from skeletal muscle detected a unique previously unreported heteroplasmic mutation in mtDNA encoded MT-ND3, coding for a subunit in CI. WGS confirmed the mtDNA mutation but did not detect any other mutation explaining the disease. Cultured myoblasts, however, did not carry the mutation, and RC activity measurements in myoblasts were normal. CONCLUSIONS: We report a case with adult-onset sensorimotor axonal polyneuropathy caused by a novel mtDNA mutation in MT-ND3. Loss of heteroplasmy in blood, cultured fibroblasts and myoblasts from the patient, and normal measurement of RC activity of the myoblasts support pathogenicity of the mutation. These findings highlight the importance of mitochondrial investigations in patients presenting with seemingly idiopathic polyneuropathy, especially if muscle also is affected.

Parkinson's disease with restless legs syndrome-an in vivo corneal confocal microscopy study.

Small fiber neuropathy (SFN) has been suggested as a trigger of restless legs syndrome (RLS). An increased prevalence of peripheral neuropathy has been demonstrated in Parkinson's disease (PD). We aimed to investigate, in a cross-sectional manner, whether SFN is overrepresented in PD patients with concurrent RLS relative to PD patients without RLS, using in vivo corneal confocal microscopy (IVCCM) and quantitative sensory testing (QST) as part of small fiber assessment. Study participants comprised of age- and sex-matched PD patients with (n = 21) and without RLS (n = 21), and controls (n = 13). Diagnosis of RLS was consolidated with the sensory suggested immobilization test. Assessments included nerve conduction studies (NCS), Utah Early Neuropathy Scale (UENS), QST, and IVCCM, with automated determination of corneal nerve fiber length (CNFL) and branch density (CNBD) from wide-area mosaics of the subbasal nerve plexus. Plasma neurofilament light (p-NfL) was determined as a measure of axonal degeneration. No significant differences were found between groups when comparing CNFL (p = 0.81), CNBD (p = 0.92), NCS (p = 0.82), and QST (minimum p = 0.54). UENS scores, however, differed significantly (p = 0.001), with post-hoc pairwise testing revealing higher scores in both PD groups relative to controls (p = 0.018 and p = 0.001). Analysis of all PD patients (n = 42) revealed a correlation between the duration of L-dopa therapy and CNBD (ρ = -0.36, p = 0.022), and p-NfL correlated with UENS (ρ = 0.35, p = 0.026) and NCS (ρ = -0.51, p = 0.001). Small and large fiber neuropathy do not appear to be associated with RLS in PD. Whether peripheral small and/or large fiber pathology associates with central neurodegeneration in PD merits further longitudinal studies.

Primary Human Hepatocyte Spheroid Model as a 3D In Vitro Platform for Metabolism Studies.

3D cultures of primary human hepatocytes (PHH) are emerging as a more in vivo-like culture system than previously available hepatic models. This work describes the characterisation of drug metabolism in 3D PHH spheroids. Spheroids were formed from three different donors of PHH and the expression and activities of important cytochrome P450 enzymes (CYP1A2, 2B6, 2C9, 2D6, and 3A4) were maintained for up to 21 days after seeding. The activity of CYP2B6 and 3A4 decreased, while the activity of CYP2C9 and 2D6 increased over time (P < 0.05). For six test compounds, that are metabolised by multiple enzymes, intrinsic clearance (CLint) values were comparable to standard in vitro hepatic models and successfully predicted in vivo CLint within 3-fold from observed values for low clearance compounds. Remarkably, the metabolic turnover of these low clearance compounds was reproducibly measured using only 1-3 spheroids, each composed of 2000 cells. Importantly, metabolites identified in the spheroid cultures reproduced the major metabolites observed in vivo, both primary and secondary metabolites were captured. In summary, the 3D PHH spheroid model shows promise to be used in drug discovery projects to study drug metabolism, including unknown mechanisms, over an extended period of time.

Chronic axonal idiopathic polyneuropathy: is it really benign.

PURPOSE OF REVIEW: Chronic idiopathic axonal polyneuropathy (CIAP), a common neurological condition, is considered to be a benign neurological condition with a small risk of disability. However, many studies have shown a reduced quality of life and a nonnegligible affection of daily activities in patients with CIAP. Here we summarize recent data about CIAP. RECENT FINDINGS: We discuss some of the latest articles regarding risk factors, comorbidities, and possible pathogenic factors regarding CIAP. Patients with chronic polyneuropathy have impaired walking capacity, disturbed balance, and an increased risk of falls. Idiopathic polyneuropathy has a negative impact on activities of daily living. Patients with CIAP may develop plantar ulcers and neuropathic arthropathy. Small fiber involvement may occur, and two recent studies indicate that neuropathic pain is present in about two thirds of the CIAP group. Furthermore, patients with CIAP with neuropathic pain have increased fatigue and poorer emotional well being. SUMMARY: Despite the relatively mild motor impairment seen in most patients with CIAP, the condition causes limitations in life with decreased mobility, pain, and affection of basal daily activities. Because the pathogenesis of CIAP in unclear, there is no disease modifying treatment. Further studies regarding pathogenesis, and randomized controlled clinical trials regarding possible treatment options are needed.

Altered CSF levels of monoamines in hereditary spastic paraparesis 10: A case series.

OBJECTIVE: To perform a comprehensive clinical characterization and biochemical CSF profile analyses in 2 Swedish families with hereditary spastic paraparesis (HSP) 10 (SPG10) caused by 2 different mutations in the neuronal kinesin heavy chain gene (KIF5A). METHODS: Structured clinical assessment, genetic studies, and neuroradiologic and electrophysiological evaluations were performed in 4 patients from 2 families with SPG10. Additional CSF analysis was conducted in 3 patients with regard to levels of neurodegenerative markers and monoamine metabolism. RESULTS: All patients exhibited a complex form of HSP with a mild to moderate concurrent axonal polyneuropathy. The heterozygous missense mutations c.767A>G and c.967C>T in KIF5A were found. Wide intrafamilial phenotype variability was evident in both families. CSF analysis demonstrated a mild elevation of neurofilament light (NFL) chain in the patient with longest disease duration. Unexpectedly, all patients exhibited increased levels of the dopamine metabolite, homovanillic acid, whereas decreased levels of the noradrenergic metabolite, 3-methoxy-4-hydroxyphenylglycol, were found in 2 of 3 patients. CONCLUSIONS: We report on CSF abnormalities in SPG10, demonstrating that NFL elevation is not a mandatory finding but may appear after long-standing disease. Impaired transportation of synaptic proteins may be a possible explanation for the increased dopaminergic turnover and noradrenergic deficiency identified. The reasons for these selective abnormalities, unrelated to obvious clinical features, remain to be explained. Our findings need further confirmation in larger cohorts of patients harboring KIF5A mutations.

The cerebellar phenotype of Charcot-Marie-Tooth neuropathy type 4C.

BACKGROUND: Friedreich ataxia (FRDA) is the most common familial ataxia syndrome in Central and Southern Europe but rare in Scandinavia. Biallelic mutations in SH3 domain and tetratricopeptide repeats 2 (SH3TC2) cause Charcot-Marie-Tooth disease type 4C (CMT4C), one of the most common autosomal recessive polyneuropathies associated with early onset, slow disease progression and scoliosis. Beyond nystagmus reported in some patients, neither ataxia nor cerebellar atrophy has been documented as part of the CMT4C phenotype. METHODS: Here we describe a single centre CMT4C cohort. All patients underwent a comprehensive characterization that included physical examination, neurophysiological studies, neuroimaging and genetic testing. In a patient with cerebellar features, an evaluation of the vestibular system was performed. RESULTS: All five patients in this cohort harbored the R954X mutation in SH3TC2 suggesting a founder effect. Two patients had been diagnosed as FRDA. One of them, an 80-year-old woman had onset of unsteadiness during childhood leading to gradual loss of mobility. She also had scoliosis and hearing loss. On examination she had generalized muscle atrophy, leg flaccidity, pes cavus, facial myokymia, limb dysmetria, dysarthria and gaze-evoked nystagmus. She exhibited bilateral vestibular areflexia. Neuroimaging demonstrated atrophy in the frontoparietal regions and cerebellar hemispheres. CONCLUSIONS: CMTC4A may present with a cerebellar phenotype and mimic a flaccid-ataxic form of FRDA. Absence of cardiomyopathy or endocrine abnormalities and lack of pathological dentate iron accumulation in CMT4C distinguish it from FRDA.

Screening for Fabry disease and Hereditary ATTR amyloidosis in idiopathic small-fiber and mixed neuropathy.

INTRODUCTION: In this study we assessed the value of genetic screening for Fabry disease (FD) and hereditary ATTR amyloidosis in patients with idiopathic small-fiber neuropathy (SFN) or mixed neuropathy in a clinical setting. METHODS: This was a Nordic multicenter study with 9 participating centers. Patients with idiopathic SFN or mixed neuropathy were included. Genetic sequencing of the TTR and GLA genes was performed. RESULTS: There were 172 patients enrolled in the study. Genetic screening was performed in 155 patients. No pathogenic mutations in the TTR gene were found. A single patient had a possible pathogenic variant, R118C, in the GLA gene, but clinical investigation showed no firm signs of FD. DISCUSSION: Screening for hereditary ATTR amyloidosis and FD in patients with idiopathic SFN or mixed neuropathy without any additional disease-specific symptoms or clinical characteristics in a Nordic population appears to be of little value in a clinical setting. Muscle Nerve 59:354-357, 2019.

The Swedish motor neuron disease quality registry.

OBJECTIVE: We set up the Swedish Motor Neuron Disease (MND) Quality Registry to assure early diagnosis and high-quality health care for all MND patients (mainly amyotrophic lateral sclerosis, ALS), and to create a research base by prospectively following the entire MND population in Sweden. METHODS: Since 2015, the MND Quality Registry continuously collects information about a wide range of clinical measures, biological samples, and quality of life outcomes from all MND patients recruited at the time of MND diagnosis in Sweden and followed at each clinic visit approximately every 12 weeks. The Registry includes an Internet based patient own reporting portal that involves patients in the registration of their current symptoms and health status. RESULTS: As of 20th January 2017, the MND Quality Registry included 99% of the MND patients of the Stockholm area (N = 194), consisting mostly of ALS patients (N = 153, 78.9%), followed by patients labeled as MND due to a neurophysiology finding but not fulfilling the criteria for ALS (N = 20, 10.3%), primary lateral sclerosis (N = 13, 6.7%), and progressive spinal muscular atrophy patients (N = 8, 4.1%). A higher proportion of these patients were women (N = 100, 52%), and women and men had a similar age at symptoms onset (59 years). CONCLUSIONS: Main strengths of the MND Quality Registry are its clinical, quantitative, qualitative, and prospective nature, providing the researchers potential means of identifying appropriate candidates for clinical trials and other research projects, as well as assuring to the patients an effective and adequate time spent on-site with the healthcare professionals.

The Fate of a Hapten - From the Skin to Modification of Macrophage Migration Inhibitory Factor (MIF) in Lymph Nodes.

Skin (contact) allergy, the most prevalent form of immunotoxicity in humans, is caused by low molecular weight chemicals (haptens) that penetrate stratum corneum and modify endogenous proteins. The fate of haptens after cutaneous absorption, especially what protein(s) they react with, is largely unknown. In this study the fluorescent hapten tetramethylrhodamine isothiocyanate (TRITC) was used to identify hapten-protein conjugates in the local lymph nodes after topical application, as they play a key role in activation of the adaptive immune system. TRITC interacted with dendritic cells but also with T and B cells in the lymph nodes as shown by flow cytometry. Identification of the most abundant TRITC-modified protein in lymph nodes by tandem mass spectrometry revealed TRITC-modification of the N-terminal proline of macrophage migration inhibitory factor (MIF) - an evolutionary well-conserved protein involved in cell-mediated immunity and inflammation. This is the first time a hapten-modified protein has been identified in lymph nodes after topical administration of the hapten. Most haptens are electrophiles and can therefore modify the N-terminal proline of MIF, which has an unusually reactive amino group under physiological conditions; thus, modification of MIF by haptens may have an immunomodulating role in contact allergy as well as in other immunotoxicity reactions.

Microangiopathy-A Potential Contributing Factor to Idiopathic Polyneuropathy: A Mini Review.

Chronic idiopathic axonal polyneuropathy (CIAP) is a slowly progressive predominantly sensory axonal polyneuropathy. The prevalence of CIAP increases with age. The pathogenic cause of CIAP is unknown although there are several prevailing etiological hypotheses. In this mini review, we focus on the hypothesis of disturbed microcirculation in the vasa nervorum of peripheral nerves as a pathogenic cause of CIAP. There is an association between CIAP and metabolic risk factors. Furthermore, the phenotype of CIAP resembles diabetic neuropathy both clinically and electrophysiologically. In sural nerve biopsies from patients with diabetes mellitus, structural abnormalities indicating microangiopathy in the endoneurial microvessels are well documented. Similarly, sural microvessel abnormalities have been shown in patients with atherosclerotic non-diabetic peripheral vascular disease. However, the reported histopathological alterations of microvasculature in sural nerves of CIAP patients are inconsistent. Two studies report microangiopathic changes in CIAP sural nerves comparable with those found in patients with diabetic neuropathy. Conversely, another recent study showed no significant differences in the microangiopathic parameters in the endoneurial microvessels in the sural nerve biopsies from CIAP patients compared to controls without polyneuropathy. However, this CIAP patient group was younger compared to the patient groups in the other two studies. A general limitation with the published morphological studies are that different methods have been used in the assessment of microangiopathy, and there is also a risk of subjectivity in the results. Immunohistochemistry studies of sural nerves with verification of microangiopathy using specific biomarkers would be of great interest to develop.