Multifaceted superoxide dismutase 1 expression in amyotrophic lateral sclerosis patients: a rare occurrence?

Amyotrophic lateral sclerosis (ALS) is a neuromuscular condition resulting from the progressive degeneration of motor neurons in the cortex, brainstem, and spinal cord. While the typical clinical phenotype of ALS involves both upper and lower motor neurons, human and animal studies over the years have highlighted the potential spread to other motor and non-motor regions, expanding the phenotype of ALS. Although superoxide dismutase 1 (SOD1) mutations represent a minority of ALS cases, the SOD1 gene remains a milestone in ALS research as it represents the first genetic target for personalized therapies. Despite numerous single case reports or case series exhibiting extramotor symptoms in patients with ALS mutations in SOD1 (SOD1-ALS), no studies have comprehensively explored the full spectrum of extramotor neurological manifestations in this subpopulation. In this narrative review, we analyze and discuss the available literature on extrapyramidal and non-motor features during SOD1-ALS. The multifaceted expression of SOD1 could deepen our understanding of the pathogenic mechanisms, pointing towards a multidisciplinary approach for affected patients in light of new therapeutic strategies for SOD1-ALS.

Diagnostic delay in achalasia.

BACKGROUND: Achalasia is a rare disorder characterized by impaired esophageal motility and symptoms like dysphagia, regurgitation, chest pain, and weight loss. A timely diagnosis is crucial to adequately manage this condition. AIMS: This study aimed to assess the diagnostic delay from symptom onset to a definite diagnosis of achalasia, and to identify associated factors. METHODS: This retrospective, single-center study included patients diagnosed with achalasia between January 2013 and September 2023. Demographic data, symptoms, manometric, endoscopic, and radiological findings were collected. We also considered socio-economic deprivation. Early diagnosis was defined as occurring within 12 months of symptom onset, while late diagnosis was defined as occurring more than 12 months. RESULTS: We included 278 patients (142 males, median age 58 years). Dysphagia was the most common symptom (96 %), followed by regurgitation (70.1 %). The median diagnostic delay was 24 months (IQR 12-72, range 0-720), with 213 patients (76.6 %) experiencing late diagnosis. Early diagnosis was more common in patients with weight loss (63.1% vs. 42.0 %, p = 0.003). Lower material deprivation correlated with shorter diagnostic delay (24 months, IQR 10-60 vs. 60 months, IQR 18-300, p = 0.001). CONCLUSIONS: Achalasia diagnosis is often delayed. Weight loss along with socio-economic factors, influence the timeliness of diagnosis. Improving awareness of disease and relevance of initial symptoms may facilitate earlier diagnosis and treatment.

SerpinA1 levels in amyotrophic lateral sclerosis patients: An exploratory study.

BACKGROUND: SerpinA1, a serine protease inhibitor, is involved in the modulation of microglial-mediated inflammation in neurodegenerative diseases. We explored SerpinA1 levels in cerebrospinal fluid (CSF) and serum of amyotrophic lateral sclerosis (ALS) patients to understand its potential role in the pathogenesis of the disease. METHODS: SerpinA1, neurofilament light (NfL) and heavy (NfH) chain, and chitinase-3-like protein-1 (CHI3L1) were determined in CSF and serum of ALS patients (n = 110) and healthy controls (n = 10) (automated next-generation ELISA), and correlated with clinical parameters, after identifying three classes of progressors (fast, intermediate, slow). Biomarker levels were analyzed for diagnostic power and association with progression and survival. RESULTS: SerpinA1serum was significantly decreased in ALS (median: 1032 µg/mL) compared with controls (1343 µg/mL) (p = 0.02). SerpinA1CSF was elevated only in fast progressors (8.6 µg/mL) compared with slow (4.43 µg/mL, p = 0.01) and intermediate (4.42 µg/mL, p = 0.03) progressors. Moreover, SerpinA1CSF correlated with neurofilament and CHI3L1 levels in CSF. Contrarily to SerpinA1CSF , neurofilament and CHI3L1 concentrations in CSF correlated with measures of disease progression in ALS, while SerpinA1serum mildly related with time to generalization (rho = 0.20, p = 0.04). In multivariate analysis, the ratio between serum and CSF SerpinA1 (SerpinA1 ratio) and NfHCSF were independently associated with survival. CONCLUSIONS: Higher SerpinA1CSF levels are found in fast progressors, suggesting SerpinA1 is a component of the neuroinflammatory mechanisms acting upon fast-progressing forms of ALS. Both neurofilaments or CHI3L1CSF levels outperformed SerpinA1 at predicting disease progression rate in our cohort, and so the prognostic value of SerpinA1 alone as a measure remains inconclusive.

Reduction of Fecal Calprotectin Levels Induced by a Short Course of Escherichia Coli Nissle is Associated with a Lower Likelihood of Disease Flares in Patients with Ulcerative Colitis in Clinical Remission.

BACKGROUND AND AIMS: Fecal calprotectin (FC) is a biomarker of gut inflammation, and Escherichia coli Nissle 1917 (EcN) is a probiotic strain able to reduce gut inflammation and maintain disease remission in patients with inflammatory bowel disease (IBD). The aim is to assess the effects of EcN administration in patients with IBD in clinical remission and altered FC values. METHODS: We prospectively included 82 patients with ulcerative colitis (UC) (n=49) and Crohn's disease (CD) (n=33) in clinical remission and with FC values above 250 mcg/g (T0) who were treated with EcN alone for 2 months. FC values were assessed at the end of EcN treatment (T1) and clinical disease activity at 3 months (T2). RESULTS: At T1 median FC values were significantly lower compared to T0 both in patients with CD (312 mcg/g vs 626 mcg/g, p<0.0001) and UC (100 mcg/g vs 584 mcg/g; p<0.0001). Patients with UC who experienced disease relapse at T2 had lesser reduction in median FC values at T1 (-229 mcg/g, vs -397 mcg/g, p=0.049), while in patients with CD we observed no statistically significant difference (-358 mcg/g, vs -427; p=0.568). In patients with UC, a reduction of at least 532 mcg/g in FC had an accuracy of 69.7% and a positive predictive value of 65.7% in predicting maintenance of remission. CONCLUSIONS: A short course of EcN was associated with a reduction of FC values in patients with IBD in clinical remission and baseline altered FC values, and in patients with UC this decrease was associated with maintenance of clinical remission.

Effect of tauroursodeoxycholic acid on survival and safety in amyotrophic lateral sclerosis: a retrospective population-based cohort study.

Background: Oral tauroursodeoxycholic acid (TUDCA) is a commercial drug currently tested in patients with amyotrophic lateral sclerosis (ALS) both singly and combined with sodium phenylbutyrate. This retrospective study aimed to investigate, in a real-world setting, whether TUDCA had an impact on the overall survival of patients with ALS who were treated with this drug compared to those patients who received standard care only. Methods: This propensity score-matched study was conducted in the Emilia Romagna Region (Italy), which has had an ALS regional registry since 2009. Out of 627 patients with ALS diagnosed from January 1st, 2015 to June 30th, 2021 and recorded in the registry with available information on death/tracheostomy, 86 patients took TUDCA and were matched in a 1:2 ratio with patients who received only usual care according to age at onset, sex, phenotype, diagnostic latency, ALS Functional Rating Scale-Revised (ALSFRS-R) at first visit, disease progression rate at first visit, and BMI at diagnosis. The primary outcome was survival difference (time from onset of symptoms to tracheostomy/death) between TUDCA exposed and unexposed patients. Findings: A total of 86 patients treated with TUDCA were matched to 172 patients who did not receive treatment. TUDCA-exposed patients were stratified based on dosage (less than or equal to 1000 mg/day or greater) and duration (less than or equal to 12 months or longer) of treatment. The median overall survival was 49.6 months (95% CI 41.7-93.5) among those treated with TUDCA and 36.2 months (95% CI 32.7-41.6) in the control group, with a reduced risk of death observed in patients exposed to a higher dosage (defined as ≥ 1000 mg/day) of TUDCA (HR 0.56; 95% CI 0.38-0.83; p = 0.0042) compared to both the control group and those with lower TUDCA dosages (defined as < 1000 mg/day). TUDCA was generally well-tolerated, except for a minority of patients (n = 7, 8.1%) who discontinued treatment due to side effects, primarily gastrointestinal and mild in severity; only 2 adverse events required hospital access but resolved without sequelae. Interpretation: In this population-based exploratory study, patients with ALS who were treated with TUDCA may have prolonged survival compared to patients receiving standard care only. Additional prospective randomized studies are needed to confirm the efficacy and safety of this drug. Funding: Emilia-Romagna Region.

Predictors for progression in amyotrophic lateral sclerosis associated to SOD1 mutation: insight from two population-based registries.

BACKGROUND: Uncovering distinct features and trajectories of amyotrophic lateral sclerosis (ALS) associated with SOD1 mutations (SOD1-ALS) can provide valuable insights for patient' counseling and stratification for trials, and interventions timing. Our study aims to pinpoint distinct clinical characteristics of SOD1-ALS by delving into genotype-phenotype correlations and factors that potentially impact disease progression. METHODS: This is a retrospective observational study of a SOD1-ALS cohort from two Italian registers situated in the regions of Emilia-Romagna, Piedmont and Valle d'Aosta. RESULTS: Out of 2204 genotyped ALS patients, 2.5% carried SOD1 mutations, with a M:F ratio of 0.83. SOD1-ALS patients were younger, and more frequently reported a family history of ALS and/or FTD. SOD1-ALS had a longer survival compared to patients without ALS-associated gene mutations. However, here was considerable variability in survival across distinct SOD1 mutations, with an average survival of less than a year for the L39V, G42S, G73S, D91N mutations. Among SOD1-ALS, multivariate analysis showed that, alongside established clinical prognostic factors such as advanced age at onset and high progression rate at diagnosis, mutations located in exon 2 or within highly conserved gene positions predicted worse survival. Conversely, among comorbidities, cancer history was independently associated with longer survival. INTERPRETATION: Within the context of an overall slower disease, SOD1-ALS exhibits some degree of heterogeneity linked to the considerable genetic diversity arising from the multitude of potential mutations sites and specific clinical prognostic factors, including cancer history. Revealing the factors that modulate the phenotypic heterogeneity of SOD1-ALS could prove advantageous in improving the efficacy of upcoming therapeutic approaches.

Retrospective observational study on the use of acetyl-L-carnitine in ALS.

ALCAR (Acetyl-L-carnitine) is a donor of acetyl groups and increases the intracellular levels of carnitine, the primary transporter of fatty acids across the mitochondrial membranes. In vivo studies showed that ALCAR decrease oxidative stress markers and pro-inflammatory cytokines. In a previous double-blind placebo-controlled phase II trial showed positive effects on self-sufficiency (defined as a score of 3+ on the ALSFRS-R items for swallowing, cutting food and handling utensils, and walking) ALSFRS-R total score and FVC. We conducted an observational, retrospective, multicentre, case-control study to provide additional data on the effects of ALCAR in subjects with ALS in Italy. Subjects treated with ALCAR 1.5 g/day or 3 g/day were included and matched with not treated subjects by sex, age at diagnosis, site of onset, and time from diagnosis to baseline, (45 subjects per group). ALCAR 3 g/day vs not treated: 22 not treated subjects (48.9%) were still alive at 24 months after baseline, compared to 23 (51.1%) treated subjects (adj. OR 1.18, 95% CI 0.46-3.02). No statistically significant differences were detected in ALSFRS nor FVC nor self-sufficiency. ALCAR 1.5 g/day vs not treated: 22 not treated subjects (48.9%) were still alive at 24 months after baseline, compared to 32 (71.1%) treated subjects (adj. OR 0.27, 95% CI 0.10-0.71). For ALSFRS-R, a mean slope of - 1.0 was observed in treated subjects compared to - 1.4 in those not treated (p = 0.0575). No statistically significant difference was detected in the FVC nor self-sufficiency. Additional evidence should be provided to confirm the efficacy of the drug and provide a rationale for the dosage.

Insight into Elderly ALS Patients in the Emilia Romagna Region: Epidemiological and Clinical Features of Late-Onset ALS in a Prospective, Population-Based Study.

Few studies have focused on elderly (>80 years) amyotrophic lateral sclerosis (ALS) patients, who represent a fragile subgroup generally not included in clinical trials and often neglected because they are more difficult to diagnose and manage. We analyzed the clinical and genetic features of very late-onset ALS patients through a prospective, population-based study in the Emilia Romagna Region of Italy. From 2009 to 2019, 222 (13.76%) out of 1613 patients in incident cases were over 80 years old at diagnosis, with a female predominance (F:M = 1.18). Elderly ALS patients represented 12.02% of patients before 2015 and 15.91% from 2015 onwards (p = 0.024). This group presented with bulbar onset in 38.29% of cases and had worse clinical conditions at diagnosis compared to younger patients, with a lower average BMI (23.12 vs. 24.57 Kg/m2), a higher progression rate (1.43 vs. 0.95 points/month), and a shorter length of survival (a median of 20.77 vs. 36 months). For this subgroup, genetic analyses have seldom been carried out (25% vs. 39.11%) and are generally negative. Finally, elderly patients underwent less frequent nutritional- and respiratory-supporting procedures, and multidisciplinary teams were less involved at follow-up, except for specialist palliative care. The genotypic and phenotypic features of elderly ALS patients could help identify the different environmental and genetic risk factors that determine the age at which disease onset occurs. Since multidisciplinary management can improve a patient's prognosis, it should be more extensively applied to this fragile group of patients.

Missense mutation in ATXN2 gene (c.2860C > T) in an amyotrophic lateral sclerosis patient with aggressive disease phenotype.

BACKGROUND: ALS symptoms have been previously described only in the context of ATXN2 CAG expansions, whereas missense mutations of the gene have never been described in ALS patients. CASE PRESENTATION: We identified a novel missense mutation (c.2860C > T) of ATXN2, for which in silico analysis showed a possible pathogenic effect on protein expression, in a patient presenting an aggressive disease phenotype. DISCUSSION: Our findings raise the possibility for unknown genetic factors interacting with ATXN2 mutations, or for an autonomous pathogenic role for this specific point mutation in ATXN2 gene in driving the clinical phenotype toward ALS. We also found that stress granules in the fibroblasts from the patient entrapped higher amounts of defective ribosomal products compared to fibroblasts from three healthy subjects, suggesting that ATXN2 mutation-related toxicity may have implication in protein quality control.

Case Report: Pituitary metastasis as a presenting manifestation of silent gastric cardia adenocarcinoma.

Introduction: Pituitary metastases are very rare in cancer patients and often originate from lung or breast tumors. They usually occur in patients with known metastatic disease, but rarely may be the first presentation of the primary tumor. Methods: We present the case of a 58 years-old-man who reported a three-month history of polyuria-polydipsia syndrome, generalized asthenia, panhypopituitarism and bitemporal hemianopsia. Brain-MRI showed a voluminous pituitary mass causing posterior sellar enlargement and compression of the surrounding structures including pituitary stalk, optic chiasm, and optic nerves. Results: The patient underwent neurosurgical removal of the mass. Histological examination revealed a poorly differentiated adenocarcinoma of uncertain origin. A total body CT scan showed a mass in the left kidney that was subsequently removed. Histological features were consistent with a clear cell carcinoma. However, endoscopic examination of the digestive tract revealed an ulcerating and infiltrating adenocarcinoma of the gastric cardia. Total body PET/CT scan with 18F-FDG confirmed an isolated area of accumulation in the gastric cardia, with no hyperaccumulation at other sites. Conclusion: To the best of our knowledge, there are no reports of pituitary metastases from gastric cardia adenocarcinoma. Our patient presented with symptoms of sellar involvement and without evidence of other body metastases. Therefore, sudden onset of diabetes insipidus and visual deterioration should lead to the suspicion of a rapidly growing pituitary mass, which may be the presenting manifestation of a primary extracranial adenocarcinoma. Histological investigation of the pituitary mass can guide the diagnostic workup, which must however be complete.