Despite tremendous efforts in basic research and a growing number of clinical trials aiming to find effective treatments, amyotrophic lateral sclerosis (ALS) remains an incurable disease. One possible reason for the lack of effective causative treatment options is that ALS may not be a single disease entity but rather may represent a clinical syndrome, with diverse genetic and molecular causes, histopathological alterations, and subsequent clinical presentations contributing to its complexity and variability among individuals. Defining a way to subcluster ALS patients is becoming a central endeavor in the field. Identifying specific clusters and applying them in clinical trials could enable the development of more effective treatments. This review aims to summarize the available data on heterogeneity in ALS with regard to various aspects, e.g., clinical, genetic, and molecular.

Spinal muscular atrophy (SMA) is a disabling disease that affects not only the patient’s health-related quality of life (HRQoL), but also causes a high caregiver burden (CGB). The aim of this study was to evaluate HRQoL, CGB, and their predictors in SMA. In two prospective, cross-sectional, and multi-center studies, SMA patients (n = 39) and SMA patient/caregiver couples (n = 49) filled in the EuroQoL Five Dimension Five Level Scale (EQ-5D-5L) and the Short Form Health Survey 36 (SF-36). Caregivers (CGs) additionally answered the Zarit Burden Interview (ZBI) and the Hospital Anxiety and Depression Scale (HADS). Patients were clustered into two groups with either low or high HRQoL (EQ-5D-5L index value 0.679). The latter group was mostly composed of ambulatory type III patients with higher motor/functional scores. More severely affected patients reported low physical functioning but good mental health and vitality. The CGB (mean ZBI = 22/88) correlated negatively with patients’ motor/functional scores and age. Higher CGB was associated with a lower HRQoL, higher depression and anxiety, and more health impairments of the CGs. We conclude that patient and CG well-being levels interact closely, which highlights the need to consider the health of both parties while evaluating novel treatments.

Objective: To evaluate the performance of serum neurofilament light chain (NfL) and cerebrospinal fluid (CSF) phosphorylated neurofilament heavy chain (pNfH) as diagnostic biomarkers for the differentiation between motor neuron disease (MND) and multifocal motor neuropathy (MMN). Methods: This retrospective, monocentric study included 16 patients with MMN and 34 incident patients with MND. A subgroup of lower motor neuron (MN) dominant MND patients (n = 24) was analyzed separately. Serum NfL was measured using Ella automated immunoassay, and CSF pNfH was measured using enzyme-linked immunosorbent assay. Area under the curve (AUC), optimal cutoff values (Youden’s index), and correlations with demographic characteristics were calculated. Results: Neurofilament concentrations were significantly higher in MND compared to MMN (p < 0.001), and serum NfL and CSF pNfH correlated strongly with each other (Spearman’s rho 0.68, p < 0.001). Serum NfL (AUC 0.946, sensitivity and specificity 94%) and CSF pNfH (AUC 0.937, sensitivity 90.0%, specificity 100%) performed excellent in differentiating MND from MMN. Optimal cutoff values were ≥ 44.15 pg/mL (serum NfL) and ≥ 715.5 pg/mL (CSF pNfH), respectively. Similar results were found when restricting the MND cohort to lower MN dominant patients. Only one MMN patient had serum NfL above the cutoff. Two MND patients presented with neurofilament concentrations below the cutoffs, both featuring a slowly progressive disease. Conclusion: Neurofilaments are valuable supportive biomarkers for the differentiation between MND and MMN. Serum NfL and CSF pNfH perform similarly well and elevated neurofilaments in case of diagnostic uncertainty underpin MND diagnosis.

Background: This study aimed to evaluate changes in compound muscle action potential (CMAP) amplitude in adults with spinal muscular atrophy (SMA) undergoing nusinersen treatment and its association with motor function improvements. Methods: This multicenter study assessed median, ulnar, and peroneal CMAP over a follow‐up of up to 4.5 years using linear mixed models. Motor function was measured using the Revised Upper Limb Module (RULM) and the Hammersmith Functional Motor Scale Expanded (HFMSE). Correlations between CMAP and motor function scores were analyzed. Results: Seventy‐eight patients (27 ambulatory, 51 non‐ambulatory) were included. Baseline ulnar CMAP ≥ 2.0 mV distinguished SMA type 3 from type 2 with 91.3% sensitivity and 88.9% specificity (AUC 0.96, 95% CI 0.92–1.0), while baseline median nerve CMAP ≥ 6.5 mV showed 91.7% sensitivity and 77.3% specificity (AUC 0.84, 95% CI 0.72–0.96). No significant changes over time were observed in median, ulnar, and peroneal CMAP amplitudes ( p > 0.05). CMAP trajectories did not differ between SMA types 2 and 3 ( p > 0.05). No significant difference in the change in RULM or HFMSE at any time point was observed between SMA patients with baseline median nerve CMAP < 5 mV and those with CMAP of ≥ 5 mV ( p > 0.05). No significant correlations were found between changes in median nerve CMAP and HFMSE or RULM ( p > 0.05). Discussion: CMAP amplitudes remained stable during nusinersen treatment, with no differences in trajectories between SMA types 2 and 3. Our findings suggest that while CMAP amplitude correlates with disease severity, it may not serve as a sensitive biomarker of treatment response in adult SMA patients.

Introduction/Aims: Spinal muscular atrophy (SMA) is a multisystem disorder. We assessed metabolic syndrome (MetS) prevalence in adults with SMA and its association with motor function, quality of life (QoL), fatigue, and depression.Methods: MetS was diagnosed using 2009 consensus criteria. Hammersmith Functional Motor Scale Expanded (HFMSE), Revised Upper Limb Module (RULM), Fatigue Severity Scale (FSS), Beck Depression Inventory (BDI), and 36‐Item Short Form Health Survey (SF‐36) were recorded and correlations between muscle function, depression, fatigue, QoL, and MetS were analyzed.Results: We included 36 individuals (18 males; mean age: 38.7 ± 14.6 years). MetS was present in 25.0%. The most common component of MetS was central obesity (69.7%). Nearly half of the SMA individuals exhibited at least one abnormal lipid level result. Individuals with MetS more frequently were SMA type 3 (77.8% vs. 37.0%, p = .02) and had higher levels of fatigue (48.4 ± 6.7 vs. 39.5 ± 11.6, p = .03) than those without MetS. No associations of the presence of MetS with ambulatory status or HFMSE/RULM scores were observed. SMA individuals with MetS scored significantly lower in mental and social domains of QoL and total SF‐36 score (p = .04). We observed weak to moderate correlations between the presence of MetS and SMA type, presence of comorbidities, QoL, and fatigue.Discussion: The frequency of MetS was modestly higher among adults with SMA than in the general population, particularly in SMA type 3. MetS was associated with reduced QoL and increased fatigue. Larger studies are needed to fully understand the significance of MetS in adults with SMA.

Background: 5q-Spinal muscular atrophy (SMA) is a lower motor neuron disease. However, peripheral organ involvement might contribute to its complex clinical picture, especially in severe forms. This study evaluated frequency and characteristics of autonomic symptoms, prevalence of electrocardiographic (ECG) abnormalities, and the impact of autonomic dysfunction on quality of life (QoL) in adults with SMA. Methods: Autonomic function was assessed using the SCales for Outcomes in PArkinson’s disease-Autonomic Dysfunction (SCOPA-AUT). 12-Lead ECG was recorded. The Hammersmith Functional Motor Scale Expanded (HFMSE), Revised Upper Limb Module (RULM), Fatigue Severity Scale (FSS), Beck Depression Inventory (BDI), and 36-Item Short Form Health Survey (SF-36) were collected to assess motor function, fatigue, depression, and QoL. Results: Forty-three SMA patients (23 males; mean age: 37.6 ± 14.1 years) and forty-three age- and sex-matched healthy controls were included. Compared to healthy controls, SMA patients scored worse on gastrointestinal domain (2.9 ± 2.9 vs. 1.1 ± 1.5, p < 0.001) and in total SCOPA-AUT score (9.8 ± 7.3 vs. 5.7 ± 4.4, p = 0.002). More severely affected patients reported a greater burden of autonomic symptoms compared to those with milder phenotypes. Burden of autonomic symptoms correlated with QoL ( ρ = − 0.33, p = 0.028). The presence of major ECG abnormalities showed a negative correlation with SMA type ( ρ = − 0.39, p = 0.027), age at the time of testing ( ρ = − 0.45, p = 0.009), and ambulatory status ( ρ = − 0.39, p = 0.027). Conclusion: Adults with SMA demonstrate a substantial burden of autonomic symptoms, especially those with more severe disease. This burden significantly compromises patients’ QoL. Further studies are needed to better understand autonomic dysfunction in this population.