Dysferlinopathies are autosomal recessive disorders caused by mutations in the dysferlin (DYSF) gene encoding the dysferlin protein. DYSF mutations lead to a wide range of muscular phenotypes, with the most prominent being Miyoshi myopathy (MM) and limb girdle muscular dystrophy type 2B (LGMD2B).

The origin and pathophysiological background of MS-associated fatigue is poorly understood. There is no unifying concept of its nature and its determinants to date. This paper reviews possible influences of factors determining personality profile on mental fatigue in MS. Likewise, the role of psychological factors and their interaction with personality to promote fatigue is discussed. Current data suggests that fatigue, especially in early MS states, may be influenced by vulnerable personality traits and personality-associated features. Among them are depressive disease coping, avoidance behavior and inhibition, irritability, less extraversion, neuroticism, disturbed reward responsiveness and somatization behavior. However, among the validated personality factors no genuine influences that are independent of depression have been documented. From a psychological perspective, depressiveness, anxiety and perhaps somatization may be relevant mediators of fatigue. Interesting to note that in early MS a psychiatric diagnosis is significantly more likely than on a later stage of the disease and that fatigue and motivation might share neural circuits. It is hypothesized that psychological factors promote fatigue in MS by psychological distress and sustained neuro-endocrine and neurovegetative stress response. Despite there are limitations of data as discussed in the paper, personality research might help to disentangle specific promoting factors of fatigue in MS. Further research efforts are warranted since they might open ways to early psychological intervention of MS-associated fatigue. This is all the more important since medication is insufficient until now.

Mutations in the SACS gene have been initially reported in a rare autosomal recessive cerebellar ataxia syndrome featuring prominent cerebellar atrophy, spasticity and peripheral neuropathy as well as retinal abnormalities in some cases (autosomal recessive spastic ataxia of Charlevoix–Saguenay, ARSACS). In the past few years, the phenotypic spectrum has broadened, mainly owing to the availability and application of high-throughput genetic testing methods. We identified nine patients (three sib pairs, three singleton cases) with isolated, non-syndromic hereditary motor and sensory neuropathy (HMSN) who carried pathogenic SACS mutations, either in the homozygous or compound heterozygous state. None of the patients displayed spasticity or pyramidal signs. Ataxia, which was noted in only three patients, was consistent with a sensory ataxia. Nerve conduction and nerve biopsy studies showed mixed demyelinating and axonal neuropathy. Brain MRI scans were either normal or revealed isolated upper vermis atrophy of the cerebellum. Our findings confirm the broad clinical spectrum associated with SACS mutations, including pure polyneuropathy without characteristic clinical and brain imaging manifestations of ARSACS.

Background: A high proportion of patients with relapsing remitting multiple sclerosis convert to secondary progressive multiple sclerosis (SPMS) characterized by irreversibly progressing disability and cognitive decline. Siponimod (Mayzent), a selective sphingosine-1-phosphate receptor modulator, was recently approved by the European Medicines Agency for the treatment of adult SPMS patients with active disease, as evidenced by relapses or magnetic resonance imaging features of ongoing inflammatory activity. Approval by the Food and Drug Administration covers a broader range of indications, comprising clinically isolated syndrome, relapsing remitting multiple sclerosis, and active SPMS. However, treatment effects of siponimod have not been assessed in a structured setting in clinical routine so far. Objective: The objectives of AMASIA (impAct of Mayzent [siponimod] on secondAry progressive multiple Sclerosis patients in a long-term non-Interventional study in GermAny), a prospective noninterventional study, are to assess the long-term effectiveness and safety of siponimod in clinical routine and to evaluate the impact of disease burden on quality of life and socioeconomic conditions. Here, we report the study design of AMASIA. Methods: Treatment effects of siponimod will be evaluated in 1500 SPMS patients during a 3-year observational phase. According to the genetic polymorphism of CYP2C9, the initial dose will be titrated to the maintenance dose of 1 mg (CYP2C9*1*3 and *2*3) or 2 mg (all other polymorphisms of CYP2C9 except *3*3, which is contraindicated) taken orally once daily. Primary endpoint is the 6-month confirmed disability progression, as assessed by a functional composite endpoint comprising the Expanded Disability Status Scale and symbol digit modalities test to take appropriate account of cognitive changes and increase sensitivity. Further measures including multiple sclerosis activity data; assessments of functional domains; questionnaires addressing the patients’, physicians’, and relatives’ perspectives of disability progression; cognitive worsening; quality of life; and socioeconomic aspects will be documented using the multiple sclerosis documentation system MSDS3D. Results: AMASIA is being conducted between February 2020 and February 2025 in up to 250 neurological centers in Germany. Conclusions: AMASIA will complement the pivotal phase III–derived efficacy and safety profile of siponimod with real-world data and will further evaluate several individual treatment aspects such as quality of life and socioeconomic conditions of patients and caregivers. It might help to establish siponimod as a promising option for the treatment of SPMS patients in clinical routine. International Registered Report Identifier (IRRID): DERR1-10.2196/19598

Background: Multiple sclerosis (MS) subtypes—relapsing–remitting (RRMS), secondary-progressive (SPMS), and primary-progressive (PPMS) – have been associated with distinct cognitive impairment profiles, with progressive subtypes, in contrast to RRMS, showing additional deficits in more widespread domains. Research has largely focused on RRMS, leaving SPMS and PPMS underexplored due to their lower prevalence and limited therapeutic targeting. Data on the interplay between cognitive impairment, mood, and fatigue over time are also scarce. This study examined cognition, fatigue, and psychopathology over a period of one year to identify subtype-specific impairments and progression trajectories. Methods: Sixty-six MS patients (22 each with RRMS, SPMS, and PPMS) and 22 healthy controls (HC) were assessed using neuropsychological tests for attention, memory, processing speed, working memory, fluency and visuospatial functions. Patient-reported outcomes for depression, anxiety, and fatigue were also collected. Analyses included correlations, within-group comparisons (paired t-tests), and between-group comparisons (ANOVAs/ANCOVAs). Results: Progressive MS subtypes exhibited more severe cognitive impairments, fatigue, and mood disturbances than RRMS. Over one year, treated RRMS patients improved in various cognitive domains, while PPMS patients showed gains only in visuospatial abilities. On the other hand, SPMS patients exhibited no significant changes, suggesting more pronounced cognitive deficits. Conclusions: Cognitive impairments differed significantly across MS subtypes. While RRMS patients improved over one year and PPMS patients showed selective gains in one domain, SPMS showed no significant changes, indicating reduced cognitive reserve. These between-group differences suggest different cognitive trajectories. The findings underscore the need for tailored, holistic interventions for different MS subtypes.