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BackgroundCognitive and behavioural dysfunction may occur in people with motor neuron disease (MND), with some studies suggesting an association with the C9ORF72repeat expansion. Their onset and progression, however, is poorly understood. We explored how cognition and behaviour change over time, and whether demographic, clinical and genetic factors impact these changes.MethodsParticipants with MND were recruited through the Phenotype-Genotype-Biomarker study. Every 3–6 months, the Edinburgh Cognitive and Behavioural ALS Screen (ECAS) was used to assess amyotrophic lateral sclerosis (ALS) specific (executive functioning, verbal fluency, language) and ALS non-specific (memory, visuospatial) functions. Informants reported on behaviour symptoms via semi-structured interview.ResultsParticipants with neuropsychological data at ≥3 visits were included (n=237, mean age=59, 60% male), of which 18 (8%) were C9ORF72positive. Baseline cognitive impairment was apparent in 18 (8%), typically in ALS specific domains, and associated with lower education, but not C9ORF72status. Cognition, on average, remained stable over time, with two exceptions: (1) C9ORF72carriers declined in all ECAS domains, (2) 8%–9% of participants with baseline cognitive impairment further declined, primarily in the ALS non-specific domain, which was associated with less education. Behavioural symptoms were uncommon.ConclusionsIn this study, cognitive dysfunction was less common than previously reported and remained stable over time for most. However, cognition declines longitudinally in a small subset, which is not entirely related to C9ORF72status. Our findings raise questions about the timing of cognitive impairment in MND, and whether it arises during early clinically manifest disease or even prior to motor manifestations.

In this study, we examined the long-term social and health impacts of the coronavirus disease 2019 (COVID-19) pandemic on people with muscular dystrophy. We modified our prior COVID-19 Impact Survey to assess impacts from the continuing pandemic using feedback from muscular dystrophy experts, patients, and advocacy group/registry representatives. The survey assessed COVID-19 medical history, and the effects of the pandemic on social aspects, muscle disease, and medical care. We also used the validated 10-item Perceived Stress Scale. The de-identified, electronic survey was distributed to adults with muscular dystrophy via international patient registries and advocacy group websites from February 8, 2021 to March 22, 2021. Respondents (n = 1243 : 49% Facioscapulohumeral Muscular Dystrophy (FSHD); 43% Myotonic Dystrophy (DM), and 8% Limb-Girdle Muscular Dystrophy (LGMD)) were mostly women and middle-aged (range 18–90 years). Rates of COVID-19 infections were low at 8% with zero deaths. Reported recovery times were also short with only 9% reporting a recovery period greater than eight weeks, and 7% requiring hospitalization with one individual requiring a ventilator. Major challenges reported during the pandemic included: stress management, particularly for those with LGMD, (27%) and wearing a mask (24%). The majority reported a slight worsening in their disease state. Respondents reported moderate stress levels (stress score = 16.4; range = 0–39), with higher stress levels reported by women and those under age 30 years. Seventy-percent of participants who had telemedicine visits were satisfied with the encounters; however, most reported a preference for in-person visits. People with MD found ways to manage their stress and overcome obstacles during the COVID-19 pandemic. COVID-19 infection rates and medical complications were similar to a general population. Telemedicine visits may have a more permanent role in care.

Background: Edasalonexent (CAT-1004) is an orally-administered novel small molecule drug designed to inhibit NF-?B and potentially reduce inflammation and fibrosis to improve muscle function and thereby slow disease progression and muscle decline in Duchenne muscular dystrophy (DMD).Objective: This international, randomized 2?:?1, placebo-controlled, phase 3 study in patients =4?–?

Edasalonexent (CAT-1004) is an orally-administered novel small molecule drug designed to inhibit NF-κB and potentially reduce inflammation and fibrosis to improve muscle function and thereby slow disease progression and muscle decline in Duchenne muscular dystrophy (DMD). This international, randomized 2 : 1, placebo-controlled, phase 3 study in patients ≥4 – <  8 years old with DMD due to any dystrophin mutation examined the effect of edasalonexent (100 mg/kg/day) compared to placebo over 52 weeks. Endpoints were changes in the North Star Ambulatory Assessment (NSAA; primary) and timed function tests (TFTs; secondary). Assessment of health-related function used the Pediatric Outcomes Data Collection tool (PODCI). One hundred thirty one patients received edasalonexent (n = 81) or placebo (n = 38). At week 52, differences between edasalonexent and placebo for NSAA total score and TFTs were not statistically significant, although there were consistently less functional declines in the edasalonexent group. A pre-specified analysis by age demonstrated that younger patients (≤6.0 years) showed more robust and statistically significant differences between edasalonexent and placebo for some assessments. Treatment was well-tolerated and the majority of adverse events were mild, and most commonly involved the gastrointestinal system (primarily diarrhea). Edasalonexent was generally well tolerated with a manageable safety profile at the dose of 100 mg/kg/day. Although edasalonexent did not achieve statistical significance for improvement in primary and secondary functional endpoints for assessment of DMD, subgroup analysis suggested that edasalonexent may slow disease progression if initiated before 6 years of age. (NCT03703882)

Primary lateral sclerosis (PLS) is a neurodegenerative disorder of the adult motor system. Characterised by a slowly progressive upper motor neuron syndrome, the diagnosis is clinical, after exclusion of structural, neurodegenerative and metabolic mimics. Differentiation of PLS from upper motor neuron-predominant forms of amyotrophic lateral sclerosis remains a significant challenge in the early symptomatic phase of both disorders, with ongoing debate as to whether they form a clinical and histopathological continuum. Current diagnostic criteria for PLS may be a barrier to therapeutic development, requiring long delays between symptom onset and formal diagnosis. While new technologies sensitive to both upper and lower motor neuron involvement may ultimately resolve controversies in the diagnosis of PLS, we present updated consensus diagnostic criteria with the aim of reducing diagnostic delay, optimising therapeutic trial design and catalysing the development of disease-modifying therapy.

Amyotrophic lateral sclerosis (ALS), a rapidly progressive, invariably fatal disease, involves mixed upper and lower motor neurons in different spinal cord regions. Patients with bulbar onset progress more rapidly than patients with limb onset or with a lower motor neuron presentation. Recent descriptions of regional variants suggest some patients have ALS isolated to a single spinal region for many years, including brachial amyotrophic diplegia, leg amyotrophic diplegia, and isolated bulbar palsy. Clearer definitions of regional variants will have implications for prognosis, understanding the pathophysiology of ALS, identifying genetic factors related to slower disease progression, and future planning of clinical trials.

Primary lateral sclerosis is characterized by insidious onset of progressive upper motor neuron dysfunction in the absence of clinical signs of lower motor neuron involvement. Patients experience stiffness; decreased balance and coordination; mild weakness; and, if the bulbar region is affected, difficulty speaking and swallowing, and emotional lability. The diagnosis is made based on clinical history, typical examination findings, and diagnostic testing negative for other causes of upper motor neuron dysfunction. Electromyogram is normal, or only shows mild neurogenic findings in a few muscles, not meeting El Escorial criteria. Treatment is largely supportive.

When approaching a patient with suspected motor neuron disease (MND), the pattern of weakness on examination helps distinguish MND from other diseases of peripheral nerves, the neuromuscular junction, or muscle. MND is a clinical diagnosis supported by findings on electrodiagnostic testing. MNDs exist on a spectrum, from a pure lower motor neuron to mixed upper and lower motor neuron to a pure upper motor neuron variant. Amyotrophic lateral sclerosis (ALS) is a progressive mixed upper and lower motor neuron disorder, most commonly sporadic, which is invariably fatal. This article describes a pattern approach to identifying MND and clinical features of sporadic ALS.

Background:Posited pathological mechanisms in Facioscapulohumeral Muscular Dystrophy (FSHD) include activation in somatic tissue of normally silenced genes, increased susceptibility to oxidative stress, and induction of apoptosis.Objective:To determine the histopathological changes in FSHD muscle biopsies and compare to possible pathological mechanisms of disease.Methods:We performed a cross-sectional study on quadriceps muscle biopsies from 32 genetically confirmed FSHD participants, compared to healthy volunteers and myotonic dystrophy type 1 as disease controls. Biopsies were divided into groups to evaluate apoptosis rates, capillary density, myonuclear and satellite cell counts.Results:Apoptosis rates were increased in FSHD (n = 10, 0.74% ) compared to myotonic dystrophy type 1 (n = 10, 0.14% , P = 0.003) and healthy volunteers (n = 14, 0.13% , P = 0.002). Apoptosis was higher in FSHD patients with the smallest residual D4Z4 fragments. Capillary density was decreased in FSHD1 (n = 10, 316 capillaries/mm2) compared to healthy volunteers (n = 15, 448 capillaries/mm2, P = 0.001). No differences were seen in myonuclear or satellite cell counts.Conclusions:Preliminary evidence for increased apoptosis rates and reduced capillary density may reflect histopathological correlates of disease activity in FSHD. The molecular-pathological correlates to these changes warrants further investigation.

Facioscapulohumeral muscular dystrophy (FSHD) is a common type of adult muscular dystrophy and is divided into types 1 and 2 based on genetic mutation. Clinically, both FSHD types often show asymmetric and progressive muscle weakness affecting initially the face, shoulder, and arms followed by the distal then proximal lower extremities. Approximately 95% of patients, termed FSHD1, have a deletion of a key number of repetitive elements on chromosome 4q35. The remaining 5%, termed FSHD2, have no deletion on chromosome 4q35. Nevertheless, both types share a common downstream mechanism, making it possible for future disease-directed therapies to be effective for both FSHD types.

Skeletal muscle channelopathies are rare heterogeneous diseases with marked genotypic and phenotypic variability. Despite advances in understanding of the molecular pathology of these disorders, the diverse phenotypic manifestations remain a challenge in diagnosis and therapeutics. These disorders can cause lifetime disability and affect quality of life. There is no treatment of these disorders approved by the US Food and Drug Administration at this time. Recognition and treatment of symptoms might reduce morbidity and improve quality of life. This article summarizes the clinical manifestations, diagnostic studies, pathophysiology, and treatment options in nondystrophic myotonia, congenital myasthenic syndrome, and periodic paralyses.

The muscle channelopathies are a group of rare inherited diseases caused by mutations in muscle ion channels. Mutations cause an increase or decrease in muscle membrane excitability, leading to a spectrum of related clinical disorders: the nondystrophic myotonias are characterized by delayed relaxation after muscle contraction, causing muscle stiffness and pain; the periodic paralyses are characterized by episodes of flaccid muscle paralysis. This review describes the clinical characteristics, molecular pathogenesis, and treatments of the nondystrophic myotonias and periodic paralyses.

Myasthenia gravis (MG) is the most common autoimmune disease affecting neuromuscular junction transmission. MG is characterized by muscle weakness that worsens with activity and fluctuates over the course of the day. Involvement of respiratory musculature can lead to life-threatening crisis requiring intensive care unit care. Antibody testing is positive in most patients with MG. Treatment of MG includes short-term symptomatic treatment, chronic immunosuppression, surgical intervention, and immunomodulatory therapies for severe disease or crisis. We review advances in 5 areas relevant to diagnosis and management of MG: the role of IV immunoglobulin vs plasmapharesis in myasthenic crisis and severe disease; the clinical characterization of patients with antibodies to muscle-specific tyrosine kinase receptors; old and new investigational treatments; management of MG in pregnancy; and new confirmatory diagnostic tests.

To investigate the frequency of Coats syndrome and its association with D4Z4 contraction size in patients with facioscapulohumeral muscular dystrophy type 1 (FSHD1).

Recent advances have provided a model for understanding the underlying molecular genetic changes in facioscapulohumeral muscular dystrophy (FSHD). This review will highlight our current understanding and future research directions.

Augmenting the heat shock response with arimoclomol ameliorates pathology in cellular and animal models of inclusion body myositis.

Mesenchymal stem cells engineered to secrete neurotrophic growth factors appear to be safe and show modest benefit in patients with amyotrophic lateral sclerosis.

A pathway involved in clearing myelin debris offers new potential therapeutic targets for chronic demyelinating diseases.

Loss of awareness of a cognitive decline occurs before the onset of dementia and is associated with post mortem dementia pathology.

Alterations in brain phosphodiesterase 10A are visible by brain imaging in people who carry the mutant gene for Huntington’s disease but do not yet show signs of disease.

Conditional knockdown of C9orf72in mice does not cause loss of motor function or decrease survival, arguing against a loss-of-function role for C9orf72 in ALS.

Sleep/wake cycles and timing of meals affect glucose tolerance, emphasizing the intricate homeostatic mechanisms behind glucose control.