Motor neurone disease: progress and challenges

Abstract

Major progress has been made over the past decade in the understanding of motor neurone disease (MND), changing the landscape of this complex disease. Through identifying positive prognostic factors, new evidence-based standards of care have been established that improve patient survival, reduce burden of disease for patients and their carers, and enhance quality of life. These factors include early management of respiratory dysfunction with non-invasive ventilation, maintenance of weight and nutritional status, as well as instigation of a multidisciplinary team including neurologists, general practitioners and allied health professionals. Advances in technology have enhanced our understanding of the genetic architecture of MND considerably, with implications for patients, their families and clinicians. Recognition of extra-motor involvement, particularly cognitive dysfunction, has identified a spectrum of disease from MND through to frontotemporal dementia. Although riluzole remains the only disease-modifying medication available in clinical practice in Australia, several new therapies are undergoing clinical trials nationally and globally, representing a shift in treatment paradigms. Successful translation of this clinical research through growth in community funding, awareness and national MND research organisations has laid the foundation for closing the research-practice gap on this debilitating disease. In this review, we highlight these recent developments, which have transformed treatment, augmented novel therapeutic platforms, and established a nexus between research and the MND community. This era of change is of significant relevance to both specialists and general practitioners who remain integral to the care of patients with MND.

Amyotrophic Lateral Sclerosis Mortality in the United States, 2011–2014

“…In summary, compared with other MND subtypes, ALS is the most malignant with shortest survival [4]. Excluding deaths from other MNDs and progressive supranuclear palsy in data coded using the pre-2017 ICD-10 rubric reduces the total number of deaths attributed to ALS and the adjusted death rate by about 21%.…”

“…ALS makes up about 70% of cases in a disease class known as the motor neuron disease (MND); other main clinical phenotypes of MND are isolated bulbar palsy (4-8% of cases), progressive muscular atrophy (5%), and primary lateral sclerosis (1-3%) [4]. Although ALS is the most common MND, it did not have its own code in the US prior to the 2017 update of the International Classification of Diseases, 10th Revision (ICD-10) rubric.…”

Structural Variants May Be a Source of Missing Heritability in sALS

“…These methodologies have failed to identify disease-associated genetic variations in the majority of sALS patients, highlighting the complexity and genetic heterogeneity contributing to this disease phenotype. Approximately 10% of sALS cases can be explained by mutations in 25 known ALS-linked genes, with the remaining 90% of cases as yet having an undetermined genetic contributor (Andersen and Al-Chalabi, 2011;Renton et al, 2014;Dharmadasa et al, 2017). At a glance these data may imply that the genetic contributions to sALS are minor, however, heritability estimates and twin studies suggest a genetic contribution of up to 65% (Al-Chalabi et al, 2010;Al-Chalabi and Visscher, 2014).…”

Commentary: Amyotrophic Lateral Sclerosis and Myasthenia Gravis Overlap Syndrome: A Review of Two Cases and the Associated Literature

“…A recent study of motor axonopathy induced in mice by overexpression of an inhibitory binding protein for IGF-1, led to the suggestion that a defect in well-known neurotrophic and myotrophic effects of IGF-1 might be common to both diabetic neuropathy and ALS (13). There is no doubt that disruption of the NMJ, seen as fasciculation and motor unit enlargement is an early feature of ALS (14, 15), and associations between excessive motor activity or enlarged motor units and the development of ALS have been recognized (16). Thus muscles, similarly to glial cells, can promote a vicious cycle of energy impairment and lack of trophic factor release that interacting with other systems, when set in motion, amplify their own processes and may accelerate the development of ALS.…”