Abstract Body

Distinguishing between diseases of the anterior horn cell and motor-predominant neuropathies can be challenging. However, making this distinction is important as potentially reversible conditions can otherwise be missed. The disease spectrum ranges from inherited neuronopathies, such as spinal muscular atrophy to acquired neuropathies, such as multifocal motor neuropathy with conduction block.

The approach to differentiating between these two groups of disorders through careful evaluation of clinical characteristics, investigations and response to therapy will be discussed.

Abstract Body

Amyotrophic lateral sclerosis (ALS) can be conceptualized as a multifactorial disorder, characterized by the interaction between multiple genes and environmental factors. The heritability of ALS has been estimated to range between 20 to 60 percent, although in the clinical setting, the frequency of patients with a family history of ALS is about 10%. The gap between these figures is likely represented by gene variants with a reduced expressivity or penetrance.

The two last decades have seen an incredible improvement of our understanding of ALS genetics. Genetics was instrumental to definitely determine the strict link between ALS and frontotemporal dementia as a clinical and pathological continuum. At least ‘Mendelian’ 40 genes have been identified, although some uncertainty remains for some of these genes. In addition, several genetic variants emerged as risk factors with non-Mendelian effect (i.e., CAG intermediate expansions of ATXN2 gene) or as modifiers of ALS genotype (such as the rs12608932A>C variant of UNC13A gene).

A recent advancement has been the application in ALS of two novel techniques, i.e., LD score regression and Mendelian randomization, which allow to test distinct aspects of the genetic architecture underlying the disease.

Genetics is also changing the therapeutic landscape of ALS. Several trials based on the antisense oligonucleotide technology are underway to address ‘Mendelian’ ALS genes, namely SOD1, C9orf72 and FUS. In addition, vectors derived from adeno-associated virus (AAV) can efficiently target genes and have been tested in several preclinical settings, including the SOD1 transgenic mouse, with promising outcomes.

Abstract Body

Many types of mutations underlie motor neuron disease (MND) including repeat expansions, loss of function and missense mutations. This spectrum of disorders has heralded in a new era of genetic therapies in neuromuscular disease. New major treatment strategies in neuromuscular disorders include the use of antisense oligonucleotides (ASOs), exon-skipping ASO applications, RNA interference therapy (RNAi), genome editing technology, gene and enzyme replacement therapy. In MND, the most common current approach is the use of ASOs to eliminate protein expression and are used to block pathogenic mutations. ASOs penetrate the cell and enter the nucleus to bind to pre-mRNA or remain in the cytosol to bind mRNA. The ASO-RNA duplex blocks mRNA transcription, thereby eliminating protein expression. In MND, targeted ASO therapy is in clinical trials for SOD1 and C9ORF72 inherited ALS. ASOs can also be designed to "skip" and repair exon mutations by binding to pre-mRNA at splice motifs that flank and "mask" the mutant exon, leading to a newly splices mRNA that does not carry the mutation. The exon-skipping ASO nusinersen masks a splicing site downstream of exon 7 of the SMN2 gene leading to sufficient SMN production to overcome loss of function mutations in SMN1. Nusinersen is now in clinical use for spinal muscular atrophy (SMA) with clear clinical efficacy. In addition to ASOs, gene replacement therapy is also clinically approved for children with SMA1 under the age of 2. Adeno-associated virus 9 (AAV9) onasemnogene abeparvovec is systemically delivered as a one time dose with good therapeutic response. Genetic approaches however are not currently suitable for sporadic MND, leading to the continued development of regenerative therapies. In this realm, the most common approach is the use of stem cells, particularly in the treatment of ALS. Mesenchymal, neural and glial progenitor stem cells have all been used in persons with ALS, with either limited or as yet undetermined clinical efficacy. As the field of genetic and regenerative therapies in MND continues to expand, it is anticipated the next decade will bring both new approaches and new therapeutic successes.