Genetic Basis of Motor Neuron Diseases: Insights, Clinical Management, and Future Directions

Abstract

Motor neuron diseases (MNDs) are a heterogeneous group of neurodegenerative disorders characterized by the progressive loss of motor neurons, resulting in debilitating physical decline. Advances in genetics have revolutionized the understanding of MNDs, elucidating critical genes such as SOD1, TARDBP, FUS, and C9orf72, which are implicated in their pathogenesis. Despite these breakthroughs, significant gaps persist in understanding the interplay between genetic and environmental factors, the role of rare variants, and epigenetic contributions. This review synthesizes current knowledge on the genetic landscape of MNDs, highlights challenges in linking genotype to phenotype, and discusses the promise of precision medicine approaches. Emphasis is placed on emerging strategies, such as gene therapy and targeted molecular interventions, offering hope for personalized treatments. Addressing these challenges is imperative to harness the full potential of genomics for improving outcomes in MNDs.

Keywords: gene therapy; genetics; motor neuron diseases; neurodegeneration; precision medicine.

Figure 1

Genes implicated in various MNDs. In PLS, HSP, and IASHP, upper motor neurons are affected, while in SMA, PMA, LCCS, and SBMA, lower motor neurons are affected. ALS: amyotrophic lateral sclerosis; ALS2: amyotrophic lateral sclerosis 2; AR: androgen receptor; ERBB3: Erb-B2 receptor tyrosine kinase 3; FUS: Fused in Sarcoma; GLE1: GLE1 RNA export mediator; HSP: hereditary spastic paraplegia; IAHSP: infantile-onset ascending hereditary spastic paraplegia; LCCS: lethal congenital contracture syndrome; MND: motor neuron disease; PIP5K1C: phosphatidylinositol-4-phosphate 5-kinase type I gamma; SBMA: spinal and bulbar muscular atrophy; SMA: spinal muscular atrophy; SMN: survival motor neuron; SOD1: superoxide dismutase 1; SPG4: spastin; SPG7: paraplegin; TARDBP: TAR DNA-binding protein gene.