Some are fatal (e.g. ALS), while others are not (e.g. PLS). Patterns of weakness Various patterns of muscle weakness occur in different motor neuron diseases. Weakness can be symmetric or asymmetric, and it can occur in body parts that are distal, proximal, or both. According to Statland et al., there are three main weakness patterns that are seen in motor neuron diseases, which are: Asymmetric distal weakness without sensory loss (e.g. ALS, PLS, PMA, MMA) Symmetric weakness without sensory loss (e.g. PMA, PLS) Symmetric focal midline proximal weakness (neck, trunk, bulbar involvement; e.g. ALS, PBP, PLS) Lower and upper motor neuron findings Motor neuron diseases are on a spectrum in terms of upper and lower motor neuron involvement. Some have just lower or upper motor neuron findings, while others have a mix of both. Lower motor neuron (LMN) findings include muscle atrophy and fasciculations, and upper motor neuron (UMN) findings include hyperreflexia, spasticity, muscle spasm, and abnormal reflexes. Pure upper motor neuron diseases, or those with just UMN findings, include PLS. Pure lower motor neuron diseases, or those with just LMN findings, include PMA. Motor neuron diseases with both UMN and LMN findings include both familial and sporadic ALS. Causes Most cases are sporadic and their causes are usually not known. It is thought that environmental, toxic, viral, or genetic factors may be involved. DNA damage TARDBP (TAR DNA-binding protein 43), also referred to as TDP-43, is a critical component of the non-homologous end joining (NHEJ) enzymatic pathway that repairs DNA double-strand breaks in pluripotent stem cell-derived motor neurons. TDP-43 is rapidly recruited to double-strand breaks where it acts as a scaffold for the recruitment of the XRCC4-DNA ligase protein complex that then acts to repair double-strand breaks. About 95% of ALS patients have abnormalities in the nucleus-cytoplasmic localization in spinal motor neurons of TDP43. In TDP-43 depleted human neural stem cell-derived motor neurons, as well as in sporadic ALS patients’ spinal cord specimens there is significant double-strand break accumulation and reduced levels of NHEJ. Associated risk factors In adults, men are more commonly affected than women. Diagnosis Differential diagnosis can be challenging due to the number of overlapping symptoms, shared between several motor neuron diseases. Frequently, the diagnosis is based on clinical findings (i.e. LMN vs. UMN signs and symptoms, patterns of weakness), family history of MND, and a variation of tests, many of which are used to rule