The cause of motor neuron disease is unknown. Several possibilities have been suggested:

- Ageing: Premature ageing in certain motor cells may result in increasing metabolic demand upon survivors. As a consequence the survivors also suffer premature loss. This process could be 'triggered' by genetic and environmental factors.

- Viruses: Chronic virus infection has been suggested. Polio virus will acutely damage the anterior horn cell and chronic polio infection could theoretically produce motor neuron disease. Some claim that motor neuron disease follows acute poliomyelitis; however, when this occurs the clinical picture is not typical and may resemble more closely Spinal Muscular Atrophy (see later). Polio antibody titres remain normal. Virus-like particles have been reported in some patients with MND, but transmission to non-human primates has been unsuccessful.

- Toxins: Certain metals, lead, selenium, mercury and manganese have been incriminated, but again evidence is inconclusive.

- Minerals: Clinical similarities between MND and neurological involvement in hyperparathyroidism and phosphate deficiency suggest a relationship with chronic calcium deficiency.

- Genetic - in a proportion of such cases the gene for familial ALS has been localised to chromosome 21 at the locus for the enzyme superoxide dismutase (S.O.D.)

- Excitotoxins - excitatory amino acids are implicated in many 'degenerative' disorders. Glutamate may be important in ALS.

An increased incidence of gastric surgery in sufferers, the presence of immune complexes in small bowel biopsies and disordered cellular immunity have been noted but causative relationships are unclear. Antibodies against voltage-gated Ca' + channels have been detected.

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