This group of degenerative disorders is characterized clinically by weakness and variable wasting of affected muscles, without accompanying sensory changes.
Motor neuron disease in adults generally commences between 30 and 60 years of age. There is degeneration of the anterior horn cells in the spinal cord, the motor nuclei of the lower cranial nerves, and the corticospinal and corticobulbar pathways. The disorder is usually sporadic, but familial cases may occur and several genetic mutations or loci have been identified. Cigarette smoking may be one risk factor.
Five varieties have been distinguished on clinical grounds.
A. Progressive Bulbar Palsy
Bulbar involvement predominates owing to disease processes affecting primarily the motor nuclei of the cranial nerves.
Bulbar involvement predominates in this variety also, but it is due to bilateral corticobulbar disease and thus reflects upper motor neuron dysfunction. There may be a “pseudo-bulbar affect,” with uncontrollable episodes of laughing or crying to stimuli that would not normally have elicited such marked reactions.
C. Progressive Spinal Muscular Atrophy
This is characterized primarily by a lower motor neuron deficit in the limbs due to degeneration of the anterior horn cells in the spinal cord.
D. Primary Lateral Sclerosis
There is a purely upper motor neuron deficit in the limbs.
E. Amyotrophic Lateral Sclerosis (ALS)
A mixed upper and lower motor neuron deficit is found in the limbs. This disorder is sometimes associated with cognitive decline (in a pattern consistent with frontotemporal dementia), a pseudobulbar affect, or parkinsonism. Approximately 10% of ALS cases are familial and have been associated with mutations at several different genetic loci, including a hexanucleotide repeat on chromosome 9 that also associates with frontotemporal dementia.
The spinal muscular atrophies (SMAs) are inherited syndromes caused most often by mutations of the survival motor neuron 1 (SMN1) gene on chromosome 5. Different mutations result in more or less severe disruptions of the protein, resulting in an age of onset that ranges from infancy (SMA type I; Werdnig-Hoffmann disease), to early (type II) or late childhood (type III; Kugelberg-Welander syndrome), to adulthood (type IV). X-linked bulbospinal neuronopathy (Kennedy syndrome) is associated with an expanded trinucleotide repeat sequence on the androgen receptor gene and carries a more benign prognosis than other forms of motor neuron disease.
There are reports of juvenile SMA due to hexosaminidase deficiency. Pure motor syndromes resembling motor neuron disease may also occur in association with monoclonal gammopathy or multifocal motor neuropathies with conduction ...