axonopathies

Axonopathies are disorders in which the primary site of injury is the axon of a neuron, leading to degeneration of the distal axon and its terminals with relative sparing of the soma in the early stages. The resulting axonal loss typically manifests as a sensorimotor neuropathy that can be confined to peripheral nerves or can involve central pathways in some conditions. Axonopathies may be hereditary or acquired and can affect motor, sensory, or autonomic fibers.

Etiology and classification encompass genetic, metabolic, toxic, inflammatory, and infectious causes. Inherited conditions include distal hereditary motor neuropathies and hereditary sensory neuropathies, in which axonal degeneration is the dominant lesion. Acquired axonopathies arise from diabetes and metabolic disorders, heavy metal or alcohol exposure, nutritional deficiencies, chemotherapy (notably platinum-based drugs and taxanes), and immune-mediated processes with an axonal pattern. Infections such as certain neuropathies can contribute to axonal damage. Some central nervous system diseases also involve axonal degeneration.

Pathophysiology involves primary injury to the axon or disruption of axonal transport, followed by Wallerian degeneration of the distal stump. Secondary demyelination may occur. Mitochondrial dysfunction, cytoskeletal abnormalities, and impaired axonal maintenance contribute to progression. Electrophysiology commonly shows reduced amplitudes of compound motor and sensory action potentials with relatively preserved conduction velocities early on, reflecting axonal loss rather than demyelination.

Clinical features include distal symmetric weakness and sensory loss, foot drop, decreased deep-tendon reflexes, and variable autonomic symptoms. Diagnosis relies on clinical assessment supported by nerve conduction studies and electromyography, laboratory tests to identify underlying causes, and genetic testing when a hereditary axonopathy is suspected. Nerve biopsy is rarely required.

Management focuses on treating the underlying cause, symptom control, and rehabilitation. Prognosis varies by etiology; some hereditary forms are progressive, while other axonopathies may stabilize or partially recover after removal of the offending factor. Examples include distal hereditary motor neuropathies, hereditary sensory neuropathies, diabetic polyneuropathy, and chemotherapy-induced peripheral neuropathy.