Mutation of the motor protein dynactin is associated with a motor neuron disease that has unique clinical and electrophysiological characteristics. The symptoms begin in the second and third decades of life and progress slowly. Most patients’ initial symptom is stridor resulting from vocal fold paresis, then later hand weakness, and finally distal leg weakness. Electrophysiological studies confirm preferential involvement of distinct motor neuron populations. The motor neurons that innervate the vocal folds are severely affected, whereas those that innervate the diaphragm are spared. Similarly, the motor neurons that innervate the thenar muscles are more affected than those innervating the hypothenar and peroneal muscles. This is a distinctive clinical and electrophysiological pattern not seen in other disorders.
Vocal fold paresis may be overlooked during a typical neurological evaluation. Some disorders with laryngeal paralysis involve primarily abductor (opening) muscles leading to potentially life-threatening airway obstruction,21,22
whereas others affect mainly adductor (closing) muscles, leading to a breathy voice and risk for aspiration.23,24
When vocal fold paralysis occurs with a length-dependent axonal neuropathy, the left vocal fold usually is affected initially,25,26
because of the greater length of the left recurrent laryngeal nerve.27
In this family, stridor was the presenting symptom, indicating bilateral abductor paralysis.28 –30
This opening defect restricted air intake during exercise, and as the paresis progressed, the vocal folds were sucked into the glottis on inspiration, causing obstruction. Denervation of the thyroarytenoid muscles, however, indicates that there is also adductor muscle involvement in this disorder. The proband’s first symptom of aspiration on swallowing was likely caused by difficulties with rapid and complete laryngeal closure.
Vocal fold paresis is a prominent feature in some forms of distal spinal muscular atrophy and hereditary motor and sensory neuropathy; however, these are clinically distinct from the disorder we describe in this report. In distal spinal muscular atrophy with vocal fold paralysis, linked to chromosome 2q14,31,32
hand weakness begins in the first or second decade of life. This is coincident with or followed by unilateral more often than bilateral vocal fold paresis and no other bulbar involvement. In Charcot–Marie–Tooth disease (CMT) type 2C, linked to chromosome 12q23–24,33
involvement of the recurrent laryngeal nerves is accompanied by involvement of the phrenic nerve causing life-threatening respiratory insufficiency in the first or second decade of life.26
In CMT type 4A, which is caused by mutation in the gene encoding the ganglioside-induced, differentiation-associated protein 1,34 –36
weakness begins in the feet and hands in the first decade of life with only some patients experiencing vocal fold paralysis in the second decade of life. Patients with CMT types 2C and 4A also have clinical evidence of sensory nerve involvement. Our patients had no clinical or electrophysiological evidence of sensory nerve involvement; however, skin biopsy results showed mild morphological abnormalities of epidermal nerve axons, indicating that sensory nerves may not be completely spared in this disorder.
The unusual motor neuron disease described here is associated with a point mutation in the CAP-Gly motif of p150Glued
, the largest subunit of dynactin.8
The dynein–dynactin microtubule motor complex has multiple functions in cells, including endoplasmic reticulum to Golgi vesicular transport, neurofilament transport, messenger RNA localization, and mitotic spindle assembly.37
In neurons, the dynein–dynactin complex is the major motor that mediates the retrograde axonal transport of vesicles and organelles along microtubules. The mutation in this family impairs dynactin’s ability to bind to microtubules8
and is predicted to lead to slower or less effective retrograde transport. Motor neuron survival is dependent on neurotrophic factors that are transported retrogradely from muscle to the neuroal cell body.38
Motor neuron degeneration in this family could result from a shortage of trophic factors. Alternatively, slow transport could lead to accumulation of cargo and “axonal strangulation” with congested transport along axons in both directions.
Recently, three other mutations in the dynactin p150Glued
gene have been described in patients who carry a diagnosis of amyotrophic lateral sclerosis.39
It is not yet clear whether these mutations are disease causing; however, an increasing number of neurological disorders have now been associated with mutations in the microtubule motor proteins, including the kinesins, resulting in neuropathy and hereditary spastic paraparesis.37
This strongly suggests that impairment of axonal transport alone might be sufficient to cause neuronal dysfunction and death. However, we found striking accumulations of the dynactin–dynein complex in the hypoglossal motor neuron cell bodies and neurites. Accumulations in the cell bodies could be because of inefficient export (anterograde transport) of the complex from the perikaryon or enhanced, mis-regulated retrograde transport. The accumulated dynein and dynactin is reminiscent of the inclusions of misfolded proteins seen in other neurodegenerative disorders.40
Neurofilament was not present in the inclusions; it remains to be determined whether other proteins are sequestered. Neuronal inclusions may contain aggregates of misfolded protein that are inefficiently cleared by the ubiquitin–proteasome system. It has been debated whether inclusions are directly toxic to neurons or form as a protective response of the cell to manage accumulating, misfolded protein. Further investigations are needed to determine whether motor neuron degeneration caused by dynactin mutation occurs primarily because of a loss of function of the normal protein or a toxic gain of function, or both.
In conclusion, the distal spinal and bulbar muscular atrophy with vocal fold paralysis described in this report is a late-onset, slowly progressive syndrome that is quite distinct from other motor neuron disorders and sensorimotor neuropathies that have vocal fold involvement. Neuropathologically, there are inclusions of the dynactin–dynein complex proteins within motor neurons, suggesting that this disorder is a proteinopathy that might have a common mechanism with other neurodegenerative diseases.