Distal spinal and bulbar muscular atrophy caused by dynactin mutation.
Impaired axonal transport has been postulated to play a role in the pathophysiology of multiple neurodegenerative disorders. In this report, we describe the results of clinical and neuropathological studies in a family with an inherited form of motor neuron disease caused by mutation in the p150Glued subunit of dynactin, a microtubule motor protein essential for retrograde axonal transport. Affected family members had a distinct clinical phenotype characterized by early bilateral vocal fold paralysis affecting the adductor and abductor laryngeal muscles. They later experienced weakness and atrophy in the face, hands, and distal legs. The extremity involvement was greater in the hands than in the legs, and it had a particular predilection for the thenar muscles. No clinical or electrophysiological sensory abnormality existed; however, skin biopsy results showed morphological abnormalities of epidermal nerve fibers. An autopsy study of one patient showed motor neuron degeneration and axonal loss in the ventral horn of the spinal cord and hypoglossal nucleus of the medulla. Immunohistochemistry showed abnormal inclusions of dynactin and dynein in motor neurons. This mutation of dynactin, a ubiquitously expressed protein, causes a unique pattern of motor neuron degeneration that is associated with the accumulation of dynein and dynactin in neuronal inclusions.
Puls
Imke
I
Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892-1416, USA.
Oh
Shin J
SJ
Sumner
Charlotte J
CJ
Wallace
Karen E
KE
Floeter
Mary Kay
MK
Mann
Eric A
EA
Kennedy
William R
WR
Wendelschafer-Crabb
Gwen
G
Vortmeyer
Alexander
A
Powers
Richard
R
Finnegan
Kimberly
K
Holzbaur
Erika L F
EL
Fischbeck
Kenneth H
KH
Ludlow
Christy L
CL
D000200:Action Potentials / Q000502:physiology; D000328:Adult; D001921:Brain / Q000473:pathology; D000072159:Dynactin Complex; D004576:Electromyography; D004594:Electrophysiology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007818:Laryngeal Diseases / Q000209:etiology / Q000473:pathology; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D008875:Middle Aged; D020966:Muscular Disorders, Atrophic / Q000235:genetics* / Q000473:pathology; D020125:Mutation, Missense / Q000502:physiology*; D009410:Nerve Degeneration / Q000473:pathology; D009412:Nerve Fibers / Q000473:pathology; D009431:Neural Conduction / Q000502:physiology; D010375:Pedigree; D010525:Peripheral Nerves / Q000503:physiopathology; D012867:Skin / Q000294:innervation / Q000473:pathology; D013116:Spinal Cord / Q000473:pathology; D014826:Vocal Cord Paralysis / Q000209:etiology / Q000473:pathology; D014827:Vocal Cords / Q000473:pathology
D000072159:Dynactin Complex; D008869:Microtubule-Associated Proteins