CAG repeat size correlates to electrophysiological motor and sensory phenotypes in SBMA.
Spinal and bulbar muscular atrophy (SBMA) is an adult-onset, lower motor neuron disease caused by an aberrant elongation of a CAG repeat in the androgen receptor (AR) gene. The main symptoms are weakness and atrophy of bulbar, facial and limb muscles, but sensory disturbances are frequently found in SBMA patients. Motor symptoms have been attributed to the accumulation of mutant AR in the nucleus of lower motor neurons, which is more profound in patients with a longer CAG repeat. We examined nerve conduction properties including F-waves in a total of 106 patients with genetically confirmed SBMA (mean age at data collection = 53.8 years; range = 31-75 years) and 85 control subjects. Motor conduction velocities (MCV), compound muscle action potentials (CMAP), sensory conduction velocities (SCV) and sensory nerve action potentials (SNAP) were significantly decreased in all nerves examined in the SBMA patients compared with that in the normal controls, indicating that axonal degeneration is the primary process in both motor and sensory nerves. More profound abnormalities were observed in the nerves of the upper limbs than in those of the lower limbs. F-waves in the median nerve were absent in 30 of 106 cases (28.3%), but no cases of absent F-waves were observed in the tibial nerve. From an analysis of the relationship between CMAPs and SNAPs, patients were identified with different electrophysiological phenotypes: motor-dominant, sensory-dominant and non-dominant phenotypes. The CAG repeat size and the age at onset were significantly different among the patients with motor- and sensory-dominant phenotypes, indicating that a longer CAG repeat is more closely linked to the motor-dominant phenotype and a shorter CAG repeat is more closely linked to the sensory-dominant phenotype. Furthermore, when we classified the patients by CAG repeat size, CMAP values showed a tendency to be decreased in patients with a longer CAG repeat (> or =47), while SNAPs were significantly decreased in patients with a shorter CAG repeat (<47). In addition, we found that the frequency of aggregation in the sensory neuron cytoplasm tended to inversely correlate with the CAG repeat size in the autopsy study, supporting the view that the CAG repeat size differentially correlates with motor- and sensory-dominant phenotypes. In conclusion, our results suggest that there are unequivocal electrophysiological phenotypes influenced by CAG repeat size in SBMA.
Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Keisuke
K
Suzuki
Masahisa
M
Katsuno
Haruhiko
H
Banno
Yu
Y
Takeuchi
Naoki
N
Atsuta
Mizuki
M
Ito
Hirohisa
H
Watanabe
Fumitada
F
Yamashita
Norio
N
Hori
Tomohiko
T
Nakamura
Masaaki
M
Hirayama
Fumiaki
F
Tanaka
Gen
G
Sobue
D000200:Action Potentials / Q000235:genetics; D000328:Adult; D017668:Age of Onset; D000368:Aged; D016022:Case-Control Studies; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D004594:Electrophysiology; D005727:Ganglia, Spinal / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D009046:Motor Neurons / Q000502:physiology*; D009134:Muscular Atrophy, Spinal / Q000235:genetics* / Q000503:physiopathology; D009431:Neural Conduction / Q000235:genetics; D009475:Neurons, Afferent / Q000502:physiology*; D010641:Phenotype; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism; D013126:Spinal Nerve Roots; D018911:Trinucleotide Repeats
D011944:Receptors, Androgen