- Email: [email protected]
Are motor and sensory responses and MUNE values inherited traits?
Motor Unit Number Estimation (Supplements to Clinical Neurophysiology Vol. 55) Editor: M.B. Bromberg ß 2003 Published by Elsevier Science B.V.
155
Chapter 16
Are motor and sensory responses and MUNE values inherited traits? Catherine Lomen-Hoerth* and Richard K. Olney Department of Neurology, University of California, San Francisco, San Francisco, CA 94114, USA
Introduction
Methods
Although 90±95% of amyotrophic lateral sclerosis (ALS) cases are sporadic without known etiology and distal symmetric polyneuropathy is commonly idiopathic, hereditary single-gene forms of both diseases are well described (Schenone and Mancardi, 1999; Orrell and Figlewicz, 2001) One hypothesis of the etiology of these diseases is that they are complex genetic diseases in which multiple genes contribute to disease susceptibility. Demonstrating that sensory and motor responses and MUNE are heritable traits would support this hypothesis. A standard method to determine heritability is to compare monozygotic with dizygotic twins. Greater similarity in the trait in monozygotic twins compared with dizygotic twins supports heritability (Piccini et al., 1999; Tanner et al., 2001).
Subjects
*Correspondence to: Dr. Catherine Lomen-Hoerth, Department of Neurology, University of California, San Francisco, 505 Parnassus Ave., M348, San Francisco, CA 94114, USA. Tel.: (415) 514-0490, Fax: (415) 514-0491. e-mail: [email protected] doi:10.1016/S1567-424X(03)00016-3
Twenty-six healthy twin pairs gave informed consent and were enrolled in the study based on their response to a letter sent to all members of the Northern California Twin Registry. We obtained prior approval by our Institutional Review Board. The ages of the twins ranged from 20 to 75. All subjects underwent a neuromuscular history and examination prior to starting testing. One set of twins was excluded due to one twin having diabetes with peripheral nerve involvement, and another set of twins was excluded due to one of the twins having AIDS with peripheral nerve involvement. The remaining 24 twins (7 dizygotic and 17 monozygotic) were analyzed in the study. Two dizygotic twin pairs and one monozygotic twin pair were unable to tolerate the MUNE portion of the study and the studies were terminated prematurely. Electrophysiological techniques Bilateral antidromic ulnar and sural sensory nerve conduction studies were performed. Bilateral ulnar and peroneal motor nerve conduction studies were performed with surface stimulation
156
and recording from the hypothenar muscle group and extensor digitorum brevis muscle, respectively. F-wave responses were determined from the peroneal nerve in a standard fashion. The results were averaged for each nerve studied. Motor unit number estimation (MUNE) of the left hypothenar muscle was determined using the weighted statistical method (Shefner et al., 1999). Mean surface recorded motor unit action potential (SMUP) amplitude was measured at several stimulus levels, typically spanning 40% or more of the compound muscle action potential (CMAP) amplitude range. MUNE was calculated by dividing the maximum CMAP amplitude by the weighted mean SMUP amplitude (Lomen-Hoerth and Olney, 2000). Quantitative sensory testing was performed on CASE IV with 4-2-1 algorithm for vibration the cooling detection threshold on bilateral feet and the results were averaged (Dyck et al., 1993). Statistical analysis T-tests was used to compare the coecients of variation between pairs of monozygotic versus dizygotic twins for all electrophysiological tests. A result was considered signi®cant for P<0.05.
Results Sensory nerve action potentials Ulnar sensory nerve action potentials (SNAPs) ranged in amplitude from 10 to 76 mV, conduction velocities (CV) ranged from 36 to 54, and distal latencies (DL) ranged from 2.3 to 2.95. Sural SNAP amplitudes ranged from 0 to 43 mV, CV ranged from 36 to 54, and DL ranged from 2.7 to 3.5. The coecient of variation for dizygotic versus monozygotic was 95 versus 88% (P<0.08) for ulnar SNAP amplitude, 29 versus 4.5% (P<0.05), for ulnar CV, and 7 versus 4% (P<0.15) for DL. The coecient of variation for dizygotic versus monozygotic was 31 versus 19% (P<0.37) for the sural SNAP amplitude, 8 versus 3.5% (P<0.04) for sural CV, and 68 versus 35% (P<0.06) for DL. Thus, for sensory responses, ulnar and sural sensory nerve CV and ulnar SNAP amplitude were the only variables identi®ed as statistically signi®cantly dierent between monozygotic and dizygotic twins.
Compound muscle action potentials Ulnar CMAPs ranged in amplitude from 6 to 14 mV, CV ranged from 44 to 71, and distal motor latencies (DML) ranged from 2.7 to 3.8. Peroneal CMAP amplitudes ranged from 3.5 to 5.9 mV, CV ranged from 41 to 60, and DML ranged from 3.5 to 5.9. The coecient of variation for dizygotic versus monozygotic was 10 versus 9% (P<0.9) for ulnar CMAP amplitude, 6 versus 3.6% (P<0.16) for ulnar CV, and 3 versus 6% for ulnar DML (P<0.13). The coecient of variation for dizygotic versus monozygotic was 40 versus 15% (P<0.01) for peroneal CMAP amplitude, 8 versus 3.7% (P<0.01) for peroneal CV, and 11 versus 5.9% (P<0.11) for peroneal DML. Thus for motor responses, peroneal CMAP amplitude and CV were the only statistically signi®cant dierences between monozygotic and dizygotic twins. Ulnar CV was likely not statistically signi®cant due to the decreased variability of the response compared with peroneal CV. F-waves Peroneal F-waves performed in a subset of twins (4 dizygotic and 13 monozygotic) ranged in minimum latencies from 40 to 52. The peroneal F-waves had a coecient of variation of 5.3 versus 3.5% (P<0.2) for dizygotic versus monozygotic twins. Motor unit number estimates Hypothenar motor unit number estimates ranged from 46 to 65. The coecient of variation for dizygotic versus monozygotic twins was 6.3 versus 3.3% (P<0.06), just missing statistically signi®cance, however only 5 of the 7 dizygotic twins and 16 of the 17 monozygotic twins underwent MUNE studies, making the numbers smaller than for the nerve conduction studies. Figure 1 plots the dierences in MUNE between monozygotic and dizygotic twins. While the dizygotic numbers are small, the 16 monozygotic twins are tightly clustered together with minimal MUNE dierences. Quantitative sensory testing The detection thresholds for quantitative sensory testing ranged from 6 to 12 JND for cooling and 11±21 JND for vibration. The coecient of
157
Fig. 1. Plots of the differences in MUNE between dizygotic and monozygotic twins.
variation for dizygotic versus monozygotic twins was 11 versus 9% (P<0.69) for vibration and 16 versus 16% (P<0.99) for cooling.
Discussion Because MUNE values and motor and sensory nerve CV have at least twice the variation in dizygotic twins compared to monozygotic twins, the results of this study support the notion that the number of sensory and motor axons in normal subjects is an inherited trait. Amplitude and distal latency dierences were not statistically signi®cantly dierent between the two groups, except for ulnar sensory and peroneal motor amplitudes, but trends were noted that could be statistically signi®cant with a larger sample size. Other confounding factors could be weight and sex between the two groups. When twins were of the same sex, weights tended to be very similar between twins for both mono and dizygotic twins. Two of the dizygotic twins were male±female pairs, and when they were removed from the analysis, the trends remained but the statistical signi®cance decreased, in part due to the small sample size of the dizygotic group. With increased numbers of subjects, we will be able to take into account these variables in our comparison and restrict ourselves to same sex twin comparisons. Interestingly, quantitative sensory testing did not reveal dierences between dizygotic
and monozygotic twins suggesting that this test may be in¯uenced more by environment than genetics. The dierences are greater in the lower limbs than the upper limbs, where greater eects of aging are identi®ed with nerve conduction studies. Perhaps there are genetic dierences between the rate at which nerve responses and MUNE values decline with aging. These results support the potential heritability of normal motor and sensory responses and motor unit number estimates, supporting the hypothesis that idiopathic neurodegenerative disease may have a complex genetic basis.
Acknowledgements This work was supported by a grant from the American Academy of Neurology.
References Dyck, P.J., O'Brien, P.C., Kosanke, J.L., Gillen, D.A. and Karnes, J.L. A 4,2, and 1 stepping algorithm for quick and accurate estimation of cutaneous sensation threshold. Neurology, 1993, 43: 1508±1512. Lomen-Hoerth, C. and Olney, R.K. Comparison of multiple point and statistical motor unit number estimation. Muscle Nerve, 2000, 23(10): 1525±1533. Orrell, R.W. and Figlewicz, D.A. Clinical implications of the genetics of ALS and other motor neuron diseases. Neurology, 2001, 57: 9±17. Piccini, P., Burn, D.J., Ceravolo, R., Maraganore, D. and Brooks, D.J. The role of inheritance in sporadic Parkinson's disease: evidence from a longitudinal study of dopaminergic function in twins. Ann. Neurol., 1999, 45: 577±582. Schenone, A. and Mancardi, G.L. Molecular basis of inherited neuropathies. Curr. Opin. Neurol., 1999, 12: 603±616. Shefner, J.M., Jillapalli, D. and Bradshaw, D.Y. Reducing intersubject variability in motor unit number estimation. Muscle Nerve, 1999, 22(10): 1457±1460. Tanner, C.M., Goldman, S.M., Lyons, K.E., Aston, D.A., Tetrud, J.W., Welsh, M.D., Langston, J.W. and Koller, W.C. Essential tremor in twins: an assessment of genetic vs environmental determinants of etiology. Neurology, 2001, 57: 1389±1391.
155
Chapter 16
Are motor and sensory responses and MUNE values inherited traits? Catherine Lomen-Hoerth* and Richard K. Olney Department of Neurology, University of California, San Francisco, San Francisco, CA 94114, USA
Introduction
Methods
Although 90±95% of amyotrophic lateral sclerosis (ALS) cases are sporadic without known etiology and distal symmetric polyneuropathy is commonly idiopathic, hereditary single-gene forms of both diseases are well described (Schenone and Mancardi, 1999; Orrell and Figlewicz, 2001) One hypothesis of the etiology of these diseases is that they are complex genetic diseases in which multiple genes contribute to disease susceptibility. Demonstrating that sensory and motor responses and MUNE are heritable traits would support this hypothesis. A standard method to determine heritability is to compare monozygotic with dizygotic twins. Greater similarity in the trait in monozygotic twins compared with dizygotic twins supports heritability (Piccini et al., 1999; Tanner et al., 2001).
Subjects
*Correspondence to: Dr. Catherine Lomen-Hoerth, Department of Neurology, University of California, San Francisco, 505 Parnassus Ave., M348, San Francisco, CA 94114, USA. Tel.: (415) 514-0490, Fax: (415) 514-0491. e-mail: [email protected] doi:10.1016/S1567-424X(03)00016-3
Twenty-six healthy twin pairs gave informed consent and were enrolled in the study based on their response to a letter sent to all members of the Northern California Twin Registry. We obtained prior approval by our Institutional Review Board. The ages of the twins ranged from 20 to 75. All subjects underwent a neuromuscular history and examination prior to starting testing. One set of twins was excluded due to one twin having diabetes with peripheral nerve involvement, and another set of twins was excluded due to one of the twins having AIDS with peripheral nerve involvement. The remaining 24 twins (7 dizygotic and 17 monozygotic) were analyzed in the study. Two dizygotic twin pairs and one monozygotic twin pair were unable to tolerate the MUNE portion of the study and the studies were terminated prematurely. Electrophysiological techniques Bilateral antidromic ulnar and sural sensory nerve conduction studies were performed. Bilateral ulnar and peroneal motor nerve conduction studies were performed with surface stimulation
156
and recording from the hypothenar muscle group and extensor digitorum brevis muscle, respectively. F-wave responses were determined from the peroneal nerve in a standard fashion. The results were averaged for each nerve studied. Motor unit number estimation (MUNE) of the left hypothenar muscle was determined using the weighted statistical method (Shefner et al., 1999). Mean surface recorded motor unit action potential (SMUP) amplitude was measured at several stimulus levels, typically spanning 40% or more of the compound muscle action potential (CMAP) amplitude range. MUNE was calculated by dividing the maximum CMAP amplitude by the weighted mean SMUP amplitude (Lomen-Hoerth and Olney, 2000). Quantitative sensory testing was performed on CASE IV with 4-2-1 algorithm for vibration the cooling detection threshold on bilateral feet and the results were averaged (Dyck et al., 1993). Statistical analysis T-tests was used to compare the coecients of variation between pairs of monozygotic versus dizygotic twins for all electrophysiological tests. A result was considered signi®cant for P<0.05.
Results Sensory nerve action potentials Ulnar sensory nerve action potentials (SNAPs) ranged in amplitude from 10 to 76 mV, conduction velocities (CV) ranged from 36 to 54, and distal latencies (DL) ranged from 2.3 to 2.95. Sural SNAP amplitudes ranged from 0 to 43 mV, CV ranged from 36 to 54, and DL ranged from 2.7 to 3.5. The coecient of variation for dizygotic versus monozygotic was 95 versus 88% (P<0.08) for ulnar SNAP amplitude, 29 versus 4.5% (P<0.05), for ulnar CV, and 7 versus 4% (P<0.15) for DL. The coecient of variation for dizygotic versus monozygotic was 31 versus 19% (P<0.37) for the sural SNAP amplitude, 8 versus 3.5% (P<0.04) for sural CV, and 68 versus 35% (P<0.06) for DL. Thus, for sensory responses, ulnar and sural sensory nerve CV and ulnar SNAP amplitude were the only variables identi®ed as statistically signi®cantly dierent between monozygotic and dizygotic twins.
Compound muscle action potentials Ulnar CMAPs ranged in amplitude from 6 to 14 mV, CV ranged from 44 to 71, and distal motor latencies (DML) ranged from 2.7 to 3.8. Peroneal CMAP amplitudes ranged from 3.5 to 5.9 mV, CV ranged from 41 to 60, and DML ranged from 3.5 to 5.9. The coecient of variation for dizygotic versus monozygotic was 10 versus 9% (P<0.9) for ulnar CMAP amplitude, 6 versus 3.6% (P<0.16) for ulnar CV, and 3 versus 6% for ulnar DML (P<0.13). The coecient of variation for dizygotic versus monozygotic was 40 versus 15% (P<0.01) for peroneal CMAP amplitude, 8 versus 3.7% (P<0.01) for peroneal CV, and 11 versus 5.9% (P<0.11) for peroneal DML. Thus for motor responses, peroneal CMAP amplitude and CV were the only statistically signi®cant dierences between monozygotic and dizygotic twins. Ulnar CV was likely not statistically signi®cant due to the decreased variability of the response compared with peroneal CV. F-waves Peroneal F-waves performed in a subset of twins (4 dizygotic and 13 monozygotic) ranged in minimum latencies from 40 to 52. The peroneal F-waves had a coecient of variation of 5.3 versus 3.5% (P<0.2) for dizygotic versus monozygotic twins. Motor unit number estimates Hypothenar motor unit number estimates ranged from 46 to 65. The coecient of variation for dizygotic versus monozygotic twins was 6.3 versus 3.3% (P<0.06), just missing statistically signi®cance, however only 5 of the 7 dizygotic twins and 16 of the 17 monozygotic twins underwent MUNE studies, making the numbers smaller than for the nerve conduction studies. Figure 1 plots the dierences in MUNE between monozygotic and dizygotic twins. While the dizygotic numbers are small, the 16 monozygotic twins are tightly clustered together with minimal MUNE dierences. Quantitative sensory testing The detection thresholds for quantitative sensory testing ranged from 6 to 12 JND for cooling and 11±21 JND for vibration. The coecient of
157
Fig. 1. Plots of the differences in MUNE between dizygotic and monozygotic twins.
variation for dizygotic versus monozygotic twins was 11 versus 9% (P<0.69) for vibration and 16 versus 16% (P<0.99) for cooling.
Discussion Because MUNE values and motor and sensory nerve CV have at least twice the variation in dizygotic twins compared to monozygotic twins, the results of this study support the notion that the number of sensory and motor axons in normal subjects is an inherited trait. Amplitude and distal latency dierences were not statistically signi®cantly dierent between the two groups, except for ulnar sensory and peroneal motor amplitudes, but trends were noted that could be statistically signi®cant with a larger sample size. Other confounding factors could be weight and sex between the two groups. When twins were of the same sex, weights tended to be very similar between twins for both mono and dizygotic twins. Two of the dizygotic twins were male±female pairs, and when they were removed from the analysis, the trends remained but the statistical signi®cance decreased, in part due to the small sample size of the dizygotic group. With increased numbers of subjects, we will be able to take into account these variables in our comparison and restrict ourselves to same sex twin comparisons. Interestingly, quantitative sensory testing did not reveal dierences between dizygotic
and monozygotic twins suggesting that this test may be in¯uenced more by environment than genetics. The dierences are greater in the lower limbs than the upper limbs, where greater eects of aging are identi®ed with nerve conduction studies. Perhaps there are genetic dierences between the rate at which nerve responses and MUNE values decline with aging. These results support the potential heritability of normal motor and sensory responses and motor unit number estimates, supporting the hypothesis that idiopathic neurodegenerative disease may have a complex genetic basis.
Acknowledgements This work was supported by a grant from the American Academy of Neurology.
References Dyck, P.J., O'Brien, P.C., Kosanke, J.L., Gillen, D.A. and Karnes, J.L. A 4,2, and 1 stepping algorithm for quick and accurate estimation of cutaneous sensation threshold. Neurology, 1993, 43: 1508±1512. Lomen-Hoerth, C. and Olney, R.K. Comparison of multiple point and statistical motor unit number estimation. Muscle Nerve, 2000, 23(10): 1525±1533. Orrell, R.W. and Figlewicz, D.A. Clinical implications of the genetics of ALS and other motor neuron diseases. Neurology, 2001, 57: 9±17. Piccini, P., Burn, D.J., Ceravolo, R., Maraganore, D. and Brooks, D.J. The role of inheritance in sporadic Parkinson's disease: evidence from a longitudinal study of dopaminergic function in twins. Ann. Neurol., 1999, 45: 577±582. Schenone, A. and Mancardi, G.L. Molecular basis of inherited neuropathies. Curr. Opin. Neurol., 1999, 12: 603±616. Shefner, J.M., Jillapalli, D. and Bradshaw, D.Y. Reducing intersubject variability in motor unit number estimation. Muscle Nerve, 1999, 22(10): 1457±1460. Tanner, C.M., Goldman, S.M., Lyons, K.E., Aston, D.A., Tetrud, J.W., Welsh, M.D., Langston, J.W. and Koller, W.C. Essential tremor in twins: an assessment of genetic vs environmental determinants of etiology. Neurology, 2001, 57: 1389±1391.