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Pathogenesis of huntington's disease
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Pathogenesis of Huntington's disease In their recent TINS article i, Beal, Hyman and Koroshetz proposed the hypothesis that an impairment of energy metabolism could underlie slow excitotoxic neuronal death. The association found between several diseases and defects in mitochondrial metabolism and changes found in other neurodegenerative disorders suggest a common cause. However, the authors were cautious, stating 'it is difficult to ascertain whether the observed changes play a role in the disease process or are merely secondary to neuronal loss and astrogliosis'. This caution is required because in Huntington's disease (HD) several studies point in another direction. First, the age of onset of HD is influenced by the sex of the affected parent. When the father is affected the offspring show an earlier onset of the disease than with an affected mother 2'3. Since the offspring receive only maternal mitochondria the opposite would be expected. Furthermore, in their extensive study concerning the decreased neuronal and increased oligodendroglial densities in the HD caudate nucleus, Myers et al. 4 concluded that neuronal toss did not represent a recent event. They propose that from an early stage in the development of the CNS, the caudate nucleus of the HD gene carrier might have less than the normal complement of neurons, and perhaps more than the normal complement of oligodendrocytes. These authors believe that the age of onset of HD is also consistent with a model which implicates dysfunction in the early development of the striatum in the pathogenesis of HD. Another study, using magnetic resonance images (MRIs), by Harris et al. ~ showed that the reduction of the putamen volume exceeded the changes in the caudate nucleus in mild HD. Their findings suggest either that the putamen is congenitally small in those inheriting the HD gene, or that putamen atrophy is evident by the time a clinical diagnosis can be made. TINS, Vol. 17, No. 3, 1994
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Kremer and Kremer ~ made computer models to simulate the effects of different 'gene characteristics' on the development of the lateral tuberal nucleus and its subsequent decay resulting from an undefined 'black boxed killer effect' of the HD gene. In their view, a reduction in neuronal anlage by a very early effect of the gene is the most 'economic' explanation of how a homogeneous allelic mutation still results in widely different gene expressions later in life. These three studies together with the work of Reis e t a / . 7 strongly support our own hypothesis of hyponeuronogenesis8,9. We suggest a genetic change at the level of the neuro-epithelium, which causes a change in the numerical differentiation into neuroblasts and spongioblasts resulting in a considerable reduction ab ova in the formation of (mature) neuronal elements. With the natural cell loss (biogenic necrosis), the threshold for normal and abnormal function in the areas involved is reached much earlier in life. Depending on the (reduced) number of neurons, the natural cell loss and threshold function at the age of onset of the disease might vary. If this is the case, the energetic defects observed by Beal eta/. 1 are almost certainly secondary to the neuronal loss and astrogliosis. w. J. A. van Wolferen Dept of FunctlonalAnatomy, Utrecht University, Postbus 80039, 3508 TA Utrecht, The Netherlands. J. L. J. M. Teepen St. E/isabethHospita/ THburg, The Nether~ands. G. W. Bruyn Dept of Neuro/ogy, State University Leiden, The Netherlands.
References 1 Beal, M. F., Hyman, B. T. and Koroshetz, H. (1993) Trends Neurosci. 16, 125-131 2 Merritt, A. D., Conneally, P. M., Rahman, N. F. and Drew, A. L. (1969) in Prog. Neurogenetics (Barbeau, A. and Brunette,J. R., eds),pp. 645-650, ExcerptaMedica 3 Newcombe, R. G., Walker, D. A. and Harper, P. S. (1981) Ann. Human Genet. 45, 387-396 4 Myers, R. H. et a/. (1991)J. Neuropathol. Exp. NeuroL 50, 729-742 5 Harris,G. J. etal. (1992)Ann. Neurol. 31, 69-75
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6 Kremer, H. P. H. and Kremer, G. H. M. J. (1992) Clin. Neuro/. Neurosurg. 94 (Suppl.), 7-8 7 Reis, D. J., Fink, J. S. and Baker, H. (1983) in Genetics of Neurological and Psychiatric Disorders, pp. 55-75, Raven Press 8 Bruyn, G. W. and van Wolferen, W. J. A. (1973) Lancet I, 1382 9 van Wolferen, W. J. A., Bruyn, G. W. and Teepen,J. L. J. M. (1974) Lanceti, 1112
Reply We thank van Wolferen, Teepen and Bruyn for their interest in our work. They raise a number of points regarding our hypothesis that an impairment of energy metabolism could underlie slow excitotoxic neuronal death in HD. The first is that inheritance of the gene from a father is associated with an earlier age of onset, whereas this would not be expected to be the case with a mitochondrial defect. This is true if a gene defect is encoded on mitochondrial DNA, however this cannot be the case in an auto° somal-dominant disease such as HD. Recent work has shown that the earlier age of onset in offspring of affected fathers is due to greater instability of the number of trinucleotide repeats with this mode of inheritance 1'2. There is an expansion of the number of repeats in some of the offspring of affected fathers. Children inheriting an expanded number of repeats have an earlier onset age. Wolferen and colleagues cite the work of Myers e t a / . 3 as indicating that neuronal loss in HD might occur at an early stage of development. This was raised as one possibility by these authors. However, they also considered that a model in which neuronal loss occurs slowly after early normal development cannot be ruled out (R. Myers, pers. commun.). The other papers cited do not distinguish between developmental neuronal loss and a delayed-onset slow neuronal degeneration. In support of the latter possibility are observations that MRI and positron emission tomography (PET) studies of glucose metabolism in asymptomatic gene carriers are often 107
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Pathogenesis of Huntington's disease In their recent TINS article i, Beal, Hyman and Koroshetz proposed the hypothesis that an impairment of energy metabolism could underlie slow excitotoxic neuronal death. The association found between several diseases and defects in mitochondrial metabolism and changes found in other neurodegenerative disorders suggest a common cause. However, the authors were cautious, stating 'it is difficult to ascertain whether the observed changes play a role in the disease process or are merely secondary to neuronal loss and astrogliosis'. This caution is required because in Huntington's disease (HD) several studies point in another direction. First, the age of onset of HD is influenced by the sex of the affected parent. When the father is affected the offspring show an earlier onset of the disease than with an affected mother 2'3. Since the offspring receive only maternal mitochondria the opposite would be expected. Furthermore, in their extensive study concerning the decreased neuronal and increased oligodendroglial densities in the HD caudate nucleus, Myers et al. 4 concluded that neuronal toss did not represent a recent event. They propose that from an early stage in the development of the CNS, the caudate nucleus of the HD gene carrier might have less than the normal complement of neurons, and perhaps more than the normal complement of oligodendrocytes. These authors believe that the age of onset of HD is also consistent with a model which implicates dysfunction in the early development of the striatum in the pathogenesis of HD. Another study, using magnetic resonance images (MRIs), by Harris et al. ~ showed that the reduction of the putamen volume exceeded the changes in the caudate nucleus in mild HD. Their findings suggest either that the putamen is congenitally small in those inheriting the HD gene, or that putamen atrophy is evident by the time a clinical diagnosis can be made. TINS, Vol. 17, No. 3, 1994
~ \ ~~!~!~:~~i~~~?~ ~i%!~iii~
,i~i~i~i~ii
Kremer and Kremer ~ made computer models to simulate the effects of different 'gene characteristics' on the development of the lateral tuberal nucleus and its subsequent decay resulting from an undefined 'black boxed killer effect' of the HD gene. In their view, a reduction in neuronal anlage by a very early effect of the gene is the most 'economic' explanation of how a homogeneous allelic mutation still results in widely different gene expressions later in life. These three studies together with the work of Reis e t a / . 7 strongly support our own hypothesis of hyponeuronogenesis8,9. We suggest a genetic change at the level of the neuro-epithelium, which causes a change in the numerical differentiation into neuroblasts and spongioblasts resulting in a considerable reduction ab ova in the formation of (mature) neuronal elements. With the natural cell loss (biogenic necrosis), the threshold for normal and abnormal function in the areas involved is reached much earlier in life. Depending on the (reduced) number of neurons, the natural cell loss and threshold function at the age of onset of the disease might vary. If this is the case, the energetic defects observed by Beal eta/. 1 are almost certainly secondary to the neuronal loss and astrogliosis. w. J. A. van Wolferen Dept of FunctlonalAnatomy, Utrecht University, Postbus 80039, 3508 TA Utrecht, The Netherlands. J. L. J. M. Teepen St. E/isabethHospita/ THburg, The Nether~ands. G. W. Bruyn Dept of Neuro/ogy, State University Leiden, The Netherlands.
References 1 Beal, M. F., Hyman, B. T. and Koroshetz, H. (1993) Trends Neurosci. 16, 125-131 2 Merritt, A. D., Conneally, P. M., Rahman, N. F. and Drew, A. L. (1969) in Prog. Neurogenetics (Barbeau, A. and Brunette,J. R., eds),pp. 645-650, ExcerptaMedica 3 Newcombe, R. G., Walker, D. A. and Harper, P. S. (1981) Ann. Human Genet. 45, 387-396 4 Myers, R. H. et a/. (1991)J. Neuropathol. Exp. NeuroL 50, 729-742 5 Harris,G. J. etal. (1992)Ann. Neurol. 31, 69-75
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6 Kremer, H. P. H. and Kremer, G. H. M. J. (1992) Clin. Neuro/. Neurosurg. 94 (Suppl.), 7-8 7 Reis, D. J., Fink, J. S. and Baker, H. (1983) in Genetics of Neurological and Psychiatric Disorders, pp. 55-75, Raven Press 8 Bruyn, G. W. and van Wolferen, W. J. A. (1973) Lancet I, 1382 9 van Wolferen, W. J. A., Bruyn, G. W. and Teepen,J. L. J. M. (1974) Lanceti, 1112
Reply We thank van Wolferen, Teepen and Bruyn for their interest in our work. They raise a number of points regarding our hypothesis that an impairment of energy metabolism could underlie slow excitotoxic neuronal death in HD. The first is that inheritance of the gene from a father is associated with an earlier age of onset, whereas this would not be expected to be the case with a mitochondrial defect. This is true if a gene defect is encoded on mitochondrial DNA, however this cannot be the case in an auto° somal-dominant disease such as HD. Recent work has shown that the earlier age of onset in offspring of affected fathers is due to greater instability of the number of trinucleotide repeats with this mode of inheritance 1'2. There is an expansion of the number of repeats in some of the offspring of affected fathers. Children inheriting an expanded number of repeats have an earlier onset age. Wolferen and colleagues cite the work of Myers e t a / . 3 as indicating that neuronal loss in HD might occur at an early stage of development. This was raised as one possibility by these authors. However, they also considered that a model in which neuronal loss occurs slowly after early normal development cannot be ruled out (R. Myers, pers. commun.). The other papers cited do not distinguish between developmental neuronal loss and a delayed-onset slow neuronal degeneration. In support of the latter possibility are observations that MRI and positron emission tomography (PET) studies of glucose metabolism in asymptomatic gene carriers are often 107