Summary
The clinical and morphological features were studied in female heterozygotes of the sex-linked brindled mutant mice, which are an appropriate animal model for human Menkes' kinky hair disease (MKHD). Clinically, female heterozygotes presented phenotypical variety. In these heterozygotes, we distinguished the unique group of mice, which showed mottled white and dark brown fur and curly whiskers. We designated this unique group “heterozygote, variant type”, in contrast to the remaining group — “heterozygote, usual type” —, of which the fur was mottled dark and light brown, and the whiskers were straight. Ultrastructurally, various degrees of mitochondrial changes, from an almost normal appearance of the mitochondria to similar to those of the hemizygotes, were observed. Furthermore we noticed that, in the heterozygotes, there were positive correlations between this morphological spectrum and those phenotypical varieties. These findings were interpreted as a possible subclinical copper deficiency in the heterozygotes, and the morphological alterations in heterozygotes were probably due to X-chromosome inactivation according to Lyon's hypothesis. The presence, however, of clinical and morphological varieties in the heterozygotes leads us to the hypothesis that the inactivation rate is not necessarily the same for all carriers. Moreover, it can be speculated that pathologic changes similar to those in heterozygotes may be present in the female carriers of human MKHD.
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Akima M, Nonaka H, Senzui M, Kitazawa Y, Ichimori S, Aoki T, Kanekawa H (1978) Two autopsy cases of menkes' kinky hair disease. Adv Neurol Sci (Tokyo) 22:427–439
Camakaris J, Danks DM, Ackland L, Cartwright E, Borger P, Cotton RGH (1980) Altered copper metabolism in cultured cells from human Menkes' syndrome and mottled mouse mutant. Biochem Genet 18:117–131
Camakaris J, Danks DM (1981) A mild form of Menkes' steelhair syndrome. J Pediatr 98:97–99
Danks DM, Stevens BJ, Campbell PE, Gillespie JM, Walker-Smith J, Blomfield J, Turner B (1972a) Menkes' kinky-hair syndrome. Lancet II:1100–1102
Danks DM, Campbell PE, Stevens BJ, Mayne V, Cartwright E (1972b) Menkes' kinky hair syndrome. An inherited defect in copper absorption with widespread effect. Pediatrics 50:188–201
Danks DM, Stevens BJ, Townley RRW (1973) Menkes' kinky hair disease: further definition of the defect in copper transport. Science 179:1140–1142
Danks DM (1975) Steel hair, mottled mice and copper metabolism. N Engl J Med 293:1147–1149
Danks DM (1977) Copper transport and utilization in Menkes' syndrome and mottled mouse. Inorg Perspect Biol Med 1:73–100
Dubowitz V (1980) Clinics in developmental medicine. No 76. The floppy infant, 2nd edn. Heinemann, London
Evans GW, Reis BL (1978) Impaired copper homeostasis in neonatal male and adult female brindled (Mobr) mice. J Nutr 108:554–560
Fraser AS, Sobey S, Spicer CC (1953) Mottled, a sex-modified lethal in the house mouse. J Genet 51:217–221
French JH, Moore CL, Ghatak NR, Sternlieb I, Goldfischer, S, Hirano A (1973) Trichopoliodystrophy (Menkes' kinky hair syndrome). Pediatr Res 7:386
Chatak NR, Hirano A, Poon TP, French JH (1972) Trichopoliodystrophy. II. Pathological changes in skeletal muscle and nervous system. Arch Neurol 26:60–72
Holtzman NA (1976) Menkes' kinky hair syndrome: a genetic disease involving copper. Fed Proc 35:2276–2279
Hunt DM (1974) Primary defect in copper transport underlies mottled mutants in the mouse. Nature 249:852–854
Hunt DM (1976) A study of copper treatment and tissue copper levels in the murine congenital copper deficiency, mottled. Life Sci 19:1913–1920
Iwakawa Y, Niwa T, Tomita M, Matsubara O, Hashimoto K (1979) Menkes' kinky hair syndrome; Report on an autopsy case and his female sibling with similar clinical manifestations. Brain Dev 11:260–266
Lyon MF (1961) Gene action in the X-chromosome of the mouse (Mus musculus) Nature 22:372–373
Matsubara O, Takaoka S, Nasu M, Okeda R, Iwakawa Y (1978) A case report of Menkes' kinky hair disease, with a special reference to neuropathological changes and the previous necropsy reports. Adv Neurol Sci (Tokyo) 22:416–426
Menkes JH, Alter M, Sreigleder GK, Weakley DR, Sung JH (1962) A sex-linked recessive disorder with retardation of growth, peculiar hair, and focal cerebral and cerebellar degeneration. Pediatrics 29:764–779
Nagara H, Yajima K, Suzuki K (1981) An ultrastructural study on the cerebellum of the brindled mouse. Acta Neuropathol (Berl) 52:41–50
Nagara H, Yajima K, Suzuki K (1981) The effect of copper supplementation on the brindled mouse: A clinico-pathological study. J Neuropathol Exp Neurol 40:428–446
Osaka K, Sato N, Matsumoto S, Ogino H, Kodama S, Yokoyama S, Sugiyama T (1977) Congenital hypocupraemia syndrome with and without steel hair: Report of two Japanese infants. Dev Med Child Neurol 19:62–68
Port AE, Hunt DM (1979) A study of the copper-binding proteins in liver and kidney tissue of neonatal and mottled brindled mice. Biochem J 183:721–730
Prohaska JR, Wells WW (1975) Copper deficiency in the developing rat brain. Evidence for abnormal mitochondria. J Neurochem 25:221–228
Rezek DL, Moore CL (1977) Depletion of cytochrome oxidase in brain mitochondria from the mottled mouse mutant. Soc Neurosci [Abstr] 3:51
Sayed AK, Edwards JA, Bannerman RM (1981) Copper metabolism of cultured fibroblasts from the brindled mouse. Proc Soc Exp Biol Med 166:153–156
Suzuki K, Nagara H (1981) Brindled mottled mouse: Morphological changes of brain and visceral organs in hemizygouse males following copper supplementation. Acta Neuropathol (Berl) 55:251–255
Volpintesta EJ (1974) Menkes' kinky hair syndrome in a black infant. Am J Chil 128:244–246
Vuia O, Heye D (1974) Neuropathologic aspects in Menkes' kinky hair disease (Trichopoliodystrophy). Neuropädiatrie 5:329–339
Willemse J, Vanden Hamer CJA, Prins H, Jonker P (1982) Menkes' kinky hair disease. I. Comparison of classical and unusual clinical and biochemical features in two patients. Brain Dev 4:105–114
Williams RS, Marshall PC, Lott IT, Caviness VS (1978) The cellular pathology of Menkes' steel hair syndrome. Neurology 28:575–583
Yajima K, Suzuki K (1979a) Neuronal degeneration in the brain of the brindled mouse, a light microscope study. J Neuropathol Exp Neurol 38:35–46
Yajima K, Suzuki K (1979b) Neuronal degeneration in the brain of the brindled mouse. An ultrastructural study of the cerebral cortical neurons. Acta Neuropathol (Berl) 45:17–25
Yajima K, Suzuki K (1979c) Neuronal degeneration in the brain of the brindled mouse. I. Chronological studies on the longsurviving group. Acta Neuropathol (Berl) 48:127–132
Yoshimura N, Kudo H (1983) Mitochondrial abnormalities in Menkes' kinky hair disease (MKHD). Acta Neuropathol (Berl) 59:295–303
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Matsushima, H., Okuno, A., Eto, Y. et al. Neuropathologic study in the heterozygotes of X-linked brindled mutant mouse. Acta Neuropathol 67, 300–308 (1985). https://doi.org/10.1007/BF00687816
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DOI: https://doi.org/10.1007/BF00687816