Acta Neuropathologica

, Volume 76, Issue 2, pp 142–158

Neuropathology of Rett syndrome

  • K. Jellinger
  • D. Armstrong
  • H. Y. Zoghbi
  • A. K. Percy
Regular Papers


Rett syndrome is an increasingly recognized progressive disorder in females, commencing in infancy and characterized by autistic behavior, gait ataxia, stereotyped movements, seizures and generalized growth and mental retardation, possibly associated with disorders of central biogenic amine synthesis. The gene locus and pathogenesis of Rett syndrome are unknown. Autopsy studies in nine girls dying between 4 and 17 years, and sural nerve and muscle biopsies from two girls aged 3 and 17 years showed: (1) diffuse cortical atrophy/micrencephaly, with a decrease in brain weight by 12% to 34% of age-matched controls, apparently related to the duration of the disorder; (2) mild diffuse cortical atrophy with increased amounts of neuronal lipofuscin and occasional mild gliosis, but without signs of a storage disorder; (3) underpigmentation of the zona compacta nigrae, which showed fewer well-pigmented neurons for age and fewer melanin granules per neuron, while total numbers of nigral neurons and the substructure of neuromelanin were normal for age. No pathological changes were seen in other transmitter-specific brain stem nuclei; (4) immunoreactivity for tyrosine hydroxylase was slightly reduced in nigral and hypothalamic neurons, and the pituitary gland showed decreased immunoreaction for prolactin and growth hormone; (5) ultrastructurally, in frontal cortex and caudate nucleus, isolated abnormal neurites and reactive or degenerative axonal swellings were seen; the latter are possibly related to the nigral changes, suggesting some dysfunction of the dopaminergic nigrostriatal system, which is supported by neurochemical data; (6) preliminary biochemical studies revealed increased β-endorphines in thalamus and cerebellum; (7) peripheral nerves demonstrated increase in small fibers without demyelination and increased numbers of neurofilaments in axons, suggesting distal axonopathy, while skeletal muscle showed alterations in the sarcoplasmic reticulum with circular profiles in the Z-filaments. These nonspecific changes may be interpreted as early signs of denervation. The variety of lesions in the central, neuroendocrine and peripheral neuromuscular systems in Rett syndrome are discussed with regard to their clinical and biochemical significance.

Key words

Rett syndrome Cerebral atrophy Nigral underpigmentation Pituitary gland Distal axonopathy 


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  1. 1.
    Agamanolis DP, Potter JL, Herrick MK, Sternberger NH (1982) The neuropathology of glycine encephalopathy. A report of five cases with immunohistochemical and ultrastructural observations. Neurology 32:975–985Google Scholar
  2. 2.
    Agid Y, Javo-Agid F, Ruberg M (1987) Biochemistry of neurotransmitters in Parkinson's disease. In: Marsden DC, Gahn ST (eds) Movement disorders, vol 2. Butterworths, London, pp 66–230Google Scholar
  3. 3.
    Arluison M, Dietl M, Thibault J (1979) Ultrastructural morphology of dopaminergic nerve terminals and synapses in the striatum of the rat using tyrosine hydroxylase immunocytochemistry. A topographic study. Brain Res Bull 13:269–285Google Scholar
  4. 4.
    Arsenio-Nunes ML, Goutieres F, Aicardi J (1981) An ultramicroscopic study of skin and conjunctional biopsies in chronic neurologic disorders of childhood. Ann Neurol 9:163–173Google Scholar
  5. 5.
    Baker M, Joh TH, Ruggiero DA, Reis D (1983) Variations in number of dopamine neurons and tyrosine hydroxylase activity in hypothalamus of two mouse strains. J Neurosci 3:932–938Google Scholar
  6. 6.
    Bauman M, Kemper TL (1985) Histoanatomic observations of the brain in early infantile autism. Neurology 35:866–874Google Scholar
  7. 7.
    Bauman M, Kemper TL (1987) Limbic involvement in a second case of early infantile autism. Neurology [Suppl I] 37:147 [abstr]Google Scholar
  8. 8.
    Beal MF, Martin JB (1986) Neuropeptides in neurological disease. Ann Neurol 20:547–563Google Scholar
  9. 9.
    Benno HH, Tucker LW, Joh TH, Reis DJ (1983) Quantitative cytochemistry of tyrosine hydroxylase in rat brains. Brain Res 246:225–236Google Scholar
  10. 10.
    Boton CF, Gilbert JJ, Hahn AF, Sibbald WJ (1984) Polyneuropathy in critically ill patients. J Neurol Neurosurg Psychiatry 47:1223–1231Google Scholar
  11. 11.
    Brun A, Borjeson IM, Hultberg B, Sjoblad S, Akesson H, Litwen E (1979) Neonatal nonketotic hyperglycemia: a clinical, biochemical and neuropathological study including electron microscopic analysis. Neuropaediatrie 10:195–205Google Scholar
  12. 12.
    Bugiani O, Perdelli F, Saharani S, Leonardi A, Mancardi GL (1980) Loss of striatal neurons in Parkinson's disease. Eur Neurol 19:339–344Google Scholar
  13. 13.
    Cavanagh JB (ed) (1972) The brain in unclassified mental retardation. Churchill-Livingstone, Edinburgh LondonGoogle Scholar
  14. 14.
    Corsellis JAN (1953) The pathological report of a case of phenylpyruvic oligophrenia. J Neurol Neurosurg Psychiatry 16:139–145Google Scholar
  15. 15.
    Dyck PJ, Thomas PK, Lambert EH (1975) Peripheral neuropathy. Saunders, PhiladelphiaGoogle Scholar
  16. 16.
    Engel WK, Bishop DW, Cunningham GG (1970) Tubular aggregates in type II muscle fibers: ultrastructural and histochemical correlations. J Ultrastruct Res 31:507–525Google Scholar
  17. 17.
    Feilman JF (1958) Epinephrine metabolism and pigmentation in the central nervous system in a case of phenylpyruvic oligophrenia. J Neurol Neurosurg Psychiat 21:58–65Google Scholar
  18. 18.
    Fenichel GM, Bazelon M (1968) Studies on neuromelanin. II. Melanin in the brain stem of infants and children. Neurology 18:817–824Google Scholar
  19. 19.
    Forno LS, Norville RL (1979) Ultrastructure of the neostriatum in Huntington's and Parkinson's diseases. Adv Neurol 23:125–135Google Scholar
  20. 20.
    Friede RL (1975) Development neuropathology. Springer, Wien New York, pp 307–310Google Scholar
  21. 21.
    Gibson PH (1987) Ultrastructural abnormalities in the cerebral neocortex and hippocampus associated with Alzheimer's disease and aging. Acta Neuropathol (Berl) 73:86–91Google Scholar
  22. 22.
    Glaze DG, Frost JD, Zoghbi HY, Percy AK (1987) Rett's syndrome: characterization of respiratory patterns and sleep. Ann Neurol 21:377–382Google Scholar
  23. 23.
    Hagberg B, Aicardi J, Dias K, Ramas O (1983) A progressive syndrome of autism, dementia, ataxia and loss of purposeful hand use in girls: Rett syndrome: report of 35 cases. Ann Neurol 14:471–479Google Scholar
  24. 24.
    Harding BM, Tudmay AJC, Wilson J (1985) Rett syndrome. Neuropathological findings. Brain Dev 7:342–344Google Scholar
  25. 25.
    Henderson G, Tomlinson BE, Gibson PH (1980) Cell counts in the cerebral cortex in normal adults throughout life using an image analyzing computer. J. Neurol Sci 46:113–136Google Scholar
  26. 26.
    Hofman MA (1984) A biometric analysis of brain size in micrencephalies. J Neurol 23:87–93Google Scholar
  27. 27.
    Hsu SM, Haine L, Tanger H (1981) The use of avidin-biotinperoxidase complex (ABC) in immunoperoxidase techniques. A comparison between ABC and unlabeled antibody procedures PAP. J Histochem 29:577–590Google Scholar
  28. 28.
    Jellinger K (1986) Overview of morphological changes in Parkinson's disease. Adv Neurol 45:1–18Google Scholar
  29. 29.
    Jellinger K (1987) The pathology of Parkinsonism. In: Marsden CD, Fehn ST (eds) Movement disorders, vol 2. Butterworth, London, pp 124–165Google Scholar
  30. 30.
    Jellinger K, Seitelberger F (1986) Neuropathology of Rett syndrome. Am J Med Genet 24:259–288Google Scholar
  31. 31.
    Jolles J (1986) Neuropeptides and cognitive disorders. Prog Brain Res 65:177–192Google Scholar
  32. 32.
    Lake BD (1984) Lysosomal enzyme deficiencies. In: Adams JH, Corsellis JAN, Duchen LW (eds) Greenfield's neuropathology, 4th edn. Arnold, London, pp 492–572Google Scholar
  33. 33.
    Lampert PW (1967) A comparative electron microscopic study of reactive, degenerating, regenerating, and dystrophic axons. J Neuropathol Exp Neurol 26:345–368Google Scholar
  34. 34.
    Lillie RD (1957) Metal reactions of the melanius histochemical studies. J Histochem cytochem 5:325–333Google Scholar
  35. 35.
    Mann DMA (1986) dopamine neurons of the vertebral brain; some aspects of anatomy and pathology. In: Winslow W, Markstein H (eds) The neurobiology of dopamine systems. Manchester University Press, Manchester, pp 87–103Google Scholar
  36. 36.
    Mann DMA, Yates PO (1983) Pathological basis for neurotransmitter changes in Parkinson's disease. Neuropathol Appl Neurobiol 9:3–19Google Scholar
  37. 37.
    Mastaglia FL (1973) Pathological changes in skeletal muscle in acromegaly. Acta Neuropathol (Berl) 24:273–286Google Scholar
  38. 38.
    McCombe PA, McLeod JG (1984) The peripheral neuropathy in Vitamin B12 deficiency. J Neurol Sci 66:117–126Google Scholar
  39. 39.
    Meenke HJ, Janz D (1984) Neuropathological findings in primary generalized epilepsy. A study of eight cases. Epilepsia 25:8–21Google Scholar
  40. 40.
    Missliwetz J, Depastas H (1986) Forensic problems in Rett Syndrome. Brain Dev 7:326–328Google Scholar
  41. 41.
    Moore JW, Tuck-Muller CM, Murphy M, Naidu S, Thomas GH (1986) Chromosome studies in 10 patients with the Rett syndrome. Am J Med Genet 24:345–354Google Scholar
  42. 42.
    Moses HL, Ganota CE, Beaver DL, Shuffman SS (1966) Light and electron microscopic studies of pigment in human and rhesus monkey substantia nigra and locus ceruleus. Anat Rec 155:167–184Google Scholar
  43. 43.
    Nakashima S, Kumanaishi T, Ikuta F (1983) Immunohistochemistry of tyrosine hydroxylase in the substantia nigra of human autopsied cases. Brain Nerve (Tokyo) 35: 1023–1029Google Scholar
  44. 44.
    Nieuwenhuis R (1985) Chemoarchitecture of the brain. Springer, Berlin Heidelberg New York TokyoGoogle Scholar
  45. 45.
    Nomura Y, Segawa M, Hasegawa M (1984) Rett syndrome — Clinical studies and pathophysiological consideration. Brain dev 6:475–486Google Scholar
  46. 46.
    Opitz JM, Reynolds JF, Moser HW (1986) The Rett syndrome. Am J Med Genet [Suppl] 1:1–420Google Scholar
  47. 47.
    Papadimitriou JM, Hockey A, Tan N, Masters CL (1988) Rett Syndrome: abnormal membrane-bound lamellated inclusions in neurons and oligodendroglia. Am J Med Genet 29:365–368Google Scholar
  48. 48.
    Pearson J (1983) Neurotransmitter immunochemistry in the study of human development, anatomy and pathology. Prog Neuropathol 5:41–97Google Scholar
  49. 49.
    Percy AK (1987) The inherited neurodegenerative disorders of childhood: clinical assessment. J Child Neurol 2:82–97Google Scholar
  50. 50.
    Percy AK, Zoghbi H, Riccardi VM (1985) Rett syndrome; Initial experience with an emerging entity. Brain Dev 7:300–304Google Scholar
  51. 51.
    Philippart M (1986) Clinical recognition of Rett syndrome. Am J Med Genet 24:111–118Google Scholar
  52. 52.
    Rees S (1975) A quantitative electron microscopic study of atypical structures in normal human cerebral cortex. Anat Embryol (Berl) 148:303–331Google Scholar
  53. 53.
    Rees S (1976) A quantitative electron microscopic study of aging in the human cerebral cortex. Acta Neuropathol (Berl) 148:347–362Google Scholar
  54. 54.
    Reis D, Fink JS, Baker H (1983) Genetic control of the number of dopamine neurons in the brain: relationship to behavior and responses to psychoactive drugs. In; Kety SS, Rowland LO, Sidman RL, Matthysse SW (eds) Genetics of neurological and psychiatric disorders. Raven Press, New York, pp 55–75Google Scholar
  55. 55.
    Rett A (1966) Über ein cerebral-atrophisches Syndrom bei Hyperammonämie. Hollinek, WienGoogle Scholar
  56. 56.
    Rett A (1977) Cerebral atrophy associated with hyperammonemia. Handb Clin Neurol 29:305–329Google Scholar
  57. 57.
    Riccardi VM (1986) The Rett syndrome: genetics and the future. Am J Med Genet 24:389–402Google Scholar
  58. 58.
    Riederer P, Brucke T, Sofic E, Kienzl E, Schnecker K, Schay V, Kruzik P, Killian W, Rett A (1985) Neurochemical aspects of Rett syndrome. Brain Dev 7:351–360Google Scholar
  59. 59.
    Riederer P, Weiser M, Wichart I, Schmidt B, Killian W, Rett A (1986) Preliminary brain autopsy findings in progredient Rett syndrome. Am J Med Genet 24:305–315Google Scholar
  60. 60.
    Scheibel ME, Lindsay RD, Tomiyasu U, Scheibel AB (1975) Progressive dendritic changes in aging human cortex. Exp Neurol 47:392–403Google Scholar
  61. 61.
    Schröder JM (1982) Pathologie der Muskulatur. In: Doerr W, Seifert G, Uehlinger H (eds) Spezielle pathologische Anatomie. vol 15. Springer, Berlin Heidelberg New York, pp 157–159Google Scholar
  62. 62.
    Shuman RT, Leech RW, Scott CR (1978) The neuropathology of the nonketotic and ketotic hyperglycinemias; three cases. Neurology 28:139–146Google Scholar
  63. 63.
    Spence AM, Gilles FH (1971) Underpigmentation of the substantia nigra in chronic disease in children. Neurology 21:386–390Google Scholar
  64. 64.
    Sternberger LA (1978) Immunohistochemistry, 2nd edn. Prentice Hall, New Jersey, pp 104–122Google Scholar
  65. 65.
    Tennyson VE (1976) Development of the substantia nigra, pars compacta and neostriatum. Prog Neuropathol 3:359–381Google Scholar
  66. 66.
    Thompson R, Huestis PW, Crinella FM, Yu J (1986) The neuroanatomy of mental retardation in the rat. Neurosci Biobehav Rev 10:317–338Google Scholar
  67. 67.
    Veith G, Wicke R (1968) Cerebrale Differenzierungsstörungen bei Epilepsie, Jahrbuch 1968. Westdeutscher Verlag, Köln, pp 515–534Google Scholar
  68. 68.
    Victor M (1984) Polyneuropathy due to nutritional deficiency and alcoholism. In: Dyck PJ, Thomas PK, Lambert EH, Bunge R (eds) Peripheral neuropathy, 2nd edn. Saunders, Philadelphia, pp 1899–1940Google Scholar
  69. 69.
    Werling PL, Brown SR, Cox BM (1987) Opioid receptor regulation of the release of nonepinephrine in brain. Neuropharmacology 26:987–996Google Scholar
  70. 70.
    Williams RS, Hauser SL, Purpura DF, DeLong GR, Swisher CN (1980) Antism and mental retardation. Arch Neurol 37:749–753Google Scholar
  71. 71.
    Zoghbi HY, Percy AK, Glaze DG, Butler IJ, Riccardi VM (1985) Reduction of biogenic amine levels in the Rett syndrome. N Engl J Med 313:921–924Google Scholar

Copyright information

© Springer-Verlag 1988

Authors and Affiliations

  • K. Jellinger
    • 1
  • D. Armstrong
    • 2
  • H. Y. Zoghbi
    • 3
  • A. K. Percy
    • 3
  1. 1.Ludwig Boltzmann Institut für klinische NeurobiologieLainz-HospitalWienAustria
  2. 2.Department of PathologyBaylor College of MedicineHoustonUSA
  3. 3.Department of Pediatrics and NeurologyBaylor College of MedicineHoustonUSA

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