1. Bauman ML et al. (1995a)
    Microscopic observations of
    the brain in Rett syndrome.
  2. Bauman ML et al. (1995b)
    Pervasive neuroanatomic
    abnormalities of the brain in
    three cases of Rett's
    syndrome.
  3. Armstrong D.(1997) Recent
    developments in
    neuropathology--electron
    microscopy--brain pathology.  
  4. Lenn, N.J et al. (1986).
    Auditory processing deficit in
    a patient with Rett syndrome.  
  5. Sasaki T et al. (1991) A case
    of the Rett syndrome with
    acute encephalopathy
    induced during calcium
    hopantenate treatment.
  6. Kimura A et al. (1986) Acute
    encephalopathy with
    hyperammonemia and
    dicarboxylic aciduria during
    calcium hopantenate therapy:
    a patient report.
  7. Pastoris O et al. (1986)
    Hopantenate interference on
    the adaptation of muscular
    energy metabolism to
    intermittent hypoxia.
  8. Tahiliani AG, Beinlich CJ
    (1991) Pantothenic acid in
    health and disease.
  9. Kuzuhara S (1991) Iatrogenic
    diseases in the elderly.
  10. Jacobs HT (1997)
    Mitochondrial deafness.
  11. Schapira AH (1998) Inborn
    and induced defects of
    mitochondria.
  12. Philippart M (1986) Clinical
    recognition of Rett syndrome.
  13. Eeg-Olofsson O et al. (1989)
    Rett syndrome: genetic clues
    based on mitochondrial
    changes in muscle.
  14. Eeg-Olofsson O et al. (1990a)
    Rett syndrome: a
    mitochondrial disease?
  15. Armstrong DD (1992) The
    neuropathology of the Rett
    syndrome.
  16. Mak SC et al. (1993)
    Abnormal mitochondria in
    Rett syndrome: one case
    report.
  17. Eeg-Olofsson O et al. (1988)
    Abnormal mitochondria in the
    Rett syndrome.
  18. Leigh D (1951) Subacute
    necrotizing
    encephalomyelopathy in an
    infant.
  19. Lombes A et al. (1991)
    Biochemical and molecular
    analysis of cytochrome c
    oxidase deficiency in Leigh's
    syndrome.
  20. Campos Y et al. (1997) Leigh
    syndrome associated with
    the T9176C mutation in the
    ATPase 6 gene of
    mitochondrial DNA.
  21. Chalmers RM et al. (1997) A
    mitochondrial DNA tRNA(Val)
    point mutation associated
    with adult-onset Leigh
    syndrome.
  22. Cavanagh JB, Harding BN
    (1994) Pathogenic factors
    underlying the lesions in
    Leigh's disease. Tissue
    responses to cellular energy
    deprivation and their clinico-
    pathological consequences.
  1. Bauman ML, Kemper TL, Arin DM (1995a) Microscopic observations of the brain in Rett
    syndrome. Neuropediatrics 26:105-108.
  2. Bauman ML, Kemper TL, Arin DM (1995b) Pervasive neuroanatomic abnormalities of the
    brain in three cases of Rett's syndrome. Neurology 45:1581-1586.
  3. Armstrong D.(1997) Recent developments in neuropathology--electron microscopy--brain
    pathology.  European Child and Adolescent Psychiatry.;6 Suppl 1:69-70.
  4. Lenn, N.J., Olsho, L.W., & Turk, W.R. (1986). Auditory processing deficit in a patient with Rett
    syndrome.  American Journal of Medical Genetics, 24, 153-156 (suppl 1).
  5. Sasaki T, Minagawa M, Yamamoto T, Ichihashi H (1991) A case of the Rett syndrome with
    acute encephalopathy induced during calcium hopantenate treatment. Brain and
    Development 13:52-55.
  6. Kimura A, Yoshida I, Ono E, Matsuishi T, Yoshino M, Yamashita F, Yamamoto M, Hashimoto
    T, Shinka T, Kuhara T, et al (1986) Acute encephalopathy with hyperammonemia and
    dicarboxylic aciduria during calcium hopantenate therapy: a patient report. Brain and
    Development 8:601-605.
  7. Pastoris O, Vercesi L, Mazzocchi A, Dossena M, Benzi G (1986) Hopantenate interference on
    the adaptation of muscular energy metabolism to intermittent hypoxia. Archives
    Internationales de Pharmacodynamie et de Therapie 28:311-20
  8. Tahiliani AG, Beinlich CJ (1991) Pantothenic acid in health and disease. Vitamins and
    Hormones 1991;46:165-228.
  9. Kuzuhara S (1991) Iatrogenic diseases in the elderly (Article in Japanese) Nippon Ronen
    Igakkai Zasshi 28:493-8.
  10. Jacobs HT (1997) Mitochondrial deafness. Annals of Medicine 29:483-491.
  11. Schapira AH (1998) Inborn and induced defects of mitochondria. Arch Neurol 55:1293-1296.
  12. Philippart M (1986) Clinical recognition of Rett syndrome. American Journal of Medical
    Genetics Supplement 1:111-8.
  13. Eeg-Olofsson O, al-Zuhair AG, Teebi AS, al-Essa MM (1989) Rett syndrome: genetic clues
    based on mitochondrial changes in muscle. American Journal of Medical Genetics 32:142-
    144
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    (1990a) Rett syndrome: a mitochondrial disease? Journal of Child Neurology 5:210-214.
  15. Armstrong DD (1992) The neuropathology of the Rett syndrome.   Brain and Development.
    14 Suppl:S89-98.
  16. Mak SC, Chi CS, Chen CH, Shian WJ. (1993) Abnormal mitochondria in Rett syndrome: one
    case report. Chung Hua I Hsueh Tsa Chih (Taipei). 52:116-9.
  17. Eeg-Olofsson O, al-Zuhair AG, Teebi AS, al-Essa MM (1988) Abnormal mitochondria in the
    Rett syndrome. Brain and Development 10:260-2.
  18. Leigh D (1951) Subacute necrotizing encephalomyelopathy in an infant.  Journal of
    Neurology, Neurosurgery, and Psychiatry 14:216-221.
  19. Lombes A, Nakase H, Tritschler HJ, Kadenbach B, Bonilla E, DeVivo DC, Schon EA, DiMauro
    S (1991) Biochemical and molecular analysis of cytochrome c oxidase deficiency in Leigh's
    syndrome. Neurology 41:491-498.
  20. Campos Y, Martin MA, Rubio JC, Solana LG, Garcia-Benayas C, Terradas JL, Arenas J
    (1997) Leigh syndrome associated with the T9176C mutation in the ATPase 6 gene of
    mitochondrial DNA. Neurology 49:595-597.
  21. Chalmers RM, Lamont PJ, Nelson I, Ellison DW, Thomas NH, Harding AE, Hammans SR
    (1997) A mitochondrial DNA tRNA(Val) point mutation associated with adult-onset Leigh
    syndrome. Neurology 49:589-592.
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    disease. Tissue responses to cellular energy deprivation and their clinico-pathological
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2 -  Rett and Leigh syndromes
   Rett syndrome is a disintegrative disorder, but
differentiated from disintegrative disorder in DSM-IV
because it appears to afflict only female children.  
Neuropathological examinations indicate that brain
growth becomes arrested in Rett syndrome [1-3].  But
Harding et al. (1985) found indications of damage in
the colliculi in one patient who died [4]; they did not
specify whether inferior or inferior colliculi were
involved.  Lenn et al. (1986) reported auditory
dysfunction in a child with Rett syndrome, and
suggested a processing deficit at the level of the
inferior colliculus.  The inferior colliculi would have to
be found damaged consistently in many more cases to
be confirmed as the source of autistic behaviors,
auditory dysfunction, or any of the other traits
characteristic of Rett syndrome, and this possibility
deserves investigation.

  Sasaki et al. (1991) reported a case of Rett
syndrome that appeared to develop in a female child
following treatment with calcium hopantenate [5].  
Kimura et al (1986) reported intoxication with
hyperammonemia and dicarboxylic aciduria in another
child who was treated with the same medication [6].  
This drug is an antagonist of pantothenic acid, part of
the vitamin B-2 complex.  Pantothenic acid is so
readily available from many sources that natural
deficiency is not seen, but the artificial deficiency
produced by the antagonist hopantenate appears to
interfere with cellular energy production [7, 8].  
Hopantenate is no longer used, but is only one of
many drugs that may be more toxic than therapeutic
[9].

  Toxicity of drugs often appears to be due to
interference with aerobic enzymes within the
mitochondria.  Many of the mitochondrial disorders
have been found to be brought on by exposure to
toxic substances.  There may be a genetic
predisposition for mitochondrial disorders, but
aminoglycoside antibiotics such as streptomycin can
bring on hearing loss in susceptible people associated
with mitochondrial disorders [10, 11].  Aerobic
metabolism takes place within the mitochondria, and
disorders of aerobic metabolism are mitochondrial
disorders of one kind or another.  Several reports
have identified signs of deficient energy production in
Rett syndrome [12-16].  Eeg-Olofsson et al. (1988)
published electron microscope pictures of swollen and
misshapen mitochondria in muscle biopsy tissue of
three children with Rett syndrome [17].

  One of the best-explored mitochondrial disorders is
Leigh syndrome [18].  Leigh (1951) described
neuropathology resembling that of Wernicke’s
encephalopathy in a seven-month old infant who died
of what was suspected to be a viral infection, exposure
to an unknown toxin, or nutritional deficiency.  Since
then, many more cases of Leigh syndrome have been
reported, and the neuropathology is now thought to
result from a disorder of mitochondrial function [19-
21].  Cavanagh and Harding (1994) analyzed clinical
and pathological disturbances in 20 cases of Leigh’s
disease [22].  Damage of the inferior colliculi was
noted in as part of the neuropathology in many of
these cases.  Cytochrome oxidase deficiency was
found in one patient who died at four days of age.  
Autistic symptoms have not been reported in Leigh’s
disease, but it is a progressive disorder that leads to
severe neurological handicap and death, usually
within the first decade of life.
Full References
References
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