1. Williams RS, Hauser S, Purpura DP, deLong GR, Swisher CN (1980) Autism and mental
    retardation: Neuropathologic studies performed in four retarded persons with autistic
    behavior.  Archives of Neurology 37:748-753.
  2. Lowe TL, Tanaka K, Seashore MR, Young JG, Cohen DJ (1980). Detection of phenylketonuria
    in autistic and psychotic children. Journal of the American Medical Association 243:126-128.
  3. Chen CH, Hsiao KJ (1989) A Chinese classic phenylketonuria manifested as autism. British
    Journal of Psychiatry 155:251-3
  4. Miladi N, Larnaout A, Kaabachi N, Helayem M, Ben Hamida M (1992) Phenylketonuria: an
    underlying etiology of autistic syndrome. A case report. Journal of Child Neurology 7:22-23.
  5. Leuzzi V, Trasimeni G, Gualdi GF, Antonozzi I (1995) Biochemical, clinical and
    neuroradiological (MRI) correlations in late-detected PKU patients. Journal of Inherited
    Metabolic Disease 18:624-634.
  6. Salguero LF, Itabashi HH, Allen RJ (1968) Neuropathologic observations in phenylketonuria.
    Transactions of the American Neurological Association 93:274-276.
  7. Brismar J, Aqeel A, Gascon G, Ozand P (1990) Malignant hyperphenylalaninemia: CT and MR
    of the brain. AJNR American Journal of Neuroradiology 11:135-138.
  8. Sugita R, Takahashi S, Ishii K, Matsumoto K, Ishibashi T, Sakamoto K, Narisawa K (1990)
    Brain CT and MR findings in hyperphenylalaninemia due to dihydropteridine reductase
    deficiency (variant of phenylketonuria). Journal of Computer Assisted Tomography 14:699-
    703.
  9. Følling I (1994) The discovery of phenylketonuria. Acta Paediatrica. Supplement 407:4-10.
  10. Güttler F (1984) Phenylketonuria: 50 years since Folling's discovery and still expanding our
    clinical and biochemical knowledge.  Acta Paediatrica Scandinavica 73:705-716.
  11. Malamud N (1966) Neuropathology of phenylketonuria. Journal of Neuropapthology and
    Experimental Neurology 25:254-268.
  12. Kakulas BA, Hamilton GJL, Mastaglia FL (1968) Clinical and neuropathological observations
    in phenylketonuria. Proceedings of the Australian Association of Neurologists 5:155-158.
  13. Bauman ML, Kemper TL (1982) Morphologic and histoanatomic observations of the brain in
    untreated human phenylketonuria. Acta Neuropathologica (Berlin) 58:55-63.
  14. Wernicke C (1881b) Die chronische Poliencephalitis. Lehrbuch der Gehirnkrankheiten für
    Ärzte und Studirende, Band II.  Kassel: Theodor Fischer, pp 460-476.
  15. Levy HL, Lobbregt D, Barnes PD, Poussaint TY (1996) Maternal phenylketonuria: magnetic
    resonance imaging of the brain in offspring. Journal of Pediatrics 128:770-775.
1 -  Toxic metabolites from an aberrant liver
enzyme
    Autistic behaviors have been described in several
case reports of people with phenylketonuria [1-5].  
Phenylketonuria (PKU) is an example of a disorder
that affects wide areas of the brain.   In a few cases
PKU clearly sometimes also involves the
neuroanatomical impairment that leads to autism.
Even when autistic behaviors are not described failure
to learn to speak has been noted as one of the most
serious aspects of PKU [6].  This may be due to failure
of neural circuits for language to develop in the
cerebral cortex, but development of the auditory
receptive areas of the temporal lobes may also
depend on intact function within the brainstem
auditory pathway.

   Although PKU causes mental retardation, it can be
considered a primary disorder of the brain only in a
small percentage of cases in which a coenzyme for
synthesis of precursors for monoamine
neurotransmitters is missing [7, 8].  Most cases of PKU
are the result of a defective liver enzyme,
phenylalanine hydroxylase, which produces abnormal
metabolites.  The effects of these abnormal
metabolites are similar to those of an exogenous toxin
on the brain [9, 10].  The brain disorder is secondary
to the endogenously produced toxic byproducts of the
faulty liver enzyme; these pass into the circulatory
system, enter the brain and impair metabolic functions
in neurons.  The brainstem nuclei of high metabolic
rate are apt to be the most vulnerable as in conditions
caused by exposure to noxious substances.

   PKU is a serious disorder, but several investigators
have pointed out a lack of consistent pathology in the
brain and that the impairment that causes mental
retardation remains obscure.  Most frequently noted
are abnormalities of myelinated nerve tracts, which
may signify a process of progressive deterioration or
incomplete myelination of nerve axons [5-6, 11-13].  
Symmetric bilateral involvement of myelin tracts is
usually described, and perhaps represents the long-
term effect of on-going bilateral toxic damage
beginning early in development.  Wernicke (1881)
discussed progression of clinical signs in chronic
stages of deterioration following acute affliction of
upper brainstem nuclei, with progressive involvement
of myelin tracts [14].

   The brainstem nuclei of high metabolic rate are
susceptible to damage from the toxic products of
abnormal metabolism in PKU, auditory nuclei in
particular.  Function is likely impaired even though no
visible signs of damage have been found.  Auditory
system abnormality should be carefully investigated in
any child who does not learn to speak.  Kakulas et al.
(1968) noted one of their patients with PKU “became
extremely irritable and reacted excessively to
extraneous sounds” [12].  Hyperacusis to the degree
often described in children with autism cannot be
taken as a sign of normal hearing, and an inability to
accommodate extraneous sounds could interfere with
language development.

  Williams et al. (1980) investigated the brain of a 27-
year-old autistic man who was found to have PKU only
at age 21 [1].  The only abnormality found in the brain
was reduction in density of spines on dendrites of
pyramidal neurons.  In common with neuropathology
observed in autism are reports of hypoplasia of the
corpus callosum in children with PKU, and in children
born to mothers with PKU [15].  Pictures of cross-
sections of brains from patients with phenylketonuria
in the article by Malamud (1966) show the corpus
callosum as one of the affected myelin tracts [11].

   A rare form of PKU, 2 to 3 percent of all cases, has
been found due to deficiency of the cofactor
tetrahydrobiopterin (BH4) for the phenylalanine
hydroxylase enzyme [7, 8].  This cofactor is also
required for enzymes that synthesize L-dopa,
dopamine, and norepinephrine from tyrosine and
serotonin from tryptophan.  The cofactor BH4 is
normally synthesized in at least three steps, but two of
the enzymes required have been found defective in
cases of biopterin-dependent phenylketonuria.  
Administration of L-dopa and 5-hydroxytryptophan
reversed the neurologic symptoms and signs of
damage on brain scans in a 13-month old girl treated
by Brismar et al. (1990).

   There are likely many yet-to-be-discovered
metabolic disorders such as the two known forms of
PKU, and any biochemical defect that produces
abnormal toxic metabolites or interferes with synthesis
of neurotransmitters may by analogy be an etiologic
factor in some cases of autism.  Toxic substances in
particular can be assumed to interfere with function in
the brainstem nuclei of high metabolic rate, especially
those of the auditory system.
Full References
top
References
  1. Williams RS et al. (1980)
    Autism and mental
    retardation: Neuropathologic
    studies performed in four
    retarded persons with autistic
    behavior.
  2. Lowe TL et al. (1980).
    Detection of phenylketonuria
    in autistic and psychotic
    children.
  3. Chen CH, Hsiao KJ (1989) A
    Chinese classic
    phenylketonuria manifested
    as autism.
  4. Miladi N et al. (1992)
    Phenylketonuria: an
    underlying etiology of autistic
    syndrome. A case report.
  5. Leuzzi V et al. (1995)
    Biochemical, clinical and
    neuroradiological (MRI)
    correlations in late-detected
    PKU patients.
  6. Salguero LF et al. (1968)
    Neuropathologic
    observations in
    phenylketonuria.
  7. Brismar J et al. (1990)
    Malignant
    hyperphenylalaninemia: CT
    and MR of the brain.
  8. Sugita R et al.(1990) Brain CT
    and MR findings in
    hyperphenylalaninemia due
    to dihydropteridine reductase
    deficiency (variant of
    phenylketonuria).
  9. Følling I (1994) The discovery
    of phenylketonuria.
  10. Güttler F (1984)
    Phenylketonuria: 50 years
    since Folling's discovery and
    still expanding our clinical
    and biochemical knowledge.
  11. Malamud N (1966)
    Neuropathology of
    phenylketonuria.
  12. Kakulas BA et al. (1968)
    Clinical and
    neuropathological
    observations in
    phenylketonuria.
  13. Bauman ML, Kemper TL
    (1982) Morphologic and
    histoanatomic observations
    of the brain in untreated
    human phenylketonuria.
  14. Wernicke C (1881b) Die
    chronische Poliencephalitis.
  15. Levy HL et al. (1996) Maternal
    phenylketonuria: magnetic
    resonance imaging of the
    brain in offspring.
top