Download Genetic and Molecular Basis of Human Hereditary Diseases

Genetic and Molecular Basis of Human
Hereditary Diseases
J. Edwin See gmiller
A fresh view of some old and new diseases recognized by means of modern genetics
and biochemistry.
A.
N AREA of significant
medical
progress
over the past decade
has been
the recognition
and the biochemical
characterization
of an ever-increasing number
of human
hereditary
diseases
(1). Some
of the practical
consequences
have
been
the
development
biochemical
methods
for more
these diseases
(many
of them
new approaches
for treatment
types
of mental
hopeless
medical
retardation
curiosities.
clinical
laboratories
terminations
gives
of genetically
of
that
The
have,
in time past,
prospect
of more
of automated
analytic
promise
of the detection
determined
objective
chemical
and
precise
diagnoses
of a large number
of
newly recognized)
and the opening
of
of clinical
disorders
including
some
abnormalities
been
regarded
widespread
use
as
in
systems
for chemical
deof aim even larger
number
of body
chenmistry
in the
years
ahead.
Although
many of these inherited
diseases
are relatively
rare disorders,
there are considerations
that cause these disorders
to assume a
far greater
importance
to the medical
and
scientific
community
than
is revealed
by their
statistical
incidence.
Basic Concepts
Gene-Enzyme Relationship
These
portunities
disorders
are experiments
of nature
that
for expanding
our knowledge
of many
present
basic
unique
biologic
opproc-
esses. Some of our fundamental
concepts
of the mechanism
of gene
action can be traced to basic studies of human hereditary
diseases.
From
his studies of the rare human metabolic
disease
aleaptonuria,
the BritProm
Metabolic
the Section
on Human
Biochemical
Genetics,
National
Institute
of Arthritis
Diseases,
National
Institutes
of Health,
U. S. Public
Health
Service,
Bethesda,
and
Md.
20014.
Presented
as part
AAAS, Washington,
of the symposium
P. 0., Dec. 26-30,
“Inborn
1966.
Errors
554
of Metabolism,”
133rd
Annual
Meeting,
-
Vol. 14. No. 7, 1967
ish physician
HUMAN
Archibald
HEREDITARY
Garrod
proposed
enzyme relationship
in 1908 (2), over
ment by microbiologists
(3, 4). With
largely
by microbial
genetics,
this
mechanisms
gene
amino
or cistron
controls
the
chain (5, 6).
Another
inherited
human
acid
the basic concept
before
its
30 years
further
concept
for one of the fundamental
555
DISEASES
has
of the genefull develop-
refinements
become
contributed
time basic
premise
of gehle action ill which a single
sequence
of a single polypeptide
disease,
sickle cell anemia,
has provided
an
even more basic example of the more detailed
mechanism
by which gene
action can produce
a disease.
Substitution
of a single anliflo acidvaline
for glutamic
acid-in
the 6 position
of time beta chain of the
hemoglobin
molecule
gives rise to sickle cell hemoglobin
which has
different
physical
properties
from normal hemoglobin
(7, 8). The tendency of the sickle cell hemoglobin
to form aggregates
when deprived
of
oxygen
is the primary
cause of the red blood cell destruction
and
occlusion
of the small blood vessels that characterize
this disease to the
clinician.
Among
the possible
genetic
codes for valine
and glutamic
acid (9), codes can be found that differ by only one base, suggesting
the
possibility
that
the
mutation
responsible
for
hemoglobin
may have been a single substitution
molecule
directing
synthesis
of the beta chain
ing to the sixth amino acid.
the
appearance
of
this
of one base in the DNA
at a position
correspond-
Mutations
The above example
provides
a model for our thinking
of one of the
mechanisms
by which genetic differences
are expressed.
In time simplest
type of structural
gene mutation,
a relatively
minor alteration
in the
base sequence
of one small portion
of the DNA molecule
directing
the
assembly
of a polypeptide
chain could thereby
be expected
to produce
an altered
protein.
If the protein
product
of time gene action happens
to
be an enzyme, and time substitution
occurs at or near the active binding
site for time substrate,
the resulting
protein
may he expected
to have a
diminished
or absent enzyme activity.
A defect in a regulator
gene that
controls
the activity
of a structural
gene can produce
a similar deletion
of an enzyme in bacterial
systems
(in). Comparable
regulator
genes in
mammalian
cells have been postulated
hut are yet to be demonstrated
conclusively-.
The enzyme
deletion,
in turn, introduces
a chemical
aberration
in cellular
metabolism
which may be reflected
in bacterial
mutants
by alterations
in growth or in nutritional
requirements.
In the
human
species,
such biochemical
mutations
can produce
a metabolic
disease
(1).
Genetic mutations
produced
in microorganisms
at will have provided
556
EEGMILLE
Clinical
Ckemstry
powerful
tools for increasing
our knowledge
of the operational
details
of basic genetic and biochemical
processes
in these organisms
(ii, 1.2).
Only in the human
species do we find any significant
imumber of wellcharacterized
genetic
biochemical
deletions
in higher
life forms
that
might serve comparable
roles in aiding the study of these basic genetic
processes
in mammaliaim
cells. It seems ulilikely
that this reflects
a
higher incidence
of genetic mutation
in maii, but rather,
more intensive
study of our own species and, in particular,
the interest
of physicians
in the diseases
that have resulted
from some of these processes.
Diagnostic Procedures
Past
As might be expected,
the classic
metabolic
diseases,
the so-called
“inborn
errors of metabolism”
that were first. recognized
were brought
to the attention
of the physician
by reason
of the accumulation
of abnormal
chemical
substances
which the physician
could detect with his
five senses. One can feel and see time (leposits of crystals
of sodium urate
that constitute
the tophi located in and about time joints in patients
with
gouty arthritis,
the clinical
features
of which were first described
by
Hippocrates
around
the 4th century,
B.C.; and, of course,
the sweet
taste of glucose has provided
an unaesthetic
but, nevertheless,
useful
test of the urine for diabetes
since the 17th century-long
before chemical tests were available
to the physician.
In alcaptoimuria,
a rare disorder first definitely
described
a century
ago, one can see the blackening
of the infant’s
urine on the diapers
caused by the oxidation
by air of
homogentisic
acid, a chemical relative
of photographic
developer,
which
is excreted
in large quantities
throughout
the life of the individual.
It was only 30 years
ago that the unusual
odor of the urine of a
mentally
deficient
child led the Swedish
chemist
Foiling
to isolate
phenylpyruvic
and phenylaeetic
acid from the urine, thereby
permitting
the chemical
detection
of the disease
we now know as phenyiketonuria
(‘i).
A by-product
of the increasing
use of chemical
tests of biologic fluids
to aid in the diagnosis
of disease
has been the detection
of chemical
abnormalities
in a continually
increasing
number
of clinical disorders
and even in individuals
without
clinical symptoms.
Many of these disorders have been detected
because
of the lack of specificity
of many of
the chemical
tests in routine use. An ironic result of the “progress”
in
substitution
of more specific tests is the inability
to detect many of these
cbemieal
abnormalities,
As an example,
homogentisic
acid gives a
V01. 14,
o.
7, 1967
HUMAN
HEREDITARY
557
DISEASES
strong reducing
action with the alkaline copper solutions
that have been
in use in the past for detecting
sugar in urine. In fact, some alcaptonuric
patients
have been treated
with insulin for diabetes
on the basis of this
test. This erroneous
diagnosis
would have been avoided
if the clinical
chemist
performing
the test had been observant
and had noted that
the fluid overlying
the red copper
oxide was black instead
of blue or
green. With the use of more specific methods
for the routine
detection
of glucose in urine, the ability to detect alcaptonuria
has been lost and
patients
with this disorder
have gone undetected
by this specific chemical
test.
Present and Future
There is good reason to expect that genetically
determined
differences
in body chemistry
will be detected
at an increasing
rate during the years
immediately
ahead of us. This should come about through
the routine
determination
of an increasing
number
of chemical
components
of body
fluids in a progressively
larger portion
of the patient
population
as an
objective
aid to the clinician in his detection
of disease. Such widespread
use of chemical
determinations
is being made possible
by the use in
clinical
laboratories
of automated
analytic
equipment
for chemical
determinations.
Once an abnormal
substance
is noted, its identification
then permits
intensive
studies of not only the basic enzyme defect giving rise to this
substance
but also the way by which the chemical
aberration
produces
the clinical manifestations
of the metabolic
disease.
At the present
time
there is no way of effecting
a true cure of these diseases
by correcting
the defect in the gene. Nevertheless,
these findings
have provided
new
understanding
of the disease
process
and given new hope for successful
treatment
of a remarkable
array
of diseases
that have, until
recently,
been completely
untreatable.
Basic Metabolic Defects
A detailed
catalog
of the phenomenonally
metabolic
defects
that have been characterized
among hereditary
diseases
is not possible
ever, a few examples
of these diseases,
the
biochemical
defect gives rise to the disease
that leads to the successful
treatment
of an
diseases
will be discussed.
The proteins
formed by time cell serve one
large
imumber of basic
during
the past decade
in this presentation.
Howgeneral
ways by which the
process,
and the rationale
increasing
number
of these
of two grleral
functions-
558
SEEGMILLER
Clinical
Chemstry
either as units of structure
or as units of biochemical
function,
mostly
in time form of enzymes which catalyze
specific chemical
reactions.
These
reactions
are performed
in a detailed
sequence within the cell, somewhat
allalogous
to a factory
production
line.
The failure
of an enzyme in the metabolic
sequence
to perform
its
function
results
iii the accumulation
of the unreacted
metabolite.
It
cannot proceed
along that particular
production
line for further
processing. The interruption
of some of the metabolic
pathways
results
in
a situation
that is incompatible
with life, and it is thought
that this
situation
may account for some of the spontaneous
abortions
or deaths
in the first few weeks or months
of life, lithe
interruption
of metabolism is not a complete
disaster
to life, it can result in a wide variety
of
clinical expressions
ranging
from simple failure
of a child to thrive, to
production
of disease
late iii adult life. In still other conditions,
such
as pentosuria,
the defect seems to have no detectable
deleterious
effect
whatever,
and is called a disease only by courtesy.
Ochronotic Arthritis and Alcaptonuria
In some diseases,
the pathologic
effects
result
from time conmpound
that accumulates.
Two types
of arthritis
can he explained
by this
mechanism.
The classic metabolic
disease
alcaptollliria
already
mentioned produces
no discernible
ill effects for the first 30 years or so of
a patient’s
life. For many years it was regarded
as a medical curiosity.
It was in 1904 that Sir William
Osler at Johns Hopkins
Hospital
made
the first clinical
association
of this medical
curiosity
with a puzzling
type of artlmritis.
Timis disorder
ochronotic
arthritis
begins jim adult life
and usually
involves
the spine and other major
joints;
postmortem
examination
reveals the deposition
of a black pigment
in and about the
bones and cartilage.
Undoubtedly,
our ability to make time association
of the artimritis with
the abnormal
metaholite
was greatly
facilitated
l)y the tendency
of
homogentisic
acid to form pigmented
products
that can be readily
seen.
It is conceivable
that other types of hereditary
arthritis
could arise
from metabolites
with equally
deleterious
effects
on joint cartilage
which do not announce
their presence
by pigment
formation
and so,
remain
unrecognized.
We have already
mentioned
Archibald
Garrod’s
studies
of this disease in wimich he formulated
the first rational
hypothesis
to account for
what he named ‘‘ml)orn
errors
of metabohisni’’
(2). ITe proposed
that
homogentisic
acid accumulates
in these patients
because
they lack an
enzyme that normally
degrades
it. It was not until 1958 that there was
Vol. 14, No. 7, 1967
an o)portui1ity
to lest
required
surgery
for
tioii, a sinai! piece
of
sequence
of enzymes
tioii and time disposal
gentisic
acid oxidase
enzymes
that degrade
patient
HUMAN
HEREDITARY
559
DISEASES
G arrod ‘s hypothesis.
A 1)atiClit
wilhi a leal)toituria
uncontrollable
gastroilitestillal
l)leedillg.
At ol)efllhis liver was removed
for l)iocllemlcal
studies.
The
that are normally
responsible
for both time formaof imomogentisic
acid were studied
(14).
Honmowas the only enzynie
absent
from the series of
tyrosiime,
providing
concrete
evidence
in this
of time correctness
of (Jarrod’s
hypothesis.
Phenylketonuria and Tyrosinemia
Other
absence
results
defects
in this metabolic
sequence
are now knowii. Tinis, the
of time enzyme for formation
of tyrosilie
from pimenylalanine
iii the metabolic
disorder
)lmeny1ketonuria,
with its accom-
mental
deficiency
(1). Another
disorder,
tyrosillemia,
has
recently
been characterize(l
as a defect in the enzyme p-hydroxyphenylpyruvic
acid oxidase
respolmsible
for tile formation
of homogentisic
acid (is). The clinical manifestations
of timis (hisol’der are entirely
different from the other two and consist of renal tubular
dysfunction
and
a severe cirrhosis
of time liver, leading
to early death in many l)atie1ts
unless special treatment
is instituted
(16, 17).
I)allyiIlg
Gout
Ammother enzyme deletion,
which is presunied
to have occurred
Ill a
remote
ancestor
of both mait aimd the higher
apes, has left time whole
human species heir to the gout. 1mmall other mammals,
the enzyme uncase is present
and degrades
uric acid to its nmueim more soluble
end
product,
ahlantoimi, for excretion.
In addition,
the human kidney excretes
uric acid inefficiently.
As a result,
time mean colicentration
of mirate in
human
serum is quite iear time tlmeoretical
liniit of solul)ihity
of urate
(18).
A portion
of the hyperuriceniic
iil(livi(luals
(leposit time sparingly
soluble urate crystals
in and about time joints
which can give rise to
erosion of joints and episodes
of iimflammatory
reaction
clmaracteristics
of the acute attack of gouty arthritis
(19).
Glycogen Storage Disease
Disease
produce
disease.
in the human
can also
result
from
a needed
product,
as is the situation
Here,
there
is absence
of time liver
failure
in Type
of the enzyme to
I glycogeim storage
enzyme
glucose-6-phospha-
tase, which is responsible
for the production
of most of the blood sugar
from glycogen
(20). As a result, jimchildhood
these patients
have severe
episodes
of hypoglycemia,
producing
weakness
fainting,
and severe
560
SEEGMILLER
Clinical
Chemistry
episodes
of ketosis.
If they do live to adult life, a surprising
number
have been found to develop
gouty arthritis
(21).
The precise
mechanism by which this defect in carbohydrate
metabolism
causes hyperuricemia
and gout is another
example
of insights
derived
by studying
these disorders.
These patients
have a lacticacidemia
and ketonemiaboth of which can cause a renal retention
of uric acid. In addition,
they
have an excessive
purine biosynthesis
(22). A biochemical
link between
carbohydrate
metabolism
and punimme metabolism
can be made in the
formation
of 5-phosphoribosyl-1-pyrophosphate
(PRPP),
which is one
of the two reactants
of time first enzymatic
reaction
uniquely
committed
to purine synthesis:
Phosphoribosylpyrophosphate
+
glutamine
-
phosphoribosylamine
This reactioim is rate-linmiting
in the control
of purine
but aim increased
quaimtity of PRPP
in cells of patients
glycogen
storage
disease has not yet been demonstrated.
Nutritional
+
pyrophosphate
biosynthesis,
with Type
I
Diseases
A similar
type of eimzyme deletion
can also be used to explain
some
of the imutnitional
diseases.
Both the human and time guinea pig lack the
enzyme
which,
iii
all other
mammals,
catalyzes
the conversioim
of
ketogulonic
acid to ascorbic
acid, Vitamin
C (23). As a result, both the
imunman and time guinea
Jig nmust be supplied
witim Vitamin
C in timeir
(liet to avoid the development
of scurvy.
Scurvy
can, timerefore,
be regarded
as a metabolic
disease
simared by time entire imumaim race which
is kept in remission
by time adequate
intake of Vitamiim C. Such a consideration
provides
the key to one of the therapeutic
approaches
used
in treatment
of metabolic
diseases:
some individuals
with metabolic
disorders
will have unusual
imutritiommal requirenments
for nmaintenance
of health that are differeimt from that of the general
population.
Histidenemia
lim some cases, the biochemical
aimd clinical features
of disease are the
result of the accumulation
of a compound
that is a remote precursor
of
the blocked reaction.
Timis occurs particularly
if the reaction
preceding
time block is freely
reversible.
The accumulation
of liver glycogen
in
excessive
amounts
in Type I glycogeim storage
disease
that we have
already
mentioned
is aim exanmple of such an accumulation.
Tn still other disorders
there will be
ties of a substance
which normally
is
accumulation
of pimeimylpyruvic acid aiid
the patieiits
with phenylketonuria
is an
production
of increased
quantipresent
in small amounts.
The
pimenylacetic
acid in the urine of
example
of the way in which a
Vol. 14, No. 7, 1967
HUMAN
HEREDITARY
DISEASES
561
basic biochemical
abnormality
results iii a metabolic
diversion.
Another
example
is histidinemia,
a disorder
of’ amino acid! metabolism
for which
the enzyme defect was first demonstrated
by i)r. Lai)u et al. (24). Time
chemical
abnormality
for this disorder
was detected
as a result
of a
positive
ferric chloride
test for phenylketonuria
found ill the urine of a
child attending
a speech
clinic.
Unlike
most patients
with pheiiylketonuria,
this child was of normal intelligence
and had a normal
concentratioim of phemmylalanine in her plasma. The diagnosis
of imistidinernia
was proven
when it was demonstrated
that imidazole
pyruvic
acid
derived
from histidimme was time substance
responsible
for the positive
fem’ric chloride
test. Increased
quantities
of histidine
were also present
in plasma
and urine of both this girl and her younger
brother.
The
abseimce of the enzyme, histidase,
was demoimstrated
readily
by use of
hardened
skin removed
from aroummd the edge of the nail with fimmgernail clippers.
Such cornified
epithelium
from normal
individuals
contains a measurable
amount
of the enzyme histidase
which breaks
down
histidine
to urocanic
acid; there was nomme demonstrated
in samples
obtained from these children.
At the present
time there have been at least
15 cases of histideimemia
identified.
All but 2 of these patients
are repoi’ted to have al)mmormalities
of speech amid some have mental
retardation (i). The way iii wimich an enzyme defect could result in a specific
disorder
of speech opens miew realms iim the understanding
of time role
of biochemical
processes
iim brain function.
Our speech experts
believe
that timese patients
to learn
by their
have a simoi’tened
auditory
niemory
and so are uimable
selise of hearing
as effectively
as cami normal
iimdivid-
uals. Yet the intelligence
of our two patients
amid
by the visual route is entirely
miormal. Since the
been identified
iii individuals
over 13 years of age,
of this disorder
that might develop in adult life are
their ability to learn
disorder
has not yet
the cliiiical features
not known.
Brain Function Abnormalities
In recent years, we have become aware of an increasing
number
of
specific defects
of metabolism
that are associated
with abnormalities
of brain function.
One of tlmese is known as branched-chain
ketonuria
or
Maple Syrup Urine i)isease.
This was first described
in 1954 in a family
in whom 4 of the 6 children
had died within the first few weeks of life
from severe brain damage
(2S). The mother
brought
to the attention
of
the doctors the fact that the urilme of the affecte(l children
had a characteristic
odor similar
to that of maple
syrup.
On the basis of this
ol)servation,
the urine was examined
iii greater
detail ammdan abnormal
concentration
of organic
acids was detected
which were eventually
found to be the keto acids derived
from time branched-chain
amino acids
562
SEEGMILLER
Clinical
Chemistry
leuciiie, valine,
amid isoleucine,
whelm accumulate
as a result of a deficiency of time decarhoxylase
that normiiahly degrades
theni (1).
The severe brain damage in such instances
can be prevented
by treatment with a syntimetic diet low iii branched-chain
amino acids. This (hisease was (liagimosed in a baby S thays old; the special diet was begun
immediately
and has been colitillued
ever since (26). The child is now
5 years of age, has growil well, and has a iiornmal intelligence.
Other
patients
with this disorder
lmave 1)een similarly
treated
(1).
Ammotlmer imiherited biocimemical disorder
which gives rise to neurologic
symptoms
was first described
nearly three years ago (27). The patieimts,
two young brothers,
had spasticitv,
choreoatlmetosis,
mental retardatiomm,
and a most bizarre
behavior
which consisted
of a conmpulsive bitilig resimiting in the ends of time fingers and the lips being
chewed away. It \5
associated
with hyperuricernia
and with the lamgest 1)roduCtioll
of uric
acid i)(r kilogram
of body weighmt that has yet been found. The developmacnt of gouty arthritis
imas been a relatively
late manifestation
of the
disease.
However,
gouty
nephropathy
has contributed
to the death of
other patients
by the age of puberty
(28).
rhllie disorder
affects
only
nmales an(l simows a pattermi of inheritance
carrie(1 by the fenmales over at
least 3 generations,
thereby
suggesting
that the gene controlling
the
biochemical
defect resides
on the X chromosome
(29). The recent
discovery that these children
are lacking ammenzyme of purine metabolism
(hypoxantimine-guanine
pimosphmoril)osyltraiisferase)
provides
evidence
that function
of this enzyme is involved
iim the normal
regulation
of
purine
biosyiithesis
(30). in additiomm, it provides
a biochemical
basis
for not only aiiotlmei’ type of iteurologic
disease but also a link betweemm
a characteristic
abnormality
of behavior
and a genetically
determined
biochemical
(hsorder.
Time precise mechanism
by which a single genetic
defect gives rise to this clinical syndrome
can provide
a powerful
wedge
in our search
for knowledge
that might be used in more effectively
controlling
such disorders.
Summary
Modern genetics
aiid biochemistry
provide
new insight
into some old
and new imereditary
diseases
which in turim enlarge
the future
possibilities for recognition
and treatnient
of these thsorders.
There is a great
potential
value of mammalian
mutants-these
experiments
of natureas tools for extending
our knowledge
of the importance
of specific biochemical
reactions
in the normal
physiology
arid biochemistry
of the
imuman. Time immediate
future
holds the prospect
that an even larger
number
of genetically
controlled
individual
chemical
differences
will
be recognized
in the human
species.
This should
result
from
the
Vol. 14, No. 7, 1967
HUMAN
HEREDITARY.
DISEASES
563
performance
of a larger
number
of routimie clmemical determinations
on an increasing
segment
of the patient
populatiomm made possible
by
the widespread
use of automated
analytic
equipment
in clinical laboratories.
References
1.
Stanbury,
J. B., Wyngaarden,
J. B., and Fredrickson,
D. S. The Metabolic
Basis of Inherited
Disease (ed. 2). McGraw-Hill,
New York, 1966.
2. Garrod,
A. E., The Croonian
Lectures
on Inborn
Errors
of Metabolism.
Lecture
II.
Aikaptonuria.
Lancet
2, 73 (1908).
3. Beadle, G. W., and Tatum, E. L., Genetic control of biochemical
reactions
in Neurospora.
Proc. Nafl.
Acad. .Sci. U. S. 27, 499 (1941).
4. Beadle,
G. W., Genes and chemical
reactions
in Nenrospora.
Science
129, 1715 (1959).
5. Horowitz,
N. H., and Leupold,
F., Sonic recent studies bearing on the one gene one enzyme
hypothesis.
Cold Spring
Harbor
Symp.
Quant. Biol. 16, 65 (1951).
6. Benzer,
S., “The Elementary
Fnits
of Heredity.”
Iii The Chemical
Basis
of Heredity,
McElroy,
W. D., and Glass, B., Eds. Johns Hopkins
Press, Baltimore,
1957, p. 70.
7. Pauling,
L., Itano, H. A., Singer,
S. J., and Wells, I. C., Sickle cell anemia,
a molecular
disease.
Science
110, 543 (1949).
8. Ingram,
V. M., Gene mutations
in hunian
haeinogiobin:
The chemical
difference
between
normal and sickle cell haemoglobin.
Nature 180, 326 (1957).
9. Nirenberg,
M., Caskey,
T., Marshall,
H., Brinincombe,
H., Kellogg,
D., Doctor,
B., Hatfield, I)., Levin,
J., Rottman,
F., Pestka,
S., Wilcox,
M., and Anderson,
F., The RNA
code and protein
synthesis.
Cold Sprinq
Harbor
Synp.
Quant.
Biol. 31, 11 (1966).
10. Jacob,
F., and Monod,
J., Genetic
regulatory
mechanisms
in the synthesis
of proteins.
J. Mol. Biol. 3, 318 (1961).
1. Yanofsky,
C., Amino acid replacements
associated
with mutation
and reeombination
in the
A gene and their relationship
to iii vitro coding data. Cold Spring
harbor
Si/nip. Quant.
Biol. 28, 581 (1963).
12. Ames, B. N., and Hartman,
P. E., The iiistidimie operon. Cold Sprin#{231}j
Harbor
8pm p. Quant.
Biol. 28, 349 (1963).
13. FoIling,
A. t)ber
Aussclieidung
von
Plicnylbrenztraiibcnsiiure
in den Ham
als Stoffwechselanomnalie
in Verbindung
mit Imnbezillitiit.
ItoppeScylers
Z. Piiysiol.
Chem. 227,
169 (1934).
14. LaDu, B. N., Zammnoimi, V. G., Laster,
L., and Seegnmiller,
,T. E., The nature
of the defect
in tyrosiae
metabolism
in aicaptonuria.
J. Biol. Chem.
230, 251 (1958).
15. Taniguchi,
K., and Giessing,
L. B., Studies
on tyrosinosis.
TI. The activity
of the
transaminase,
parahydroxyphenyl-pyruvate
ovidase
and liomogemitisic-acid
oxidase.
Brit.
Med. J. 1, 968 (1965).
16. Halvorsen,
S., and Gjessing,
L. H., Studies
au tyrosinosis.
I. Effect
of low-tyrosiuue
and
low phenylalanine
diet. Brit. Mcd. J. 2, 1171 (1964).
17. Halvorsen,
S., Dietary
treatment
of tyrosinosis.
A in. ,J 1)iseases
Children
113, 38 (1967).
18. Seegmiller,
J. E., The acute attack
of gouty arthritis.
Arthritis
Rheuniat.
8, 714 (1965).
19. Seegmnilier,
J. E., Laster, L., and Howell, H. H., Biochemistry
of uric acid and its relation
to gout. New Engi.
J. Med. 268, 712, 764, and 821 (1963).
20. Con, G. T., and (‘on, C. F., Glucose-6-phosphatase
of the liver iii glycogen
storage
disease.
J. Biol. Chem. 199, 661 (1952).
21. Fine, H. N., Strauss,
J., and Donaell,
C. N., Hyperuricemia
in glycogen-storage
disease
type I. Am. J. Diseases
Children
112, 572 (1966).
22.
23.
24.
25.
Alepa,
F. P., Howell,
B.
tween glycogen
storage
Burns, .1. J., Missing
step
m.-ascorl,ie
acid. Nat nrc
B., Klinenberg,
J. B., and St’eguuuiller, J. H., Relationships
disease and tophaeeous
gout. Am. J. .1! ed. 42, 58 (1967).
in maim, monkey
and guinea pig required
for the liiosyntluesis
180, 553 (1957).
be.
of
LaDu, B. N., Howell, H. H., Jaeoby,
C .A., St’egnuiller,
.J. H., Sober, H. K., Zanuuoni, V. C.,
(‘anliy,
.1. P., and Ziegler,
L. K., Clinical
and biochemical
studies
au two eases of
histidinemia.
Pediatrics
32, 216 (1963).
Menkes,
J. H., Hurst,
P. L., and Craig,
J. M., New syndrome:
Progressive
familial
in-
564
2(i.
27.
28.
29.
3U.
EEGMILLER
Clinical
Chemistri,
fantile
cerebral
tlysfunctioii
associated
with unusual
urinary
substance.
Pediatrics
14,
462 (1954).
Westall,
Ii. C., [)ietary
treatment
of a child with maple
syrup
urine ilisease
(brauuched
chain ketoacidunia).
Arch. Disease
Childhood
38, 485 (1963).
Leselu,
M ., and Nyhiamu, W. L., A fain i lint disorder
of uric
acid
uncta I olisuui nuid central
nervous
system function.
Am. J. Med. 36, 561 (1964).
Sass, J. K., Itabashi,
H. H., and I)exter,
H .A.,
.Juveuuile gout with brain
involvement.
Arch. Neurol.
13, 639 (1965).
Shapiro,
S. L., Sheppard,
G. L., Jr., 1)reyfuss,
F. H., and Newcoinbe,
D. S., X-linked
recessive
inheritance
of a syndronme of mental
retardatious
with
hyperunieemia
(31204).
Proc. Soc. Exptl.
Biol. Med. 122, 609 (1966).
Scegni!ler,
.1. E., Hosenblooni,
F. hi., and Kelley,
W.N.,
Au euizyuume defect
assoeuate(l
with a scx-liuiked
human
neurological
disorder
and excessive
punine
synthesis.
Science.
155,
1682
(1967).