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Vitamin B12 in health and disease: part I--inherited disorders of function, absorption, and transport.
[homocystinuria without methylmalonic aciduria]
All
of
vitamin
B
12
in
nature
is
of
microbial
origin
.
Cobalamin
,
as
vitamin
B
12
should
correctly
be
termed
,
is
a
large
polar
molecule
that
must
be
bound
to
specialized
transport
proteins
to
gain
entry
into
cells
.
Entry
from
the
lumen
of
the
intestine
under
physiological
conditions
occurs
only
in
the
ileum
and
only
when
bound
to
intrinsic
factor
.
It
is
transported
into
all
other
cells
only
when
bound
to
another
transport
protein
,
transcobalamin
II
.
Congenital
absence
or
defective
synthesis
of
intrinsic
factor
or
transcobalamin
II
result
in
megaloblastic
anemia
.
The
Immerslund-
Graesbeck
syndrome
,
a
congenital
defect
in
the
transcellular
transport
of
cobalamin
through
the
ileal
cell
during
absorption
,
also
presents
with
megaloblastic
anemia
,
but
with
accompanying
albuminuria
.
In
most
bacteria
and
in
all
mammals
,
cobalamin
regulates
DNA
synthesis
indirectly
through
its
effect
on
a
step
in
folate
metabolism
,
the
conversion
of
N
5
-
methyltetrahydrofolate
to
tetrahydrofolate
,
which
in
turn
is
linked
to
the
conversion
of
homocysteine
to
methionine
.
This
reaction
occurs
in
the
cytoplasm
,
and
it
is
catalyzed
by
methionine
synthase
,
which
requires
methyl
cobalamin
(
MeCbl
)
,
one
of
the
two
coenzyme
forms
of
the
vitamin
,
as
a
cofactor
.
Defects
in
the
generation
of
MeCbl
(
cobalamin
E
and
G
diseases
)
result
in
homocystinuria
;
affected
infants
present
with
megaloblastic
anemia
,
retardation
,
and
neurological
and
ocular
defects
.
5
'
-
Deoxyadenosyl
cobalamin
(
AdoCbl
)
,
the
other
coenzyme
form
of
cobalamin
,
is
present
within
mitochondria
,
and
it
is
an
essential
cofactor
for
the
enzyme
Methylmalonyl-
CoA
mutase
,
which
converts
L-
methylmalonyl
CoA
to
succinyl
CoA
.
This
reaction
is
in
the
pathway
for
the
metabolism
of
odd
chain
fatty
acids
via
propionic
acid
,
as
well
as
that
of
the
amino
acids
isoleucine
,
methionine
,
threonine
,
and
valine
.
Impaired
synthesis
of
AdoCbl
(
cobalamin
A
or
B
disease
)
results
in
infants
with
methylmalonic
aciduria
who
are
mentally
retarded
,
hypotonic
,
and
who
present
with
metabolic
acidosis
,
hypoglycemia
,
ketonemia
,
hyperglycinemia
,
and
hyperammonemia
.
Megaloblastic
anemia
does
not
develop
in
these
children
because
adequate
amounts
of
MeCbl
are
present
,
but
the
effect
of
methylmalonic
acid
on
marrow
stem
cells
may
give
rise
to
pancytopenia
.
Congenital
absence
of
reductases
in
the
cytoplasm
,
which
normally
reduce
the
cobalt
atom
in
cobalamin
from
its
oxidized
to
its
reduced
state
(
cobalamin
C
and
D
diseases
)
,
results
in
impaired
synthesis
of
both
MeCbl
and
AdoCbl
.
Both
methylmalonic
aciduria
and
homocystinuria
therefore
develop
in
these
children
,
and
they
present
with
megaloblastosis
,
mental
retardation
,
a
host
of
neurological
and
ocular
disorders
,
and
failure
to
thrive
;
however
,
they
do
not
have
hyperglycinemia
or
hyperammonemia
.
A
similar
biochemical
profile
and
clinical
presentation
is
also
seen
in
cobalamin
F
disease
,
which
results
from
a
defect
in
the
release
of
cobalamin
from
lysosomes
,
following
receptor-mediated
endocytosis
of
the
transcobalamin
II
-cobalamin
complex
into
cells
.
It
is
important
to
recognize
these
inborn
errors
of
cobalamin
absorption
,
transport
,
or
function
as
soon
after
birth
as
possible
,
because
most
respond
(
in
some
patients
more
fully
than
others
)
to
parenteral
administration
of
cobalamin
.
Delays
in
diagnosis
can
lead
to
grave
clinical
consequences
.
Diseases
Validation
Diseases presenting
"metabolic acidosis"
symptom
congenital diaphragmatic hernia
homocystinuria without methylmalonic aciduria
neonatal adrenoleukodystrophy
pendred syndrome
pyruvate dehydrogenase deficiency
scrub typhus
systemic capillary leak syndrome
This symptom has already been validated