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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
"homocystinuria"
symptom
adrenomyeloneuropathy
cohen syndrome
homocystinuria without methylmalonic aciduria
primary hyperoxaluria type 1
pyruvate dehydrogenase deficiency
This symptom has already been validated