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Novel Deletion Mutation Identified in a Patient with Late-Onset Combined Methylmalonic Acidemia and Homocystinuria, cblC Type.
[homocystinuria without methylmalonic aciduria]
Combined
methylmalonic
aciduria
and
homocystinuria
,
cblC
type
(
MMACHC
)
,
is
the
most
common
inborn
error
of
cellular
vitamin
B
12
metabolism
and
is
caused
by
mutations
in
the
MMACHC
gene
.
This
metabolic
disease
results
in
impaired
intracellular
synthesis
of
adenosylcobalamin
and
methylcobalamin
,
coenzymes
for
the
methylmalonyl-
CoA
mutase
and
methionine
synthase
enzymes
,
respectively
.
The
inability
to
produce
normal
levels
of
these
two
coenzymes
leads
to
increased
concentrations
of
methylmalonic
acid
and
homocysteine
in
plasma
and
urine
,
together
with
normal
or
decreased
concentration
of
methionine
in
plasma
.
Here
,
we
report
a
novel
homozygous
deletion
mutation
(
NM
_
015506
.
2
:
c
.
392
_
394
del
)
resulting
in
an
in
-frame
deletion
of
amino
acid
Gln
131
and
late-onset
disease
in
a
23
-
year
-old
male
.
The
patient
presented
with
sensory
and
motoric
disabilities
,
urine
and
fecal
incontinence
,
and
light
cognitive
impairment
.
There
was
an
excessive
urinary
excretion
of
methylmalonic
acid
and
greatly
elevated
plasma
homocysteine
.
The
clinical
symptoms
and
the
laboratory
abnormalities
responded
partly
to
treatment
with
hydroxycobalamin
,
folinic
acid
,
methionine
,
and
betaine
.
Studies
on
patient
fibroblasts
together
with
spectroscopic
activity
assays
on
recombinant
MMACHC
protein
reveal
that
Gln
131
is
crucial
in
order
to
maintain
enzyme
activity
.
Furthermore
,
structural
analyses
show
that
Gln
131
is
one
of
only
two
residues
making
hydrogen
bonds
to
the
tail
of
cobalamin
.
Circular
dichroism
spectroscopy
indicates
that
the
3
D
structure
of
the
deletion
mutant
is
folded
but
perturbed
compared
to
the
wild-
type
protein
.
Diseases
Validation
Diseases presenting
"mutations in the mmachc gene"
symptom
homocystinuria without methylmalonic aciduria
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