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Spectrum of mutations in MMACHC, allelic expression, and evidence for genotype-phenotype correlations.
[homocystinuria without methylmalonic aciduria]
Methylmalonic
aciduria
and
homocystinuria
,
cblC
type
,
is
a
rare
disorder
of
intracellular
vitamin
B
(
12
)
(
cobalamin
[
Cbl
]
)
metabolism
caused
by
mutations
in
the
MMACHC
gene
.
MMACHC
was
sequenced
from
the
gDNA
of
118
cblC
individuals
.
Eleven
novel
mutations
were
identified
,
as
well
as
23
mutations
that
were
observed
previously
.
Six
sequence
variants
capture
haplotype
diversity
in
individuals
across
the
MMACHC
interval
.
Genotype-phenotype
correlations
of
common
mutations
were
apparent
;
individuals
with
c
.
394
C
>
T
tend
to
present
with
late-onset
disease
whereas
patients
with
c
.
331
C
>
T
and
c
.
271
dupA
tend
to
present
in
infancy
.
Other
missense
variants
were
also
associated
with
late
-
or
early
-onset
disease
.
Allelic
expression
analysis
was
carried
out
on
human
cblC
fibroblasts
compound
heterozygous
for
different
combinations
of
mutations
including
c
.
271
dupA
,
c
.
331
C
>
T
,
c
.
394
C
>
T
,
and
c
.
482
G
>
A
.
The
early
-onset
c
.
271
dupA
mutation
was
consistently
underexpressed
when
compared
to
control
alleles
and
the
late-onset
c
.
394
C
>
T
and
c
.
482
G
>
A
mutations
.
The
early
-onset
c
.
331
C
>
T
mutation
was
also
underexpressed
when
compared
to
control
alleles
and
the
c
.
394
C
>
T
mutation
.
Levels
of
MMACHC
mRNA
transcript
in
cell
lines
homozygous
for
c
.
271
dupA
,
c
.
331
C
>
T
,
and
c
.
394
C
>
T
were
assessed
using
quantitative
real-time
RT-PCR
.
Cell
lines
homozygous
for
the
late
onset
c
.
394
C
>
T
mutation
had
significantly
higher
levels
of
transcript
when
compared
to
cell
lines
homozygous
for
the
early
-onset
mutations
.
Differential
or
preferential
MMACHC
transcript
levels
may
provide
a
clue
as
to
why
individuals
carrying
c
.
394
C
>
T
generally
present
later
in
life
.
Diseases
Validation
Diseases presenting
"late onset"
symptom
adrenomyeloneuropathy
cadasil
canavan disease
congenital adrenal hyperplasia
cowden syndrome
cutaneous mastocytosis
homocystinuria without methylmalonic aciduria
junctional epidermolysis bullosa
kabuki syndrome
krabbe disease
neonatal adrenoleukodystrophy
omenn syndrome
phenylketonuria
primary hyperoxaluria type 1
proteus syndrome
pyruvate dehydrogenase deficiency
thoracic outlet syndrome
triple a syndrome
zellweger syndrome
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