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Mutations in GMPPA cause a glycosylation disorder characterized by intellectual disability and autonomic dysfunction.
[triple a syndrome]
In
guanosine
diphosphate
(
GDP
)
-
mannose
pyrophosphorylase
A
(
GMPPA
)
,
we
identified
a
homozygous
nonsense
mutation
that
segregated
with
achalasia
and
alacrima
,
delayed
developmental
milestones
,
and
gait
abnormalities
in
a
consanguineous
Pakistani
pedigree
.
Mutations
in
GMPPA
were
subsequently
found
in
ten
additional
individuals
from
eight
independent
families
affected
by
the
combination
of
achalasia
,
alacrima
,
and
neurological
deficits
.
This
autosomal-recessive
disorder
shows
many
similarities
with
triple
A
syndrome
,
which
is
characterized
by
achalasia
,
alacrima
,
and
variable
neurological
deficits
in
combination
with
adrenal
insufficiency
.
GMPPA
is
a
largely
uncharacterized
homolog
of
GMPPB
.
GMPPB
catalyzes
the
formation
of
GDP-mannose
,
which
is
an
essential
precursor
of
glycan
moieties
of
glycoproteins
and
glycolipids
and
is
associated
with
congenital
and
limb
-girdle
muscular
dystrophies
with
hypoglycosylation
of
α-dystroglycan
.
Surprisingly
,
GDP-mannose
pyrophosphorylase
activity
was
unchanged
and
GDP-mannose
levels
were
strongly
increased
in
lymphoblasts
of
individuals
with
GMPPA
mutations
.
This
suggests
that
GMPPA
might
serve
as
a
GMPPB
regulatory
subunit
mediating
feedback
inhibition
of
GMPPB
instead
of
displaying
catalytic
enzyme
activity
itself
.
Thus
,
a
triple-
A-
like
syndrome
can
be
added
to
the
growing
list
of
congenital
disorders
of
glycosylation
,
in
which
dysregulation
rather
than
mere
enzyme
deficiency
is
the
basal
pathophysiological
mechanism
.
Diseases
Validation
Diseases presenting
"alacrima"
symptom
neonatal adrenoleukodystrophy
triple a syndrome
This symptom has already been validated