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Clinical and genetic characterization of families with triple A (Allgrove) syndrome.
[triple a syndrome]
Triple
A
(
Allgrove
)
syndrome
is
characterized
by
achalasia
,
alacrima
,
adrenal
abnormalities
and
a
progressive
neurological
syndrome
.
Affected
individuals
have
between
two
and
four
of
these
relatively
common
clinical
problems
;
hence
the
diagnosis
is
often
difficult
in
all
but
the
classical
presentation
.
The
inheritance
is
autosomal
recessive
,
and
most
cases
of
triple
A
have
no
family
history
.
Using
genetic
linkage
analysis
in
a
small
number
of
families
,
a
locus
on
chromosome
12
q
13
was
identified
.
The
triple
A
gene
was
identified
recently
at
this
locus
and
called
ALADIN
(
alacrima
,
achalasia
,
adrenal
insufficiency
neurologic
disorder
)
.
Mutations
in
this
gene
were
reported
in
families
from
North
Africa
and
Europe
.
The
majority
of
mutations
were
homozygous
.
We
have
identified
20
families
with
between
two
and
four
of
the
clinical
features
associated
with
the
triple
A
syndrome
.
Sequencing
of
the
triple
A
gene
revealed
five
families
that
had
a
total
of
nine
compound
heterozygous
mutations
,
and
one
Portuguese
family
(
previously
published
)
had
two
homozygous
mutations
;
these
changes
were
spread
throughout
the
triple
A
gene
in
exons
1
,
2
,
7
,
8
,
10
,
11
,
12
,
13
and
16
,
and
the
poly
(
A
)
tract
.
Those
bearing
mutations
had
the
classical
triple
A
syndrome
of
achalasia
,
alacrima
,
adrenal
abnormalities
and
a
progressive
neurological
syndrome
.
We
identified
a
spectrum
of
associated
neurological
abnormalities
in
these
cases
,
including
pupil
and
cranial
nerve
abnormalities
,
frequent
optic
atrophy
,
autonomic
neuropathy
and
upper
and
lower
motor
neurone
signs
including
distal
motor
neuropathy
and
amyotrophy
with
severe
selective
ulnar
nerve
involvement
.
In
these
families
,
we
have
made
genotype-phenotype
correlations
.
Mutations
in
the
triple
A
gene
are
thus
an
important
cause
of
this
clinically
heterogeneous
syndrome
,
and
sequencing
represents
an
important
diagnostic
investigation
.
Identifying
further
mutations
and
defining
their
phenotype
along
with
functional
protein
analysis
will
help
to
characterize
this
neuroendocrine
gene
.
Diseases
Validation
Diseases presenting
"optic atrophy"
symptom
canavan disease
coats disease
cohen syndrome
congenital toxoplasmosis
homocystinuria without methylmalonic aciduria
kallmann syndrome
malignant atrophic papulosis
triple a syndrome
zellweger syndrome
This symptom has already been validated