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PREPL deficiency with or without cystinuria causes a novel myasthenic syndrome.
[cystinuria]
To
investigate
the
genetic
and
physiologic
basis
of
the
neuromuscular
symptoms
of
hypotonia
-
cystinuria
syndrome
(
HCS
)
and
isolated
PREPL
deficiency
,
and
their
response
to
therapy
.
We
performed
molecular
genetic
,
histochemical
,
immunoblot
,
and
ultrastructural
studies
,
investigated
neuromuscular
transmission
in
vitro
in
a
patient
with
isolated
PREPL
deficiency
,
and
evaluated
the
effect
of
pyridostigmine
in
this
patient
and
in
3
patients
with
the
HCS
.
HCS
is
caused
by
recessive
deletions
involving
the
SLC
3
A
1
and
PREPL
genes
.
The
major
clinical
features
of
HCS
are
type
A
cystinuria
,
growth
hormone
deficiency
,
muscle
weakness
,
ptosis
,
and
feeding
problems
.
The
proband
with
isolated
PREPL
deficiency
had
myasthenic
symptoms
since
birth
and
a
positive
edrophonium
test
but
no
cystinuria
.
She
and
1
of
3
patients
with
HCS
responded
transiently
to
pyridostigmine
during
infancy
.
The
proband
harbors
a
paternally
inherited
nonsense
mutation
in
PREPL
and
a
maternally
inherited
deletion
involving
both
PREPL
and
SLC
3
A
1
;
therefore
,
the
PREPL
deficiency
determines
the
phenotype
.
We
detected
no
PREPL
expression
in
the
patient
's
muscle
and
endplates
.
Electrophysiology
studies
revealed
decreased
quantal
content
of
the
endplate
potential
and
reduced
amplitude
of
the
miniature
endplate
potential
without
endplate
acetylcholine
receptor
deficiency
or
altered
endplate
geometry
.
Isolated
PREPL
deficiency
is
a
novel
monogenic
disorder
that
causes
a
congenital
myasthenic
syndrome
with
pre-
and
postsynaptic
features
and
growth
hormone
deficiency
.
The
myasthenic
symptoms
in
PREPL
deficiency
with
or
without
cystinuria
may
respond
to
pyridostigmine
in
early
life
.
We
attribute
the
myasthenia
to
abrogated
interaction
of
PREPL
with
adaptor
protein
1
.
Diseases
Validation
Diseases presenting
"feeding problems"
symptom
cohen syndrome
cystinuria
homocystinuria without methylmalonic aciduria
kabuki syndrome
monosomy 21
This symptom has already been validated