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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
"muscle weakness"
symptom
alexander disease
canavan disease
coats disease
cohen syndrome
cystinuria
familial mediterranean fever
focal myositis
inclusion body myositis
neuralgic amyotrophy
pyomyositis
severe combined immunodeficiency
systemic capillary leak syndrome
thoracic outlet syndrome
triple a syndrome
von hippel-lindau disease
This symptom has already been validated