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Atypical Chédiak-Higashi syndrome with attenuated phenotype: three adult siblings homozygous for a novel LYST deletion and with neurodegenerative disease.
[oculocutaneous albinism]
Mutations
in
LYST
,
a
gene
encoding
a
putative
lysosomal
trafficking
protein
,
cause
Chédiak-
Higashi
syndrome
(
CHS
)
,
an
autosomal
recessive
disorder
typically
characterized
by
infantile
-onset
hemophagocytic
syndrome
and
immunodeficiency
,
and
oculocutaneous
albinism
.
A
small
number
of
reports
of
rare
,
attenuated
forms
of
CHS
exist
,
with
affected
individuals
exhibiting
progressive
neurodegenerative
disease
beginning
in
early
adulthood
with
cognitive
decline
,
parkinsonism
,
features
of
spinocerebellar
degeneration
,
and
peripheral
neuropathy
,
as
well
as
subtle
pigmentary
abnormalities
and
subclinical
or
absent
immune
dysfunction
.
In
a
consanguineous
Pakistani
kindred
with
clinical
phenotypes
consistent
with
attenuated
CHS
,
we
performed
SNP
array-based
homozygosity
mapping
and
whole
gene
sequencing
of
LYST
.
We
identified
three
individuals
homozygous
for
a
novel
six
base
pair
in
-frame
deletion
in
LYST
(
c
.
9827
_
9832
ATACAA
)
,
predicting
the
loss
of
asparagine
and
threonine
residues
from
the
LYST
transcript
(
p
.
Asn
3276
_
Thr
3277
del
)
,
and
segregating
with
the
phenotype
in
this
family
.
We
further
characterize
the
neurologic
features
of
the
attenuated
form
of
CHS
,
and
discuss
pathophysiologic
mechanisms
underlying
the
neurodegenerative
components
of
CHS
.
Attenuated
CHS
is
phenotypically
heterogenous
and
should
be
considered
when
young
adults
develop
neurodegenerative
disease
and
have
pigmentary
abnormalities
.
We
briefly
discuss
surveillance
and
management
of
patients
with
CHS-related
neurodegeneration
.
Diseases
Validation
Diseases presenting
"spinocerebellar degeneration"
symptom
oculocutaneous albinism
This symptom has already been validated