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Neuroacanthocytosis Syndromes
Hans H Jung
1*
, Adrian Danek
2
and Ruth H Walker
3
Abstract
Neuroacanthocytosis (NA) syndromes are a group of genetically defined diseases characterized by the association
of red blood cell acanthocytosis and progressive degeneration of the basal ganglia. NA syndromes are
exceptionally rare with an estimated prevalence of less than 1 to 5 per 1’000’000 inhabitants for each disorder. The
core NA syndromes include autosomal recessive chorea-acanthocytosis and X-linked McLeod syndrome which
have a Huntington´s disease-like phenotype consisting of a choreatic movement disorder, psychiatric
manifestations and cognitive decline, and additional multi-system features including myopathy and axonal
neuropathy. In addition, cardiomyopathy may occur in McLeod syndrome. Acanthocytes are also found in a
proportion of patients with autosomal dominant Huntington’s disease-like 2, autosomal recessive pantothenate
kinase-associated neurodegeneration and several inherited disorders of lipoprotein metabolism, namely
abetalipoproteinemia (Bassen-Kornzweig syndrome) and hypobetalipoproteinemia leading to vitamin E
malabsorption. The latter disorders are characterized by a peripheral neuropathy and sensory ataxia due to dorsal
column degeneration, but movement disorders and cognitive impairment are not present. NA syndromes are
caused by disease-specific genetic mutations. The mechanism by which these mutations cause neurodegeneration
is not known. The association of the acanthocytic membrane abnormality with selective degeneration of the basal
ganglia, however, suggests a common pathogenetic pathway. Laboratory tests include blood smears to detect
acanthocytosis and determination of serum creatine kinase. Cerebral magnetic resonance imaging may
demonstrate striatal atrophy. Kell and Kx blood group antigens are reduced or absent in McLeod syndrome.
Western blot for chorein demonstrates absence of this protein in red blood cells of chorea-acanthocytosis patients.
Specific genetic testing is possible in all NA syndromes. Differential diagnoses include Huntington disease and
other causes of progressive hyperkinetic movement disorders. There are no curative therapies for NA syndromes.
Regular cardiologic studies and avoidance of transfusion complications are mandatory in McLeod syndrome. The
hyperkinetic movement disorder may be treated as in Huntington disease. Other symptoms including psychiatric
manifestations should be managed in a symptom-oriented manner. NA syndromes have a relentlessly progressive
course usually over two to three decades.
Definition
Neuroacanthocytosis (NA) refers to a heterogeneous group
of syndromes in which nervous system abnormalities coin-
cide with red blood cell acanthocytosis, i.e. deformed
erythrocytes with spike-like protrusions (Figure 1) [1].
However, acanthocytosis can be variable, and the diagnosis
of these syndromes does not require their demonstration
on peripheral blood smear. There are two broad groups of
NA disorders (Table 1). First, the so-called “core”NA
syndromes characterized by degeneration of the basal
ganglia, movement disorders, cognitive impairment and
psychiatric features, and second, conditions with alteration
of lipoprotein metabolism, namely abetalipoproteinemia
(Bassen-Kornzweig syndrome) and hypobetalipoproteine-
mia leading to vitamin E malabsorption, with the clinical
hallmarks of peripheral neuropathy and sensory ataxia due
to dorsal column degeneration, but without movement dis-
orders. In addition, there are several sporadic conditions
associated with acanthocytosis (Table 1). This review will
refer only to the first group of NA syndromes.
NA syndromes were known initially under the eponym
“Levine-Critchley syndrome”[2,3]. The clinical descrip-
tion of the subjects reported by Critchley is compatible
with autosomal recessive chorea-acanthocytosis (ChAc;
ORPHA2388) and preliminary genetic data from the
index family support this diagnosis. However, the inheri-
tance pattern and clinical features of the family described
* Correspondence: hans.jung@usz.ch
1
Department of Neurology, University Hospital Zürich, Zürich, Switzerland
Full list of author information is available at the end of the article
Jung et al.Orphanet Journal of Rare Diseases 2011, 6:68
http://www.ojrd.com/content/6/1/68
© 2011 Jung et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons
Attribution License (http://creative commons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in
any medium, pro vided the original work is properly cited.
by Levine is not fully compatible with either ChAc or
with the X-linked recessive McLeod syndrome (MLS;
ORPHA59306). A retrospective genetic analysis so far
has not been possible, as this family unfortunately
appears lost to follow-up, and thus the original eponym
appears obsolete.
MLS was named after a Harvard dental student, Hugh
McLeod, in whom an abnormal erythrocyte antigen pat-
tern (absent or weak expression of Kell antigens) was
first described [4]. Initially, the McLeod blood group
phenotype was thought to be of no clinical significance,
apart from the requirement for matched blood transfu-
sions. Later it was found that the McLeod blood group
phenotype was also observed in boys with X-linked
chronic granulomatous disease (CGD; ORPHA379) [5]
and that asymptomatic adult male carriers of the
McLeod blood group phenotype have elevated serum
levels of CK reflecting muscle cell pathology [6]. Subse-
quently it was recognized that McLeod carriers had a
“neurological disorder characterized by involuntary
dystonic or choreiform movements, areflexia, wasting of
limb muscles, elevated CK, and congestive cardiomyopa-
thy”, thus defining MLS as a multi-system disorder with
hematological, neuromuscular, and central nervous sys-
tem (CNS) involvement [7].
In 1991, Hardie and colleagues described a series of 19
NA patients, which for years was the seminal work on
NA [8]. However, with recognition of the molecular
basis of the different NA syndromes, this case series has
turned out to be heterogeneous, including patients with
ChAc, MLS and pantothenate kinase-associated neuro-
degeneration (PKAN; ORPHA157850).
The “core”NA syndromes are now defined as autosomal
recessive ChAc caused by mutations of the VPS13A gene
[9,10], and X-linked MLS, caused by mutations of the XK
gene [11]. Additionally there are several genetically defined
disorders in which acanthocytosis is occasionally seen,
such as PKAN [12] and Huntington disease-like 2 (HDL2;
ORPHA98934) [13]. Occasional rare cases or families are
reported where acanthocytes are present in concert with
other extrapyramidal features, such as paroxysmal dyski-
nesias [14] or mitochondrial disease [15].
Epidemiology
NA disorders are all exceedingly rare, but also very likely
to be underdiagnosed. Estimates suggest that there are
probably around one thousand ChAc cases and a few hun-
dred cases of MLS worldwide. ChAc appears to be more
prevalent in Japan, possibly due to a genetic founder effect
[10], and clusters have been found elsewhere in geographi-
cally isolated communities, e.g. in the French-Canadian
population [16]. MLS has been described in Europe, North
and South America, and Japan without obvious clustering
[17]. PKAN is somewhat more common with an estimated
prevalence of 1 to 3/1’000’000. HDL2 is very rare, with
less than 50 families identified worldwide. The vast major-
ity of families are of African ancestry [18], including two
Brazilian families in whom the African ethnic background
Figure 1 Acanthocytes. Peripheral blood smear showing
acanthocytosis in a patient with McLeod syndrome (May
Gruenwald-Giemsa; x100; scale bar = 10 μm).
Table 1 Neuroacanthocytosis syndromes
Core neuroacanthocytosis syndromes Neuroacanthocytosis with
lipoprotein disorders
Acanthocytosis in systemic diseases where neurological
findings may also be present
Chorea-acanthocytosis (ChAc) Abetalipoproteinemia (Bassen-
Kornzweig syndrome)
Severe malnutrition (e.g. anorexia nervosa)
McLeod syndrome (MLS) Familial hypobetalipoproteinemia Cancers, sarcoma
Huntington’s disease-like 2 (HDL2) Anderson disease Thyroid disorders, myxoedema
Pantothenate kinase associated
neurodegeneration (PKAN)
Atypical Wolman disease Splenectomy
Liver cirrhosis, hepatic encephalopathy
MELAS
Psoriasis
Eales’disease (angiopathia retinae juvenilis)
MELAS, mitochondrial encephalopathy with lactic acidosis and stroke-like episodes.
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was not apparent on initial examination [19]. One HDL2
case has been reported of “middle Eastern”origin [20], but
further details are not available.
Clinical Characteristics
The core NA syndromes ChAc and MLS have a Hunting-
ton disease-like phenotype with an involuntary hyperki-
netic movement disorder, psychiatric manifestations and
cognitive alterations, thus representing phenocopies of
HD. Both disorders have an adult onset and a slow pro-
gression. However, there are several phenotypic peculiari-
ties, in particular the neuromuscular involvement reflected
in signs of myopathy and absent tendon reflexes that allow
a clinical suspicion of these two disorders. In addition,
hepatosplenomegaly can be seen in both syndromes due
to increased hemolysis. HDL2 and PKAN, by contrast,
have a childhood or juvenile onset, and HDL2 is usually
found in patients with African ancestry.
Chorea-Acanthocytosis
ChAc is a progressive autosomal recessive neurodegenera-
tive disorder with onset of neurological symptoms usually
in the twenties, thus representing a late onset for an auto-
somal recessive disorder (Table 2) [1]. Often the initial
presentation may be subtle cognitive or psychiatric symp-
toms, and in retrospect patients may have developed
related psychiatric complaints several years before the
neurological manifestations. Administration of neurolep-
tics for psychiatric disease may confound the recognition
of the movement disorder as due to a neurodegenerative
process. In some cases, seizures may precede the appear-
ance of movement disorders by as much as a decade [21].
During the disease course, most patients develop a
characteristic phenotype including chorea, a very peculiar
“feeding dystonia”with tongue protrusion [22], orofacial
dyskinesias, involuntary vocalizations, dysarthria and invo-
luntary tongue- and lip-biting. The gait of ChAc patients
may have a “rubber man”appearance with truncal instabil-
ity and sudden, violent trunk spasms [23]. Most ChAc
patients develop generalized chorea and a minority of
ChAc patients develops Parkinsonism. In addition to oro-
faciolingual dystonia, limb dystonia is common. In at least
one third of patients, seizures, typically generalized, are
the first manifestation of disease. Impairment of memory
and executive functions is frequent, although not invari-
able. Psychiatric manifestations are common and may pre-
sent as schizophrenia-like psychosis or obsessive-
compulsive disorder. Most ChAc patients have elevated
levels of creatine phosphokinase (CK). In contrast to MLS,
myopathy and axonal neuropathy are usually mild. Clinical
neuromuscular manifestations include areflexia, sensory-
motor neuropathy, and variable weakness and atrophy.
Muscle biopsy and electromyography commonly demon-
strate neuropathic changes and rarely myopathic altera-
tions. ChAc usually slowly progresses over 15-30 years,
but sudden death, presumably caused by seizures or auto-
nomic involvement, may occur.
McLeod Neuroacanthocytosis Syndrome
TheMcLeodbloodgroupphenotypeisdefinedbythe
absence of the Kx antigen and by weak expression of the
Kell antigens, and may be incidentally detected on routine
screening (Table 2) [4,24]. Most carriers of the McLeod
blood group phenotype have acanthocytosis and elevated
CK levels, and develop MLS over several decades [17,24].
Onset of neurological symptoms ranges from 25-60 years
Table 2 Comparative Features
Disorder ChAc MLS HDL2 PKAN
Gene VPS13A XK JPH3 PANK2
Protein Chorein XK protein Junctophilin-3 Panthothenate kinase
2
Inheritance Autosomal recessive X-linked Autosomal
dominant
Autosomal recessive
Acanthocytes +++ +++ +/- +/-
Serum CK (U/L) 300 - 3000 300 - 3000 Normal Normal
Neuroimaging Striatal atrophy Striatal
atrophy
Striatal and
cortical atrophy
“Eye of the tiger”
sign
Usual onset 20 - 30 25 - 60 20 - 40 Childhood
Chorea +++ +++ +++ +++
Other movement
disorders
Feeding and gait dystonia, tongue and
lip biting, parkinsonism
Vocalizations Dystonia,
parkinsonism
Dystonia,
parkinsonism,
spasticity
Seizures Generalized, partial-complex Generalized None None
Neuromuscular
manifestations
Areflexia, weakness, atrophy Areflexia, weakness, atrophy None None
Cardiac
manifestations
None Atrial fibrillation, malignant arrhythmias,
dilative cardiomyopathy
None None
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and disease duration may be more than 30 years, usually
longer than in ChAc [17,24]. About one third of MLS
patients present with chorea indistinguishable from that
observed in HD [25], and most patients will develop
chorea during the course of the disease. Additional invo-
luntary movements include facial dyskinesias and vocaliza-
tions. In contrast to ChAc, only exceptional MLS patients
have lip- or tongue-biting, dysphagia, dystonia, or parkin-
sonism [24]. Psychiatric manifestations including depres-
sion, schizophrenia-like psychosis and obsessive-
compulsive disorder are frequent and may appear many
years prior to the movement disorders [26]. A subset of
MLS patients develops cognitive deficits, particularly in
later disease stages. Generalized seizures occur in about
half of the patients.
Elevated CK levels are almost always found, about half
of the MLS patients develop muscle weakness and atro-
phy during the disease course, but severe weakness is
only rarely observed [27]. However, MLS myopathy may
predispose to rhabdomyolysis, in particular in the context
of neuroleptic medication use [28]. Neuromuscular
pathology shows sensory-motor axonal neuropathy, neu-
rogenicmusclechangesandvariablesignsofmyopathy
[27]. About 60% of MLS patients develop a cardiomyopa-
thy manifesting with atrial fibrillation, malignant arrhyth-
mias or dilated cardiomyopathy. Cardiac complications
are a frequent cause of death, thus MLS patients and
asymptomatic carriers of the McLeod blood group phe-
notype should have a cardiologic evaluation [24,29].
Some female heterozygotes show CNS manifestations
related to MLS as well as corresponding neuropathologi-
cal changes [8]. Reduction of striatal glucose uptake was
demonstrated in asymptomatic female heterozygotes
[26].
In addition, MLS may be part of a “contiguous gene syn-
drome”on the X chromosome including CGD, Duchenne
muscular dystrophy or X-linked retinitis pigmentosa. This
is of particular importance for boys with chronic granulo-
matous disease who survive into adulthood because of
modern treatment modalities: they must be screened for
the McLeod phenotype and should be regularly monitored
for its complications.
Huntington’s Disease-like 2
HDL2 presents usually in young adulthood, but, as with
HD, the age of onset is inversely related to the size of the
trinucleotide repeat expansion (Table 2) [30]. Patients may
develop psychiatric abnormalities as the initial manifesta-
tion, with later appearance of chorea, parkinsonism and
dystonia [14]. The disease may evolve from chorea to a
more bradykinetic, dystonic phenotype, or remain parkin-
sonian throughout the disease course, but unlike HD, this
is not related to the size of the trinucleotide expansion.
Unlike in ChAc and MLS, deep tendon reflexes are usually
brisk; there are no peripheral nerve or muscle abnormal-
ities, and seizures have not been reported. Acanthocytosis
is found in about 10% of HDL2 patients and CK levels are
normal. Neuroimaging reveals bilateral striatal atrophy, in
particular of the caudate nucleus. In contrast to ChAc and
MLS, generalized cortical atrophy may develop during the
disease course. Neuropathologically, ubiquitin-immunor-
eactive intranuclear neuronal inclusions, similar to those
seen in HD, are found [30].
Pantothenate kinase-associated Neurodegeneration
PKAN is an autosomal recessive condition included in the
group of disorders known as neurodegeneration with
brain iron accumulation (NBIA). PKAN is the only NBIA
in which acanthocytosis has been reported so far, and typi-
cally presents in childhood with rapid progression over 10
years (Table 2) [12]. Initial manifestations include orofacial
and limb dystonia, choreoathetosis and spasticity. Lingual
dystonia can be prominent, but is not specifically related
to eating as in ChAc. Other speech difficulties specifically
palilalia or dysarthria, are prominent features of PKAN
[12]. Most patients develop pigmentary retinopathy and
one third cognitive impairment. About 8 to 10% of PKAN
patients have acanthocytosis, perhaps due to abnormalities
of lipid synthesis [12]. Onset can be later, with more rigid-
ity in atypical forms of PKAN [12], but the typical MRI
findings of the “eye of the tiger”sign suggest the diagnosis.
Aetiology
The genes responsible for the various NA syndromes
have been identified.
ChAc is caused by various mutations of a 73 exon gene
on chromosome 9, VPS13A, coding for chorein [9,10]. No
obvious genotype-phenotype correlations have been
observed. Chorein is implicated in intracellular protein
sorting but its physiological functions are not yet known.
Chorein is widely expressed throughout the brain and var-
ious internal organs. Almost all mutations to date appear
to result in absence of chorein and there do not appear to
be any partial manifestations of the disease, e.g. in hetero-
zygous carriers.
MLS is caused by mutations of the XK gene encoding
the XK protein, which carries the Kx erythrocyte antigen
(11). Most pathogenic mutations are nonsense mutations
or deletions predicting an absent or shortened XK protein
lacking the Kell protein binding site. Although the exact
function of the human XK protein is not elucidated, data
from a C. elegans analogue of the XK gene suggest a possi-
ble role in apoptosis regulation [31]. The XK protein has
ten transmembrane domains and probably has transport
functions. In erythrocytes it is linked to the Kell protein
via disulfide bonds. This complex carries the antigens of
the Kell blood group, the third most important blood
group system in humans. The Kx antigen (on XK) is
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absent in McLeod syndrome and expression of other Kell
system antigens (on the Kell protein) is severely depressed
[4,17]. In muscle, Kell and XK are not co-localized [32]
and only XK but not Kell is present in neuronal tissue
indicating different physiological functions of the two pro-
teins in different tissues [33,34].
HDL2 is caused by expanded trinucleotide repeats of the
junctophilin 3 gene (JPH3). As in HD, there is anticipation
and the age of onset is inversely related to the size of the
trinucleotide repeat expansion. Affected individuals have
CTG/CAG repeat expansions of 41-59 triplets (normal
population: 6-27).The expanded trinucleotide repeat in the
JPH3 gene responsible for HDL2 causes both ubiquiti-
nated intranuclear neuronal inclusions [30,35,36] and
cytoplasmic mRNA inclusions [37]. There is evidence
from cell culture studies that these latter inclusions are
responsible for cell death [37]. JPH3 plays a role in junc-
tional membrane structures, and may be involved in the
regulation of calcium.
PKAN is caused by mutations of the pantothenate
kinase 2 gene (PANK2) on chromosome 20p13. Truncat-
ing mutations are responsible for the majority of cases.
PKAN catalyses the rate-limiting step in the synthesis of
coenzyme A from vitamin B5 (pantothenate). The residual
enzymatic activity correlates with the disease phenotype,
as typical patients have no active enzyme but atypical
patients with adult onset usually harbor PANK2 missense
mutations [12]. Impaired lipid synthesis may account for
the RBC acanthocytosis. Additional genes, responsible for
further subtypes of NBIA, have recently been discovered.
Nothing is yet known about the occurrence of acantho-
cytes in these.
Diagnostic Considerations
The determination of acanthocytosis in peripheral blood
smears may be negative in a standard setting and a nega-
tive screen does not exclude an NA syndrome [38]. Auto-
mated blood counts usually show an elevated number of
hyperchromic erythrocytes. A more sensitive and specific
method for the detection of acanthocytes uses a 1:1 dilu-
tion with physiological saline and phase contrast micro-
scopy [39]. In contrast to the often elusive acanthocyte
search, serum CK is elevated in most cases of ChAc and
MLS.
ChAc patients have absent chorein expression in ery-
throcytes on Western blot (http://www.euro-hd.net/html/
na/network/docs/chorein-wb-info.pdf) [40]. Confirmatory
DNA analysis of the large VPS13A gene is difficult, due to
the large gene size and heterogeneity of mutation sites
[4-6,9,10], and is currently available only from a single
commercial laboratory (http://www.mgz-muenchen.de).
The diagnostic procedure of choice in MLS is the determi-
nation of absent Kx antigen and reduced Kell antigens on
the erythrocytes in males and fluorescence absorbent cell
sorting with Kell antigens in female heterozygotes. Analy-
sis of the XK gene is confirmatory and offered by a num-
ber of academic laboratories.
In ChAc and MLS, electroneurography may demon-
strate sensorimotor axonal neuropathy whereas electro-
myography may show neurogenic as well as myopathic
alterations. Electroencephalographic findings are not spe-
cificandmaycomprisenormalfindings,generalized
slowing, focal slowing, and epileptiform discharges. Neu-
roradiologically, there is progressive striatal atrophy espe-
cially affecting the head of caudate nucleus and impaired
striatal glucose metabolism similar to that seen in HD
(Figure 2) [24,26]. Voxel-based morphometry of MRI
scans in ChAc shows specific involvement of the head of
the caudate nucleus [41,42]. Neurodegeneration in both
core NA syndromes affects predominantly the caudate
nucleus, putamen and globus pallidus. In ChAc, thalamus
and substantia nigra are also involved. In contrast to HD,
there is no significant cortical pathology [8,43-45]. Neu-
ropathological findings consist of neuronal loss and glio-
sis of variable degree in these regions, but no inclusion
bodies of any nature or other distinct neuropathological
features have as yet been detected.
Cerebral MRI is often diagnostic in PKAN, and the
diagnosis is confirmed by analysis of the PANK2 gene
(Figure 2). Analysis of the JPH3 gene CTG expansion is
useful in patients of African ancestry with suspected
HDL2.
Differential Diagnosis
The differential diagnosis of NA syndromes depends
upon the presenting symptoms, which can be protean.
Initial symptoms may suggest psychiatric disease, includ-
ing schizophrenia, depression, obsessive-compulsive
disorder, tics, Tourette’s syndrome, cognitive impairment,
personality change, or may consist of parkinsonism,
chorea, dystonia, peripheral neuropathy, myopathy, cardi-
omyopathy, or seizures [1]. Persons harboring the
McLeod blood group phenotype are sometimes identified
upon blood donation, many years or even decades prior
to development of neurological symptoms. An important
constellation to consider McLeod testing is the diagnostic
work-up of chronic granulomatous disease, particularly if
X-linked. Both MLS and ChAc may be detected inciden-
tally by the elevation of CK or liver enzymes. Recognition
of the syndrome may avoid the need for invasive and
non-diagnostic tests such as muscle, bone marrow, or
liver biopsy.
ChAc, MLS, and HDL2 all present in young to middle
adulthood, but MLS has usually the latest onset of neu-
rological symptoms. PKAN typically presents during
childhood or adolescence, although adult-onset has been
reported, particularly in cases where mutations do not
abolish all PANK2 enzyme activity.
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A B
C D
F
E
G H
Figure 2 Neuroimaging.ChAc. Coronal FLAIR- (A) and axial T1-weighted (B) images demonstrate moderate atrophy of the caudate nucleus.
MLS. Axial T2-weighted images demonstrate moderate atrophy of caudate nucleus and putamen (C) but no relevant cortical atrophy (D). HDL2.
Axial FLAIR- (E) and coronal T1-weighted images (F) demonstrate atrophy of the caudate nucleus and the fronto-temporal cortex. In addition,
FLAIR images show periventricular white matter hyperintensities (courtesy of Nora Chan, MD, UCLA, Los Angeles, USA). PKAN. T2-weighted fast
spin echo (G) and T1-weighted (H) brain MRI scans from a child with PKAN demonstrating the “eye of the tiger”sign (courtesy of Susan J.
Hayflick, MD, Oregon Health and Science University, Portland, Oregon, USA)
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Presence of self-mutilating lip and tongue biting, or
other self-mutilation such as head-scratching or finger-bit-
ing is strongly suggestive of ChAc. Self-mutilation of a
comparable nature may be seen in boys with Lesch-Nyhan
syndrome, however in these cases the age of onset is very
much younger. Patients with PKAN may also develop
quite severe lingual dystonia, but it does not appear to be
task-specific.
Genetic Counseling
ChAc is unusual for an autosomal recessive disorder, since
its presentation is in early to middle adulthood, when the
patient’s parents relatively unlikely choose to have further
children. The chances of any sibling developing ChAc is
1:4. Children of affected subjects will inherit one mutant
allele and will not be affected. MLS is X-linked, thus
affected males will pass on the mutant X chromosome to
their daughters, whose sons will have a 1:2 chance of
developing MLS and daughters will have a 1:2 chance of
being carriers. These female carrier heterozygotes rarely
develop a neurological syndrome. PKAN is autosomal
recessive, and siblings will have a 1:4 chance of developing
disease. HDL2 is autosomal dominant, thus any child of
an affected parent has a 1:2 chance of developing the dis-
ease. Siblings of an affected subject also have a 1:2 chance
of being affected. Due to anticipation, related to expansion
of the trinucleotide repeat, age of onset can be younger
with successive generations. Since all genes are known,
routine methods for prenatal testing can be applied.
Management
So far no curative or disease-modifying treatments are
available and management of the NA disorders is purely
symptomatic. Recognition of treatable complications such
as seizures, swallowing problems, and heart involvement is
essential. Neuropsychiatric issues, particularly depression,
can have a major impact upon quality of life, and these
symptoms may be more amenable to pharmacotherapy
than others. Dopamine antagonists or depleters such as
tiapride, clozapine or tetrabenazine may ameliorate the
hyperkinetic movement disorders. Seizures usually
respond to standard anticonvulsants, including phenytoin
and valproate, although lamotrigine and carbamazepine
may worsen the involuntary movements [21]. Anticonvul-
sants may have the benefit of multiple parallel effects
upon involuntary movements, psychiatric symptoms, and
seizures. Cardiac complications in MLS need to be parti-
cularly considered and heart function should be monitored
regularly. No patient with MLS to our knowledge has yet
received a heart transplant, which could nevertheless be a
management option.
Results of deep brain stimulation (DBS) in ChAc and
MLS have been variable, and the optimal sites and pre-
ferred stimulation parameters remain to be determined
[46-48]. Benefits have been observed with stimulation of
both the ventro-oral posterior (Vop) thalamic nucleus and
the GPi [46-48]. Thalamic stimulation in one ChAc patient
resulted in a dramatic and sustained reduction of truncal
spasms, but there was no clear effect upon dysarthria or on
hypotonia. High frequency stimulation (130 Hz) of the GPi
worsened speech and chorea, but improved dystonia,
belching, dyskinetic breathing and tongue-biting. Low fre-
quency stimulation (40Hz) improved chorea, but not dys-
tonia. An ablative proceduremaybeavaluablesurgical
alternative if long-term implant management is likely to be
problematic. In general, neurosurgical options should be
considered experimental and must be tailored to individual
cases.
Non-medical therapies with a multidisciplinary approach
are often helpful. Evaluation by a speech therapist is essen-
tial to minimize problems due to dysphagia and weight
loss. Dystonia of the lower face and tongue can result in
severe tongue and lip self-mutilation in ChAc and may be
ameliorated by a bite plate. Dystonic tongue protrusion
whilst eating in ChAc may respond to local botulinum
toxin injections into the genioglossus muscle, although
this method has to be applied with caution due to possible
mechanical obstruction of the airway and inefficient swal-
lowing by paretic muscles. Placement of a feeding tube,
temporarily or even continuously, including percutaneous
gastrostomy, may be necessary to avoid nutritional com-
promise and to reduce the risk of aspiration. Physical and
occupational therapists can assist with difficulties with
gait, balance, and activities of daily living. Most impor-
tantly, extended and continuous multidisciplinary psycho-
social support should be provided for the patients and
their families.
Prognosis
All NA disorders have a relentlessly progressive course
and are eventually fatal. Sudden death may be due to sei-
zure, or possibly autonomic dysfunction, but there may be
gradually progressive, generalized debility, as seen in Hun-
tington’sorParkinson’s diseases, with patients succumbing
to aspiration pneumonia or other systemic infections.
Unresolved Questions
Much remains to be learned regarding the molecular
mechanisms which cause neurodegeneration in the NA
syndromes. The relationship between erythrocyte acantho-
cytosis and neurodegeneration is obscure, perhaps less so
in PKAN. We hope that elucidation of molecular patho-
physiology will lead to prevention and reversal of disease
at the cellular level.
Conclusions
NA syndromes must be included in the differential diag-
nosis of Huntington disease (HD). Their consideration is
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mandatory if HD genetic testing is negative. The NA
syndromes have additional clinical characteristics such
as epilepsy, peripheral neuropathy, cardiomyopathy
(MLS) as well as orofacial dyskinesia, and feeding dysto-
nia (ChAc). Paraclinical findings such acanthocytosis
and elevated CK levels may be crucial to indicate the
appropriate laboratory examination, in particular Kell
blood group phenotyping and chorein Western blotting.
Specific genetic testing may confirm the diagnosis. Man-
agement of NA syndromes is symptomatic, although life
expectancy and quality of life may be augmented consid-
erably by the appropriate measures.
Acknowledgements and Funding
The authors thank the Advocacy of Neuroacanthocytosis Patients, in
particular Glenn and Ginger Irvine, for their continuous support.
Author details
1
Department of Neurology, University Hospital Zürich, Zürich, Switzerland.
2
Department of Neurology, Ludwig-Maximilians-Universität, München,
Germany.
3
Department of Neurology, Veterans Affairs Medical Center, Bronx,
NY, USA.
Authors’contributions
All authors contributed to the conception and design of the review. HHJ
and RHW drafted the manuscript. All authors critically revised the manuscript
and gave their final approval of the version to be published.
Competing interests
The authors declare that they have no competing interests.
Received: 16 December 2010 Accepted: 25 October 2011
Published: 25 October 2011
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doi:10.1186/1750-1172-6-68
Cite this article as: Jung et al.: Neuroacanthocytosis Syndromes.
Orphanet Journal of Rare Diseases 2011 6:68.
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