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The Huntington’s disease-like syndromes:
what to consider in patients with a negative
Huntington’s disease gene test
Susanne A Schneider, Ruth H Walker and Kailash P Bhatia*
S U M M A RY
Huntington’s disease (HD), which is caused by a triplet-repeat expansion
in the IT15 gene (also known as huntingtin or HD), accounts for about 90%
of cases of chorea of genetic etiology. In recent years, several other distinct
genetic disorders have been identified that can present with a clinical
picture indistinguishable from that of HD. These disorders are termed
Huntington’s disease-like (HDL) syndromes. So far, four such conditions
have been recognized, namely disorders attributable to mutations in
the prion protein gene (HDL1), the junctophilin 3 gene (HDL2), and
the gene encoding the TATA box-binding protein (HDL4/SCA17), and a
recessively inherited HD phenocopy in a single family (HDL3), the genetic
basis of which is currently poorly understood. These disorders, however,
account for only a small proportion of cases with the HD phenotype but
a negative genetic test for HD, and the list of HDL genes and conditions is
set to grow. In this article, we review the most important HD phenocopy
disorders identified to date and discuss the clinical clues that guide further
investigation. We will concentrate on the four so-called HDL syndromes
mentioned above, as well as other genetic disorders such as dentatorubral–
pallidoluysian atrophy, neuroferritinopathy, pantothenate-kinase-associated
neurodegeneration and chorea–acanthocytosis.
keywords Huntington’s disease, Huntington’s disease-like syndromes,
junctophilin 3, prion disease, spinocerebellar ataxia type 17
Review criteria
We searched PubMed for articles published up to February 2007 using the following
search terms: “Huntington’s disease”, “Huntington’s disease-like syndromes”, “HDL”,
“chorea”, “prion protein”, “PrP”, “junctophilin”, “spinocerebellar ataxia 17” or
“SCA17”, “TATA box-binding protein”, “neuroferritinopathy”, “Pantothenate-
kinase-associated neurodegeneration” or “PKAN”, and “neuroacanthocytosis”.
Relevant articles were retrieved and prioritized for inclusion in this review.
Cross-referenced articles from retrieved papers were also considered.
cme
SA Schneider is a Clinical Research Fellow and PhD candidate and KP Bhatia
is Professor in Clinical Neurology at the Sobell Department of Motor
Neuroscience and Movement Disorders at the Institute of Neurology, University
College London, Queen Square, London, UK. RH Walker is Director of the
Movement Disorders Clinic, Department of Neurology, James J Peters Veterans
Affairs Medical Center, Bronx, and Assistant Professor in the Department of
Neurology, Mount Sinai School of Medicine, New York, NY, USA.
Correspondence
*Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology,
University College London, Queen Square, London WC1N 3BG, UK
kbhatia@ion.ucl.ac.uk
Received 9 May 2007 Accepted 19 June 2007
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doi:10.1038/ncpneuro0606
september 2007 vol 3 no 9  nature clinical practice NEUROLOGY 517
© 2007 Nature Publishing Group
Continuing Medical Education online
Medscape, LLC is pleased to provide online continuing
medical education (CME) for this journal article,
allowing clinicians the opportunity to earn CME credit.
Medscape, LLC is accredited by the Accreditation
Council for Continuing Medical Education (ACCME) to
provide CME for physicians. Medscape, LLC designates
this educational activity for a maximum of 1.0 AMA PRA
Category 1 CreditsTM. Physicians should only claim credit
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please go to http://www.medscape.com/cme/ncp
and complete the post-test.
Learning objectives
Upon completion of this activity, participants should be
able to:
1 Describe the prevalence of Huntington’s disease
(HD) among chorea disorders of genetic origin.
2 Describe the prevalence of the HD genotype among
different populations of the world.
3 Describe the clinical features of and diagnostic
criteria for HD.
4 Identify the inheritance patterns of the 4 HDL variants
of the HD phenotype.
5 Describe the clinical features of HDL variants of the
HD phenotype.
INTRODUCTION
Chorea has numerous causes, including both
genetic and acquired etiologies. The most impor­
tant genetic cause of chorea is Huntington’s
disease (HD), which is an autosomal dominant
neurodegenerative disorder attributable to muta­
tion of the IT15 (also known as huntingtin or HD)
gene on chromosome 4.1 The prevalence of HD is
high in certain regions of Scotland and Venezuela,
but is relatively low in Finland, Norway and
Japan.2,3 In North America and Europe the preva­
lence is about 4–8 cases per 100,000 individuals.
The classic triad of symptoms of HD comprises
adult-onset personality changes, general­ized
chorea, and cognitive decline. Notably, in chil­
dren or adolescents, HD tends to present as
an akinetic–rigid (Westphal) variant rather
than with chorea. Other features in both adult-
onset and young-onset forms of HD include
eye movement abnormalities (impersistence of
gaze and difficulty initiating saccades), dysarthria,
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Table 1 Summary of autosomal dominant disorders that cause chorea.

Condition Chromosomal Gene Average age at Clinical characteristics
location onset (years)
HD 4p15 IT15/huntingtin/HD <30 Chorea, personality
changes, dementia
HDL1 20p12 PRNP 20–40 HD phenocopy, prominent
psychiatric features
HDL2 16q24.3 JPH3 25–45 HD phenocopy, most
frequent in black South
Africans
HDL4 (SCA17) 6q27 TBP 25–40 Ataxia, HD phenocopy
SCA1 6p23 ATXN1 30–40 Ataxia, parkinsonism,
dystonia, chorea
SCA2 12q24 ATXN2 25–45 Ataxia, parkinsonism,
dystonia, chorea,
neuropathy, dementia
SCA3 14q32.1 ATXN3 20–50 Ataxia, parkinsonism,
dystonia, chorea
DRPLA 12p13.31 Atrophin 1 <20 Progressive myoclonus
epilepsy
>40 Ataxia, chorea, dementia
Neuroferritinopathy 19q13 FTL 40 Chorea, dystonia,
oromandibular
involvement, parkinsonism,
dysarthria
Benign hereditary 14q13 TITF-1 (and others) Childhood Non-progressive chorea
chorea (thyroid and pulmonary
abnormalities)
Abbreviations: ATXN1, ataxin 1; ATXN2, ataxin 2; ATXN3, ataxin 3; DRPLA, dentatorubral–pallidoluysian atrophy; FTL, ferritin,
light polypeptide; HD, Huntington’s disease; HDL, Huntington’s disease-like; JPH3, junctophilin 3; PRNP, prion protein;
SCA, spinocerebellar ataxia; TBP, TATA box-binding protein; TITF1, thyroid transcription factor 1.

dysphagia, pyramidal signs, and ataxia resulting
in walking difficulties with imbalance and
postural instability. Dystonia, myoclonus, tics
and tremor can also occur as part of the clinical
spectrum of HD. Brain imaging might reveal
progressive atrophy of the caudate nuclei that
can be present even before the onset of motor
symptoms. The diagnosis of HD is established
on the basis of genetic testing.
Since the ‘HD gene’ was identified in 1993,1 it
has been recognized that a small proportion of
patients with a clinical syndrome resembling HD
do not have the HD-causing trinucleotide repeat
expansion in the IT15 gene. For example, in a
report of 618 patients,4 only 93% of those with
the classic clinical phenotype of HD were found
to have the HD-associated gene mutation. This
evidence indicated the existence of other genetic
disorders, which are referred to as ‘Huntington’s
disease-like’ (HDL) syndromes. A number of
unrelated genes associated with these conditions
have been identified.5–8 Consequently, clinicians
have to consider an increasing range of differ­
ential diagnoses when confronted with a patient
with slowly progressive adult-onset chorea
and family history positive for neurological
or psychiatric disease, or both. In view of this
growing list of recognized disorders, we will
review the most common genetic causes of
chorea, focusing particularly on the spectrum
of HDL syndromes. We will concentrate on
the autosomal dominant conditions (Table 1);
however, because about 8% of patients with
HD present without an apparent family history
of the condition, chorea with other modes of
inheritance will also be mentioned.
HUNTINGTON’S DISEASE-LIKE
SYNDROMES
Huntington’s disease-like 1
Huntington’s disease-like 1 (HDL1) is an auto­
somal dominant progressive adult-onset neuro­
degenerative disorder caused by 192 or 168
base-pair insertions (encoding extra octa­peptide

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repeats) in the region of the prion protein (PRNP)
gene on chromosome 20p12.7,9,10 The clinical
picture of HDL is often similar to that of HD,
with abnormal involuntary movements, coordina­
tion difficulty, dementia, personality changes and
psychiatric symptoms;11 seizures have also been
described.7 The mean age at onset is 20–45 years.
Atrophy of the basal ganglia, the frontal and
temporal lobes and the cerebellum occurs.7 Kuru
and multicentric plaques that stain with anti-
prion antibodies have also been demonstrated on
neuropathological examination.9,11 Despite the
clinical suggestion of spongiform encephalo­pathy,
spongiosis was not prominent.
The normal form of the prion protein (PrPC)
is attached to the cellular membranes through
a glycophosphatidylinositol anchor, and one of
its structural features is a copper-binding site;
however, the normal function of the protein
is poorly understood.12 The conformational
conversion and transformation of the cellular
isoform to the pathogenic protein is believed to
have an important role in disease pathogenesis.
It has been suggested that variations in the site
of formation of the pathogenic protein and of
its subsequent accumulation might contribute
to the existence and broad phenotype of patho­
logically distinct prion disease entities.13 Overall,
PRNP mutations seem to be a rare genetic cause
of HD phenocopies.14–16
Huntington’s disease-like 2
HDL2 seems to account for about 2% of HD
phenocopies without the IT15 mutation.4,14 The
frequency is, however, higher in the black South
African population, in which HDL2 contributes
substantially to the overall incidence of the HD
phenotype.17–19 To investigate this phenomenon,
Krause et al.19 performed genetic tests on 149 South
African patients with the HD phenotype. Whereas
84% (78 out of 93) of white patients had the IT15
expansion, only 36% (18 of 50) of black patients
and 50% (3 of 6) of mixed-ancestry patients were
found to have this classic HD-causing mutation.
The authors found, however, that 24% (12 of
50) of black patients and 50% (3 of 6) of mixed-
ancestry patients had HDL2-causing expansions.
It has been suggested that the geographical
distribution of this disorder can be explained by
a founder effect that originated in Africa between
300 and 2,000 years ago.19 North American and
Mexican HDL2 families with African origins
have been described.20 With the exception of
one Brazilian family of Spanish–Portuguese
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ancestry21 HDL2 has not been reported in white
individuals; nor has this syndrome been reported
in the Japanese population.15,16,18,20
HDL2 onset occurs in the third or fourth
decade of a patient’s life, with a clinical picture
resembling classic adult-onset HD. A juvenile-
onset variant (pedigree W) has also been
described, in which seizures are absent and
eye movements are often normal.8 Recently,
adult-onset cases without chorea that resemble
juvenile HD have been reported.22 Pathological
examination has shown a picture similar, but not
identical, to that of classic HD.17,22,23 In about
10% of cases with HDL2, acanthocytes can be
detected in the peripheral blood smear.24,25
HDL2 is caused by a CTG•CAG triplet-repeat
expansion in the junctophilin 3 (JPH3) gene on
chromosome 16q24.3.26 The function of junc­
tophilin 3 remains unknown, but a role for the
protein in junctional membrane structures and
in the regulation of intracellular calcium has
been suggested.24 There is an inverse correla­
tion between age at HDL2 onset and CTG•CAG
repeat length. In the normal population, the
repeat length ranges from 6 to 28 CTG•CAG trip­
lets.22,24 Pathological repeat expansions range in
length from 44 to 57 triplets, and there is length
instability during maternal transmission.17,22
To date, the effect of alleles with 29–43 triplet
repeats is uncertain. Pathogenicity might be
related to the presence of mRNA inclusions.27
Huntington’s disease-like 3
Al-Tahan et al.28 and Kambouris et al.6 both
reported an autosomal recessive variant of HD
from Saudi Arabia that presented with early-
onset mental deterioration, dysarthria, dystonia,
pyramidal signs, ataxia and gait impairment.
Age at onset was 3–4 years. Progressive atrophy
of the frontal cortex and the caudate nuclei was
demonstrated by brain imaging. This condi­
tion was named HDL3, and the disease locus
was initially mapped to chromosome 4p15.3;6
however, it has been suggested that the evidence
for this linkage is weak.29 Although this condi­
tion has been named HDL3, it does not fit into
the group of HDL syndromes with respect to the
age of onset and the pattern of inheritance.
Huntington’s disease-like 4
(spinocerebellar ataxia type 17)
HDL4 has been identified as spinocerebellar
ataxia type 17 (SCA17), and is an autosomal
dominant triplet-repeat disorder caused by
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mutation of the TATA box-binding protein (TBP)
gene. This gene, which is located on chromo­some
6q27, encodes the TATA box-binding protein
(TBP), an important general transcription initia­
tion factor.30 Normal CAA•CAG repeat stretches
range from 25 to 42 in white individuals, with
larger repeats considered pathological. Reduced
penetrance has been reported for alleles with 43–
48 CAG repeats compared with those with longer
stretches.31 Age at onset of HDL4 is between 19
and 48 years, and childhood onset is rare.32 There
is an inverse correlation between age at onset and
number of CAA•CAG repeats, similar to HD.
Although cerebellar ataxia is the most common
feature of HDL4 (present in 94% of cases), the
phenotype is markedly heterogeneous, and extra­
pyramidal signs (73%), pyramidal signs (37%),
epilepsy (22%), dementia (76%) or psychiatric
disturbances (27%) might be prominent.33 A
clinical picture indistinguishable from that of
classic HD has been reported in both hetero­
zygous and homozygous mutation carriers.5,34
An HDL presentation is observed only sporadi­
cally within most families, but a homogeneous
HDL phenotype in all members of a family with
SCA17 has recently been described.35 The broad
spectrum of clinical manifestations in HDL4
correlates with the neuropathological findings,
which include cerebellar pathology and involve­
ment of the cerebral neocortex, basal ganglia
and hippocampus.36 Intranuclear neuronal
inclusion bodies with immunoreactivity to
anti-TBP and anti-polyglutamine antibodies
have been described to be widely distributed in
the gray matter.36
Cerebellar and cortical atrophy have been
demonstrated on brain MRI in patients with
HDL4.35 Neuroimaging studies using dopamine
transporter imaging, single-photon emission
computed tomography with 123I-iodobenzamide,
and PET have revealed reduced activity of
dopamine transporters, reduced glucose meta­
bolism in the striatum, and mildly reduced
dopa­mine D2-receptor-binding capacity.37 In
patients with the more common ataxic HDL4
phenotype, voxel-based morphometry has
shown degeneration of the gray matter in the
cerebellum, the occipitoparietal cortical areas
and the basal ganglia, which reflects and is
associated with the cerebellar, pyramidal and
extrapyramidal signs.38 Patients with HDL4
who have ataxia have also been studied electro­
physiologically.39 Electromyography, nerve
conduction studies, visual and brainstem
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auditory evoked potentials, and transcranial
magnetic stimulation-induced motor evoked
potentials seemed to be normal in all cases;
however, abnormalities in somatosensory-
evoked potentials—consisting mainly of P14
and P31 wave absence and a prolonged central
motor conduction time—were noted.
OTHER AUTOSOMAL DOMINANT
DISORDERS
Dentatorubral–pallidoluysian atrophy
Dentatorubral–pallidoluysian atrophy (DRPLA)
is in many respects similar to HD. The condition
is an autosomal dominant triplet-repeat neuro­
degenerative disorder,40,41 and the mutated gene,
atrophin 1 (ATN1), has been mapped to chromo­
some 12p13.31.42 The polyglutamine stretch
ranges from 8 to 25 repeat units in healthy indi­
viduals, and from 49 to 88 repeats in patients
with DRPLA.43,44 Instability in transmission
has been reported, with an average increase in
repeat length of four repeats for paternal trans­
mission (a phenomenon known as anticipation)
and a decrease of one repeat during maternal
transmission.44 Again, repeat size correlates
inversely with age at onset and directly with
disease severity. Three clinical phenotypes,
with an average age at onset between 20 and
30 years, have been described: presentation with
prominent chorea similar to HD, with promi­
nent ataxia, and with prominent myoclonus.
Severe progressive myoclonus epilepsy and
cognitive decline has been described in early-
onset cases.41 Late-onset disease can present
with mild cerebellar ataxia.45
DRPLA is particularly prevalent in Japan,
but has been reported rarely in white, African-
American and Chinese populations.46–50 Le Ber
et al.47 recently studied a sample of 809 patients
with ataxia and estimated the frequency of
DRPLA in Europe as 0.25% in both familial and
sporadic cases.
Four Portuguese families with DRPLA were
recently found to have two intragenic single
nucleotide polymorphisms in introns 1 and 3 of
the ATN1 gene, in addition to the CAG repeat
expansion.51 Notably, all four Portuguese fami­
lies shared a particular haplotype, which was also
shared by Japanese individuals with DRPLA.
This haplotype is the most frequent in Japanese
individuals with normal alleles but is rare in
Portuguese controls, which might explain the
relatively high frequency of DRPLA in Japan
compared with Europe.
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Table 2 Summary of autosomal recessive and X-linked disorders that cause chorea.
Condition Chromosomal Gene Age at onset Clinical characteristics
location (years)
HDL3 (AR) 4p15.3 Not known 3–4 Parkinsonism, dystonia,
chorea, pyramidal signs,
ataxia, dementia (single family)
Chorea–acanthocytosis 9q21 VPS13A 20–30 Chorea, dystonia,
(AR) orofacial involvement,
tics, self-mutilation,
seizures, neuropathy,
hepatosplenomegaly
PKAN (AR) 20p13 PANK2 Childhood Dystonia, oromandibular
involvement, parkinsonism,
chorea, dementia
Wilson’s disease (AR) 13q14 ATP7B 20–30 Dystonia, parkinsonism, rarely
chorea, psychiatric features,
Kayser–Fleischer ring, hepatic
involvement
McLeod syndrome Xp21 XK 40–60 Chorea, parkinsonism,
(X-linked) dystonia, psychiatric
features, seizures,
neuropathy, cardiomyopathy,
hepatosplenomegaly
Abbreviations: AR, autosomal recessive; ATP7B, ATPase, Cu2+ transporting beta polypeptide; HDL, Huntington’s disease-like;
PANK2, pantothenate kinase 2; PKAN, Pantothenate-kinase-associated neurodegeneration; VPS13A, vacuolar protein sorting
13 homolog A (S. cerevisiae); XK, X-linked Kx blood group (McLeod syndrome).

Neuroferritinopathy SELECTED AUTOSOMAL RECESSIVE

Mutations in the FTL gene—which codes for
ferritin light polypeptide—on chromosome 19q13
cause neuroferritinopathy, an autosomal
dominant condition that presents with extra­
pyramidal features that include chorea, dystonia
with prominent oro­mandibular dyskinesias, and
parkinsonism (without tremor). Other variably
present features include dys­arthria, spasticity,
cerebellar signs, frontal lobe syndrome and
dementia.52,53 The mean age at onset is 40 years.
Neuroferritinopathy is particularly common
in the Cumbrian region of the UK owing to a
founder effect. A French family with exactly the
same gene mutation as the Cumbrian family, and
possibly sharing a common ancestor, has also
been described.53
Patients with neuroferritinopathy have low
serum ferritin levels. MRI imaging reveals
abnormal deposition of iron in the brain, cystic
changes in the basal ganglia, and bilateral pallidal
necrosis.53,54 The sensitivity of T2* imaging55 was
emphasized by Chinnery et al.; particularly in early
disease the use of T2* MRI could demonstrate
the character­istic pattern of iron deposition even
in a pre­symptomatic carrier.56 Abnormalities
of the mitochondrial respiratory chain were
demonstrated in skeletal muscle biopsy.56
DISORDERS
Numerous autosomal recessive disorders can
present with prominent chorea and dementia.
Space restrictions limit a detailed discussion of
all these conditions, but those in which HDL
phenotypes might be seen are listed in Table 2.
Of particular importance is Wilson’s disease, for
which a broad phenotype has been described.57
Although chorea is a rather rare symptom, the
diagnosis of Wilson’s disease should not be
missed as it is a treatable condition.
Chorea–acanthocytosis
In a sporadic case of chorea without autosomal
dominant family history, the autosomal reces­
sive disorder chorea–acanthocytosis is one of
the first conditions to consider in the differ­
ential diagnosis. Chorea–acanthocytosis is
one of the so-called core ‘neuroacanthocytosis
syndromes with neurodegeneration of the basal
ganglia’, and is caused by mutations of the vacu­
olar protein sorting 13 homolog A (VPS13A)
gene—which codes for the protein chorein—
on chromosome 9q21.58–60 Onset is usually
in young adulthood, and the clinical features,
which include chorea, tics, parkinsonism, eye
movement abnormalities, subcortical dementia

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and psychiatric features, can be similar to those
of HD.61,62 Dystonia with prominent orofacial
involvement63 and self-mutilation, as well as the
presence of myo­pathy and neuropathy, might,
however, indicate a diagnosis distinct from
classic HD.
Blood tests in patients with chorea–acantho­
cytosis reveal the presence of acanthocytes in the
blood smear, and elevated creatine kinase. Liver
function tests might be abnormal, indicating
hepatomegaly. MRI demonstrates progres­
sive caudate atrophy, with a more prominent
pre­dilection for the head of the nucleus than that
seen in HD.64 Extensive neuronal loss and gliosis
affecting the striatum, pallidum and substantia
nigra have been found on postmortem.65
Pantothenate-kinase-associated
neurodegeneration
Pantothenate-kinase-associated neurodegenera­
tion (PKAN) was first described in 1922 by
Hallervorden and Spatz,66 and is caused by muta­
tions of the pantothenate kinase (PANK2) gene
on chromosome 20p13. PKAN is character­ized
clinically by extrapyramidal symptoms (in 98%
of cases)—in particular, generalized dystonia
with oromandibular involvement, 63 and
parkinsonism–spasticity (25%), behavioral
changes followed by dementia (29%), and
pigmentary retinal degeneration. The mean
age at onset is between 3 and 4 years.67,68 The
presentation of PKAN might be atypical if onset
is later, and chorea as the main feature has been
reported in a late-adult-onset pathologically
proven case.69
PKAN is also referred to as neurodegenera­tion
with brain iron accumulation type 1, or NBIA1.
This new term reflects the findings on patho­
logical examination—brown dis­coloration of the
globus pallidus and substantia nigra, and iron
deposition most abundant in the globus pallidus
interna.66 The pallidal abnormalities and the
iron deposits can be detected in vivo by MRI.
T2-weighted images show a central hyper­intensity
(probably representing fluid accumulation or
edema) of the globus pallidus interna in combi­
nation with a rim of signal hypo­intensity (iron
deposition). This ‘eye-of-the-tiger’ sign is highly
correlated with PANK2 mutations,68,70 and is
usually seen early in the disease course.67 By
contrast, patients with a clinical picture similar
to that of PKAN and evidence of iron deposition
on MRI, but without a PANK2 gene mutation,
do not show the classic ‘eye-of-the-tiger’ sign,
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but show hypointensity in the globus pallidus
only.71 Recently, mutations of the PLA2G6
gene—which encodes a calcium-independent
phospholipase A2—on chromosome 22q13,
were identified as the cause of disease in some
of these cases.67,72
Phenotypic variability has been recognized
for PLA2G6 mutations—some cases present as
a mainly pyramidal syndrome with infantile
neuroaxonal dystrophy, spastic tetraplegia, hyper­
reflexia and visual impairment,72 as opposed to
the extrapyramidal syndrome with dystonia,
parkinsonism and choreoathetosis (mentioned
above) that can be clinically indistinguishable
from the phenotype of patients with PANK2
gene mutations.73 Additional cerebellar atrophy
might also be present in patients with PLA2G6
mutations (reported as Karak syndrome).74
Acanthocytes are found in the blood in
approxi­mately 10% of PKAN cases, and are
possibly related to abnormalities of lipid
meta­bolism.25,68 Some cases of PKAN with
acanthocytes and additional features such as
hypo­prebetalipoproteinemia, acanthocytosis,
retinitis pigmentosa and pallidal degeneration
were given the acronym HARP syndrome. HARP
is now known to be allelic to PKAN and not a
separate entity.75 In addition to the classic neuro­
acanthocytosis syndrome, the diagnosis of PKAN
should also, therefore, be considered if acanthocytes
are found in a patient with chorea.
X-linked McLeod syndrome
McLeod syndrome—the other core neuro­
acanthocytosis syndrome—is clinically similar to
chorea–acanthocytosis, with seizures, peripheral
neuropathy and myopathy, and can also present
with an HDL phenotype.76 The diagnosis is again
indicated by elevated liver enzymes and creatine
kinase , and can be confirmed by demonstration
of the absence of Kx antigens and a reduction in
kell antigens on erythrocytes. Cardiomyopathy
and arrhythmia are distinguishing features, and
might be a cause of sudden death.
CLINICAL APPROACH AND TREATMENT
CONSIDERATIONS
To sift through the HDL disorders, it is impor­
tant to pay attention to certain clinical features.
For example, prominent myoclonus might indi­
cate HDL1 or DRPLA. If cerebellar signs are
marked, or cerebellar atrophy is demonstrated on
neuro­imaging, the SCAs and DRPLA should be
consider­ed. In the latter condition, high-intensity
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signals in the cerebral white matter, basal ganglia
and brainstem may be present on T2-weighted
MRI, in addition to atrophy of the brainstem
and cerebellum. These signs are predominantly
observed in late-onset adult patients with DRPLA
with long disease duration, however, and are only
rarely observed in juvenile patients with a short
disease history.
PKAN and neuroferritinopathy have character­
istic features on MRI imaging. Chorea is rarely
an isolated movement disorder in these condi­
tions; dystonia and other features are often
dominant. Prominent orolingual involvement
with dystonic tongue protrusion is character­
istic of PKAN and chorea–acanthocytosis,63 and
these disorders also differ from classic HD in
their pattern of inheritance.
Treatment for the HDL disorders is sympto­matic.
Tetrabenazine or dopamine-receptor-blocking
agents can alleviate the chorea. More disabling
for the patient, however, can be the psychiatric
features and mood disturbances associated with
the disorders, in which case anti­depressants
might be indicated. Genetic counseling is recom­
mended on the basis of the molecular diagnosis.
The support of social services and ancil­
lary agencies, as well as occupational therapy,
speech therapy and physio­therapy, are impor­
tant components of treatment, and should not
be neglected.
CONCLUSIONS
As summarized above, there are a growing
number of distinct genetic disorders with an
HDL clinical phenotype. Overall, these disorders
are rare, and HD remains the leading inherited
cause of chorea. It is also clear that the four so-
called HDL syndromes account for only a small
proportion of cases with the HD phenotype but
a negative genetic test for the disorder, and we
anticipate that the list of HDL-associated genes
will continue to expand. For example, in a study
of 252 patients with HDL syndromes, most
of whom were white, only two cases of HDL2
and a further two of SCA17 were identified.14
Similarly, Costa et al. screened 107 Portuguese
patients with an HDL phenotype and found
no mutations in the PRNP, JPH3, TBP or FTL
genes, or in two additional candidate genes,
CREBBP and POU3F2.15 Absence of mutations
in the PRNP and JPH3 genes was also reported
by Keckarevic et al.16 for 48 patients from
Yugoslavia with an HDL phenotype. Our own
experience is that a recognized HDL syndrome
september 2007 vol 3 no 9 SCHNEIDER ET AL. 
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will be genetically confirmed in only about 3% of
patients with the HD phenotype who are nega­
tive for the HD gene mutation. HDL4 (SCA17)
seems to be the most common HDL syndrome,
followed by HDL2 and then HDL1 (E Wild et al.,
personal communication). As the prevalence of
the various disorders might vary between ethnic
groups, however, information about patient
background might influence the priority level of
requested genetic tests. In Japanese populations,
DRPLA occurs relatively frequently, whereas in
African Americans it is important to consider a
diagnosis of HDL2.
The use of HDL terminology is pragmatic
for the discussion of these disorders in the
context of the differential diagnosis of progres­
sive adult-onset choreiform conditions, but is
grammatically clumsy. The term HDL might
obscure the potential phenotypic variation or
the critical distinguishing features of some of
these dis­orders. The use of HDL terminology for
each of these conditions should probably be ulti­
mately replaced by names that reference genetic
etiology, as has occurred for HDL4, which was
identified to be SCA17.
Key Points
■ Huntington’s disease (HD) caused by mutation
of the IT15 gene is the most important genetic
cause of chorea
■ A diagnosis of HD should be considered in
patients presenting with the classic triad of
symptoms, comprising adult-onset
personality changes, generalized chorea and
cognitive decline
■ The syndrome of chorea in combination
with other neurological and neuropsychiatric
features seen in HD is known to be genetically
heterogeneous; phenocopies are termed
Huntington’s disease-like (HDL) syndromes
■ Mutations underlying HDL syndromes have
been identified in the prion gene (HDL1),
the junctophilin 3 gene (HDL2) and the gene
encoding the TATA box-binding protein
(HDL4/SCA17)
■ One family with a recessively inherited HD
phenocopy (HDL3) of poorly-understood
genetic etiology has also been reported
■ HDL syndromes account for only a small
proportion of cases with the HD phenotype,
but should be considered in patients who test
negative for the classic HD gene mutation
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review
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