Supplementary Table 1a. HD-like syndromes with typical onset in adulthood.
Demographic
Core
Cognitive
neurological
features
features
Ancillary
Molecular
investigations
genetics
AD
and
behavioural
abnormalities
HDL-1
Prevalence:
Chorea,
Cognitive
MRI: atrophy
unknown;
rigidity,
deterioration,
of frontal and
ataxia,
personality
temporal lobes,
dysarthria,
changes,
cerebellum and
Observed only
in Caucasian
PRNP gene:
192seizures
mania-like
basal ganglia
nucleotide
families
symptoms
insertion
leading to
extraoctapeptide
repeats in the
prion protein
HDL-2
Prevalence
Chorea or
Dementia,
MRI: atrophy
unknown;
parkinsonism
depression,
of caudate and
South African
(2 forms),
apathy,
cortex
ancestry
dysarthria,
irritability
hyperreflexia,
AD
JPH3 gene
(TMA):
Acanthocytosis
CTG repeat
jerky
saccades
SCA17 (HDL4)
expansion
Prevalence
Ataxia,
Dementia,
MRI: atrophy
0.5-1.6/million
chorea,
depression,
of cerebellum,
dystonia, eye
apathy,
brainstem,
movement
psychosis
caudate, cortex
All ethnic
groups
AD
TBP gene
(TMA):
abnormalities
CAA/CAG
, pyramidal
repeat
signs, rigidity
expansion
DRPLA
Prevalence
Ataxia,
Dementia or
MRI: atrophy
4.8/million in
chorea,
progressive
of cerebellum
the Japanese
dystonia,
intellectual
and brainstem
population;
myoclonus,
deterioration
(esp. pontine
much rarer in
epilepsy
(in children),
tegmentum)
AD
ATN1 gene
(TMA):
CAG repeat
other ethnic
personality
expansion
groups
changes,
psychosis
Chorea-
Prevalence
Chorea,
MRI: atrophy
unknown
dystonia,
of caudate and
dysarthria,
T2-weighted
dysphagia,
signal increase
tongue/lip
in caudate and
biting,
putamen
Acanthocytosis
All ethnic
groups
AR
VPS13A:
Sequence
analysis or
deletionseizures,
myopathy,
Acanthocytosis
sensorimotor
duplication
analysis
Raised serum
axonopathy
CK
McLeod
syndrome
Prevalence
Chorea,
Mild cognitive
MRI: atrophy
unknown
seizures,
deficits,
of caudate and
sensorimotor
personality
putamen
axonopathy,
disorder,
myopaty,
anxiety,
dilated CMP
depression,
and
OCD, bipolar
arrhythmias
or schizo-
All ethnic
groups
affective
XR
XK: Direct
DNA
McLeod blood
methods
group
(available
phenotype (Kx
only for
erythrocyte
research)
antigen)
disorder
Acanthocytosis
Compensated
hemolysis
Raised serum
CK, LDH,
AST, ALT
Abnormal
EMG/NCS
Muscle CT or
biopsy: fatty
degeneration of
lower leg
muscles
Cardiac
abnormalities
on echo and
ECG
Neuroferritinopathy
Prevalence
Dystonia,
Mild cognitive
MRI: iron
unknown
chorea,
difficulties
deposition in
parkinsonism
with cognitive
basal ganglia,
, dysarthria,
and
cystic
dysphonia,
behavioural
degeneration
dysphagia,
changes only
hyperreflexia
later on in the
Possible
common
founder in
Europe
disease course
AD
FTL:
Sequence
analysis
detecting
Low serum
point
ferritin levels
mutations
and small
deletions or
insertions in
80% of
familial
cases (much
less in
sporadic
presentations
)
SCA14
Prevalence
Ataxia,
Dementia,
MRI: Mild-to-
unknown
dysarthria,
depression
moderate
Different
ethnic groups
dysphagia,
cerebellar
dysphonia,
atrophy
AD
PRKCG:
Sequence
analysis
eye
detecting
movement
point
abnormalities
mutations
, sensory
and small
loss,
deletions
pyramidal
(unknown
signs, chorea
detection
rate)
SCA8
Prevalence
Ataxia,
Cognitive
MRI: mild-to-
unknown
dysarthria,
deterioration
moderate
May be
hyperreflexia,
cerebellar
chorea
atrophy
AD
SCA8/ATXN
8:
especially
common in
Finland
Trinucleotide
repeat
expansion
within two
overlapping
genes
AD: autosomal dominant; TMA: targeted mutation analysis; AR: autosomal recessive; XR: Xlinked recessive; CMP: cardiomyopathy.
Supplementary Table 1b. HD-like syndromes with typical onset in the first two decades.
Demographic
features
Core
Cognitive
Ancillary
Molecular
neurological
and
investigations
genetics
features
behavioural
None
AD
abnormalities
Benign
hereditary
Prevalence:
Chorea, very
Psychosis
unknown;
rarely
very rare
NKX2-1
dysarthria,
chorea
Observed all
ethnic groups
gene in a
dystonia,
proportion
myoclonus
of patients:
point
mutations
or large
deletion
Friedreich
ataxia
Prevalence 20-
Ataxia,
Mild
MRI: atrophy
40/million
areflexia,
abnormalities
of cervical
dysarthria, loss
of executive
spinal cord and
in position
functioning
cerebellum later
Well
documented in
Europe, Middle
East, India,
North Africa
and/or vibration
AR
FXN gene
(TMA):
on in the course
GAA repeat
sense, pyramidal
signs, chorea,
scoliosis, pes
Glucose
tolerance test
expansion
(not in
cavus,
Southeast Asia,
cardiomyopathy,
sub-saharan
optic atrophy,
Africa, Native
deafness,
Americans)
glucose
abnormal
Echocardiograp
Sequence
hy and ECG
analysis or
abnormalities
deletion-
Abnormal NCS
duplication
and central
analysis
motor
also
conduction time
possible
AR
intolerance
Ataxia-
Prevalence 10-
Ataxia, head
Learning
Raised serum
teleangiectasia
20/million live
tilting,
disabilities
AFP
births
dysarthria,
possible
teleangiectasias,
All ethnic
groups
oculomotor
apraxia, chorea,
dystonia,
immunodeficien
cy and increased
rate of infections
(especially
respiratory tract)
and neoplasms
ATM gene
Severe
(TMA):
depletion of
ATM protein
on
immunoblotting
or other cellbased
functional
assays
c.103C>T
(common
allele in
specific
ethnic
populations
)
Sequence,
deletionduplication
and
haplotype
analyses
also
possible
Ataxia with
Type 1:
oculomotor
apraxia types
1 and 2
Prevalence
0.041/million in
Portugal
(unknown
elsewhere)
Ataxia,
Cognitive
MRI: atrophy
oculomotor
impairment
of cerebellum
apraxia, axonal
(different
neuropathy,
degrees)
Type 1:
AR
Abnormal NCS
APTX gene
chorea, dystonia
Hypercholester
(type 1)
olemia
SETX gene
All ethnic
groups
Hypoalbumine
(type 2):
mia (type 1)
Sequence or
Raised serum
deletion-
AFP and CK
duplication
Type 2:
(type 2)
analyses
approx.
Elevated IgG
2/million in
and IgA levels
Alsace
(type 2)
(unknown
elsewhere);
mainly FrenchCanadian and
Anglo-Norman
populations
PKAN
Prevalence
Dystonia,
MRI: ‘eye-of-
estimated to
rigidity,
the-tiger’ sign
approximately
dysarthria,
in globus
1-3/million
dysphagia, eye
pallidus
AR
PANK2
gene:
movement
All ethnic
groups
Acanthocytosis
abnormalities,
Sequence
analysis
chorea, gait
Low or absent
disorder,
plasma pre-beta
pyramidal signs,
lipoprotein
retinal
fraction
degeneration or
optic atrophy
PLA2G6-
Prevalence
Dystonia,
Dementia or
MRI: iron
associated
unknown
parkinsonism
global
deposition in
(L-dopa
developmental
globus pallidus
responsive),
delay
or normal
neurodegenera
tion
Different ethnic
groups
pyramidal signs,
dysphagia,
dysarthria, optic
atrophy,
AR
PLA2G6
gene: Direct
DNA
methods
(available
only for
cerebellar
research)
features, chorea,
sensorimotor
axonopathy
Kufor Rakeb
syndrome
Prevalence
Parkinsonism
Dementia,
MRI: iron
unknown
(L-dopa
hallucinations,
deposition in
responsive),
aggressive
basal ganglia or
dysarthria,
behaviour
normal
Different ethnic
groups
AR
ATP13A2
gene: Direct
DNA
lip/chin
methods
myoclonic/trem
(available
or, dysphonia,
only for
dysphagia,
research)
pyramidal signs,
supranuclear
gaze palsy
Wilson’s
Prevalence 30-
Tremor, loss of
Depression,
MRI: copper
disease
35/million All
fine motor
anxiety,
accumulation in
ethnic groups,
control, chorea,
compulsions,
putamen and
higher in China,
dystonia,
phobias,
globus pallidus
Japan, and
rigidity, Kaiser-
personality
Sardinia
Fleischer rings,
changes,
liver disease
cognitive
impairment
AR
ATP7B
gene
(TMA):
Low serum
Sequence
ceruloplasmin,
analysis and
increased basal
deletion-
urinary copper
duplication
excretion,
testing also
increased
available
hepatic copper
concentration
Aceruloplasmi
Prevalence
Ataxia,
Cognitive
MRI: iron
nemia
estimated as
dysarthria,
deterioration
accumulation in
approximately
nystagmus,
0.5/million in
dystonia,
Japan
tremor, chorea,
parkinsonism,
Also other
ethnic groups
diabetes mellitus
basal ganglia
Serum
ceruloplasmin
undetectable on
Western blot,
low serum
copper, iron
and ferritin,
plasma
ceruloplasmin
ferroxidase
activity
undetectable
Raised iron
levels in liver
and pancreatic
AR
CP gene:
Sequence
analysis
(available
only for
research)
islet beta cells
AD: autosomal dominant; TMA: targeted mutation analysis; AR: autosomal recessive.