Huntington’s Disease and HD-like Disorders
Prof. Sarah Tabrizi MD PhD FMedSci
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Huntington’s Disease
and HD-like Disorders
Prof. Sarah Tabrizi MD PhD FMedSci
UCL Institute of Neurology
and National Hospital for Neurology and Neurosurgery
Queen Square London
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Genetic causes of chorea:
HD and HD-like disorders (HD phenocopies)
Characterised by variable presentations of:
• Chorea, dystonia, parkinsonism
• Cognitive impairment (frontal-subcortical)
• Psychiatric disturbance
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CAG repeat diseases
• Huntington’s disease
• Dentatorubropallidoluysian atrophy (DRPLA)
• Spinobulbar muscular atrophy or Kennedy disease (SBMA)
• Spinocerebellar ataxias (SCA)
– 1, 2, 3, 6, 7, 17
Huntington’s Disease and HD-like Disorders
Prof. Sarah Tabrizi MD PhD FMedSci
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Huntington’s disease
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‘If the thread is broken then the grandchildren
of the original shakers may rest assured
that they are free from the disease’
• Commonest genetic cause
of chorea
• Autosomal dominant
• Mean age of onset
is 40 years - movement
disorder, cognitive
and neuropsychiatric symptoms
• ~8% new cases
have no family history
Neurographs., 1, Browning, W., Huntington number., 1-164, 1908
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HD is caused by a CAG repeat expansion
in HTT gene encoding huntingtin protein HTT -
cloned in 1993
Cell, 1993 Mar 26;72(6):971-83
Huntington’s Disease and HD-like Disorders
Prof. Sarah Tabrizi MD PhD FMedSci
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Normal
Paternal
meiotic
instability
Reduced
penetrance HD
< 29 29 → 35 36 → 39 > 39
• Not pathogenic
• Not unstable
• Not pathogenic
• May expand
into disease range
in future generations
‘new mutation’
• Pathogenic
• Risk HD:
36 ~ 25%
37 ~ 50%
38 ~ 75%39 ~ 90%
Always
causes HD
HD genetics - CAG repeat threshold and HD
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HD CAG repeat length frequencies
Private image
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Genetic anticipation in HD
Private image
Huntington’s Disease and HD-like Disorders
Prof. Sarah Tabrizi MD PhD FMedSci
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11Private image
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Pathobiology of HD
Huntington’s Disease and HD-like Disorders
Prof. Sarah Tabrizi MD PhD FMedSci
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The HD mutation and Huntingtin protein
350 kDa
GlutaminesQQQHH.
HD protein (huntingtin)
Huntingtin
is expressed
in all tissues
in the body
180 kb DNA65 66 67321
CAG CAG CAGH.
40
36
70
>200
Unaffected
Adult onset HD
Juvenile onset HD
14EMBO Rep., 5(10), Landles C, Bates GP., Huntingtin and the molecular pathogenesis of Huntington's disease; Fourth in molecular medicine review series., 958-63, Copyright 2004 Nature Publishing Group. www.nature.com
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Clinical features of HD
Huntington’s Disease and HD-like Disorders
Prof. Sarah Tabrizi MD PhD FMedSci
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HD is not just a disease of the basal ganglia
• Selective neurodegeneration
begins in the MSNs
in the striatum –
caudate and putamen
• Generalized atrophy
• Loss of functional
and structural connectivity
between the cortex
and striatum plays a major
role in the disease
symptomatology ControlHuntington’sdisease
Figure above from naota.medgen.iupui.edu/hdrosternew/AboutHD/brainAndHD.asp courtesy of www.brainbank.mclean.org/
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HD is more than a disease of the brain;
HTT is expressed in all tissues in the body
Van der Burg Lancet Neurology 2009
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Onset and early disease in HD
• Onset described age 2- 80+ yrs of age
– Mean age of onset 39y
• Often prior history of mood disorder
• Insidious and slow deterioration of intellectual function
with mild personality change
• Minor motor abnormalities
• Diagnostic onset currently classified as the observation
of unequivocal motor signs
Huntington’s Disease and HD-like Disorders
Prof. Sarah Tabrizi MD PhD FMedSci
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Subclinical chorea
Personal video
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Mid-course adult-onset HD –
‘the classic HD phenotype’
• Extrapyramidal signs – chorea is seen in 90% of adult-onset,
dystonia, parkinsonism, bradykinesia, akinetic-rigid forms
of the disease in young adult onset (Westphal variant)
• Oculomotor disturbance
• Impairment of voluntary motor function – clumsiness,
disturbances in fine motor control, motor speed
• Gait disturbance
• Speech and swallowing problems common
(dysarthria and dysphagia)
• Cognitive and psychiatric problems
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Ballistic chorea
Huntington’s Disease and HD-like Disorders
Prof. Sarah Tabrizi MD PhD FMedSci
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Juvenile HD with onset less than 20y
• More severe and widespread clinical disease
• Shorter life expectancy
• The most common clinical presentation is of rigidity, dystonia,
and parkinsonism (Westphal variant)
• Often very painful dystonic spasms and seizures
that are difficult to treat
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Elderly onset HD – over 75 years of age
Usually a very benign phenotype –
typically
Huntington’s Disease and HD-like Disorders
Prof. Sarah Tabrizi MD PhD FMedSci
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Psychiatric/behavioural
• Affective disorder
– Depression
– Suicide (5 times normal)
• Anxiety/panic disorder
• Obsessions/compulsions
• Psychosis
– Similar to schizophrenia
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Cognitive phenotype
• Universal feature
• Often presenting feature 10+ years before motor onset
• Subcortical/frontal impairment
– Planning
– Multi-tasking
– Impulsivity
– Irritability
– Self-centred
• Psychomotor function
• Normal language
• Memory less impaired
• Emotion recognition
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Genetic testing
• Predictive
– Specialist HD clinic or clinical genetics
• Diagnostic
– When onset suspected
Never underestimate the need for specialist genetic counselling!
If in doubt, refer
Huntington’s Disease and HD-like Disorders
Prof. Sarah Tabrizi MD PhD FMedSci
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Internationally agreed protocol
for predictive genetic testing for HD
• Initial visit
• Cooling off period of 3 months
• Second visit and blood test
• Follow-up with result
• Seen 2-4 weeks later and thereafter
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Genetic HD-like disorders
• C9orf72 (hexanucleotide repeat expansion)
• Inherited prion disease (includes HDL1)
• HDL2 (triplet repeat expansion in junctophilin-3 gene)
• HDL3 (2 families; causative mutation not known)
• SCA17 aka HDL4 (triplet repeat expansion in TBP)
• SCA1-3 (triplet repeat expansions)
• Dentatorubro-pallidoluysian atrophy (DRPLA)
• Neuroacanthocytosis (choreo-acanthocytosis (chorein)
and MacLeod’s Syndrome (XK gene – X chromosome)
• Neuroferritinopathy (ferritin light chain) bvg
• NBIA/PKAN (PANK2 mutations)
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Genetic causes of chorea 2:
Conditions less likely to mimic HD
• Wilson’s disease
– (Copper transporting ATPase)
• Benign hereditary chorea
– (Thyroid transcription factor)
• Friedreich’s ataxia
– (Triplet expansion in frataxin gene)
• Mitochondrial
– (mtDNA / nuclear mitochondrial genes)
• Ataxia telangiectasia
Huntington’s Disease and HD-like Disorders
Prof. Sarah Tabrizi MD PhD FMedSci
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HDL2
• First described in large African-American pedigree
(Margolis et al. 2001; Walker et al. 2003)
• Clinically closely resembles HD
– Mid-age onset
– Chorea or parkinsonism
– Frontal-subcortical dementia
– Psychiatric disturbance
– Weight loss
– Death in 15-20 years – similar course to HD
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Genetics of HDL2
• CTG/CAG repeat expansion in JPH3 (Holmes et al. 2001)
• Normal 8-28 repeats, disease 40-59 repeats
Longer repeat correlates with younger age of onset
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Epidemiology and pathology of HDL2
• Most families of definite or probable African ancestry
• HDL2 accounts for ~1% of all HD-negative cases tested
in the USA
• Frequency high in black South Africans and as common
as HD
• Pathology very similar to HD
(Greenstein et al. 2007, Rudnicki et al. 2008)
• Prominent striatal and cortical atrophy
• Dorsal to ventral gradient of striatal neuronal loss
Huntington’s Disease and HD-like Disorders
Prof. Sarah Tabrizi MD PhD FMedSci
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Spinocerebellar ataxia 17
SCA17 presents with a variable combination of:
• Ataxia (commonest typical presentation)
• Dementia
• Prominent psychiatric features
• Chorea
• Dystonia
• Oculomotor abnormalities are common
• Epilepsy
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Genetics of SCA17
• Autosomal dominant
• Polyglutamine disorder like HD, SCA1, 2, 3 and DRPLA
• CAG repeat expansion in the TBP —
TATA binding protein (Koide et al. 1999)
• Disease range is >43 CAG repeats
• Similar intergenerational instability to HD:
anticipation, especially with paternal transmission
(Rasmussen et al. 2007, Gao et al. 2008)
• Reduced penetrance range reported: 44-48 repeats
in asymptomatic mutation-transmitting parents
(Zulkhe et al. 2003, Oda et al. 2004)
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T2-weighted axial brain MRI in SCA17
• Imaging useful as commonly shows cerebellar atrophy
• Putaminal signal change reported (Loy et al. 2005)
Huntington’s Disease and HD-like Disorders
Prof. Sarah Tabrizi MD PhD FMedSci
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Neuroferritinopathy
Novel autosomal dominant disorder first described
in families in the north of England that were previously
misdiagnosed as Huntington’s disease
(Curtis et al. 2001)
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Clinical features of neuroferritinopathy
• Mean age of onset - 39 years
• Choreic onset in 50% - typically presentations of chorea,
parkinsonism or limb and oro-facial dyskinesias
(Crompton et al. 2005)
• Asymmetry is common
• Eye movements normal
• Progressive over 5-15 years
• Subcortical/frontal cognitive dysfunction in late stages only
(unlike HD)
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Genetics of neuroferritinopathy
• Autosomal dominant
• Mutation in the ferritin-light chain gene (FTL)
• Four pathogenic mutations described all affecting exon 4
of the FTL gene
• Original and best described clinically is the FTL 460InsA
mutation - a single adenine insertion at position 460
Huntington’s Disease and HD-like Disorders
Prof. Sarah Tabrizi MD PhD FMedSci
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Neuroferritinopathy –
investigations and pathology
• T2* MRI distinguishes it
from other brain iron disorders:
– Hypointensity of dentate,
globus pallidus and putamen
plus caudate in some
(McNeill et al. 2008)
• Serum ferritin levels low in males
and post-menopausal women
• Deposition of extracellular iron
and ferritin within the brain,
particularly the basal ganglia
Figure from web
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T2* MRI in neuroferritinopathy
Signal loss in the globus pallidus, internal capsule, putamen, caudate, and thalami
(McNeill et al.2008)
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Neuroacanthocytosis
• Choreoacanthocytosis (AR)
• Macleod’s syndrome (X-linked)
• Orofacial dystonia and tongue-biting
Blood acanthocytes
Figure from web
Huntington’s Disease and HD-like Disorders
Prof. Sarah Tabrizi MD PhD FMedSci
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Chorea-acanthocytosis (1)
• Autosomal recessive
• Huge gene VPS13A (chorein)
– DNA analysis difficult
– Western blotting in RBC – no chorein expression
• Search for acanthocytosis can be misleading:
low sensitivity!
• Adult-onset (3rd decade)
• Slow progression over 15-30 years
• Onset with subtle cognitive or psychiatric symptoms
• Seizures may be present at onset in about one third
of cases (generalized)
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Movement disorder
• Chorea
– “Feeding dystonia”
– Orofacial dyskinesias
– Tongue and lip biting
(self-mutilation)
– Vocalizations
– Dysarthria
• GAIT: “rubber man” appearance
• Parkinsonism rare
Peculiar features:
• Myopathy or mild neuropathy
(raised CK)
• Hepatosplenomegaly
due to increased hemolysis
(raised liver enzymes)
Chorea-acanthocytosis (2)
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McLeod syndrome (1)
• X-linked recessive (XK gene)
• Worldwide distribution
• Absence of Kell antigen on erythocytes in affected males
• Multi-system disorder
• “Contiguous gene syndrome” – clusters with other contiguous
genes to XK gene
Figure from the web
Huntington’s Disease and HD-like Disorders
Prof. Sarah Tabrizi MD PhD FMedSci
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McLeod syndrome (2)
• Chorea
• Facial dyskinesias
• Vocalizations
Cognitive deterioration
Psychiatric symptoms:• Depression
• Schizophrenia-like illness
• OCD
Seizures
• Age at onset: 25-60 years
• Slower progression
Acanthocytosis
• Myopathy
• Risk of rhabdomyolysis
• Raised CK
Peripheral neuropathy
• CMP
• Arrhythmias
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Benign hereditary chorea
• Rare
• Childhood onset of chorea
• Benign progression with normal life expectancy
• No cognitive impairment
• Linked to thyroid and lung problems (BTL syndrome)
• Autosomal dominant with mutations
in thyroid-transcription factor TTF-1
• MRI normal
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Prion diseases
• HDL1
• Inherited prion diseases may present with chorea
in addition to ataxia, parkinsonism, myoclonus
• All autosomal dominant with mutations
in the prion protein gene
Huntington’s Disease and HD-like Disorders
Prof. Sarah Tabrizi MD PhD FMedSci
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PKAN (PANK2 mutation)
• Generalized dystonia
with buccolinguofacial
involvement and dysarthria
• Parkinsonism
• Gait abnormalities
• Pyramidal signs
• Choreoathetosis
Cognitive impairment
Pigmentary retinopathy
Reduced total sleep time
• Autosomal recessive; truncating mutations in most cases
• Age at onset:
Huntington’s Disease and HD-like Disorders
Prof. Sarah Tabrizi MD PhD FMedSci
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52
• After discovery explosion of interest probably
the single most important neurological disease gene
• Accounts for ~10% of all FTD and ALS
• Very broad spectrum of phenotype
including ~1% of AD-like syndromes
• Can present with HD-like syndromes
(Hensman et al., Neurology 2013)
C9orf72 (3)
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Phenotypic heterogeneity of C9orf72
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HD mimics (phenocopies)
Wild et al., Mov Disord 2007; Wild et al., Curr Opin Neurol2007
Huntington’s Disease and HD-like Disorders
Prof. Sarah Tabrizi MD PhD FMedSci
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Genetic HD mimics
HD
SCA17
AtaxiaSCA1-3
Friedreich’s
Myoclonus/dementia
Prion
Mitochondrial
Africanheritage HDL2
Seizures DRPLA
Blood filmabnormal
Neuro-
acanthocytosis
MRIabnormal
Neuroferritinopathy
NBIA
Negative
Negative
C9orf72
Negative
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hdresearch.ucl.ac.uk
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• Huntington’s disease research news
• In plain language
• Written by scientists
• For the global HD community
Huntington’s Disease and HD-like Disorders
Prof. Sarah Tabrizi MD PhD FMedSci
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Huntington’’’’s disease: reading
1. Novak & Tabrizi 2011
– Huntington’s Disease; BMJ 340:c3109
2. Ross & Tabrizi 2011
– Huntington's disease: from molecular pathogenesis
to clinical treatment; Lancet Neurology 10:83-98
3. Wild & Tabrizi 2007
– The differential diagnosis of chorea;
Practical Neurology 7:360
4. Wild & Tabrizi 2007
– Huntington’s disease phenocopy syndromes;
Current Opinion in Neurology 20:681
5. G Bates, Tabrizi SJ, Jones L – Huntington’s Disease, OUP
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Acknowledgements
Edward Wild, Davide Martino, Russell Margolis,
Patrick Chinnery, Susanne Schneider, Simon Mead,
Kailash Bhatia and Ray Young
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