prof.sarah tabrizimd phd fmedsci - hstalks · 2015. 12. 25. · never underestimate the need for...

Huntington’s Disease and HD-like Disorders

Prof. Sarah Tabrizi MD PhD FMedSci

1The screen versions of these slides have full details of copyright and acknowledgements

1

Huntington’s Disease

and HD-like Disorders


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

3

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




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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




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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




10Private image

11Private image

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Pathobiology of HD




13

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




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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




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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




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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




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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




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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




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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




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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


• 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)




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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


• 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




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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

41

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




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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)

45

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




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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

48

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




49

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:




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• 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




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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




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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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prof.sarah tabrizimd phd fmedsci - hstalks · 2015. 12. 25. · never underestimate the need for...

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