Huntington s Disease and HD-like Disorders Prof. Sarah Tabrizi MD PhD FMedSci

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1 Huntington s Disease and HD-like Disorders UCL Institute of Neurology and National Hospital for Neurology and Neurosurgery Queen Square London 1 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 2 CAG repeat diseases Huntington s disease Dentatorubropallidoluysian atrophy (DRPLA) Spinobulbar muscular atrophy or Kennedy disease (SBMA) Spinocerebellar ataxias (SCA) 1, 2, 3, 6, 7,

2 Huntington s disease 4 5 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 HD is caused by a CAG repeat expansion in HTT gene encoding huntingtin protein HTT - cloned in Cell, 1993 Mar 26;72(6):

3 HD genetics - CAG repeat threshold and HD Normal Paternal meiotic instability Reduced penetrance HD < > 39 Not pathogenic Not unstable 7 Not pathogenic Pathogenic May expand Risk HD: 36 ~ 25% into disease range 37 ~ 50% in future generations 38 ~ 75% new mutation 39 ~ 90% Always causes HD HD CAG repeat length frequencies 8 Private image Genetic anticipation in HD 9 Private image 3

4 10 Private image Private image 11 Pathobiology of HD 12 4

5 The HD mutation and Huntingtin protein CAG CAG CAG. > Juvenile onset HD 40 Adult onset HD 36 Unaffected kb DNA Glutamines QQQ. 350 kda Huntingtin is expressed in all tissues in the body HD protein (huntingtin) EMBO Rep., 5(10), Landles C, Bates GP., Huntingtin and the molecular pathogenesis of Huntington's disease; Fourth in molecular medicine review series., , Copyright 2004 Nature Publishing Group. Clinical features of HD 15 5

6 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 Huntington s disease Control Figure above from naota.medgen.iupui.edu/hdrosternew/abouthd/brainandhd.asp courtesy of 16 HD is more than a disease of the brain; HTT is expressed in all tissues in the body 17 Van der Burg Lancet Neurology 2009 Onset and early disease in HD Onset described age 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 18 6

7 Subclinical chorea 19 Personal video 20 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 Ballistic chorea 21 7

8 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 22 Elderly onset HD over 75 years of age Usually a very benign phenotype typically <42 CAG repeats Advanced stage HD Pts do not die of HD; they die of causes associated with the disease. Disease duration is average yrs End-stage disease is dominated by hypokinesia, rigidity and dystonia Anarthria, mutism and severe swallowing problems (dysphagia) Severe eye movement abnormalities bird-like head movements Marked bradyphrenia profound blunting of affect and slowness Agitation common Profound weight loss and emaciation 8

9 Psychiatric/behavioural Affective disorder Depression Suicide (5 times normal) Anxiety/panic disorder Obsessions/compulsions Psychosis Similar to schizophrenia 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 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 27 9

10 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 28 Genetic HD-like disorders 29 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) 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 30 10

11 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 years similar course to HD 31 Genetics of HDL2 CTG/CAG repeat expansion in JPH3 (Holmes et al. 2001) Normal 8-28 repeats, disease repeats 32 Longer repeat correlates with younger age of onset 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 33 11

12 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 Autosomal dominant 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: repeats in asymptomatic mutation-transmitting parents (Zulkhe et al. 2003, Oda et al. 2004) T2-weighted axial brain MRI in SCA17 36 Imaging useful as commonly shows cerebellar atrophy Putaminal signal change reported (Loy et al. 2005) 12

13 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) 37 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) 38 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

14 40 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 T2* MRI in neuroferritinopathy 41 (McNeill et al. 2008) Signal loss in the globus pallidus, internal capsule, putamen, caudate, and thalami Neuroacanthocytosis Choreoacanthocytosis (AR) Macleod s syndrome (X-linked) Orofacial dystonia and tongue-biting Blood acanthocytes 42 Figure from web 14

15 43 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 (3 rd decade) Slow progression over years Onset with subtle cognitive or psychiatric symptoms Seizures may be present at onset in about one third of cases (generalized) Chorea-acanthocytosis (2) 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) 44 X-linked recessive (XK gene) Worldwide distribution McLeod syndrome (1) Absence of Kell antigen on erythocytes in affected males Multi-system disorder Contiguous gene syndrome clusters with other contiguous genes to XK gene 45 Figure from the web 15

16 McLeod syndrome (2) Age at onset: years Slower progression Myopathy Risk of rhabdomyolysis Raised CK Chorea Facial dyskinesias Vocalizations Cognitive deterioration Peripheral neuropathy Acanthocytosis CMP Arrhythmias Seizures 46 Psychiatric symptoms: Depression Schizophrenia-like illness OCD 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 47 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 48 16

17 PKAN (PANK2 mutation) Autosomal recessive; truncating mutations in most cases Age at onset: <6y in almost 90%; rapid progression over 10 years Gene related to CoA synthesis from B5 vitamin; association with lipid metabolism Generalized dystonia with buccolinguofacial involvement and dysarthria Parkinsonism Gait abnormalities Pyramidal signs Choreoathetosis Cognitive impairment Pigmentary retinopathy Eye movement abnormalities Reduced total sleep time Acanthocytosis 49 C9orf72 (1) As of 2012, it is the most common mutation identified that is associated with familial FTD and/or ALS Autosomal dominant The mutation of C9orf72 is a hexanucleotide repeat expansion of the six letter string of nucleotides GGGGCC In a normal person, there are up to 30 repeats of this hexanucleotide, but in people with the mutation, the repeat can occur in the order of hundreds 50 C9orf72 (2) (GGGGCC)n Alternative last exon Alternative last exon 1a 1b Alternative first exon Alternative first exon 17

18 C9orf72 (3) 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) 52 Phenotypic heterogeneity of C9orf72 53 HD mimics (phenocopies) 54 Wild et al., Mov Disord 2007; Wild et al., Curr Opin Neurol

19 Genetic HD mimics HD Negative C9orf72 Negative Ataxia Myoclonus/ dementia African heritage Seizures SCA1-3 Friedreich s Prion Mitochondrial HDL2 DRPLA SCA17 Negative Blood film abnormal Neuroacanthocytosis 55 MRI abnormal Neuroferritinopathy NBIA 56 hdresearch.ucl.ac.uk Huntington s disease research news In plain language Written by scientists For the global HD community 57 19

20 58 Huntington s disease: reading 1. Novak & Tabrizi 2011 Huntington s Disease; BMJ 340:c Ross & Tabrizi 2011 Huntington's disease: from molecular pathogenesis to clinical treatment; Lancet Neurology 10: Wild & Tabrizi 2007 The differential diagnosis of chorea; Practical Neurology 7: Wild & Tabrizi 2007 Huntington s disease phenocopy syndromes; Current Opinion in Neurology 20: G Bates, Tabrizi SJ, Jones L Huntington s Disease, OUP Acknowledgements Edward Wild, Davide Martino, Russell Margolis, Patrick Chinnery, Susanne Schneider, Simon Mead, Kailash Bhatia and Ray Young