Neurogenetic disorders: Huntington’s Disease +

1. Neurogenetic disorders: Huntington’s Disease + British Neuropsychiatry Association Neurology & Psychiatry SpRs Teaching Weekend 10th - 12th December 2010 David Craufurd University of Manchester, Manchester Academic Health Sciences Centre and Central Manchester University Hospitals NHS Foundation Trust Genetic Medicine, St. Mary’s Hospital, Oxford Road, Manchester M13 9WL david.craufurd@manchester.ac.uk

2. George Huntington1850 - 1916 • born 9th April 1850 in East Hampton, Connecticut, USA • father and grandfather were doctors • graduated Columbia University 1871 • lecture ‘On Chorea’ presented 15th February 1872 (age 22) • published same year (Medical & Surgical Reporter of Philadelphia 1872; 26: 320-21) Source: Wellcome Trust Medical Photography

3. Huntington's diseaseclinical features • motor disorder (hyperkinetic and hypokinetic aspects) • cognitive impairment • behavioural (non-cognitive) symptoms

4. Huntington's diseaseprevalence • 6 – 10 /100,000 • 3,600 affected in UK (?) • HDA (England and Wales) in contact with about 6,000 affected individuals • 10 at risk (50% or 25%) for every 1 affected • adult onset (but 5% have JHD – onset <20 years)

5. Huntington’s diseaseinheritance • autosomal dominant inheritance (children of affected person have 50% risk) • delayed onset • expanded (CAG)n repeat mutation accounts for all cases

6. Huntington’s diseasemolecular genetics • gene localised to chromosome 4p by linkage analysis (1983) – the first autosomal gene to be mapped in this way • gene / mutation isolated in 1993 • contains (CAG)n triplet repeat mutation • number of repeats expanded (and unstable) on affected chromosome

7. Huntington’s Disease IT-15 or htt • Autosomal dominant • Monogenic • (CAG)n effect • Differential cell vulnerability • Natural History Short Arm of Chromosome 4 (4p16.3) • Ubiquitous expression • Spatial & Temporal • Unknown function • Embryonic lethal • Loss of function vs Gain of function (toxicity)

8. Huntington’s diseasetrinucleotide repeat mutation van Dellen & Hannan 2004

9. Differential diagnosis of HDother neurogenetic disorders resembling HD • Neuroacanthocytosis (CHAC) • areflexia, distal amyotrophy, oral and lingual chorea, may be tics, tongue biting • acanthocytes in blood, creatine kinase elevated • autosomal recessive • Benign hereditary chorea • slow progression, lack of cognitive or psychiatric changes • mutation in thyroid transcription factor 1 (TTF1) • McLeod syndrome • motor neuropathy, cardiomyopathy, anaemia • X-linked, mutation in Kell erythrocyte antigen (XK) gene

10. Differential diagnosis of HDother neurogenetic disorders resembling HD • Huntington Disease-like 1 (HDL1) • phenotype may be indestinguishable from HD • mutation in PRNP (prion) gene • Huntington Disease-like 2 (HDL2) • all cases to date have had black African ancestry • CAG/CTG repeat mutation in junctophilin-3 gene • Huntington Disease-like 3 (HDL3) • phenotype indestinguishable from HD • gene unknown

11. Differential diagnosis of HDother neurogenetic disorders resembling HD • Neurodegeneration with Brain Iron Accumulation (NBIA) • phenotype may be indestinguishable from HD • foci of hyperintensity in globus pallidus (eye of tiger sign) • mutations in pantothenate kinase (PANK2) gene • aka Hallervorden-Spatz syndrome • Neuroferritinopathy (NBIA2) • phenotype may be indestinguishable from HD (less symmetrical) • MRI T2 signal loss in basal ganglia, serum ferritin may be reduced • mutations in ferritin light chain (FTL) gene

12. Huntington’s diseaseproblems facing those at risk • childhood – behaviour of affected parent • fear of being affected • difficult to plan for future • reproduction: worry and guilt • parents: burden of care

14. Huntington’s diseasedisadvantages of predictive testing • emotional impact • self • family • discrimination • employment • insurance • long-term adjustment • hopelessness • suicide

15. Huntington’s disease protocol of UK Huntington’s prediction consortium • clinical genetic centres only • previous genetic counselling • two pre-test counselling sessions • results given in person • follow-up always offered Craufurd & Tyler, J. Med. Genet. 1992

16. Huntington's diseaseproblems associated with diagnostic genetic testing • requests for testing on presymptomatic individuals • testing when no FH or previous knowledge of HD • person tested is unaware of symptoms • pressure from relatives to test someone who is not yet ready for diagnosis • testing an at-risk person with possible features of HD (eg. psychotic symptoms) • results given by post or telephone • lack of follow-up

17. Huntington's diseasemotor abnormalities • hyperkinetic • chorea • dystonia • hypokinetic • bradykinesia (slowing of movement) • rigidity • clumsiness, impaired control • abnormalities of gait  reduced mobility • loss of automatic motor routines  fatigue • problems with speech and swallowing

18. HD: time course of motor disorder

19. Huntington's diseasemotor abnormalities • patients tend to be unaware of involuntary movements (especially in early stages) and less concerned about them than carers [Snowden et al., Archives of Neurology 1998; 55: 801-5] • treatment of chorea with tetrabenazine or neuroleptics tends to increase the hypokinetic disorder (also apathy and impairment of cognitive function) – risk of worsening functional disability • tetrabenazine and haloperidol are the only drugs licensed for treatment of chorea, but are probably the worst in this respect • sulpiride and tiapride (selective D2 and D3 antagonists) are best tolerated • olanzapine, risperidone, quetiapine are reasonable alternatives • amantadine has also been shown to reduce chorea in HD • pridopidine (Huntexil) (aka ACR16) may have a role in future

20. “In all the families, or nearly all in which the choreic taint exists, the nervous temperament greatly predominates, and….nervous excitement in a marked degree almost invariably attends upon every disease these people may suffer from…..The tendency to insanity, and sometimes that form of insanity which leads to suicide, is marked.” George Huntington (1872)

21. Huntington's diseasebehavioural aspects • often more distressing than motor and cognitive components • greater impact on carers and viability of community care • respond to symptomatic treatments available now

22. Huntington's diseasebehavioural aspects • mood changes • depression and suicide • anticipatory anxiety and tension • personality changes • irritability and aggressive outbursts • situational apathy • blunting of affect • obsessive-compulsive phenomena (especially perseveration) • psychotic symptoms • auditory hallucinations / delusions • sleep abnormalities • insomnia, day / night reversal • REM sleep behaviour disorder? • impaired insight

23. Huntington's disease depression in Maryland HD patients (N=186) • epidemiological survey (1st April 1980) • interviewed using DIS and DSM-III • major affective disorder 61/186 (33%) • dysthymic disorder 9/186 (5%) • population lifetime prevalence of major affective disorder in Baltimore (ECA study) was 4.3% • affective disorder preceded chorea and dementia by average of 5.1 years Folstein et al. (1987)

24. Major Depressive EpisodeDSM-IIIR diagnostic criteria • 5 or more of the following in same 2-week period (at least one must be low mood or anhedonia): • depressed mood most of the day, nearly every day • markedly diminished interest or pleasure in all, or almost all, activities • significant weight loss (when not dieting) or weight gain • insomnia or hypersomnia • psychomotor agitation or retardation • fatigue or loss of energy • feelings of worthlessness or excessive/inappropriate guilt • diminished ability to think or concentrate, or indecisiveness • recurrent thoughts of death, or suicidal ideation • symptoms are not due to substance abuse or a general medical condition

25. Lifetime prevalence of Major Affective disorder (DSM-III) and relationship to clinical onset in presymptomatic gene carriers requesting predictive testing (N=89 carriers, 115 non-carriers) Significant effect of closeness to clinical onset on prevalence of major affective disorder (χ² = 17.4, p< .01) and on subthreshold depressive symptoms (χ² = 10.8 , p < .05) Julien et al., JNNP2007; 78: 939-943

26. Huntington's diseasetreatment of depression • responds to conventional antidepressant medication • Selective Serotonin Reuptake Inhibitors (SSRIs) are first-line treatment (also useful for irritability) • higher doses may be necessary • tendency to relapse when treatment discontinued • SNRIs (venlafaxine) / mirtazapine / moclobamide if poor response • avoid tricyclics (except clomipramine for perseveration) • may be a place for CBT in early stages • general psychological support is important

27. Huntington's diseasefactors influencing irritability and aggression • hunger • fatigue • frustration (e.g. clumsiness, communication) • cognitive overload • depression • impaired ability to defer gratification • inability to anticipate consequences • emotional blunting

28. Huntington's diseasetreatment of irritability and aggression • psychological measures • SSRIs (high doses): citalopram or sertraline to avoid drug interactions with tetrabenazine – other SSRIs inhibit CYP2D6 • propranolol (usually 80mg twice daily) • mood-stabilising anti-epileptics (sodium valproate / carbamazepine) – but beware interactions with neuroleptics due to induction of CYP3A4 (especially quetiapine, risperidone) • neuroleptics e.g. sulpiride, olanzapine (last resort)

29. Mean PBA score (factor 1) by duration Craufurd et al., Neuropsychiat Neuropsychol Behav Neurol, 2001

30. Mean PBA score (factor 2) by duration Craufurd et al., Neuropsychiat Neuropsychol Behav Neurol, 2001

31. Mean PBA score (factor 3) by duration Craufurd et al., Neuropsychiat Neuropsychol Behav Neurol, 2001

32. Huntington's diseasedo we misdiagnose apathy as depression? • research diagnostic criteria for depression rely heavily on loss of motivation and vegetative symptoms • apathy is a common feature of many other neuropsychiatric disorders e.g. Alzheimers disease, Parkinson’s disease, stroke and acquired brain injury as well as HD • apathy is more common than mood changes in HD patients and there is evidence to suggest a different aetiology • clinical experience suggests that antidepressants improve low mood and irritability, but not apathy, in HD patients

33. Huntington's diseasetreatment of apathy • education of patient and family • psychological measures – structured environment (day care, exercise, etc.) • no established pharmacological treatments • avoidance of neuroleptics where possible • clinical trial of bupropion planned • possible role for methylphenidate?

34. The end