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Huntington's disease; Huntington's chorea (progressive hereditary chorea)

Etiology: 1) associated with trinucleotide repeat (CAG) in coding region of huntingtin gene on chromosome 4 2) 11-34 Gln repeats are seen in N-terminal region of IT15 protein in normal individuals, whereas HD patients have 37-86 Gln repeats. Epidemiology: 1) overall prevalence of 5-10 per 100,000 2) onset of symptoms in mid life (generally 4th-5th decade) Genetics: - autosomal dominant - Gln repeat (CAG) expansion in N-terminal region of IT15 - CAG repeat lengths of 36-39 associated with older age of HD onset compared to longer repeats - CAG repeats of length 36-39 in 1 of 400 asymptomatic elderly [7], thus penetrance low - other implicated genes: - COP1, CPLX2, SETDB1, TCERG1 Pathology: 1) striatum a) loss of striatal GABA/enkephalin containing medium sized spiny neurons projecting to the external globus pallidus is seen earlier in the disease than those containing GABA/substance P projecting to the internal globus pallidus or substantia nigra, pars reticulata b) striatal peptidergic neurons containing somatostatin & neuropeptide Y tend to be spared c) RASD2 (Rhes)-dependent sumoylation of huntingtin renders huntingtin cytotoxic; striatal-specific expression may explain specificity of Huntington's disease pathology for striatum [3] d) Vonsattel grade [8] - grade 0: - no macroscopic change - 30-40% loss of neurons in head of caudate - grade 1: - atrophy of body & tail of caudate - macroscopically normal appearance of head of caudate & putamen - neuronal loss & gliosis more pronounced in tail of caudate, head & body & putamen less affected - macroscopic & microscopic appearance of accumbens nucleus unremarkable - grade 2: - enlarged lateral ventricles - neuronal loss & gliosis of dorsal portion of caudate (medial > lateral) & putamen - degeneration in globus pallidus (external > internal) - grade 3: - atrophy of head of caudate (macroscopic) - neuronal loss & gliosis severe in caudate & putamen, mild in nucleus accumbens - grade 4: - striatum severely atrophic - severe striatal neuronal loss (~95%) 2) cerebral cortex [8]: - severe atrophy, all cortical lobes, specific layer specific loss in some areas 3) thalamus [8]: - precerebellar ventrolateral nucleus - intralaminar centromedian-parafascicular complex (may play role in cognitive, psychiatric & oculomotor symptoms) - mediodorsal nucleus 4) cerebellum [8]: - reduction of cerebellar volume & surface area of cerebellar arbor vitae, atrophy of anterior & posterior lobes - neuronal loss in cerebellar cortex (mostly Purkinje cells) & deep cerebellar nuclei (fastigial, globose, emboliform & dentate) 5) brainstem [8]: - neuronal loss dopaminergic & GABAergic pars reticulata of the substantia, precerebellar pontine nuclei, inferior olive, oculomotor reticulotegmental nucleus - severe loss of neurons in premotor oculomotor area of the excitatory burst neurons for horizontal saccades & raphe interpositus nucleus, auditory superior olive, lateral & medial vestibular nuclei 6) other - altered inflammatory signalling, immune activation in hematopoietic cells [10] - decreased selenium in all regions of the brain examined [12] - increased sodium/potassium ratios in every region of the brain examined except the substantia nigra [12] Clinical manifestations: 1) onset of symptoms in mid life (generally 4th-5th decade) 2) gradual onset of memory loss & progressive dementia - impaired executive function - inattention, difficulty focusing on tasks 3) choreiform movements 4) psychiatric symptoms: impulsiveness 5) restlessness, anxiety, insomnia, impulsiveness 6) lack of initiative, depression, substance abuse common [2] 7) parkinsonism [2], shuffling gait 8) deep tendon reflexes (DTR) normal or increased 9) other neurologic findings including - dysarthria, ataxia (wide-based gait), incoordination, falls, impaired rapid alternating movements (dysdiadochokinesia), impaired fine motor skills - twitching 9) duration of illness is 15 years or longer 10) skeletal muscle atrophy [10] 11) weight loss & increased metabolic rate [10] 12) glucose intolerance [10] 13) cardiac failure (~30% of HD patients compared to ~2% in age matched controls) [10] 14) osteoporosis [10] 15) testicular atrophy [10] Laboratory: - specific marker on chromosome 4 - Huntington's disease genotyping - HTT gene CAG repeats - HTT gene mutation - genetic counseling prior to genetic testing [1,6] - see ARUP consult [4] Radiology: - neuroimaging: caudate atrophy Differential diagnosis: - Tourette syndrome - often presents in childhood - uncontrollable vocal & motor tics, not chorea - progression to dementia rare - amyotrophic lateral sclerosis - muscle weakness, muscle atrophy, bulbar palsy, fasciculations - chorea not a characteristic Management: 1) symptomatic treatment of psychosis 2) chorea: [5] a) tetrabenazine up to 100 mg/day or amantadine 300-400 mg/day or riluzole 200 mg/day [5] - deutetrabenazine (Austedo) FDA-approved April 2017 - valbenazine b) nabilone may be of benefit for short term use c) ethyl-eicosapentaenoate, minocycline, or creatine may or may not be useful d) coenzyme Q10 may or may not be useful e) insufficient data to recommend clozapine, other neuroleptics, or donepezil [5]

General

basal ganglia disease polyglutamine expansion disorder

Properties

AFFECTED-CELL-TYPE[S]: spiny neuron :QUALITIES MEDIUM-SIZE :TRANSMITTER gamma-aminobutyric acid enkephalin :AXON GLOBUS_PALLIDUS_EXTERNAL_SEGMENT

References

  1. DeGowin & DeGowin's Diagnostic Examination, 6th edition, RL DeGowin (ed), McGraw Hill, NY 1994, pg 875
  2. Medical Knowledge Self Assessment Program (MKSAP) 11, 17, 18, 19. American College of Physicians, Philadelphia 1998, 2015, 2018, 2021
  3. Subramaniam S et al Rhes, a Striatal Specific Protein, Mediates Mutant-Huntingtin Cytotoxicity Science. 2009 Jun 5;324(5932):1327-1330. PMID: 19498170 DOI: 10.1126/science.1172871
  4. ARUP Consult: Huntington Disease - HD The Physician's Guide to Laboratory Test Selection & Interpretation https://www.arupconsult.com/content/huntington-disease - ARUP Consult: Huntington Disease https://arupconsult.com/ati/huntington-disease
  5. Armstrong MJ, Miyasaki JM. Evidence-based guideline: pharmacologic treatment of chorea in Huntington disease: Report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology 2012 Aug 7;79(6):597-603. [31 references] PMID: 22815556 Free PMC Article
  6. Bordelon YM. Clinical neurogenetics: huntington disease. Neurol Clin. 2013 Nov;31(4):1085-94. Review. PMID: 24176425
  7. Kay C, Collins JA, Miedzybrodzka Z et al. Huntington disease reduced penetrance alleles occur at high frequency in the general population. Neurology 2016 Jun 22; PMID: 27335115 - Delatycki MB, Bandmann O. Huntington disease: More common than you think? Neurology 2016 Jun 22 PMID: 27335111
  8. Rub U et al Huntington's disease (HD): the neuropathology of a multisystem neurodegenerative disorder of the human brain. Brain Pathol. 2016 Nov;26(6):726-740 PMID: 27529157
  9. Rub U et al Huntington's disease (HD): degeneration of select nuclei, widespread occurrence of neuronal nuclear and axonal inclusions in the brainstem. Brain Pathol. 2014 Apr;24(3):247-60. PMID: 24779419
  10. van der Burg JM, Bjorkqvist M, Brundin P Beyond the brain: widespread pathology in Huntington's disease. Lancet Neurol. 2009 Aug;8(8):765-74. PMID: 19608102
  11. Dayalu P, Albin RL Huntington disease: pathogenesis and treatment. Neurol Clin. 2015 Feb;33(1):101-14. Review. PMID: 25432725
  12. George J Widespread Selenium Deficiency Seen in Huntington's Disease Brains - Researchers caution about self-medicating MedPage Today October 24, 2023 https://www.medpagetoday.com/neurology/generalneurology/106970 - Scholefield M, Patassini S, Xu J, Cooper GJS. Widespread selenium deficiency in the brain of cases with Huntington's disease presents a new potential therapeutic target. eBioMedicine. 2023 Oct 6:97:104824 PMID: 37806287 https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(23)00390-0/fulltext
  13. NINDS Huntington's Disease Information Page https://www.ninds.nih.gov/Disorders/All-Disorders/Huntingtons-Disease-Information-Page

Databases, Figures & Images

OMIM 143100 Kegg hsa/hsa05040 Huntington's disease pathology images related to Huntington's disease