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

Etiology

• associated with trinucleotide repeat (CAG) in coding region of huntingtin gene on chromosome 4
• 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

• overall prevalence of 5-10 per 100,000
• onset of symptoms in mid life (generally 4th-5th decade)

Pathology

• striatum
  • 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
  • striatal peptidergic neurons containing somatostatin & neuropeptide Y tend to be spared
  • RASD2 (Rhes)-dependent sumoylation of huntingtin renders huntingtin cytotoxic; striatal-specific expression may explain specificity of Huntington's disease pathology for striatum
  • Vonsattel grade
    • 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%)
• cerebral cortex:
  • severe atrophy, all cortical lobes, specific layer specific loss in some areas
• thalamus:
  • precerebellar ventrolateral nucleus
  • intralaminar centromedian-parafascicular complex (may play role in cognitive, psychiatric & oculomotor symptoms)
  • mediodorsal nucleus
• cerebellum:
  • 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)
• brainstem:
  • 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
• other
  • altered inflammatory signalling, immune activation in hematopoietic cells
  • decreased selenium in all regions of the brain examined
  • increased sodium/potassium ratios in every region of the brain examined except the substantia nigra

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, thus penetrance low
• other implicated genes:
  • COP1, CPLX2, SETDB1, TCERG1

Clinical manifestations

• onset of symptoms in mid life (generally 4th-5th decade)
• gradual onset of memory loss & progressive dementia
  • impaired executive function
  • inattention, difficulty focusing on tasks
• choreiform movements
• psychiatric symptoms: impulsiveness
• restlessness, anxiety, insomnia, impulsiveness
• lack of initiative, depression, substance abuse common
• parkinsonism, shuffling gait
• deep tendon reflexes (DTR) normal or increased
• other neurologic findings including
  • dysarthria, ataxia (wide-based gait), incoordination, falls, impaired rapid alternating movements (dysdiadochokinesia), impaired fine motor skills
  • twitching
• duration of illness is 15 years or longer
• skeletal muscle atrophy
• weight loss & increased metabolic rate
• glucose intolerance
• cardiac failure (~30% of HD patients compared to ~2% in age matched controls)
• osteoporosis
• testicular atrophy

Laboratory

• specific marker on chromosome 4
  • Huntington's disease genotyping
    • HTT gene CAG repeats
    • HTT gene mutation
  • genetic counseling prior to genetic testing
• see ARUP consult

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

• beta-blockers are associated with a later age at onset & a slower rate of clinical progression
• symptomatic treatment of psychosis
• chorea:
  • tetrabenazine up to 100 mg/day or amantadine 300-400 mg/day or riluzole 200 mg/day
    • deutetrabenazine (Austedo) FDA-approved April 2017
    • valbenazine
  • nabilone may be of benefit for short term use
  • ethyl-eicosapentaenoate, minocycline, or creatine may or may not be useful
  • coenzyme Q10 may or may not be useful
  • insufficient data to recommend clozapine, other neuroleptics, or donepezil

More general terms

• polyglutamine expansion disorder
• basal ganglia disease

Patient information

Huntington's disease patient information

Database

• OMIM: https://mirror.omim.org/entry/143100
• Kegg: http://www.genome.jp/dbget-bin/www_bget?