Huntington's Disease

Ayesha Mubashir (1), Adeel Memon (2)
1 - Dow University of Health Sciences
2 - University of Alabama at Birmingham


Introduction

An Autosomal Dominant (AD) neuro-degenerative disorder comprising of:
  • Involuntary movements
  • Cognitive disorder
  • Neuropsychiatric change
 

Epidemiology

  • Prevalence of approximately 10 cases per 100,000 people in North America, NorthWestern Europe, Middle-East and Australia
  • Prevalence is lower in Asia: 0.41-0.70 per 100,000 people
  • Sex: ♂ = ♀
  • Peak incidence: 40 yrs (symptoms appear between the 3rd-5th decade of life)
 

Etiology

  • CAG triplet repeat expansion in the Huntingtin gene (chromosome 4)
  • Exhibits anticipation (A phenomenon in which the signs and symptoms of some genetic conditions tend to become more severe and/or appear at an earlier age as the disorder is passed from one generation to the next).
  • Age of onset in terms of anticipation is younger when the mutated allele is passed from the father to his offspring
 

Pathophysiology

  • Mutation in chromosome 4 leads to atrophy of the caudate nucleus and putamen
  • Decrease in levels of GABA and Acetylcholine
  • Increase in levels of dopamine resulting in hyperkinesis and psychomotor symptoms
 

Clinical Features

Movement Dysfunction

  • Choreiform movement of all limbs: involuntary, sudden, irregular, nonrepetitive, arrhythmic movements of the limbs, neck, head, and/or face ( seen earlier in the course of the disease).
    • Dysphagia occurs in the following stages of ingestion and increases with disease progression:
      • Preparatory oral
      • Oral
      • Pharyngeal phase
  • Athetosis: involuntary, writhing movements, particularly of the hands and fingers.
  • Oculomotor disorders: reduced velocity in optokinetic nystagmus, hypometric saccades.
  • Ataxia
💡
Parkinsonian motor phenotype with bradykinesia is often seen in late manifesting patients and pediatric HD patients
 

Neuropsychiatric and Behavioral Dysfunction

  • Autonomic Features
    • Urinary incontinence
    • Incomplete bladder emptying,
    • Fecal incontinence
    • Hyperhidrosis
  • Aggression
  • Apathy
  • Depression

Cognitive Decline

☝️
Cognitive decline is seen later in the course of the disease
  • Most common: Slow cognitive processing
  • Other areas of cognitive decline:
    • Attention
    • Executive functions
    • Visuospatial
  • Dementia
 
 

Diagnosis and Evaluation

  • Patient history and examination
    • 💡
      Unified Huntington Disease Rating Scale (UHDRS) is used to quantify the severity of HD using four domains:
      • Motor function
      • Cognitive function
      • Behavioral abnormalities
      • Functional capacity
       
  • Genetic testing (Polymerase Chain Reaction)
  • MRI: atrophy of the caudate and putamen along with enlargement of frontal horns of the lateral ventricles as shown in Figure 1.
  • PET/CT scan demonstrates hypometabolism by decreased FDG (Fluorodeoxyglucose) uptake in the basal ganglia and frontal cortex even before noticeable caudate nucleus volume loss.
 
notion image

Figure 1: MRI Brain findings in Huntington's Disease

57-year-old with Huntington's Disease showing atrophy of caudate and putamen, dilation of frontal horn, and prominent sulci in the frontal lobe
Source: Radiopedia.org; Case courtesy of Dr. Frank Gaillard
 

 

Differential Diagnoses:

  • Tourette Syndrome
  • Sydenham Chorea
  • Wilsons Disease
  • Creutzfeldt Jacob Disease
  • Spinocerebellar Ataxia
  • Schizophrenia
  • Ballismus
  • Drug-induced Chorea:
    • Medical: Levodopa, Oral contraceptives, Antipsychotics
    • Recreational: Cocaine
  • Carbon Monoxide Poisoning
  • Pantothenate Kinase-associated Neurodegeneration (PKAN Acute hypoxic encephalopathy)

Treatment and Management

General Treatment Recommendations

  • Identify and treat co-morbid conditions that can exacerbate neuropsychiatric symptoms
  • Identify current medications possibly contributing to presenting symptoms
  • Modify external environmental factors
  • Behavioral Therapy

Pharmacologic Treatment

  • Sleep disorders:
    • Melatonin
      • Start with 3mg at night
      • Increase in 3mg increments until disruptive behavior ceases
      • Significant improvement is seen with 6-18 mg dosage/night
       
  • Acute agitation: Benzodiazepine
 
  • Chronic Agitation/Psychosis:
    • Anti-psychotics
      • Fluphenazine
        • Starting dose should be 0.5-2.5mg
        • Max dose: 20-30 mg
      • Risperidone
        • Starting dose should be 0.5-1mg
        • Max dose: 4-6mg
    • Mood stabilizers
      • Carbamazepine
        • Starting dose should be 100-200mg
        • Max dose: 1200-1600mg
  • Anxiety/Depression: SSRI
    • Fluoxetine
      • Starting dose should be 10-20mg
      • Max dose: 60-80mg
    • Sertraline
      • Starting dose should be 25-50mg
      • Max dose: 200mg
      •  
  • Hyperkinesia: Tetrabenazine
☝️
A common side effect of Tetrabenazine is depression
Total daily dose up to 50 mg/day
  • 12.5 mg PO once a day initially; after 1 week, the dose should be increased to 12 mg twice daily
  • Maintenance: Titrate slowly by weekly intervals of 12.5mg/day to identify a dose that reduces chorea and is tolerated.
  • Maximum single dose should not exceed 25mg

Prognosis

  • Progressive: Worsens over time
  • Mean duration of illness: 15-20 years after the onset of symptoms
  • Most common cause of death:
    • Respiratory insufficiency
    • Aspiration pneumonia
    • Suicide

Further Reading:

Bibliography

  • Anderson, K. E., van Duijn, E., Craufurd, D., Drazinic, C., Edmondson, M., Goodman, N., van Kammen, D., Loy, C., Priller, J., & Goodman, L. V. (2018). Clinical Management of Neuropsychiatric Symptoms of Huntington Disease: Expert-Based Consensus Guidelines on Agitation, Anxiety, Apathy, Psychosis and Sleep Disorders. Journal of Huntington’s Disease, 7(4), 355–366. https://doi.org/10.3233/JHD-180293
 
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