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  Disease summary:

  
  
  
  
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    Huntington disease (HD) is a neurodegenerative condition that usually manifests as a triad of movement disorder, cognitive dysfunction, and behavioral or psychiatric abnormalities; however, these features can vary widely between individuals.

    
    
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    HD is the most prevalent inherited neurodegenerative disease affecting up to 1 in 10,000 individuals in most populations of European descent.

    
    
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    HD is caused by expansion of the trinucleotide CAG (polyglutamine-encoding) repeat sequence in exon 1 of the huntingtin gene (HTT) to greater than 35 repeats. The age of disease onset in HD is inversely correlated with the size of the CAG repeat expansion.

    
    
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    Following identification of the causative gene defect in 1993, at-risk individuals (with an affected parent) can be offered direct predictive genetic testing prior to the onset of symptoms.

  
  
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  Hereditary basis:

  
  
  
  
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    HD is a familial condition with autosomal dominant inheritance and is fully penetrant (in most cases with expansions of greater than 40 CAG trinucleotide repeats).

  
  
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  Differential diagnosis:

  
  
  
  
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    The high prevalence of HD compared to genetic disorders with similar presentation means that, even without a family history, HD is the major diagnostic consideration in the choreic individual.

    
    
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    In the event of a negative HD test or atypical presentation, the differential diagnoses become a focus of investigation.

    
    
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    Any individual with an otherwise unexplained clinical presentation consistent with HD should be offered the direct genetic test for HD, since it is easily the most common inherited cause of such a presentation. The main inherited disorders with similar clinical presentation (HD phenocopies) are outlined in Table 125-1. Of these, HDL-2 and SCA17 are probably the most common HD phenocopies. For a useful algorithm for the screening of potential HD phenocopies, see Wild and Tabrizi (2007).

    
    
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    In the event of a negative HD test or an atypical presentation, it is most important to exclude any treatable (and/or potentially reversible) acquired causes. Wilson disease is a genetic case which is also treatable. Acquired causes of an HD presentation include (1) medication-related tardive dyskinesia or chorea following use of typical neuroleptics or the oral contraceptive pill, and L-dopa-induced dyskinesias, (2) postinfectious, for example, Sydenham chorea (poststreptococcal) or tertiary syphilis, (3) metabolic thyrotoxicosis and chorea gravidarum of pregnancy, (4) inflammatory lupus and antiphospholipid syndrome.

Diagnostic Criteria

The clinical diagnosis of HD should be made by a clinician with expertise in the evaluation of HD. It requires

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  The presence of a defined motor phenotype consisting of an otherwise unexplained extrapyramidal movement disorder in an individual with either a positive HD test result or a family history of HD

And the absence of

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  A clear alternative cause of the clinical presentation

Clinical Characteristics

Classically HD presents with a combined cognitive, psychiatric, and extrapyramidal movement phenotype. Clinical onset for most adults is between ages 35 and 44. The movement disorder usually comprises both involuntary and voluntary components. The involuntary movement disorder may follow a biphasic pattern with initial, increasing hyperkinesia, and chorea reaching a peak usually in the mid-stages of disease. This hyperkinesia gradually diminishes, giving rise to bradykinesia and rigidity which eventually develops into a rigid-akinetic state. The voluntary component of the movement disorder is also progressive. Gait abnormalities present as a broad-based ataxia. Mobility deteriorates until the individual becomes bed-bound. Progressive dysarthria, dysphagia, ocular pursuit abnormalities, and loss of fine motor co-ordination also characterize the motor phenotype. Eventually the patient becomes mute and unable to tolerate oral nutrition.