Huntington’s disease is an autosomal dominant disorder that is clinically characterised by a triad of symptoms and signs:-
1.) A prominent movement disorder, i.e. chorea – rapid, jerky, ‘dance-like’ movements . of the body.
2.) Behavioural and emotional alterations 3.) Cognitive decline.
Huntington’s disease is characterised by both extrapyramidal motor abnormalities and an impairment of voluntary movements that effects gait, speech and swallowing. Choreic movements, which are the major symptom of Huntington’s disease, are involuntary, abrupt, irregularly timed and randomly distributed movements of the body – with typical accentuation in the fingers and toes (Yang et al. (1996)). Choreic severity over time ranges from restlessness, hand fidgeting and an unstable ‘dance-like’ gait, to a continuous flow of violent movements that are severely disabling and exhausting to the patient. After this first phase of the disease, typically lasting around ten years, the severity of chorea tends to decrease, progressively becoming replaced by bradykinesia and rigidity (core features of parkinsonism) and dystonia (involuntary spasms of muscle contraction that causes abnormal movements/ postures) (Young et al. (1986)).
In Huntington’s disease, cognitive and intellectual function typically start to slow soon after the chorea begins (Paulsen et al. (2001)). As the disease progresses, patients become significantly impaired in an array of cognitive areas including attention and concentration, memory, speech and language, visuospatial skills and frontal executive functions (Snowden
et al. (2001)). Memory deficits occur in retrieval and procedural learning (Bylsma et al.
greater difficulty retrieving both recent and remote information, with less difficulty in actually storing memories (Rohrer et al. (1999)). Speech and language changes include dysarthria (a disturbance in the strength and coordination of speech muscles), a decreased verbal fluency, and a decreased speech output which ultimately progresses to mutism (Murray & Lenz (2001)). The frontal-executive deficits in Huntington’s disease are prominent, and interfere with a patient’s ability to perform tasks that require organisation, planning and/ or sequential arrangement of information (Zakzanis (1998)). As the disease advances, all intellectual abilities deteriorate to the point where patients are mute and intellectually devastated in the final stages.
Huntington’s disease is equally common in men and women, and effects three to ten people per 100’000 (Folstein (1989)). The disease usually begins in the fourth to fifth decade (in 90-95% of patients), and typically has a 13- to 16-year course (Folstein (1989)).
On autopsy, macroscopic inspection of advanced Huntington’s disease patients’ brains reveal a weight reduction of 10-20% compared with age matched controls. Much of this weight loss can be attributed to the shrunken neostriatum, the main neuropathological feature in Huntington’s disease, with gross atrophy of the putamen and especially the caudate nucleus – which is reduced from a robust structure to a thin ribbon of tissue as little as two or three millimetres thick (Myers (1988)). At the microscopic level, histological changes are concordantly most prominent in the neostriatum, i.e. caudate and putamen, where there is a loss of small spiny neurons, which is hypothesised to have the inhibitory effect on movement mechanisms through a 70-90% reduction in γ-amino butyric acid (GABA) production – an inhibiting neurotransmitter. The striatum also realises shrunken larger neurons, with a conspicuous increase in glial cells (Myers (1988)). It is this striatal pathology which likely underlies the involuntary movements of Huntington’s disease chorea and dystonia, as well as the disordered planning, impulsive behaviours, diminished emotional control and some of the other Huntington’s disease symptoms (Albin et al. (1989)). While the hippocampus also displays moderate neuronal loss, the cerebellum, brainstem and spinal cord are little affected in Huntington’s disease (Albin et al. (1989)). The extent of the striatal pathology forms the basis of the grading severity of the disease (grades naught to four), which clearly correlates with the clinical progression of Huntington’s disease (Myers et al. (1988)).
The Huntington’s disease gene contains 67 exons (Huntington’s Disease Collaborative Research Group (1993)) and encodes a 350 KDa protein called Huntingtin. Huntington’s disease has been shown to be caused by an expanded CAG repeat located within the first exon (+36 to 120bp), which is translated into a polyglutamine tract. The number of CAG repeats in the Huntington’s disease gene correlates with a younger age of onset and an increased DNA fragmentation in the striatum (Butterworth et al. (1998)). It is hypothesised that the abnormal Huntingtin protein aggregates within neurons and glia to form abnormal intracytoplasmic inclusions/ filaments (Lunkes et al. (1998)). Furthermore, cysteine aspartate- specific proteases (caspase) may cleave the mutant huntingtin, generating toxic protein fragments that lead to abnormal metabolism, oxidative stress and mitochondrial dysfunction in the cells of the caudate and putamen (Wellington & Hayden (2000)).
Current treatment of Huntington’s disease is aimed at the symptomatic control of the motor and psychiatric aspects of the disorder. Neuroleptics such as haloperidol, which is a dopamine antagonist, are used to suppress abnormal movements, though in the later stages of the illness as dopamine receptors are destroyed, this medication will gradually become less useful and may aggravate dystonia, bradykinesia & dysphagia, gait and balance problems (Chua & Chiu (2005)).
The depression in Huntington’s disease responds to the same treatments as it does in the general population, but Huntington’s disease sufferers may become more sensitive to the side effects such as sedation and anticholinergic-induced cognitive decline. Psychotic symptoms, irritability or behavioural disturbance all respond to neuroleptics (Chua & Chiu (2005)).
Specific treatments which theoretically target the disease process to slow functional decline in disease manifestation, such as antioxidants and other neuroprotective drugs, are under trial. Drugs which may slow progression or improve the chorea whilst being tolerated include antioxidant coenzyme Q, and remacemide, a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist (Chua & Chiu (2005)).
Clinical research determining the early onset and progressive symptoms of Huntington’s disease is currently being undertaken by an international collaboration of
researchers in Huntington’s disease – the Huntington Study Group. Part of their remit is to research and develop new restorative therapies that rejuvenate or replace malfunctioning neurons in order to restore functions.