Huntington's disease: clinical and aetiologic aspects

Abstract

Huntington's disease is the most prevalent inherited human neurodegenerative disorder worldwide, affecting between 2 to 8 per 100000 inhabitants of Western countries, with an average age of onset close to 40 (range 2-80) and a usually slow progression over 10 to 30 years. Tremendous progress has been made in the understanding of the mechanisms implicated in this disease since the original description by George Huntington in 1872, marked by the identification of the locus in 1983 and the responsible gene in 1993. Clinical features include impaired motor control, manifesting as motor impersistence and inability to perform tasks that require motor sequences, along with abnormal movements such as chorea, athetosis, impaired ocular saccades and characteristic gait disturbances. Psychiatric and cognitive symptoms are also prominent, including depression and psychosis, with a high incidence of suicide, personality changes, aggressive or uncontrolled behaviour, impaired problem-solving abilities and ultimately more diffuse neuropsychological deficits leading to dementia. Genetically, the disease demonstrates fully penetrant autosomal dominant inheritance through a CAG trinucleotide repeat expansion in the protein-coding region of the huntingtin gene. There is an inverse correlation between the number of repeats and the patient's age at onset of the disease. Due to a phenomenon referred to as anticipation, the number of CAG trinucleotide repeats tends to increase when the disease is inherited from the father (paternal transmission), with disease onset at a younger age in the affected children. Despite 10 years of intensive study, the exact route between mutant protein and neurodegenerative illness remains elusive. Protein aggregation, mitochondrial dysfunction, transcriptional dysregulation, calcium homoeostasis and signalling anormalities, and organellar transport defects are leading candidate disease mechanisms. Huntington's disease pathology is characterised by marked atrophy of the caudate and putamen, with involvement of cerebral cortex, thalamus, subthalamus, nucleus accumbens, globus pallidus and substantia nigra pars reticulata. Within the caudate and putamen, the medium spiny GABA-ergic projection neurons are selectively vulnerable. Huntington's disease progresses slowly but irremediably to a state where patients are bedridden and demented, followed by death from secondary complications such as pneumonia. Current disease treatment is limited to pharmacologic management of symptoms, mostly antipsychotics, both for the abnormal movements and some psychiatric symptoms, and antidepressants. Future therapies targeting underlying disease mechanisms are currently under evaluation, raising tremendous hope for the development of curative treatments. They include metabolic support, neurotrophic intervention, cell replacement, transcriptional regulation and reducing the expression of the causative gene using small interfering RNA.