Huntington disease (HD) is an autosomal-dominant disorder, characterized as disease of progressive brain degeneration in late adulthood with subsequent brain atrophy. The affected areas of degeneration are the basal ganglia, which play an important role in the control of movement. This degeneration causes various motor problems such as behavioral abnormality, chorea, incoordination and dystonia (Folstein, 1989). George Huntington was the first man that described HD in the 19th century in detail especially its hereditary nature of chorea (Huntington, 1872). New findings have shown that HD involves the mutant protein huntigtin. This protein is translated from a CAG repeat forming a polyglutamine strand of variable length at the N-terminus. The molecular mechanism of HD is not fully understood but new findings using animal models have provided valuable information.
The gene associated with HD is termed the HD gene and can be found on the short arm of chromosome four. As the disease is autosomal dominant, only one HD gene is sufficient to cause the disorder. The HD gene is composed of a trinucleotide CAG repeats.The alleles of the HD gene are grouped as normal, intermediate or HD-causing. Each group has a characteristic number of CAG repeats. The normal alleles have 26 or fewer CAG repeats whereas intermediate alleles have 27-35 CAG repeats (Potter et al., 2004). Carriers of normal alleles and intermediate alleles are not at risk of developing HD. However, individuals with intermediate alleles are at risk of giving birth to a child with an allele of HD-causing characteristic (Semaka et al., 2006). Thus, intermediate alleles are also termed mutable alleles as they may mutate to cause HD phenotype in the offspring. The reason for the mutation lies in the instability of the replication. The longer the number of trinucleotides, the greater the instability. In 73% of the cases, the instability leads to an expansion of the trinucleotide repeats and thus an increase in the risk of developing HD whereas only 23% show a contraction of the number of repeats associated with a low risk of developing HD (Chattapadhyay et al., 2005; Djousse et al.,2004, MacDonald et al., 1999).
HD-causing alleles usually contain 36 or more CAG repeats and pose the carrier at an increased risk of developing HD. HD-causing alleles have been categorized into two groups: Reduced-penetrance HD-causing alleles and Full-penetrance HD-causing alleles. Reduced-penetrance or incomplete HD-causing alleles are composed of 36-39 trinucleotide CAG repeats (Rubinsztein, 2003; Rubinsztein et al., 1996; McNeil et al., 1997). Carriers of this allele may be asymptomatic and not show the symptoms. On the other hand, full-penetrance HD-causing alleles are characterized by 40 or more CAG repeats and carriers of this allele have a high probability of developing HD (Rubinsztein et al., 1996; McNeil et al., 1997; Langebehn et al., 2004).
The instability of the trinucleotide repeats occurs more often in males (spermatogenesis) than in females (oogenesis). This phenomenon can also be observed in the offspring with paternal inheritance of the HD gene where the onset of HD is more potent and occurs in the early youth. In addition, families with no history of HD may develop HD via new mutations arising by the amplification of trinucleotide CAG repeats and most of these new mutations come from the paternal side (Anca et al., 2004; Squitieri et al., 2003). Somatic instability of CAG repeats can also arise and have been observed in human beings as well as animal models. Furthermore, identical twins demonstrate different clinical syndromes and have almost a similar age of onset. Twins that are carriers of homozygous alleles have no difference in the age of onset (Georgiou et al., 1999).
Carriers of the HD allele are clinically healthy before the onset of the HD disease symptoms. However, in the so called presymptomatic phase, there are slight changes occurring in motor skills, cognition and personality (Walker, 2007). The onset of HD disease symptoms usually occurs in the mean age of onset which is 35 to 44 years (Bates et al., 2002). In 66%, initial symptoms are abnormalities in the neurological function or psychiatric changes. Other symptoms are minor involountary movements, difficulty in mental planning, depression and slight changes in the eye movement. In 25% of HD carriers, the appearance of initial symptoms such as chorea, dysphagia and gait disturbance is delayed until after 50 years with the disease symptoms taking a more prolonged and gentle course. At the same time, the lifestyle of the affected individuals does not change and they can still continue with their current employment.
The initial onset of the symptoms is followed by an increased symptomatic chorea, difficulty in controlling voluntary movement as well as exacerbation of dysarthria and dysphagia. As a result of the worsening symptoms, the affected individuals must leave employment and may require additional help to cope with some activities in their daily life.
The final stage of HD demonstrates severe motor disability. The symptoms have worsened so much that so that the carriers cannot deal with their impairment at all and require the assistance of other people. The carriers are mute and incontinent and show a median survival time of 15 to 18 years after the first onset of HD related symptoms. The life expectancy is suggested to be at 54 to 55 years (Harper, 2005).
The diagnosis of HD is based on mutation analysis. For this purpose, PCR based methods can be utilized which spots alleles up to about 115 CAG repeats. Likewise, southern blot is employed for alleles with more than 115 CAG (Potter et al., 2004). Such large expansions are linked with juvenile-onset of HD triggered by homozygous HD genotypes. Moderate-to-severe Huntington’s disease illustrate larger frontal horns of the lateral ventricles and deficiency in striatal volume when routine MRI and CT scans are performed (Stober et al., 1984). However, scans are not helpful for the diagnosis of early disorder. Functional MRI studies and data from PET have displayed that affected brains started to alter before the onset of symptoms (Kunig et al., 2000, Paulsen et al., 2004). Using these techniques, it is possible to recognize caudate atrophy as easrly as 11 years before the expected onset of the disease, and it is possible to recognze putaminal atrophy 9 years before the expected onset (Aylward et al., 2004). Tensor-based magnetic resonance morphometry demonstrates increasing loss of striatal loss in individuals who are presymptomatic carrying the HD gene and do not show evidence of progresson by clinical or neuropsychological tests over 2 years (Kipps et al., 2005).
Genetic testing for HD is only considered by 5% of HD risk carriers due to family planning and employment. Many HD risk carriers do not undergo testing as there is no efficient treatment for HD available (Laccone et al., 1999). Moreover, predictive testing can have psychological consequences for HD risk carriers leading to suicide due to mental depression (Almqvist et al., 2003). Therefore, it is crucial to identify suicidal patterns in young HD risk carriers and give pretest counseling.
Epidemiological studies suggest that HD is most prevalent in the white Caucasian population with 5-7 people affected per 100000. There are also exceptions in areas where the entire population is derived from a few founders such as in Lake Maracaibo in Venezuela or Tasmania (Pridmore, 1990). Across most of Asia and Africa the incidences of HD are much lower. The reason for the various distribution of HD incidence lies in the CAG repeats. White Caucasians have a much higher frequency of HD alleles that are composed of 28-35 CAG repeats (Kremer, 2002; Harper & Jones, 2002). The high frequency of this HD alleles in the white population is not fully understood. The HD gene may give a health benefit as in other genetic disorders such as sickle cell trait. It is thought that the HD gene is associated with a lower risk of developing cancer, possibly due to the upregulation of TP53 in HD disease (Bae et al., 2005; DiFiglia etal., 1995).
The pathogenesis of HD involving the protein huntingtin is poorly understood. Even though orthologs of that protein have been detected in zebrafish, drosophilia and slime moulds, the role of the protein is still unknown (Jones, 2002). Huntingtin has a high dominance in all human cells. Most of it is expressed in the brain and testes whereas heart, lungs and liver show moderate amounts of it (DiFiglia et al.,1995). One hypothesis suggests that happloinsufficiency plays an essential role in the pathogenesis of HD. This would mean that insufficient amounts of huntingtin protein are generated for the cells to function properly (Ambrose et al.,1994).
However, this hypothesis also have been refuted by other findings which suggest that a deficiency of HD gene in man does not cause HD in man (Rubinsztein, 2003; Ambrose et al., 1994). This is also supported by transgenic mouse models. One allele of the HD gene does not cause HD in transgenic mouse models and complete absence of the HD gene is linked to mortality in mouse embryos (Squitieri et al., 2003). Thus, new findings explain the pathogenesis of HD as a toxic gain of function derived from the mutant HD gene. Likewise, this phenomenon can also be observed in other genetic diseases such as muscular atrophy or dentatorubropallidoluysian (Ambrose et al., 1994; Andrew et al., 1993). There is not sufficient evidence to support the claim of happloinsufficiency in any of these genetic disease but an accumulation of polyglutamines with subsequent neurodegeneration. This is further supported by the relationship between length of polyglutamine repeat and age of onset. Longer polyglutamine repeat chains are associated with more aggressive progression of HD disease symptoms and the juvenile onset of HD (Mahant et al., 2003; Squitieri et al., 2002; Forproud et al., 1999). The biological structure of polyglutamine gives more insight into the toxic gain of function in HD. Experiments performed in vitro show that polyglutamine aggregates by forming dimmers, trimers and oligomers. For this aggregation to be efficient, a minimum number of 37 glutamine residues in sequence is required. The rate of aggregation increases as more glutamine repeats are added to the long chain of glutamine polypeptide. This in vitro observation may be an explaination why some individuals experience late onset of HD while others have a juvenile onset of HD.
Some key points have been discovered in the mechanism explaining how aggregated polyglutamine leads to neuronal dysfunction. The mutant huntingtin protein is more prone to proteleolysis than its wild type counterpart. This higher risk of protein degradation creates truncated proteins, which lead to the formation of aggregates of truncated huntingtin. Additionally, shorter glutamine repeats are less likely to form steric clashes than longer ones. It is believed that these aggregates are toxic and locate in the cell nucleus. (Saudou et al., 1998; Peter et al., 1999; Wellington et al., 2000). Eventually, the rate of aggregation overcomes the rate at which proteosomes or autophagic vacuolization degrade the proteins in the cell. This further exacerbates the formation of aggregated protein in conjunction with the ability of aggregates to recruit normal body proteins to their matrix. Examples of normal body proteins are those proteins that interact with the wild type form of huntingtin directly (Mills et al., 2005). Some papers also propose that the protein huntingtin may exert not only a toxic gain of function but also a dominant negative effect on the typical function of the wild type protein huntingtin. This way, mutant huntingtin could interfere with proteins that regulate transcription, apoptosis, tumor suppression or axonal transport (Bae et al., 2005; Busch et al., 2003; Charrin et al., 2005; Gauthier et al., 2004 , Hickey & Chesselet, 2003). Lastly, one other hypothesis states that mutant huntingtin may interfere in neuron-neuron interaction. This has been illustrated in mice where the mutant protein huntingtin disrupts the axonal transport and vesicle release of neurotrophic factor in neurons leading to intrinsic dysfunction of striatal neurons (Pulst et al., 1996; Komure et al., 1995).
Almqvist EW, Brinkman RR, Wiggins S, Hayden MR. Psychological consequences and predictors of adverse events in the fi rst 5 years after predictive testing for Huntington’s disease. Clin Genet 2003; 64: 300-09.
Ambrose CM, Duyao MP, Barnes G, et al. Structure and expression of the Huntington’s disease gene: evidence against simple inactivation due to expanded CAG repeat. Somat Cell Mol Genet 1994; 20: 27-38.
Anca MH, Gazit E, Lowewenthal R, Ostrovsky O, Frydman M, Giladi N. Diff erent phenotypic expression in monozygotic twins with Huntington disease. Am J Med Genet 2004; 124: 89-91.
Andrew SE, Goldberg YP, Kremer B, et al. The relationship between trinucleotide (CAG) repeat length and clinical features of Huntington’s disease. Nat Genet 1993; 4: 398-403.
Aylward EH, Sparks BF, Field KM, et al. Onset and rate of striatal atrophy in preclinical Huntington disease. Neurology 2004; 63: 66-72.
Bae BI, Xu H, Igarashi S, et al. P53 mediates cellular dysfunction and behavioral abnormalities in Huntington’s disease. Neuron 2005; 47:29-41.
Bates G, Harper P, Jones L (2002) Huntington’s Disease. Oxford University Press, New York.
Busch A, Engemann S, Lurz R, et al. Mutant huntingtin promotes the fibrillogenesis of wild-type huntingtin: a potential mechanism for loss of huntingtin function in Huntington’s disease. J Biol Chem 2003; 278: 41452-61.
Charrin BC, Saudou F, Humbert S. Axonal transport failure in neurogenerative disorders: the case of Huntington’s disease. Pathol Biol 2005; 53: 189-92.
Chattapadhyay B, Baksi K, Mukhopadhyay S, Bhattacharyya NP. Modulation of age at onset of Huntington’s disease patients by variations in TP53 and human caspase activated DNase (hCAD) genes. Neurosci Lett 2005; 374: 81-86.
DiFiglia M, Sapp E, Chase K, et al. Huntingtin is a cytoplasmic protein association with vesicles in human and rat brain neurons. Neuron 1995; 14: 1075-81.
Djousse L, Knowlton B, Hayden MR, et al. Evidence for a modifier of onset age in Huntington disease linked to the HD gene in 4p16. Neurogenetics 2004; 5: 109-14.
Foroud T, Gray J, Ivashina J, Conneally PM. Differences in duration of Huntington’s disease based on age at onset. J Neurol Neurosurg Psychiatry 1999; 66: 52-56.
Folstein S. Huntington’s disease: a disorder of families. Maryland: The Johns Hopkins University Press, 1989.
Gauthier LR, Charrin BC, Borrell-Pages M, et al. Huntingtin controls neurotrophic support and survival of neurons by enhancing BDNF vesicular transport along microtubules. Cell 2004; 118: 127-38.
Georgiou N, Bradshaw JL, Chiu E, Tudor A, O’Gorman L, Phillips JG. Diff erential clinical and motor control function in a pair of monozygotic twins with Huntington’s disease. Mov Disord 1999; 14:320-25.
Harper PS, Jones L. Huntington’s disease: genetic and molecular studies. In: Bates G, Harper P, Jones L, eds. Huntington’s disease. New York: Oxford University Press, 2002: 113-58.
Harper B.Huntington disease.J R Soc Med.2005;98:550.
Hickey MA, Chesselet MF. Apoptosis in Huntington’s disease. Prog Neuropsychopharmacol Biol Psychiatry 2003; 27: 256-65.
Huntington G. On chorea. Med Surg Rep 1872; 26: 317-21
Kipps CM, Duggins AJ, Mahant N, Gomes L, Ashburner J, McCusker EA. Progression of structural neuropathology in preclinical Huntington’s disease: a tensor based morphometry study. J Neurol Neurosurg Psychiatry 2005; 76: 650-55.
Kunig G, Leenders KL, Sanchez-Pernaute R, et al. Benzodiazepine receptor binding in Huntington’s disease: [11C]fl umazenil uptake measured using positron emission tomography. Ann Neurol 2000; 47: 644-48.
Kremer B. Clinical neurology of Huntington’s disease. In: Bates G, Harper P, Jones L, eds. Huntington’s disease. New York: Oxford University Press, 2002: 3-27.
Komure O, Sano A, Nishino N, et al. DNA analysis in hereditary dentatorubral-pallidoluysian atrophy: correlation between CAG repeat length and phenotypic variation and the molecular basis of anticipation. Neurology 1995; 45: 143-49.
Jones L. The cell biology of Huntington’s disease. In: Bates G, Harper P, Jones L, eds. Huntington’s disease. New York: Oxford University Press, 2002: 348-62.
Laccone F, Engel U, Holinski-Feder E, et al. DNA analysis of Huntington’s disease: fi ve years experience in Germany, Australia, and Switzerland. Neurology 1999; 53: 801-06.
Langbehn DR, Brinkman RR, Falush D, Paulsen JS, Hayden MR.A new model for prediction of the age of onset and penetrance for Huntington’s disease based on CAG length.Clin Genet.2004;65:267-77.
MacDonald ME, Vonsattel JP, Shrinidhi J, et al. Evidence for the GluR6 gene associated with younger onset of Huntington’s disease. Neurology 1999; 53: 1330-32
Mahant N, McCusker EA, Byth K, Graham S. Huntington’s disease: clinical correlates of disability and progression. Neurology 2003; 61:1085-92.
McNeil SM, Novelletto A, Srinidhi J, Barnes G, Kornbluth I, Altherr MR, Wasmuth JJ, Gusella JF, MacDonald ME, Myers RH.Reduced penetrance of the Huntington’s disease mutation.Hum Mol Genet.1997;6:775-9.
Mills IG, Gaughan L, Robson C, et al. Huntingtin interacting protein 1 modulates the transcriptional activity of nuclear hormone receptors. J Cell Biol 2005; 170: 191-200.
Paulsen JS, Zimbelman JL, Hinton SC, et al. fMRI biomarker of early neuronal dysfunction in presymptomatic Huntington’s disease. AJNR Am J Neuroradiol 2004; 25: 1715-21.
Peter MF, Nucifora FC Jr, Kushi J, et al. Nuclear targeting of mutant Huntingtin increases toxicity. Mol Cell Neurosci 1999; 14: 121-81.
Potter NT, Spector EB, Prior TW.Technical standards and guidelines for Huntington disease testing.Genet Med.2004;6:61-5.
Pridmore SA. The large Huntington’s disease family of Tasmania.Med J Aust 1990; 153: 593-95.
Pulst SM, Nechiporuk A, Nechiporuk T, et al. Moderate expansion of a normally biallelic trinucelotide repeat in spinocerebellar ataxia type 2. Nat Genetics 1996; 14: 237-38.
Rubinsztein DC. Molecular biology of Huntington’s disease (HD) and HD-like disorders. In: Pulst S, ed. Genetics of movement disorders. California: Academic Press, 2003: 365-77.
Rubinsztein DC, Leggo J, Coles R, Almqvist E, Biancalana V, Cassiman JJ, Chotai K, Connarty M, Crauford D, Curtis A, Curtis D, Davidson MJ, Differ AM, Dode C, Dodge A, Frontali M, Ranen NG, Stine OC, Sherr M, Abbott MH, Franz ML, Graham CA, Harper PS, Hedreen JC, Hayden MR.et al.Phenotypic characterization of individuals with 30-40 CAG repeats in the Huntington disease (HD) gene reveals HD cases with 36 repeats and apparently normal elderly individuals with 36-39 repeats.Am J Hum Genet.1996;59:16-22.
Rubinsztein DC. Molecular biology of Huntington’s disease (HD) and HD-like disorders. In: Pulst S, ed. Genetics of movement disorders. California: Academic Press, 2003: 365-77.
Rubinsztein DC, Leggo J, Coles R, et al. Phenotypic characterization of individuals with 30-40 CAG repeats in the Huntington disease (HD) gene reveals HD cases with 36 repeats and apparently normal elderly individuals with 36-39 repeats. Am J Hum Genet 1996; 59:16-22.
Saudou F, Finkbeiner S, Devys D, Greenberg ME. Huntingtin acts in the nucleus to induce apoptosis but death does not correlate with the formation of intranuclear inclusions. Cell 1998; 95: 55-56.
Squitieri F, Cannella M, Simonelli M. CAG mutation eff ect on rate of progression in Huntington’s disease. Neurol Sci 2002;23 (suppl 2): S107-08.
Squitieri F, Gellera C, Cannella M, et al. Homozygosity for CAG mutation in Huntington’s disease is associated with a more severe clinical course. Brain 2003; 126: 946-55.
Stober T, Wussow W, Schimrigk K. Bicaudate diameter: the most specifi c and simple CT parameter in the diagnosis of Huntington’s disease. Neuroradiology 1984; 26: 25-28.
O’Hearn E, Holmes SE, Calvert PC, et al. SCA-12: tremor with cerebellar and cortical atrophy is associated with a CAG repeat expansion. Neurology 2001; 56: 299-303. Walker FO.Huntington’s disease.Lancet.2007;369:218-28.
Wellington CL, Leavitt BR, Hayden MR. Huntington disease: new insights on the role of huntingtin cleavage. J Neural Transm Suppl 2000; 58: 1-17.