Huntington disease: Genetics and pathogenesis
- Huda Y Zoghbi, MD
Huda Y Zoghbi, MD
- Professor, Departments of Pediatrics, Neurology, Neuroscience, and Molecular and Human Genetics
- Baylor College of Medicine
- Harry T Orr, PhD
Harry T Orr, PhD
- University of Minnesota
- Institute for Translational Neuroscience
- Section Editors
- Marc C Patterson, MD, FRACP
Marc C Patterson, MD, FRACP
- Section Editor — Pediatric Neurology
- Professor of Neurology, Pediatrics, and Medical Genetics
- Chair, Division of Child and Adolescent Neurology
- Mayo Clinic College of Medicine
- Helen V Firth, DM, FRCP, DCH
Helen V Firth, DM, FRCP, DCH
- Section Editor — Genetics
- Consultant Clinical Geneticist
- Addenbrooke's Hospital, Cambridge, UK
Unstable trinucleotide repeats are associated with a variety of neurodegenerative diseases. Nine of these disorders are associated with expansion of cytosine-adenine-guanine (CAG) repeats that encode for polyglutamine tracts in the protein products. Included in this group are Huntington disease (HD), spinobulbar muscular atrophy, dentatorubral pallidoluysian atrophy, and some of the spinocerebellar ataxias.
The most common presenting symptom of HD in adults is chorea (hence the name Huntington chorea). Other usual findings at presentation include memory deficits, affective disturbances, personality changes, and other manifestations of motor dysfunction such as parkinsonism and dystonia. Patients with juvenile-onset HD have minimal or no chorea, but develop myoclonus and seizures as well as cognitive and behavioral problems. Children also have a more rapidly progressive disease.
The genetics and pathogenesis of HD will be reviewed here. Clinical aspects and management of HD are discussed separately. (See "Huntington disease: Clinical features and diagnosis" and "Huntington disease: Management".)
Huntington disease (HD) is caused by expansion of the cytosine-adenine-guanine (CAG) trinucleotide repeats in the HTT gene (also known as the HD or IT15 gene) located on chromosome 4p16.3 that encodes the protein huntingtin [1-3]. Mutant huntingtin contains an expanded tract of glutamine residues, which is located near its amino terminal. The disease is transmitted in an autosomal dominant manner.
HD shares several clinical features with the other polyglutamine diseases:
- A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. The Huntington's Disease Collaborative Research Group. Cell 1993; 72:971.
- Walker FO. Huntington's disease. Lancet 2007; 369:218.
- Gil JM, Rego AC. Mechanisms of neurodegeneration in Huntington's disease. Eur J Neurosci 2008; 27:2803.
- Trottier Y, Devys D, Imbert G, et al. Cellular localization of the Huntington's disease protein and discrimination of the normal and mutated form. Nat Genet 1995; 10:104.
- Dayalu P, Albin RL. Huntington disease: pathogenesis and treatment. Neurol Clin 2015; 33:101.
- Ha AD, Jankovic J. Exploring the correlates of intermediate CAG repeats in Huntington disease. Postgrad Med 2011; 123:116.
- Semaka A, Kay C, Doty C, et al. CAG size-specific risk estimates for intermediate allele repeat instability in Huntington disease. J Med Genet 2013; 50:696.
- 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.
- Stine OC, Pleasant N, Franz ML, et al. Correlation between the onset age of Huntington's disease and length of the trinucleotide repeat in IT-15. Hum Mol Genet 1993; 2:1547.
- Lee JM, Ramos EM, Lee JH, et al. CAG repeat expansion in Huntington disease determines age at onset in a fully dominant fashion. Neurology 2012; 78:690.
- Wexler NS, Lorimer J, Porter J, et al. Venezuelan kindreds reveal that genetic and environmental factors modulate Huntington's disease age of onset. Proc Natl Acad Sci U S A 2004; 101:3498.
- Arning L, Kraus PH, Valentin S, et al. NR2A and NR2B receptor gene variations modify age at onset in Huntington disease. Neurogenetics 2005; 6:25.
- Furtado S, Suchowersky O, Rewcastle B, et al. Relationship between trinucleotide repeats and neuropathological changes in Huntington's disease. Ann Neurol 1996; 39:132.
- Brandt J, Bylsma FW, Gross R, et al. Trinucleotide repeat length and clinical progression in Huntington's disease. Neurology 1996; 46:527.
- Aylward EH, Li Q, Stine OC, et al. Longitudinal change in basal ganglia volume in patients with Huntington's disease. Neurology 1997; 48:394.
- Mahant N, McCusker EA, Byth K, et al. Huntington's disease: clinical correlates of disability and progression. Neurology 2003; 61:1085.
- Rosenblatt A, Liang KY, Zhou H, et al. The association of CAG repeat length with clinical progression in Huntington disease. Neurology 2006; 66:1016.
- Vonsattel JP, DiFiglia M. Huntington disease. J Neuropathol Exp Neurol 1998; 57:369.
- Duyao M, Ambrose C, Myers R, et al. Trinucleotide repeat length instability and age of onset in Huntington's disease. Nat Genet 1993; 4:387.
- Zühlke C, Riess O, Bockel B, et al. Mitotic stability and meiotic variability of the (CAG)n repeat in the Huntington disease gene. Hum Mol Genet 1993; 2:2063.
- Telenius H, Almqvist E, Kremer B, et al. Somatic mosaicism in sperm is associated with intergenerational (CAG)n changes in Huntington disease. Hum Mol Genet 1995; 4:189.
- Zühlke C, Riess O, Schröder K, et al. Expansion of the (CAG)n repeat causing Huntington's disease in 352 patients of German origin. Hum Mol Genet 1993; 2:1467.
- Brinkman RR, Mezei MM, Theilmann J, et al. The likelihood of being affected with Huntington disease by a particular age, for a specific CAG size. Am J Hum Genet 1997; 60:1202.
- Nahhas FA, Garbern J, Krajewski KM, et al. Juvenile onset Huntington disease resulting from a very large maternal expansion. Am J Med Genet A 2005; 137A:328.
- Wexler NS, Young AB, Tanzi RE, et al. Homozygotes for Huntington's disease. Nature 1987; 326:194.
- Squitieri F, Gellera C, Cannella M, et al. Homozygosity for CAG mutation in Huntington disease is associated with a more severe clinical course. Brain 2003; 126:946.
- Duyao MP, Auerbach AB, Ryan A, et al. Inactivation of the mouse Huntington's disease gene homolog Hdh. Science 1995; 269:407.
- Nasir J, Floresco SB, O'Kusky JR, et al. Targeted disruption of the Huntington's disease gene results in embryonic lethality and behavioral and morphological changes in heterozygotes. Cell 1995; 81:811.
- Zeitlin S, Liu JP, Chapman DL, et al. Increased apoptosis and early embryonic lethality in mice nullizygous for the Huntington's disease gene homologue. Nat Genet 1995; 11:155.
- Persichetti F, Carlee L, Faber PW, et al. Differential expression of normal and mutant Huntington's disease gene alleles. Neurobiol Dis 1996; 3:183.
- White JK, Auerbach W, Duyao MP, et al. Huntingtin is required for neurogenesis and is not impaired by the Huntington's disease CAG expansion. Nat Genet 1997; 17:404.
- Graham RK, Deng Y, Slow EJ, et al. Cleavage at the caspase-6 site is required for neuronal dysfunction and degeneration due to mutant huntingtin. Cell 2006; 125:1179.
- Gu X, Greiner ER, Mishra R, et al. Serines 13 and 16 are critical determinants of full-length human mutant huntingtin induced disease pathogenesis in HD mice. Neuron 2009; 64:828.
- Carroll JB, Bates GP, Steffan J, et al. Treating the whole body in Huntington's disease. Lancet Neurol 2015; 14:1135.
- DiFiglia M, Sapp E, Chase K, et al. Huntingtin is a cytoplasmic protein associated with vesicles in human and rat brain neurons. Neuron 1995; 14:1075.
- Keryer G, Pineda JR, Liot G, et al. Ciliogenesis is regulated by a huntingtin-HAP1-PCM1 pathway and is altered in Huntington disease. J Clin Invest 2011; 121:4372.
- Liu JP, Zeitlin SO. The long and the short of aberrant ciliogenesis in Huntington disease. J Clin Invest 2011; 121:4237.
- Caviston JP, Holzbaur EL. Huntingtin as an essential integrator of intracellular vesicular trafficking. Trends Cell Biol 2009; 19:147.
- Trottier Y, Lutz Y, Stevanin G, et al. Polyglutamine expansion as a pathological epitope in Huntington's disease and four dominant cerebellar ataxias. Nature 1995; 378:403.
- Jou YS, Myers RM. Evidence from antibody studies that the CAG repeat in the Huntington disease gene is expressed in the protein. Hum Mol Genet 1995; 4:465.
- DiFiglia M, Sapp E, Chase KO, et al. Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain. Science 1997; 277:1990.
- Davies SW, Beardsall K, Turmaine M, et al. Are neuronal intranuclear inclusions the common neuropathology of triplet-repeat disorders with polyglutamine-repeat expansions? Lancet 1998; 351:131.
- Ross CA. Intranuclear neuronal inclusions: a common pathogenic mechanism for glutamine-repeat neurodegenerative diseases? Neuron 1997; 19:1147.
- Krobitsch S, Lindquist S. Aggregation of huntingtin in yeast varies with the length of the polyglutamine expansion and the expression of chaperone proteins. Proc Natl Acad Sci U S A 2000; 97:1589.
- Michalik A, Van Broeckhoven C. Pathogenesis of polyglutamine disorders: aggregation revisited. Hum Mol Genet 2003; 12 Spec No 2:R173.
- 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.
- Okamoto S, Pouladi MA, Talantova M, et al. Balance between synaptic versus extrasynaptic NMDA receptor activity influences inclusions and neurotoxicity of mutant huntingtin. Nat Med 2009; 15:1407.
- Graham RK, Slow EJ, Deng Y, et al. Levels of mutant huntingtin influence the phenotypic severity of Huntington disease in YAC128 mouse models. Neurobiol Dis 2006; 21:444.
- Paul BD, Sbodio JI, Xu R, et al. Cystathionine γ-lyase deficiency mediates neurodegeneration in Huntington's disease. Nature 2014; 509:96.
- Seo H, Sonntag KC, Isacson O. Generalized brain and skin proteasome inhibition in Huntington's disease. Ann Neurol 2004; 56:319.
- Bence NF, Sampat RM, Kopito RR. Impairment of the ubiquitin-proteasome system by protein aggregation. Science 2001; 292:1552.
- Marco S, Giralt A, Petrovic MM, et al. Suppressing aberrant GluN3A expression rescues synaptic and behavioral impairments in Huntington's disease models. Nat Med 2013; 19:1030.
- Cummings DM, Cepeda C, Levine MS. Alterations in striatal synaptic transmission are consistent across genetic mouse models of Huntington's disease. ASN Neuro 2010; 2:e00036.
- Zuccato C, Ciammola A, Rigamonti D, et al. Loss of huntingtin-mediated BDNF gene transcription in Huntington's disease. Science 2001; 293:493.
- Fernández-Nogales M, Cabrera JR, Santos-Galindo M, et al. Huntington's disease is a four-repeat tauopathy with tau nuclear rods. Nat Med 2014; 20:881.
- Vuono R, Winder-Rhodes S, de Silva R, et al. The role of tau in the pathological process and clinical expression of Huntington's disease. Brain 2015; 138:1907.
- Gratuze M, Cisbani G, Cicchetti F, Planel E. Is Huntington's disease a tauopathy? Brain 2016; 139:1014.
- Mochel F, Haller RG. Energy deficit in Huntington disease: why it matters. J Clin Invest 2011; 121:493.
- Song W, Chen J, Petrilli A, et al. Mutant huntingtin binds the mitochondrial fission GTPase dynamin-related protein-1 and increases its enzymatic activity. Nat Med 2011; 17:377.
- Duan W, Jiang M, Jin J. Metabolism in HD: still a relevant mechanism? Mov Disord 2014; 29:1366.
- Subramaniam S, Sixt KM, Barrow R, Snyder SH. Rhes, a striatal specific protein, mediates mutant-huntingtin cytotoxicity. Science 2009; 324:1327.
- Vonsattel JP, Myers RH, Stevens TJ, et al. Neuropathological classification of Huntington's disease. J Neuropathol Exp Neurol 1985; 44:559.
- Aylward EH, Sparks BF, Field KM, et al. Onset and rate of striatal atrophy in preclinical Huntington disease. Neurology 2004; 63:66.
- Kipps CM, Duggins AJ, Mahant N, et al. Progression of structural neuropathology in preclinical Huntington's disease: a tensor based morphometry study. J Neurol Neurosurg Psychiatry 2005; 76:650.
- Guo Z, Rudow G, Pletnikova O, et al. Striatal neuronal loss correlates with clinical motor impairment in Huntington's disease. Mov Disord 2012; 27:1379.
- Rosenblatt A, Abbott MH, Gourley LM, et al. Predictors of neuropathological severity in 100 patients with Huntington's disease. Ann Neurol 2003; 54:488.