Huntington disease: Genetics and pathogenesis

INTRODUCTION — 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".)

CLINICAL GENETICS — HD is caused by expansion of the cytosine-adenine-guanine (CAG) trinucleotide repeats in the huntingtin (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:

●Delayed-onset phenotype – They typically present in middle age, with progressive neuronal dysfunction and eventual neuronal loss over the ensuing 10 to 20 years.

●Correlation with repeat length – The greater the number of CAG repeats on expanded alleles, the earlier the age of onset and more severe the disease.

●Somatic and germline instability – The repeats show both somatic and germline instability. As a result of the latter, there can be expansion of the CAG repeat number over successive generations. This may cause earlier disease onset and a progressive worsening of the phenotype in subsequent generations, a phenomenon termed "anticipation." Anticipation is more common following paternal transmission of the disease allele.

●Selective vulnerability – A certain subset of neurons is preferentially vulnerable to dysfunction, even though the relevant protein is widely expressed throughout the brain and other tissues [4].

Wildtype HTT alleles have 6 to 26 CAG repeat units. Intermediate alleles have 27 to 35 repeats and rarely cause disease [5-7]. However, alleles of ≥27 repeats are unstable and have a tendency to expand in future generations with paternal transmission.

The generally accepted threshold for the potential to develop HD is 36 repeats. Alleles with 36 to 39 CAG repeats have reduced penetrance and a phenotype more typically characterized by cognitive dysfunction before the onset of chorea, which may result in delayed diagnosis [8]. An individual with an allele in the 36 to 39 range is at risk for HD but may not develop symptoms; full penetrance occurs with ≥40 repeats.

Trinucleotide repeat size is estimated to account for 30 to 70 percent of the variance in age of HD symptom onset [3,9-11]. Alleles with 40 to 50 CAG repeats are found in most patients with the adult form of HD [3]. Juvenile HD is typically associated with alleles containing more than 60 CAG repeats, and some patients have more than 100 repeats. Additional factors predicting age of onset are thought to be environmental and other genetic determinants [12,13].

In addition to its effect on the age of presentation, it is generally believed that CAG repeat length is positively correlated with the rate of clinical disease progression [14-18]. There also appears to be a positive correlation between CAG repeat length and the severity of neuropathologic changes [19]. These findings suggest that large CAG expansions produce more widespread injury than smaller expansions and may affect neuronal subtypes that would otherwise be spared with smaller repeat sizes.

PATHOGENESIS

Anticipation and transmitting parent effect — Expansion of the cytosine-adenine-guanine (CAG) repeat number over successive generations causes an earlier and more severe phenotype, termed "anticipation."

Intergenerational transmissions are associated with either slight increases of one to four CAG units or slight decreases of one to two units [1]. However, paternal transmission can sometimes produce much larger increases, on the order of seven or more CAG repeats [20,21]. The high number of cellular divisions that occur during spermatogenesis may account for the pronounced paternal-repeat instability [20,22].

Because of the tendency for paternal transmission to result in greater expansion of the CAG repeat size, anticipation shows a major transmitting parent effect, as approximately 70 to 88 percent of symptomatic patients with juvenile HD inherit the mutant HD gene from their father [23-25].

Toxic gain of function — Expansion of CAG repeats is thought to cause toxicity through a "gain-of-function" mechanism (ie, disease develops because the mutant form of the protein gains a function that is deleterious to the cell).

Three observations are compatible with HD being caused by a dominant gain-of-function rather than loss-of-function mechanism:

●Patients with homozygous disease have clinical manifestations and age of onset similar to those of heterozygous siblings [26,27]. By contrast, the data conflict on whether the clinical course is more severe with more rapid progression in those with homozygous disease [26,27].

●Reduction of normal huntingtin activity does not cause HD in both animal models and in humans. The clinical manifestations in mice with deletion or complete inactivation of wildtype Htt, the homologue of the HD gene, are different from those in humans with HD. These mice die in gestation between days 8.5 and 10.5, before the emergence of the nervous system [28-30]. Thus, huntingtin is critical for early embryonic development. Mice heterozygous for Htt inactivation are phenotypically normal [28,29].

Similar findings have been noted in humans, providing further support for a gain-of-function mechanism. In addition, a patient with a breakpoint in the HD gene that led to reduced expression of huntingtin was phenotypically normal [31].

●In mice, replacing wildtype Htt with a mutant Htt allele containing 50 glutamine repeats results in normal embryonic and brain development [32]. This finding indicates that the HD defect in humans does not mimic complete or partial Htt inactivation.

Of note, HTT residues outside of the polyglutamine tract impact disease severity, suggesting that the toxic gain of function is related to a normal function of huntingtin [33,34].

Somatic expansion in striatum — Considerable evidence supports the concept that somatic CAG/cytosine-thymine-guanine (CTG) expansion in the gene encoding huntingtin in the striatum of affected individuals occurs and plays a critical role in the heightened susceptibility of the striatum to HD [35]. In addition, deoxyribonucleic acid (DNA) repair genes significantly modify age at onset in HD [36,37], suggesting a mechanism that could contribute to somatic expansion of HTT CAG/CTG repeats [38].

A small molecule, naphthyridine-azaquinolone (NA), has been developed that selectively binds to hairpin structures formed by expanded HTT CAG/CTG repeats [39]. Injections of NA into the striatum of an HD mouse model induced contractions of the expanded repeat. Thus, somatic instability is a novel therapeutic target for HD [40].

Distribution and function of huntingtin — Huntingtin is widely expressed throughout the brain and is present in a large number of tissues throughout the body [41]. However, the neuropathology of HD appears to be limited to the central nervous system, with neuronal cell loss and atrophy of the caudate and putamen (the neostriatum) being most prominent [19]. Thus, the distribution of huntingtin does not correlate with the pattern of neuronal cell loss seen in HD.

Wildtype huntingtin exists primarily as a soluble cytoplasmic protein in somatodendritic regions and in axons [4,42]. It is associated with cellular organelles including the Golgi apparatus, mitochondria, endoplasmic reticulum, cytoskeleton, and synaptic vesicles, and is also present to a lesser degree in the nucleus [16]. The full-length protein exists in a complex with HTT-associated protein 40 (HAP40), which supports the concept that the protein functions as a multivalent interaction hub [43].

Although it is essential for normal embryonic development, the role of wildtype huntingtin in the adult is poorly understood [2]. Huntingtin interacts with numerous proteins, raising the possibility that huntingtin is involved in multiple cellular events. Proposed functions for wildtype huntingtin include roles in the regulation of ciliogenesis, protein trafficking, vesicular transport and anchoring to the cytoskeleton, endocytosis, and postsynaptic signaling [3,44-46]. In addition, wildtype huntingtin may have a prosurvival (anti-apoptotic) function.

Mutant huntingtin — Mutant huntingtin is widely expressed in the brain [4,47,48]. Yet, a key neuropathologic feature of HD is selective neuronal loss in the caudate and putamen (striatum).

In HD, electron microscopy reveals both cytoplasmic and nuclear abnormalities, including the presence of large neuronal intranuclear inclusions or aggregates similar to those in other polyglutamine disorders [49-51]. The aggregates are also found in dystrophic neurites. The aggregates consist of amino-terminus fragments of the expanded mutant huntingtin [49,52]. The degree of aggregation varies with the length of the polyglutamine expansion (ie, the number of CAG repeats) [52].

Formation of mutant huntingtin aggregates may occur by one or both of two proposed mechanisms [3]:

●The normal tertiary protein conformation of huntingtin may be destabilized by the presence of the expanded polyglutamine tract, leading to the formation of insoluble beta pleated sheets

●The expanded polyglutamine tract may result in increased transglutaminase-mediated crosslinking with other polyglutamine-containing proteins, including mutant and wildtype huntingtin

While aggregation of mutant huntingtin is a pathologic hallmark of the disease process, the precise role of aggregates in the pathogenesis of HD is controversial [3,53-55]. As discussed below, the interaction of Rhes with mutant huntingtin results in both neurotoxicity and diminished aggregation of mutant huntingtin. This finding suggests that aggregation is a protective rather than a deleterious mechanism. (See 'Rhes' below.)

Experimental evidence consistently shows that the phenotypic severity of HD is directly related to levels of mutant huntingtin [56]. This concept has promoted therapeutic efforts to reduce and even reverse HD pathology and symptoms by inhibiting huntingtin expression or by altering its clearance. This approach is discussed elsewhere. (See "Huntington disease: Management", section on 'Investigational therapies'.)

Although the pathophysiology of neuronal loss is incompletely understood, there is evidence that mutant huntingtin may disrupt a number of intracellular pathways and thereby cause cellular demise by interfering with key components of these pathways and/or by sequestration of normal proteins into the huntingtin aggregates [2,3].

Proteins and pathways that are potentially disrupted by mutant huntingtin include the following [2,3]:

●Transcription disruption. One study showed that mutant huntingtin binds to and inhibits specificity protein 1 (Sp1), a transcription factor for cystathionine gamma-lyase (CSE), thereby leading to depletion of CSE, an enzyme necessary for the biosynthesis of the amino acid cysteine in the brain [57]. Furthermore, profoundly low levels of CSE were found in the striatum in mouse models of HD and in humans with HD; supplementation with cysteine reduced cytotoxicity in cell cultures of HD tissue and improved motor outcomes and survival in live mouse models of HD. These results suggest that mutant huntingtin causes cysteine depletion, which in turn mediates HD striatal neurodegeneration.

●Activation of proteases, leading to proteolysis.

●Inhibition of essential native proteins that contain polyglutamine repeats.

●Reduction in protein degradation, perhaps by blocking or overloading the proteosome degradation system [58]; the importance of this mechanism is related to the central role of the ubiquitin protease system in the removal of damaged, mutated, mislocated, or misfolded proteins that could be toxic to the cell [59].

●Interference with axonal transport.

●Increased ciliogenesis [44].

●Disruption of synaptic transmission [60,61].

●Interference with the normal action of wildtype huntingtin [62].

●Alteration of tau splicing and promotion of tau hyperphosphorylation [63-65].

●Impaired nuclear-cytoplasmic transport, found during normal brain aging, has a role in HD pathogenesis [66,67].

Although not necessarily a direct consequence of mutant huntingtin, a variety of additional mechanisms may contribute to neurodegeneration and the clinical manifestations of HD [3,68-70]. These include:

●Excitotoxicity

●Metabolic dysfunction, mitochondrial dysfunction, and oxidative stress

●Promotion of apoptosis and/or autophagy

●Dysfunction of neuronal interaction and circuits, primarily involving the corticostriatal and nigrostriatal pathways

●Abnormal cerebrospinal fluid flow and impaired neuroblast migration [44,45]

Role of autophagy — Mutant huntingtin is degraded through autophagy [71]. Efforts are ongoing to explore whether the degradation pathway of mutant huntingtin can be altered therapeutically.

As an example, compounds that bind to both the mutant polyglutamine tract and to LC3B, which resides in the autophagosome, could lead to the engulfment and clearance of mutant huntingtin. Screens for small molecules that might potentially interact with mutant huntingtin and LC3B have identified compounds that enhance the clearance of mutant huntingtin but not wildtype HTT [72]. Further, testing in fruit fly and mouse models of HD demonstrated functional benefits. These results are encouraging in that they might lead to therapeutics that target the mutant protein while sparing the wildtype counterpart.

Rhes — A possible explanation for the restriction of HD pathology mainly to the neostriatum involves the role of Rhes (Ras homolog enriched in striatum), a small guanine nucleotide-binding protein that is selectively localized to the striatum. Rhes interacts with both wildtype and mutant huntingtin, but binds more strongly with mutant huntingtin [73]. In cultured lines of human embryonic and murine brain cells, Rhes induces the small ubiquitin-like modifier (SUMO) protein to covalently attach to mutant huntingtin in a process known as sumoylation. This process reduces the aggregation of mutant huntingtin and elicits neurotoxicity.

NEUROPATHOLOGY — The characteristic pathologic change in HD is diffuse, marked atrophy of the neostriatum that may be worse in the caudate than in the putamen [19,74]. The caudate atrophy can often be detected on brain imaging with computed tomography (CT) scan or magnetic resonance imaging (MRI). Caudate and putamen volume measurements by MRI suggest that striatal atrophy begins 9 to 20 years before the clinical diagnosis of HD [75,76].

Although a general correlation exists between clinical severity of motor impairment and the degree of neuronal loss [77,78], some symptomatic patients (5 of 163 in one postmortem series) with HD have no pathologic abnormalities [74]. Symptoms in such patients presumably are caused by cellular dysfunction related to mutant huntingtin and its associated biochemical changes.

The pathologic changes are more dramatic in early-onset HD. Affected patients typically show generalized brain atrophy and loss of cerebellar Purkinje cells [19].

At the cellular level, protein aggregates are seen both in the cytoplasm and nucleus. (See 'Mutant huntingtin' above.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Huntington disease".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Huntington disease (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Clinical genetics

•Huntingtin (HTT) gene – 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. The disease is transmitted in an autosomal dominant manner. (See 'Clinical genetics' above.)

•Number of repeats – Wildtype HTT alleles have 6 to 26 CAG repeat units. Intermediate alleles have 27 to 35 repeats and rarely cause disease. The generally accepted threshold for developing HD is 36 repeats, but alleles with 36 to 39 CAG repeats have variable penetrance and more typically present with cognitive dysfunction, with chorea being less evident. Full penetrance occurs at repeat sizes ≥40. (See 'Clinical genetics' above.)

•Genotype-phenotype correlation – Individuals with early-onset HD tend to have a large number of CAG repeats, while those developing HD late in life typically have a low repeat number. Alleles with 40 to 50 CAG repeats are found in most patients with the adult form of HD. In comparison, juvenile HD is typically associated with alleles containing more than 60 CAG repeats. (See 'Clinical genetics' above.)

•Genetic anticipation – Expansion of the CAG repeat number over successive generations may cause an earlier and more severe phenotype, termed "anticipation." (See 'Anticipation and transmitting parent effect' above.)

●Pathogenesis

•Wildtype huntingtin – Wildtype huntingtin is essential for normal embryonic development. While its role in adults is not completely understood, wildtype huntingtin participates in the regulation of ciliogenesis, protein trafficking, vesicular transport and anchoring to the cytoskeleton, endocytosis, and postsynaptic signaling. (See 'Distribution and function of huntingtin' above.)

•Toxic gain of function – Expansion of CAG repeats is thought to produce a toxic "gain of function" (ie, disease develops because the mutant form of the protein gains a new function or has enhanced function that is deleterious to the cell). (See 'Toxic gain of function' above.)

Aggregation of mutant huntingtin is a pathologic hallmark of the disease process. However, the precise role of aggregates in the pathogenesis of HD is controversial. Mutant huntingtin may disrupt a number of intracellular pathways and thereby cause cellular demise by interfering with key components of these pathways and/or by sequestration of normal proteins into the huntingtin aggregates. (See 'Mutant huntingtin' above.)

•Localization to striatum – The predominant localization of HD neuropathology to the striatum may be explained by the interaction of mutant huntingtin with Rhes, a small guanine nucleotide-binding protein that is selectively localized to the striatum. (See 'Rhes' above.)

●Neuropathology – The characteristic pathologic change in HD is diffuse, marked atrophy of the neostriatum that may be worse in the caudate than in the putamen. (See 'Neuropathology' above.)