Huntington Disease

A number sign (#) is used with this entry because Huntington disease (HD) is caused by a heterozygous expanded trinucleotide repeat (CAG)n, encoding glutamine, in the gene encoding huntingtin (HTT; 613004) on chromosome 4p16.

In normal individuals, the range of repeat numbers is 9 to 36. In those with HD, the repeat number is above 37 (Duyao et al., 1993).

Description

Huntington disease (HD) is an autosomal dominant progressive neurodegenerative disorder with a distinct phenotype characterized by chorea, dystonia, incoordination, cognitive decline, and behavioral difficulties. There is progressive, selective neural cell loss and atrophy in the caudate and putamen. Walker (2007) provided a detailed review of Huntington disease, including clinical features, population genetics, molecular biology, and animal models.

Clinical Features

The classic signs of Huntington disease are progressive chorea, rigidity, and dementia. A characteristic atrophy of the caudate nucleus is seen radiographically. Typically, there is a prodromal phase of mild psychotic and behavioral symptoms which precedes frank chorea by up to 10 years. Chandler et al. (1960) observed that the age of onset was between 30 and 40 years. In a study of 196 kindreds, Reed and Neel (1959) found only 8 in which both parents of a single patient with Huntington chorea were 60 years of age or older and normal. The clinical features developed progressively with severe increase in choreic movements and dementia. The disease terminated in death on average 17 years after manifestation of the first symptoms.

Folstein et al. (1984, 1985) contrasted HD in 2 very large Maryland pedigrees: an African American family residing in a bayshore tobacco farming community and a white Lutheran family living in a farming community in the western Maryland foothills and descended from an immigrant from Germany. They differed, respectively, in age at onset (33 years vs 50 years), presence of manic-depressive symptoms (2 vs 75), number of cases of juvenile onset (6 vs 0), mode of onset (abnormal gait vs psychiatric symptoms), and frequency of rigidity or akinesia (5/21 vs 1/15). In the African American family, the mean age at onset was 25 years when the father was affected and 41 years when the mother was affected; the corresponding figures in the white family were 49 and 52 years. Allelic mutations were postulated. In another survey in Maryland, Folstein et al. (1987) found that the prevalence of HD among African Americans was equal to that in whites.

Adams et al. (1988) found that life-table estimates of age of onset of motor symptoms have produced a median age 5 years older than the observed mean when correction for truncated intervals of observation (censoring) was made. The bias of censoring refers to the variable intervals of observation and loss to observation at different ages. For example, gene carriers lost to follow-up, those deceased before onset of disease, and those who had not yet manifested the disease at the time of data collection were excluded from the observed distribution of age at onset.

Kerbeshian et al. (1991) described a patient with childhood-onset Tourette syndrome (137580) who later developed Huntington disease.

Shiwach (1994) performed a retrospective study of 110 patients with Huntington disease in 30 families. He found the minimal lifetime prevalence of depression to be 39%. The frequency of symptomatic schizophrenia was 9%, and significant personality change was found in 72% of the sample. The age at onset was highly variable: some showed signs in the first decade and some not until over 60 years of age.

The results of a study by Shiwach and Norbury (1994) clashed with the conventional wisdom that psychiatric symptoms are a frequent presentation of Huntington disease before the development of neurologic symptoms. They performed a control study of 93 neurologically healthy individuals at risk for Huntington disease. The 20 asymptomatic heterozygotes showed no increased incidence of psychiatric disease of any sort when compared to the 33 normal homozygotes in the same group. However, the whole group of heterozygous and homozygous normal at-risk individuals showed a significantly greater number of psychiatric episodes than did their 43 spouses, suggesting stress from the uncertainty associated with belonging to a family segregating this disorder. Shiwach and Norbury (1994) concluded that neither depression nor psychiatric disorders are likely to be significant preneurologic indicators of heterozygous expression of the disease gene.

Giordani et al. (1995) performed extensive neuropsychologic evaluations on 8 genotype-positive individuals comparing them to 8 genotype-negative individuals from families with Huntington disease. They found no significant differences between these 2 groups, casting further doubt on earlier reports that suggested cognitive impairments are premonitory signs of the classical neurologic syndrome of Huntington disease.

Rosenberg et al. (1995) performed a double-blind study on 33 persons at risk for HD who had applied for genetic testing. Significantly inferior cognitive functioning was disclosed in gene carriers by a battery of neuropsychologic tests covering attentional, visuospatial, learning, memory, and planning functions. Primarily, attentional, learning, and planning functions were affected.

Bamford et al. (1995) performed a prospective analysis of neuropsychologic performance and CT scans of 60 individuals with Huntington disease. They found that psychomotor skills showed the most significant consistent decline among cognitive functions assessed.

Lovestone et al. (1996) described an unusual HD family in which all 4 affected members presented first with a severe psychiatric syndrome which in 3 cases was schizophreniform in nature. Two other living members with no apparent signs of motor disorder had received psychiatric treatment, 1 for schizophrenia.

Mochizuki et al. (1999) described a case of late-onset Huntington disease with the first symptom of dysphagia. The 61-year-old man was admitted with dysphagia and dysarthria, which had developed gradually over 2 years. The patient had no psychologic signs, dementia, paresis, involuntary movements, ataxia, or sensory disturbance in the limbs. Dysphagia and dysarthria appeared to be caused by a 'cough-like movement' just before or during speaking or swallowing. Because the 'cough-like movement' progressed for 3 years and was eventually suppressed with disappearance of dysphagia after administration of haloperidol, this symptom was thought to be due to HD.

Paulsen et al. (2006) studied the brain structure of 24 preclinical HD patients as measured by brain MRI and compared them to 24 healthy control subjects matched by age and gender. Preclinical HD individuals had substantial morphologic differences throughout the cerebrum compared to controls. The volume of cerebral cortex was significantly increased in preclinical HD, whereas basal ganglion and cerebral white matter volumes were substantially decreased. Although decreased volumes of the striatum and cerebral white matter could represent early degenerative changes, the finding of an enlarged cortex suggested that developmental pathology occurs in HD.

Marshall et al. (2007) compared psychiatric manifestations among 29 HD mutation carriers with no clinical symptoms, 20 HD mutation carriers with mild motor symptoms, 34 manifesting HD patients, and 171 nonmutation controls. The mild motor symptoms group and the manifesting HD group showed significantly higher scores for obsessive-compulsive behavior, interpersonal sensitivity, anxiety, paranoia, and psychoticism compared to the nonmutation control group. The mutation carriers without symptoms had higher scores for anxiety, paranoid ideation, and psychoticism compared to the nonmutation control group. The results indicated that individuals in the preclinical stage of HD exhibit specific psychiatric symptoms and that additional symptoms may manifest later in the disease course. Walker (2007) noted that suicidal ideation is a frequent finding in Huntington disease and that physicians should be aware of increased suicide risk both in asymptomatic at-risk patients and symptomatic patients.

Clinical Variability

Behan and Bone (1977) reported hereditary chorea without dementia. The oldest affected person in their family was aged 61 years.

Juvenile Onset

Juvenile-onset Huntington disease, typically defined as onset before age 20 years, is estimated to comprise less than 10% of all HD cases. It is usually transmitted from an affected father, is associated with very large CAG repeat sizes (60 or more) in the HTT gene, and typically shows rigidity and seizures (Nance and Myers, 2001; Ribai et al., 2007).

The juvenile form of Huntington disease was first described by Hoffmann (1888) using data from a 3-generation family. He identified 2 daughters with onset at 4 and 10 years who showed rigidity, hypokinesia, and seizures.

Barbeau (1970) pointed out that patients with the juvenile form of Huntington chorea seem more often to have inherited their disorder from the father than from the mother. Ridley et al. (1988) showed that Huntington disease shows anticipation, but only on paternal inheritance, with the consequence that patients with juvenile Huntington disease inherit the disease from their fathers.

Navarrete et al. (1994) described a family in which a brother and sister had very early onset of Huntington disease. Clinical manifestations were apparent in both sibs at the age of 8 years; the brother died at age 10. The father of these sibs was affected from the age of 29 years.

Milunsky et al. (2003) described 1 of the youngest children ever reported with juvenile HD. The girl, 5 years old at the time of report, had been adopted because of the inability of her biologic parents to care for her. Her biologic father was subsequently found to have HD. The girl demonstrated near-normal development until about 18 months of age. Brain MRI had been normal at 2 years of age; at 3.5 years of age, there was marked cerebellar atrophy involving the vermis and cerebellar hemispheres, diminutive middle cerebellar peduncles, and an enlarged fourth ventricle. By age 3 years and 10 months, the patient required gastric tube feeding. Choreiform movements, predominantly on the right side, developed at approximately 4 years of age. Milunsky et al. (2003) developed a modified PCR method using XL (extra long)-PCR that allowed them to diagnose 265 triplet repeats on one HTT allele and 14 on the other.

Nahhas et al. (2005) reported a girl with a maternal family history of HD who had onset of symptoms at age 3 and died at age 7 due to complications of HD. The patient's mother had symptoms of HD at age 18. Molecular analysis revealed that the mother had 70 CAG repeats whereas the daughter had approximately 130 CAG repeats. Nahhas et al. (2005) stated that this was the largest reported molecularly confirmed CAG expansion from a maternal transmission, demonstrating that very large expansions can also occur through the maternal lineage.

Yoon et al. (2006) reported 3 patients with onset of HD before age 10 years. All had speech delay in early childhood as the first symptom, which predated motor symptoms by at least 2 years. All children later developed severe dysarthria. Initial gross motor symptoms included ataxic gait and falls; initial behavioral problems included aggression, irritability, and hyperactivity. CAG repeats were 120, 100, and 93, respectively, and all children inherited the disorder from their fathers.

Ribai et al. (2007) performed a retrospective analysis of 29 French patients with juvenile-onset HD. The mean delay before diagnosis was 9 years. The most common signs at onset were severe cognitive and psychiatric disturbances (65.5% of patients), including severe alcohol or drug addiction and psychotic disorder. In these patients, motor signs occurred a mean of 6 years after cognitive or psychiatric signs. Three other patients presented with myoclonic head tremor, 3 with chorea, and 1 with progressive cerebellar signs. Thirteen (46%) had fewer than 60 CAG repeats (range, 45 to 58). Six patients inherited the disease from their fathers, and 7 from their mothers, with similar anticipation. However, all cases with onset before age 10 years were paternally inherited.

Sakazume et al. (2009) reported a girl with onset of HD beginning at age 2 years with motor regression, speech difficulties due to oromotor dysfunction, and frequent temper tantrums. Onset of severe prolonged generalized seizures began at age 4 years. Brain MRI showed severe cerebellar atrophy in the vermis and cortex, in addition to atrophy in the caudate, putamen, and globus pallidus. Her mother, grandparent, and great-grandparent were affected. Molecular analysis showed that the child had 160 CAG repeats, whereas her mother had 60 repeats. A review of 7 reported patients with early-onset HD showed that 4 had inherited the expanded allele from the mother, and that the mothers were relatively young at the time of pregnancy, ranging from 20 to 27 years. These findings suggested that the incidence of maternal transmission in early-onset HD may be higher than that in adult-onset HD. Three of the 7 previously reported patients with early-onset HD had cerebellar atrophy.

Biochemical Features

Enna et al. (1976) found 50% reduction in binding at serotonin and muscarinic cholinergic receptors in the caudate nucleus but not the cerebral cortex of patients with Huntington chorea. Goetz et al. (1975) could not confirm a report that fibroblasts grew poorly. Contrariwise, they found that Huntington disease cells grew to a higher maximal density than did control fibroblasts.

Reiner et al. (1988) used immunohistochemical methods to study neurons producing substance P and enkephalin, projecting to the globus pallidus and to the substantia nigra, in brains from 17 patients with Huntington disease in various stages of the disorder. The authors found that in the early and middle stages of HD, the enkephalin-producing neurons with projections to the external portion of the globus pallidus were more affected than substance P-containing neurons projecting to the internal pallidal segment. This result was confirmed by Sapp et al. (1995). Reiner et al. (1988) also found that substance P-producing neurons projecting to the substantia nigra pars reticulata were more affected than those projecting to the pars compacta. In the advanced stages of the disease, neurons projecting to all striatal areas were depleted. Richfield and Herkenham (1994) found greater loss of cannabinoid receptors on striatal nerve terminals in the lateral globus pallidus compared to the medial pallidum in Huntington disease of all neuropathologic grades, supporting the preferential loss of striatal neurons that project to the lateral globus pallidus.

Aronin et al. (1995) detected mutant huntingtin protein in cortical synaptosomes isolated from brains of Huntington disease heterozygotes and demonstrated that the mutant species is synthesized and transported with the normal protein to nerve endings. In half of the juvenile cases, huntingtin resolved as a complex of bands after electrophoresis and immunostaining, which confirmed previous DNA evidence for somatic mosaicism. Mutant huntingtin was present in both normal and affected regions.

Using genetic and pharmacologic approaches in yeast, mammalian cells, and Drosophila, Mason et al. (2013) found that glutathione peroxidase (GPX; see 138320) activity robustly ameliorates Huntington disease-relevant metrics and is more protective than other antioxidant approaches tested in their study. Mason et al. (2013) found that GPX activity, unlike many antioxidant treatments, does not inhibit autophagy, which is an important mechanism for clearing mutant HTT.

Inheritance

Huntington disease is an autosomal dominant disorder. When the number of CAG repeats reaches 41 or more, the disease is fully penetrant. Incomplete penetrance can occur with 36 to 40 repeats. The number of repeats accounts for approximately 60% of the variation in age at onset, with the remainder determined by modifying genes and environment (Walker, 2007).

Intrafamilial variability of Huntington disease was illustrated by the report by Campbell et al. (1961) of the juvenile rigid form in 2 brothers in a kindred in which 3 preceding generations had disease of the more classic type. Brackenridge (1972) showed a relationship between age at onset of symptoms in parent and child. Wallace and Hall (1972) suggested that in Queensland, Australia, 2 possibly allelic forms of HD may exist, one with early onset and the other with late onset.

Myers et al. (1982) confirmed the preponderance of inheritance from the father when HD had an early onset. 'Anticipation' was thought to reflect the finding that persons with early onset in prior generations were selectively nonreproductive because of manifestation of the disorder. In 238 patients, Myers et al. (1983) correlated age at onset with whether inheritance was from the father or the mother. More than twice as many of the late-onset cases (age 50 or later) inherited the HD gene from an affected mother than from an affected father. Affected offspring of late-onset females also had late-onset disease while those of late-onset males had significantly earlier ages of onset. The authors interpreted these findings as suggesting a heritable extrachromosomal factor, perhaps mitochondrial. They cited Harding (1981) as suggesting that autosomal dominant late-onset spinocerebellar ataxia is marked by earlier age at onset and death in offspring of affected males. After it was found that both Huntington disease and some forms of spinocerebellar ataxia are caused by expanded repeats, the mechanism of anticipation in the paternal line was interpreted as an increase in the extent of the repeats during paternal meiosis.

Boehnke et al. (1983) tested models to account for the stronger parent-offspring age-of-onset correlation when the mother is the affected parent and the excess of paternal transmission in cases with onset at less than 21 years. They proposed 2 models in which a maternal factor acts to delay onset: cytoplasmic, possibly mitochondrial, or autosomal/X-linked.

Went et al. (1984) confirmed the earlier report that early-onset HD is almost always inherited from the father, but could not confirm the notion that late-onset disease is more often inherited from the mother. Farrer and Conneally (1985) postulated that age at onset is governed generally by a set of independently inherited aging genes, but expression of the HD genes may be significantly delayed in persons with a particular maternally transmitted factor. Myers et al. (1985) presented data that suggested a protective effect conferred on the offspring of affected women, who show an older mean age at onset than offspring of affected men, regardless of the onset age in the parent. Pointing out that some repetitive elements in many chromosomes of the mouse are methylated differently in males and females, Erickson (1985) suggested differences such as chromosomal imprinting may be responsible for the greater severity and earlier onset of Huntington disease in offspring of affected males and greater severity of myotonic dystrophy (DM1; 160900) in offspring of affected females.

Among 195 reported cases of juvenile Huntington disease, van Dijk et al. (1986) found a preponderance of 'rigid cases,' whose affected parent was the father in a significantly high number of cases. Rigid paternal cases have a significantly lower age at onset as well as a shorter duration of disease than choreic paternal cases.

Ridley et al. (1988) found that while the mean age at onset in offspring of affected mothers did not differ greatly from that in their mothers, the distribution of age at onset in the offspring of affected fathers fell into 2 groups; the larger group showed an age at onset only slightly younger than that in their affected fathers, and a smaller group had, on average, an age at onset 24 years younger than that of their affected fathers. Analysis of the grandparental origin of the Huntington allele suggested that while propensity to anticipation could be inherited for a number of generations through the male line, it originated at the time of differentiation of the germline of a male who acquired the Huntington allele from his mother. Ridley et al. (1988) suggested that major anticipation indicates an epigenetic change in methylation of the nucleic acid of the genome, which is imposed in the course of 'genomic imprinting,' that is, in the mechanism by which the parental origin of alleles is indicated (Reik et al., 1987; Sapienza et al., 1987). Differences in gene expression according to the parent from whom the gene was derived, in HD, in myotonic dystrophy (DM1; 160900) and perhaps in other conditions, might be due to a difference in methylation of the genes in the 2 sexes (see review by Marx, 1988).

In South Wales over a 10-year period, Quarrell et al. (1986) found 192 patients with HD in whom there was a positive family history and an additional 37 patients who had clinical features consistent with HD but who had no affected relatives despite detailed inquiries. After review, 22 of the 37 were still thought to have HD on clinical grounds; the diagnosis was considered less likely in 15. Postmortem supported the diagnosis in 6 of 7 cases so studied; a patient labeled HD on the death certificate had Kufs disease (204300) at postmortem.

Adams et al. (1988) also found that the offspring of affected males had significantly younger onset than did offspring of affected females, and a trend suggested an excess of paternal descent among juvenile-onset cases. Reik (1988) also suggested genomic imprinting as an alternative mechanism to maternally inherited extrachromosomal factors to account for the parental origin effect. By imprinting, the gene itself becomes modified in a different way depending on whether it passes through the maternal or the paternal germline. The modification may involve methylation of DNA and could result in earlier or higher level of expression of the gene when it is transmitted by the father. Ridley et al. (1988) reviewed extensively the ascertainment bias producing or working against the observation of anticipation. Reik (1989) reviewed the topic of genomic imprinting in relation to genetic disorders of man, and as possible examples pointed to the earlier onset of spinocerebellar ataxia (164400) with paternal transmission, the increased severity of neurofibromatosis I (NF1; 162200) with maternal transmission, the earlier onset of neurofibromatosis II (NF2; 101000) with maternal transmission, and the preferential loss of maternal alleles in sporadic osteosarcoma.

Wolff et al. (1989) reported an isolated case of HD in an extensively studied family. Nonpaternity appeared to be excluded, and DNA markers closely linked to the HD gene indicated several clearly unaffected sibs who shared 1 or the other or both of the patient's haplotypes. The posterior probability of a new mutation to HD in the patient was calculated to exceed 99%, even if an a priori probability of nonpaternity of 10% and a mutation rate of HD of 1 in 10 million gametes were assumed.

In 2 families with Huntington disease linked to the short arm of chromosome 4, Sax et al. (1989) demonstrated remarkable intrafamilial variability. In 1 family, affected persons of 3 generations showed a 50-year variation in age at onset. The member with the latest onset (at age 67) died at age 91 with autopsy-confirmed HD. The next generation had hypotonic chorea beginning in the fourth decade with death in the fifth. In the third generation, a rigid patient, inheriting the illness from an affected father, had onset at age 16, while her sibs had chorea beginning in the third decade. In the second family, several members had cerebellar signs as well as chorea and dementia; MRI and CT showed olivopontocerebellar and striatal atrophy. Whether these phenotypes were the result of different allelic genes at the HD locus or of unlinked autosomal modifying loci was unknown.

A large Tasmanian family with Huntington disease was first described by Brothers (1949). Pridmore (1990) traced 9 generations, starting with the father of the woman who brought the disease to Tasmania. From that woman, 6 lines had living affected descendants and a total of 765 living descendants at risk. The numbers of affected males and females were equal. The mean age at onset was 48.6 years and the mean age of death, 61.8 years. Affected members were at least as fertile as members of the general population. Pridmore (1990) concluded that late-onset disease (defined as death after 63 years of age) was associated with significantly greater fertility (in men more so than women) compared with that of affected sibs of the same sex. Unaffected sibs produced fewer offspring than in the general population.

Ridley et al. (1991) showed that the age at onset varies between families and between paternal and maternal transmission and that rigidity is associated specifically with very early onset, major anticipation, paternal transmission, and young parental age at onset. Major anticipation was defined as an age at onset of the proband more than 15 years less than that in the affected parent. They proposed that age at onset depends on the state of methylation of the HD locus, which varies as a familial trait, and as a consequence of 'genomic imprinting' determined by parental transmission. They further suggested that young familial age at onset and paternal imprinting occasionally interact to produce a major change in gene expression, that is, the early-onset/rigid variant.

Farrer et al. (1993) tested the hypothesis that the normal HD allele or a closely linked gene on the nonmutant chromosome influences age at onset of HD. Analysis of the transmission patterns of genetically linked markers at the D4S10 locus in the normal parent against age at onset in the affected offspring in 21 sibships and 14 kindreds showed a significant tendency for sibs who have similar onset ages to share the same D4S10 allele from the normal parent. Affected sibs who inherited different D4S10 alleles from the normal parent tended to have more variable ages at onset, thus providing support for the hypothesis.

Goldberg et al. (1993) reported findings in 3 families in which a new mutation for HD had arisen. In all 3 families, a parental intermediate allele (with expansion to 30-38 CAG repeats, greater than that seen in the population but below the range seen in patients with HD) had expanded in more than 1 offspring. In one of the families, 2 sibs with the expanded CAG repeat were clinically affected with HD, thus presenting a pseudorecessive pattern of inheritance.

The U.S.-Venezuela Collaborative Research Project and Wexler (2004) genotyped 3,989 members of the 83 Venezuelan HD kindreds for their HD alleles, representing a subset of the population at greatest genetic risk. There were 938 heterozygotes, 80 people with variably penetrant alleles, and 18 homozygotes. Analysis of the 83 Venezuelan HD kindreds demonstrated that residual variability in age at onset had both genetic and environmental components. A residual age at onset phenotype was created from a regression analysis of the log of age at onset on repeat length. Familial correlations (correlation +/- SE) were estimated for sib (0.40 +/- 0.09), parent-offspring (0.10 +/- 0.11), avuncular (0.07 +/- 0.11), and cousin (0.15 +/- 0.10) pairs, suggesting a familial origin for the residual variance in onset. By using a variance-components approach with all available familial relationships, the additive genetic heritability of this residual age at onset trait was 38%. A model, including shared sib environmental effects, estimated the components of additive genetic (0.37), shared environment (0.22), and nonshared environment (0.41) variances, confirming that approximately 40% of the variance remaining in age at onset was attributable to genes other than the HD gene and 60% was environmental.

Homozygosity

Wexler et al. (1985, 1987) identified persons homozygous for the Huntington gene by study of branches of the large Venezuelan kindred in which there are instances of both parents being affected. Homozygosity was indicated by homozygosity for the G8 probe. Remarkably, comparison with the usual heterozygotes revealed no difference of phenotype. Wexler et al. (1987) suggested that this is the first human disease in which complete dominance has been demonstrated. Myers et al. (1989) performed molecular genetic studies in 4 offspring of 3 different affected x affected matings for possible homozygosity. One of the 4 was found to have a 95% likelihood of being an HD homozygote. The individual's age at onset and symptoms were similar to those in affected HD heterozygous relatives. Thus, the findings from the New England Huntington Disease Research Center corroborated the finding of Wexler et al. (1987). Connarty et al. (1996) identified 2 patients in Wessex in the U.K. in whom expansion of the HD triplet repeat was found on both chromosomes. Both were males who presented in middle age with typical clinical features. Unfortunately, no other family members were available for analysis.

Twin Studies

Bird and Omenn (1975) reported a family in which a pair of male monozygotic twins were concordant for Huntington disease. At age 30 years, the twins had a similar degree of cognitive defect but differed slightly in the severity of chorea. The daughter of 1 of the twins had childhood-onset HD, and the mother of the twins had the adult-onset rigid form of HD. Sudarsky et al. (1983) reported a pair of monozygotic twins with Huntington disease. Although they were raised in separate households from birth, age at onset, disease course, and behavioral abnormalities were strikingly similar. The findings supported the hypothesis that the main features of the disorder are genetically determined.

Georgiou et al. (1999) reported a pair of monozygotic twins with HD confirmed by genetic analysis. Twin A was more impaired at a motor level, with a hyperkinetic hypotonic variant of the disease, whereas twin B showed greater attentional impairment and demonstrated a more hypokinetic hypertonic, or rigid, variant. Twin B, who was the more impaired, showed more progressive deterioration. Georgiou et al. (1999) concluded that epigenetic environmental factors must play a role in disease modification.

Norremolle et al. (2004) reported a pair of 34-year-old male monozygotic twins belonging to a family segregating Huntington disease. The mother died of the disorder at the age of 41 years. The twins were reported to have been monochorionic and diamniotic. Twin A had no symptoms and only minor abnormalities in the form of slight impersistence of lateral gaze and mild upper limb ataxia. In contrast, twin B had a slow and slurred speech, headthrust, slow saccades, orolingual apraxia, impaired coordination, positive milk maid sign, and discrete choreic movements of the limbs and head. Mini-Mental Status Examination (MMSE) was 29 of 30 in twin A and 26 of 30 in twin B. Twin A worked as a full-time smith, whereas twin B was unemployed after he was dismissed 2 years previously from a job he had held for 15 years. The wife of twin B stated that he had become more introverted and unenterprising. Two different cell lines, carrying the normal allele together with either an expanded allele with 47 CAGs or an intermediate allele with 37 CAGs, were detected in blood and buccal mucosa from both twins. This appeared to have been the first case described of HD gene CAG repeat length mosaicism in blood cells. Haplotype analysis established that the 37 CAG allele most likely arose by contraction of the maternal 47 CAG allele. The contraction must have taken place postzygotically, possibly at a very early stage of development, and probably before separation of the twins. Twin B had presented symptoms of HD for 4 years; his skin fibroblasts and hair roots carried only the cell line with the 47 CAG repeat allele. Twin A, who was without symptoms at the time of report, displayed mosaicism in skin fibroblasts and hair roots. Norremolle et al. (2004) concluded that if the proportion of the 2 cell lines in the brain of each twin resembled that of the hair roots (another tissue originating from the ectoderm), the mosaicism in the unaffected twin would mean that only a part of his brain cells carried the expanded allele, which could explain why he, in contrast to his brother, had no symptoms at the time of report.

Friedman et al. (2005) reported a pair of female monozygotic twins who were discordant for HD. The affected twin had onset of declining gait and cognition at age 65 years, and genetic analysis showed a 39-CAG repeat in the HTT gene, which is considered a borderline expansion in which the disease may be less than 100% penetrant. Although MRI showed no caudate atrophy, she had generalized chorea, ataxia, and mild cognitive impairment. Her twin sister shared the 39-CAG repeat but was unaffected 7 years after disease onset in the affected twin. Detailed history suggested possible environmental influences: both twins grew up near a factory that was later made a federal toxic cleanup site, but the asymptomatic twin moved away at age 23 years, whereas the affected twin remained in the same house. The affected twin also smoked until her sixties, while the unaffected twin quit smoking at age 35 years. Finally, the affected twin had several comorbid conditions, including type II diabetes mellitus, chronic bronchitis, rheumatoid arthritis, hypertension, and chronic anemia, for which she took several medications. The unaffected twin had only hypertension. Friedman et al. (2005) suggested that the borderline CAG expansion of 39 repeats as well as different environmental factors contributed to the disparity in disease manifestation in these twins.

Panas et al. (2008) reported a pair of 55-year-old monozygotic twin sisters with HD due to a 45-CAG repeat who showed phenotypic discordance for the disease. At age 43, twin 1 showed anxiety, irritability, and mildly aggressive behavior. At age 46, she had prominent hyperkinesias, behavioral disturbances, and mild cognitive deterioration. By age 54, she had an independence scale of 30%. Twin 2 had onset at age 51 of depressive symptoms and mild hyperkinesias. By age 54, she had an independence scale of 50%. The age of onset differed by 8 years with regard to behavioral changes, or by 6 years with regard to choreic movements. The first twin showed prominent choreic hyperkinesias and aggressivity, while the second had severe depression with marked withdrawal and mild choreic hyperkinesias. Panas et al. (2008) postulated that the phenotypic differences may be due to epimutations in critical DNA regions.

Mapping

Huntington disease was first mapped to the tip of the short arm of chromosome 4 in 1983; the HD gene was not isolated until 1993. The Huntington's Disease Collaborative Research Group, comprising 58 researchers in 6 research groups, used haplotype analysis of linkage disequilibrium to spotlight a small segment of 4p16.3 as the likely location of the defect (MacDonald et al., 1992).

The Huntington disease gene was assigned to chromosome 4 by demonstration of close linkage to an arbitrary DNA segment that had been mapped to chromosome 4 by somatic cell hybridization. The DNA segment was detected by a sequence called 'G8' and renamed 'D4S10' at the seventh Human Gene Mapping Workshop in Los Angeles in August 1983 (Gusella et al., 1984; Wexler et al., 1984).

Gusella et al. (1984) found close linkage of G8 to Huntington disease in a large Venezuelan kindred and a smaller American kindred. In the initial study, the total lod score was 8.53 at theta = 0.00. No obligatory recombinants were found. Linkage was with different haplotypes in the 2 kindreds studied. The upper limit of 99% confidence was set at 10 cM. D4S10 and HD were found to be remote from GC and MNS (known to be on 4q), as indicated by negative lod scores. Gusella et al. (1984) identified further restriction enzyme polymorphism of the G8 probe found to be linked to HD; with this, the frequency of identifiable heterozygosity could be raised to about 90%. Folstein et al. (1985) found close linkage of HD and the G8 probe in both of 2 large Maryland kindreds (Folstein et al., 1984).

Harper et al. (1985) stated that the polymorphism with 4 enzymes (HindIII, EcoRI, NciI, and BstI) applied to the G8 locus shows that over 80% of subjects are heterozygous. They further stated that the latest estimate of the interval between the G8 and the HD loci was 5 cM.

The G8 locus (D4S10) and presumably the Huntington disease locus are deleted in the Wolf-Hirschhorn (4p-) syndrome (WHS; 194190) (Gusella et al., 1985). This information helped map the HD locus to 4p. Most 4p- syndrome patients do not survive long enough to develop manifestations of HD. Tranebjaerg et al. (1984) concluded that the 'critical segment' in Wolf syndrome is 4p16.3. McKeown et al. (1987) found that the G8 locus was not deleted in a case of 4p- syndrome.

In 16 British kindreds, Youngman et al. (1986) found 2 recombinants yielding a maximum lod score of 17.6 at theta = 0.02 for marker D4S10, providing evidence against multilocus heterogeneity in Huntington disease.

By in situ hybridization (Wang et al., 1985; Magenis et al., 1985; Zabel et al., 1985; Wang et al., 1986), the HD-linked marker, G8, was mapped to 4p16.1. From studies by in situ hybridization to partially deleted chromosomes with known breakpoints, Magenis et al. (1986) concluded that the G8 probe is located in the distal half of band 4p16.1. Wang et al. (1986), also by in situ hybridization in patients with deletions of 4p, mapped G8 to 4p16.1-p16.3. Of their 2 patients, 1 had the typical phenotype of the Wolf-Hirschhorn syndrome (WHS) with a minute deletion of the segment p16.1-p16.3. Wang et al. (1986) concluded that the 4pter region could be excluded as a site.

Landegent et al. (1986) used a nonfluorescent method of in situ hybridization to assign the D4S10 locus to 4p16.3 rather than 4p16.1. The in situ hybridization method involved haptenization of nucleic acids in the probe by chemical attachment of 2-acetylaminofluorene (AAF) groups, marking of the hybridized probe by an indirect immunoperoxidase/diaminobenzidine reaction, and reflection-contrast microscopic visualization of the precipitated dye.

Froster-Iskenius et al. (1986) described a kindred in which an apparently balanced reciprocal translocation between 4q and 5p was segregating together with Huntington disease in 2 generations. In situ hybridization studies revealed that the linked DNA marker (G8) was located in the region 4p16 of both the normal and translocated chromosome 4. Thus, the association may be a chance occurrence.

Collins et al. (1987) applied the strategy of chromosome jumping to identify new probes from the terminal portion of 4p. Jumping clones were identified that traveled in each direction from G8. In 2 of 3 persons recombinant for G8 and HD who were also informative for the newly identified probes, the jumping clone traveled with HD. Thus, a jump of approximately 200 kb had crossed 2 out of 3 recombination points between G8 and HD. The information defined unequivocally the location of HD distal to G8, and suggested that the physical distance between them may not be as large as previously suspected.

Gilliam et al. (1987) presented evidence that the HD gene lies in 4p16.3 between D4S10 proximally and the telomere distally. Multipoint linkage analysis of the 4 loci--HD, D4S10, RAF2 (see 164760), and D4S62--indicated that D4S62 is close to D4S10 and centromeric to it. One particularly informative individual from the large Venezuelan kindred showed recombination between 2 RFLPs within the D4S10 segment. The 2 are located about 33 kb apart. The information at hand indicated the direction of cloning necessary for reaching the HD gene.

Gilliam et al. (1987) described an anonymous DNA segment, D4S43, which is exceedingly tightly linked to HD. Like the disease gene, it is located in the most distal portion of 4p, flanked by D4S10 and the telomere. In 3 extended HD kindreds, no recombination with HD was found, placing it less than 1.5 cM from the genetic defect. Expansion of the region to include 108 kb of cloned DNA led to the identification of 8 RFLPs and at least 2 independent coding segments. These genes might be candidates for the site of the HD defect; however, D4S43 RFLPs did not display linkage disequilibrium with the disease gene as one would expect if such were the case. Wasmuth et al. (1988) characterized a new RFLP marker, D4S95, a highly polymorphic locus which displayed no recombination with HD in the families tested. Robbins et al. (1989) used genetic linkage analysis to demonstrate that the gene causing Huntington disease is telomeric to D4S95 and D4S90, both markers known to be tightly linked to the HD locus.

The fact that no evidence of linkage disequilibrium has been found in HD with the G8 marker (Conneally et al., 1989) may suggest that the mutation is ancient and has occurred on very few occasions.

Doggett et al. (1989) prepared a physical map that extended from the most distal of the loci linked to HD (but proximal to HD) to the telomere of chromosome 4. The mapping identified at least 2 CpG islands and placed the most likely location of the HD defect remarkably close (within 325 kb) to the telomere. Conneally et al. (1989) pooled linkage data on G8 versus HD from 63 HD families (57 Caucasian, 4 Black American, and 2 Japanese). The combined maximum lod score was 87.69 at theta = 0.04 (99% confidence interval, 0.018-0.071). The maximum frequency of recombination was 0.03 in males and 0.05 in females. The data suggested that there is only 1 HD locus, though a second rare locus could not be ruled out. Kanazawa et al. (1990) presented linkage data in 9 Japanese families supporting the view that the Japanese Huntington disease gene is identical with the 'Western gene,' in spite of the lower prevalence rate in Japan. The linkage relationships appear to be the same as those that have been observed in European families.

Pyrimidine oligodeoxyribonucleotides bind in the major groove of DNA parallel to the purine Watson-Crick strand through formation of specific Hoogsteen hydrogen bonds to the purine Watson-Crick base. Specificity is derived from thymine (T) recognition of adenine/thymine (AT) basepairs (TAT triplets); and N3-protonated cytosine (C+) recognition of guanine/cytosine (GC) basepairs (C + GC triplets). By combining oligonucleotide-directed recognition with enzymatic cleavage, near quantitative cleavage at a single target site can be achieved. Strobel et al. (1991) used this approach to 'liberate' the tip of 4p that contains the entire candidate region for the HD gene. A 16-base pyrimidine oligodeoxyribonucleotide was used with success.

Buetow et al. (1991) provided a genetic map of chromosome 4 with extensive information on the mapping of 4p16.3. They presented evidence for linkage heterogeneity in this region and suggested that it might explain the fact that in some families (Doggett et al., 1989; Robbins et al., 1989), HD has been localized to the most distal 325 kb of 4p16.3, telomeric to D4S90, the most distal marker in the map presented by Buetow et al. (1991), whereas in other families (MacDonald et al., 1989; Snell et al., 1989) HD has been localized proximal to D4S90. A microinversion in 4p16.3 in HD patients could provide an explanation. In 10 South African families of black, white, and mixed ancestry, Greenberg et al. (1991) found tight linkage to D4S10 (G8); maximum lod score = 8.14 at theta = 0.00. Because of the diverse ethnic backgrounds, the data provided evidence that there is only a single HD locus.

The existence of many genes in the telomeric region of 4p is indicated by the work of Saccone et al. (1992). By chromosomal in situ hybridization, they determined the localization of the G+C-richest fraction of human DNA. Bernardi (1989) pointed out that the human genome is a mosaic of isochores, i.e., large DNA regions (more than 300 kb, on the average) that are compositionally homogeneous (above a size of 3 kb) and belong to a small number of families characterized by different G+C levels. The G+C-richest fraction of DNA has the highest gene concentration, the highest concentration of CpG islands, the highest transcriptional and recombinational activity, and a distinct chromatin structure. The in situ hybridization results showed a concentration of this isochore family, called H3, in telomeric bands and in chromomycin A3-positive/4-prime,6-diamidino-2-phenylindole-negative bands. Mouchiroud et al. (1991) found that the gene density in the GC-richest 3% of the genome is about 16 times higher than in the GC-poorest 62%. Figure 2 of Saccone et al. (1992) showed dramatically the concentration of G+C-rich DNA in the telomeric band of 4p as well as regions on other chromosomes that have been found to be rich in genes by mapping studies, e.g., distal 1p and much of chromosomes 19 and 22.

Sabl and Laird (1992) proposed an epigenetic mechanism to explain inconsistencies in mapping of the candidate HD gene. Dominant position-effect variegation (PEV) is a variable but clonally stable inactivation of a euchromatic gene that has been placed adjacent to heterochromatic sequences. In an example in Drosophila melanogaster, a fully dominant mutant phenotype, such as HD, results from stable epigenetic inactivation of an allele adjacent to the structural alteration (cis-inactivation) combined with a complementary inactivation of the homologous normal allele (trans-inactivation). Sabl and Laird (1992) proposed that the trans-inactivation of the normal allele may occasionally persist through meiosis. This so-called epigene conversion occurring at the HD locus in a few percent of meioses could account for anomalies in the region's genetic map.

Bates et al. (1992) characterized a YAC contig spanning the region most likely to contain the HD mutation. Zuo et al. (1992) prepared a set of YAC clones spanning 2.2 Mb at the tip of the short arm of chromosome 4 presumably containing the HD gene. Skraastad et al. (1992) detected highly significant linkage disequilibrium with D4S95 in 45 Dutch families, consistent with studies in other populations. The area of linkage disequilibrium extended from D4S10 proximally to D4S95, covering 1,100 kb. The results confirmed the suggestion that the HD gene maps near D4S95.

Using a direct cDNA selection strategy, Goldberg et al. (1993) identified at least 7 transcription units within the 2.2-Mb DNA interval thought to contain the HD gene. Screening with one of the cDNA clones identified an Alu insertion in genomic DNA from 2 persons with HD, which showed complete cosegregation with the disease in these families but was not found in 1,000 control chromosomes. A gene