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. ... 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.
Harper and Sarfarazi (1985) pointed out that predictive testing can be done in prenatal diagnosis without determining the status of the at-risk parent. For example, if the affected grandparent of the fetus is ... - Prenatal Diagnosis Harper and Sarfarazi (1985) pointed out that predictive testing can be done in prenatal diagnosis without determining the status of the at-risk parent. For example, if the affected grandparent of the fetus is deceased, the other grandparent is genotype BB, and the parent at risk is AB married to a CC individual, the fetus is unlikely to have inherited HD if it is BC, while the risk is 50% if the fetus is AC. The likelihood of the BC fetus being affected is a function of recombination. Bloch and Hayden (1987) pointed out that this 'no news' or 'good news' option has some important consequences. The 'no news' outcome increases the risk of the fetus's having inherited the gene for HD from 25% to about 50%; thus, persons given this information may need long-term support. Also, the implication of linking the status of an at-risk child to that of the at-risk parent may be more serious than realized. Quarrell et al. (1987) suggested the usefulness of the G8 marker in exclusion testing for HD. They cited studies of 52 families from various parts of the world, indicating a maximum total lod score of 75.3 at a recombination fraction of about 5 cM. The 95% confidence intervals were 2.4 and 6.5 cM, with no evidence of multilocus heterogeneity. The marker could be applied either for presymptomatic predictive testing or for exclusion testing in pregnancy, where the estimated risk to the parent is not altered. The requirements for family structure were much less stringent in the case of exclusion testing. In South Wales they found that nearly 90% of couples have the minimum structure required for an exclusion test, whereas for a presymptomatic predictive test only 15% have the ideal 3-generation family structure and only 10% have a suitably extended 2-generation family. The distribution of G8 haplotypes presented the same difficulty whichever test was being considered; only about two-thirds of couples would be informative. If the fetus acquired the G8 haplotype of the affected grandparent, then the risk to the fetus was the same as that of the parent, i.e., 50%. If the fetus has the G8 haplotype of the unaffected grandparent, then the risk to the fetus became 2.5%. If termination of pregnancy was unacceptable despite an adverse result of the test and HD subsequently developed in the parent in generation 2, it would be immediately known that HD would also be likely to arise in the offspring since their risks are the same (apart from the possibility of recombination). To prevent this complication, Quarrell et al. (1987) told couples that if termination of pregnancy was unacceptable for whatever reason, then an exclusion test would be inappropriate. Millan et al. (1989) pointed out the importance of not acquiring more information than necessary to exclude or include the diagnosis of HD in a fetus. In a family they studied, the probability of the fetus being affected, approaching 50%, could be deduced from the genotype of the fetus, the 2 parents, and the unaffected paternal grandfather of the conceptus. Genotyping of the unaffected maternal grandmother of the father refined downward somewhat (from 47 to 42%) the risk of HD in the conceptus; however, it ran the risk of making the diagnosis of HD in the father and the information was really unnecessary for genetic counseling. Information about the prenatal exclusion test for HD was given to an unselected series of couples who attended a genetic counseling clinic in Glasgow from 1986 onwards. Ten couples underwent 13 prenatal tests during this period with expressed intention of stopping a pregnancy if the results indicated a high risk (almost 50%) that the fetus carried the HD gene. Although 9 fetuses at nearly 50% risk of carrying the HD gene were identified, only 6 such pregnancies were terminated. In each of the 3 high-risk pregnancies that continued, the mother made a 'final hour' decision not to undergo the scheduled, first-trimester termination. Bloch and Hayden (1990) opposed the testing of children at risk for Huntington disease and questioned the usefulness of DNA tests to support a diagnosis of HD in either adulthood or childhood. They opposed testing in adoption cases because of the negative effects on the child's upbringing and education as well as the necessity to adhere to the principle of autonomy on the part of the individual tested. Prenatal testing was undertaken in their practice only if the parents were prepared to make a decision about continuing the pregnancy on the basis of the outcome of the prenatal testing. The parents were given to understand that prenatal testing is similar to testing a minor child. In the program of Bloch and Hayden (1990), 8 exclusion prenatal tests had been performed, with 5 resulting in an increased risk for the fetus. In 4 of these, the parents decided to terminate the pregnancy. In the experience of Tolmie et al. (1995), late reversal of a previous decision to undergo first-trimester pregnancy termination for a genetic indication was frequent among couples who had undergone the prenatal exclusion test for HD. - Testing in Adults Early results of predictive testing using D4S10 RFLPs were reported by Meissen et al. (1988). MacDonald et al. (1989) characterized genetically 5 highly informative multiallele RFLPs of value in the presymptomatic diagnosis of HD. Morris et al. (1989) and Craufurd et al. (1989) outlined problems associated with programs for presymptomatic predictive testing for HD. Positron-emission tomography (PET scanning) demonstrating loss of uptake of glucose in the caudate nuclei may be a valuable indication of affection in the presymptomatic period (Hayden et al., 1986). Hypometabolism of glucose precedes tissue loss and caudate nucleus atrophy. Mazziotta et al. (1987) used PET studies of cerebral glucose metabolism in 58 clinically asymptomatic persons at risk for HD, 10 symptomatic patients with HD, and 27 controls. They found that 31% of the persons at risk showed metabolic abnormalities of the caudate nuclei, qualitatively identical to those in the patients. Taking into account the age of each at-risk subject and the sex of the affected parent, they averaged individual risk estimates of the members of the asymptomatic group and estimated the probability of having the clinically unexpressed HD gene at 33.9% for the group--a remarkably good agreement with the percentage of metabolic abnormalities found. Wiggins et al. (1992) reported on the psychologic consequences of predictive testing for HD on the basis of observations in 135 participants in the Canadian program of genetic testing. The participants were in 3 groups according to their test results: the increased-risk group (37 persons); the decreased-risk group (58 persons); and the group with no change in risk (40 persons). They showed that predictive testing had benefits for the psychologic health of persons who received results that indicated either an increase or a decrease in the risk of inheriting the gene. In an accompanying editorial, Catherine V. Hayes (1992), president of the Huntington's Disease Society of America, described what it meant to grow up as an 'at-risk' person and to have genetic testing. Read (1993) commented that the problems arising in connection with HD testing resembled those of HIV testing. The 10 years during which testing for HD required family studies have given clinical geneticists an opportunity to work out proper procedures. A great deal of effort has gone into ensuring that presymptomatic testing is always voluntary and is undertaken only after due consideration by fully informed patients. Testing of children has been firmly discouraged. It is vital that these practices should be continued. Kremer et al. (1994) reported a worldwide study assessing the sensitivity and specificity of the CAG expansion as a diagnostic test. The study covered 565 families from 43 national and ethnic groups containing 1,007 patients with signs and symptoms compatible with the diagnosis of HD. Of these, 995 had an expanded CAG repeat that included from 36 to 121 repeats; sensitivity = 98.8%, with 95% confidence limits = 97.7-99.4. Included among those contributing to the sensitivity estimate were 12 patients with previously diagnosed HD in whom the number of CAG repeats was in the normal range. Reevaluation of these established that 11 had clinical features atypical of HD. In 1,581 of 1,595 control chromosomes (99.1%), the number of CAG repeats ranged from 10 to 29. The remaining 14 control chromosomes had 30 or more repeats, with 2 of these chromosomes having expansions of 37 and 39 repeats. An estimate of specificity was made from 113 subjects with other neuropsychiatric disorders with which HD is frequently confused. The number of repeats found in these disorders was similar to the number found on normal human chromosomes and showed no overlap with HD; specificity = 100%, with 95% CI = 95.5-100. The study confirmed that CAG expansion is the molecular basis of HD worldwide. Decruyenaere et al. (1996) examined the psychologic effects of HD predictive testing on 53 patients after 1 year. The authors found that the test result had a definite impact on reproductive decision making and that the single best predictor of the patient's post-test ego strength was the patient's pre-test ego strength. They concluded that persons who opt for HD testing are themselves a self-selected group with good ego strength and positive coping strategies. Gellera et al. (1996) reported that ideally a series of 3 PCR reactions should be performed to rule out Huntington disease. They reviewed the evidence that the huntingtin gene contains an unstable polyglutamine-encoding (CAG)n repeat which is located in the N-terminal portion of the protein beginning 18 codons downstream of the first ATG codon (613004.0001). The unstable (CAG)n repeat lies immediately upstream from a moderately polymorphic polyproline encoding (CCG)n repeat. Gellera et al. (1996) noted further that a number of reports in the literature indicated that in normal subjects the number of (CAG)n polyglutamine repeats ranges from 10 to 36, while in HD patients it ranges from 37 to 100. The (CCG)n polyproline repeat may vary in size between 7 and 12 repeats in both affected and normal individuals. They reported the occurrence of a CAA trinucleotide deletion (nucleotides 433-435) in HD chromosomes in 2 families that, because of its position within the conventional antisense primer hd447, hampered HD mutation detection if only the (CAG)n tract were amplified. Therefore, Gellera et al. (1996) stressed the importance of using a series of 3 diagnostic PCR reactions: one that amplified the (CAG)n tract alone, one that amplified the (CCG)n tract alone, and one that amplified the whole region. The first predictive testing for HD was based on analysis of linked polymorphic DNA markers. Limitations to accuracy included recombination between the markers and the mutation, pedigree structure, and availability of DNA samples from family members. With availability of direct tests for the HD mutation, Almqvist et al. (1997) assessed the accuracy of results obtained by linkage approaches when requested to do so by the test individuals. For 6 such individuals, there was significant disparity between the tests: 3 went from a decreased risk to an increased risk, while in another 3 the risk was decreased. Harper et al. (2000) reviewed data on presymptomatic testing over a 10-year period in the U.K. A total of 2,937 tests had been performed, 2,502 based on specific mutation testing: 93.1% of these individuals were at 50% prior risk, with 58.3% of them female; 41.4% were abnormal or high risk, including 29.4% in subjects aged 60 or over. Almost all of the tests were performed in National Health Service genetic centers, with a defined genetic counseling protocol. Lindblad (2001) discussed some of the ethical issues that arise when an adult child at 25% risk for HD wishes to have the test, but the parent(s) at 50% risk refuses to have one. If the child tests positive, the genetic status of the parent will also be disclosed. No matter what course of action is chosen in this situation, the ethically legitimate interests of either child or parent might be violated (the same dilemma arises in connection with prenatal testing). Lindblad (2001) concluded that in this situation one should start with an exclusion test by the linkage principle. In this way, she believed, less harm would be caused than by direct mutation analysis. By analysis of diffusion tensor MRI data from 25 presymptomatic HD gene carriers using a multivariate support vector machine, Kloppel et al. (2008) identified a pattern of structural brain changes in the putamen and anterior parts of the corpus callosum that differed significantly from controls. The pattern enabled correct classification of 82% of scans as that of either mutation carrier or control. In addition, probabilistic fiber tracking detected changes in connections between the frontal cortex and the caudate, a large proportion of which play a role in the control of voluntary saccades. Voluntary saccades are specifically impaired in presymptomatic mutation carriers and are an early clinical sign of motor abnormalities. In 14 carriers, there was a correlation between impairment of voluntary saccades and fewer fiber tracking streamlines connecting the frontal cortex and caudate body, suggesting selective vulnerability of these white matter tracts. Kloppel et al. (2009) used T1-weighted MRI scans to evaluate whole brain structural changes in 96 presymptomatic mutation carriers in whom the estimated time to clinical manifestation was based on age and CAG repeat length. Individuals with at least a 33% chance of developing signs of HD in 5 years were correctly assigned to the mutation carrier group 69% of the time. This accuracy was below that reported by Kloppel et al. (2008) using diffusion-weighted analysis. However, accuracy in the study of Kloppel et al. (2009) improved to 83% when regions affected by the disease (i.e., the caudate head) were selected a priori for analysis. The results were no better than chance when the probability of developing symptoms in 5 years was less than 10%. Kloppel et al. (2009) noted that T1-weighted MRI scans are more readily available than diffusion-weighted imaging as used in the study by Kloppel et al. (2008). - Differential Diagnosis Warner et al. (1994) searched for possible missed cases of Huntington disease in a set of 368 patients with psychiatric disorders, including schizophrenia, presenile dementia, and senile dementia. One schizophrenic patient, who died at age 88, had a CAG repeat size of 36; a 68-year-old patient, who died of presenile dementia of Alzheimer disease type, had a CAG repeat size of 34. Neither patient had neuropathologic or clinical evidence of Huntington disease.
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 ... 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.
The Huntington's Disease Collaborative Research Group (1993) identified an expanded (CAG)n repeat on 1 allele of the HTT gene (613004.0001) in affected members from all of 75 HD families examined. The families came from a variety of ethnic ... The Huntington's Disease Collaborative Research Group (1993) identified an expanded (CAG)n repeat on 1 allele of the HTT gene (613004.0001) in affected members from all of 75 HD families examined. The families came from a variety of ethnic backgrounds and demonstrated a variety of 4p16.3 haplotypes. The findings indicated that the HD mutation involves an unstable DNA segment similar to those previously observed in several disorders, including the fragile X syndrome (300624), Kennedy syndrome (313200), and myotonic dystrophy. The fact that the phenotype of HD is completely dominant suggested that the disorder results from a gain-of-function mutation in which either the mRNA product or the protein product of the disease allele has some new property or is expressed inappropriately (Myers et al., 1989). Duyao et al. (1993), Snell et al. (1993), and Andrew et al. (1993) analyzed the number of CAG repeats in a total of about 1,200 HD genes and in over 2,000 normal controls. Read (1993) summarized and collated the results. In all 3 studies, the normal range of repeat numbers was 9-11 at the low and 34-37 at the high end, with a mean ranging from 18.29 to 19.71. Duyao et al. (1993) found a range of 37-86 in HD patients with a mean of 46.42. Ambrose et al. (1994) found that both normal and HD alleles are represented in the mRNA population in HD heterozygotes, indicating that the defect does not eliminate transcription. In a female carrying a balanced translocation with a breakpoint between exons 40 and 41, the HD gene was disrupted but the phenotype was normal, arguing against simple inactivation of the gene as the mechanism by which the expanded trinucleotide repeat causes HD. The observation suggested that the dominant HD mutation either confers a new property on the mRNA or, more likely, alters an interaction at the protein level. Rubinsztein et al. (1996) studied a large cohort of individuals who carried between 30 and 40 CAG repeats in the IT15 (HTT) gene. They used a PCR method that allowed the examination of CAG repeats only, thereby excluding the CCG repeats, which represent a polymorphism, as a confounding factor. No individual with 35 or fewer CAG repeats had clinical manifestations of HD. Most individuals with 36 to 39 CAG repeats were clinically affected, but 10 persons (aged 67-95 years) had no apparent symptoms of HD. The authors concluded that the HD mutation is not fully penetrant in individuals with a borderline number of CAG repeats. Gusella et al. (1996) gave a comprehensive review of the molecular genetic aspects of Huntington disease. - Genetic Anticipation Brinkman et al. (1997) defined the relationship between CAG repeat size and age at onset of HD in a cohort of 1,049 persons, including 321 at-risk and 728 affected individuals with a CAG size of 29 to 121 repeats. Kaplan-Meier analysis provided curves for determining the likelihood of onset at a given age, for each CAG repeat length in the 39 to 50 range. These curves were significantly different, with relatively narrow 95% confidence intervals, indicating the correlation between CAG repeat size and age at onset. Brinkman et al. (1997) stated that, although complete penetrance of HD was observed for CAG sizes equal to or greater than 42, 'only a proportion of those with a CAG repeat length of 36-41 showed signs or symptoms of HD within a normal life span.' Their data provided information concerning the likelihood of being affected, by a specific age, with a particular CAG size, and may be useful in predictive-testing programs and for the design of clinical trials for persons at increased risk for HD. Snell et al. (1993) found a negative correlation between the number of repeats on the normal paternal allele and the age at onset in individuals with maternally transmitted disease. They interpreted this as suggesting that normal gene function varies because of the size of the repeat in the normal range and a sex-specific modifying effect. However, Read (1993) commented that this was not seen by the other groups and 'is hard to square with the reported normal age at onset in homozygotes.' In an examination of 8 probands with sporadic HD whose parental DNA was available, Goldberg et al. (1993) found that 1 of the parental HD alleles was significantly greater than that seen in the general population, but smaller than that seen in patients. The CAG repeats were in the range of 30 to 38, and were designated 'intermediate alleles.' These alleles were found to be unstable and prone to expansion upon transmission. The expansions occurred on the paternal allele in the 7 cases in which sex of the parent could be determined and were associated with advanced paternal age. In a study of the HD mutation and the characteristics of its transmission in 36 HD families, Trottier et al. (1994) found that instability of the CAG repeats was more frequent and stronger upon transmission from a male than from a female, with a clear tendency toward increased size. They found a significant inverse correlation (p = 0.0001) between the age at onset and the CAG repeat length. The observed scatter would, however, not allow an accurate individual prediction of age at onset. An HD mutation of paternal origin was found in 3 juvenile-onset cases analyzed. In at least 2 of these cases, a large expansion of the HD allele upon paternal transmission may explain the major anticipation observed. Illarioshkin et al. (1994) found significant positive correlation between the rate of progression of clinical symptoms and CAG repeat length in a group of 28 Russian patients with Huntington disease. Ranen et al. (1995) found that the change in repeat length with paternal transmission was significantly correlated with the change in age at onset between the father and offspring. They confirmed an inverse relationship between repeat length and age at onset, the higher frequency of juvenile-onset cases arising from paternal transmission, anticipation as a phenomenon of paternal transmission, and greater expansion of the trinucleotide repeat with paternal transmission. Coles et al. (1997) identified 7 alleles in the conserved 303-bp region upstream of the +1 translation start site in the HD gene in a sample of 208 English Huntington patients and 56 unrelated control East Anglians, 30 black Africans, and 34 Japanese. There was no correlation between these alleles and age at onset in the Huntington disease patients. Using a logarithmic model to regress the age of HD onset on the number of CAG triplets, Rosenblatt et al. (2001) found that CAG number alone accounts for 65 to 71% of the variance in age at onset. The 'siblingship' to which an individual belonged accounted for 11 to 19% of additional variance. They suggested that a linkage study of modifiers would be feasible given the cooperation of major centers and might be rendered more efficient by concentrating on sib pairs that are highly discordant for age at onset. Djousse et al. (2003) presented evidence that the size of the normal HD allele influences the relationship between the size of the expanded repeat and age at onset of HD. Data collected from 2 independent cohorts were used to test the hypothesis that the unexpanded CAG repeat interacts with the expanded CAG repeat to influence age at onset. The effect of the normal allele was seen among persons with large HD repeat sizes (47 to 83 repeats). The findings suggested that an increase in the size of the normal repeat may mitigate disease expression among HD-affected persons with large expanded CAG repeats. Among 921 patients with HD, Aziz et al. (2009) observed a significant interaction between CAG repeats in the normal HTT allele and CAG repeats in the disease allele with age at onset. At the low range of mutant CAG repeat size (36 to 44 repeats), higher normal CAG repeat sizes were related to an earlier age at onset, while in the high range of the mutant repeat size (44 to 64 repeats), higher values of the normal repeat size were related to a later age at onset. Thus, the known association between mutant CAG repeat size and age at onset progressively weakens for higher normal CAG size, suggesting a protective effect of the normal allele. Statistical modeling indicated that this interaction term could account for 53.4% of the variance in the age at onset. Among 512 patients, there was also a significant and similar interaction between normal and mutant CAG repeat sizes on severity or progression of motor, cognitive, and functional skills, but not on behavioral symptoms. Among 16 premanifest HTT mutation carriers, there was a similar interaction effect on basal ganglia size. Aziz et al. (2009) concluded that increased CAG size in the normal allele diminishes the association between mutant CAG repeat size and disease severity in HD, suggesting an interaction between the 2 proteins. In 51 families, Semaka et al. (2010) found that 54 (30%) of 181 transmissions of intermediate alleles, defined as 27 to 35 CAG repeats, were unstable. The unstable transmissions included both 37 expansions and 17 contractions. Of the expanded alleles, 68% expanded into the HD range (greater than 36 CAG). Thus, 14% (25 of 181) of the intermediate allele transmissions examined were consistent with a new mutation for HD. However, Semaka et al. (2010) cautioned that additional studies were needed before their findings are used for genetic counseling. - Modifier Genes MacDonald et al. (1999) analyzed the age at onset in 258 individuals with Huntington disease. Variability in the age at onset attributable to the CAG repeat length alone in this sample was found to be R(2) = 0.743. The presence of a TAA repeat polymorphism in the GluR6 gene (GRIK2; 138244) explained an additional 0.6% of the variability in age of onset. Kehoe et al. (1999) showed that the APOE (107741) epsilon-2/epsilon-3 genotype is associated with significantly earlier age at onset of Huntington disease in males than in females. This sex difference was not apparent for any other APOE genotypes. Andresen et al. (2007) could not replicate the findings of Kehoe et al. (1999). Li et al. (2003) stated that although the variation in age at onset of HD is partly explained by the size of the expanded CAG repeat, it is strongly heritable, which suggests that other genes modify the age at onset. They performed a 10-cM genomewide scan in 629 sib pairs affected with HD, using ages at onset adjusted for the expanded and normal CAG repeat sizes. Because all those studied were affected with HD, estimates of allele sharing identical by descent at and around the HD locus were adjusted by a positionally weighted method to correct for the increased allele sharing at 4p. Suggestive evidence for linkage was found at 4p16 (lod = 1.93), 6p23-p21 (lod = 2.29), and 6q24-q26 (lod = 2.28). Djousse et al. (2004) used data from 535 patients with HD and the cohort involved in the genome scan of Li et al. (2003) to assess whether age at onset was influenced by any of 3 markers in the 4p16 region: MSX1 (142983), a deletion within the HD coding sequence, and D4S127 (BJ56). Suggestive evidence for an association was seen between MSX1 alleles and age at onset, after adjustment for normal CAG repeat, expanded repeat, and their product term. Individuals with MSX1 genotype 3/3 tended to have younger age at onset. No association was found between the other 2 markers and age at onset. These findings supported previous studies suggesting that there may be a significant genetic modifier for age at onset in Huntington disease in the 4p16 region. Djousse et al. (2004) concluded that the modifier may be present on both the HD chromosome and the chromosome bearing the 3 allele of the MSX1 marker. Many genetic polymorphisms had been shown to be associated with age of onset of HD in several different populations. As reviewed by Andresen et al. (2007), these included 12 polymorphisms in 9 genes. Andresen et al. (2007) undertook to replicate these genetic association tests in 443 affected people from a large set of kindreds from Venezuela. GRIN2A (138253) and TCERG1 (605409) were thought to show true association with residual age of onset for Huntington disease. The purported genetic association of the other genes could not be replicated. The most surprising negative result was that for the GRIK2 (TAA)n polymorphism, which had previously shown association with age of onset in 4 independent populations with Huntington disease. Andresen et al. (2007) suggested that the lack of association in the Venezuelan kindreds may have been due to the exceedingly low frequency of the key (TAA)16 allele in that population. In a study of 250 HD patients and 15 presymptomatic female mutation carriers, Arning et al. (2007) observed significant associations between age at onset in women and 2 intronic SNPs (dbSNP rs2650427 and dbSNP rs8057394) in the GRIN2A gene and a synonymous 2664C-T SNP in exon 12 of the GRIN2B gene (138252). The significant findings were predominantly due to premenopausal women, suggesting a role for hormones. Arning et al. (2007) concluded that together GRIN2A and GRIN2B genotype variations explain 7.2% additional variance in age at onset for HD in women. Among 889 patients with Huntington disease, Metzger et al. (2008) found a significant association between age at onset and a thr441-to-met (T441M) substitution in the HAP1 gene (dbSNP rs4523977). In HD patients with less than 60 CAG repeats, those who were homozygous for the met/met allele developed symptoms about 8 years later than HD patients with the thr/met or thr/thr genotypes (p = 0.015). In vitro studies showed that met441 bound mutated HTT more tightly than thr441, stabilized HTT aggregates, reduced the number of soluble HTT degraded products, and protected neurons against HTT-mediated toxicity. Metzger et al. (2008) concluded that the T441M SNP can modify the age at onset in adult patients with HD. They estimated that the T441M SNP may represent 2.5% of the variance in age at onset that cannot be accounted for by expanded CAG repeats in the HTT gene.
Huntington disease has a frequency of 4 to 7 per 100,000 persons. Reed and Chandler (1958) estimated the frequency of recognized Huntington chorea in the Michigan lower peninsula to be about 4.12 x 10(-5) and the total frequency ... Huntington disease has a frequency of 4 to 7 per 100,000 persons. Reed and Chandler (1958) estimated the frequency of recognized Huntington chorea in the Michigan lower peninsula to be about 4.12 x 10(-5) and the total frequency of heterozygotes to be about 1.01 x 10(-4). Wright et al. (1981) estimated the minimal prevalence of HD in blacks in South Carolina to be 0.97 per 100,000 persons--about one-fifth the prevalence for whites in that state. Clinical features seemed identical. Even lower prevalence has been observed in blacks in Africa. The higher prevalence in South Carolina blacks may be because of white admixture and longer life expectancy in South Carolina blacks than in African blacks. Walker et al. (1981) estimated a prevalence of 7.61 per 100,000 in South Wales. Heterozygote frequency was estimated as about 1 in 5,000. Simpson and Johnston (1989) found an unusually high prevalence of Huntington disease in the Grampian region of Scotland; they arrived at an incidence of 9.94 per 100,000. There were 46 individuals ascertained from 98 pedigrees. New mutations are probably rare. Bundey (1983) concluded 'that it is incorrect to say that new mutations for Huntington's chorea occur in less than 0.1% of sufferers. I believe the evidence shows that the true figure is nearer 10%. I therefore consider that the absence of a known affected relative should not deter a neurologist from diagnosing Huntington's chorea in a patient who shows the characteristic clinical features of the disease.' She based her conclusion particularly on estimates of fitness and the Haldane formula for estimating proportion of new mutation cases. However, Mastromauro et al. (1989) could find no evidence of difference in fitness of HD-affected persons from their unaffected sibs or from the general population of Massachusetts. Palo et al. (1987) estimated the frequency of HD in Finland to be 5 cases per million as contrasted with frequencies of 30 to 70 per million in most Western countries. The lowest frequencies have been found in South African blacks (0.6), in Japan (3.8), and in North American blacks (15). The findings in Finland are consistent with almost all cases having originated from a single source and illustrate founder effect, which is shown by so many other diseases in that country. For example, PKU (261600) has been found in only 5 cases over all time, whereas aspartylglycosaminuria (208400) has been identified in almost 200 living cases in a population of 4.9 million. The part of Finland that is an exception to the above statement is the Aland archipelago where the frequency of HD is high, but this is an exception that proves the rule: the islands have been exposed to other populations (including the British) for centuries. Quarrell et al. (1988) presented data suggesting that there has been a steady decline in births at risk for HD in both North Wales and South Wales in the period between 1973 and 1987. Lanska et al. (1988) determined an overall mortality rate for HD in the U.S. of 2.27 per million population per year. Age-specific mortality rates peaked around age 60. Lanska et al. (1988) suggested from their experience that the risk of suicide may have been overstated. Stine and Smith (1990) studied the effects of mutation, migration, random drift, and selection on the changes in the frequency of genes associated with HD, porphyria variegata (176200), and lipoid proteinosis (247100) in the Afrikaner population of South Africa. By limiting analyses to pedigrees descendant from founding families, it was possible to exclude migration and new mutation as major sources of change. Calculations which overestimated the possible effect of random drift demonstrated that drift did not account for the changes. Therefore, these changes must have been caused by natural selection, and a coefficient of selection was estimated for each trait. A value of 0.34 was obtained for the coefficient of selection demonstrated by the HD gene, indicating a selective disadvantage rather than advantage suggested by some other studies. In Finland, Ikonen et al. (1992) reported further studies by RFLP haplotype analysis in combination with genealogic study of all the Finnish HD families. They found that a high percentage (28%) of the families had foreign ancestors. Furthermore, most of the Finnish ancestors were localized to border regions or trade centers of the country, following the old postal routes. The observed high-risk haplotypes formed with markers from the D4S10 and D4S43 loci were evenly distributed among the HD families in different geographic locations. Ikonen et al. (1992) concluded that the HD gene(s) probably arrived in Finland on several occasions via foreign immigrants. On the basis of a review of the epidemiology of Huntington disease, Harper (1992) predicted that molecular studies in the future would show that more than 1 mutation has occurred at the HD locus. A very small number of mutations, possibly a single common one, will be found to account for most HD cases in populations of European origin. Any predominant mutation will probably have an extremely ancient origin, possibly dating back millennia. No single focus in northern Europe will be found as the point of origin of such a principal mutation. Phenotype will correlate poorly with specific mutations. Leung et al. (1992) stated that the prevalence of HD in Hong Kong Chinese for the period 1984-1991 was 3.7 per million. They traced the ancestral origin of the patients mainly to the coastal provinces and proposed that Chinese HD had a European origin. They found a male preponderance: 63 males to 26 females. They made no comment on the provinces of origin of the Hong Kong Chinese population generally. Almqvist et al. (1994) constructed haplotypes for 23 different HD families, 10% of the 233 known HD families in the Swedish Huntington disease register. Ten different haplotypes were observed. Analysis of 2 polymorphic markers within the HD gene indicated that there are at least 3 origins of the HD mutation in Sweden. One of the haplotypes accounted for 89% of the families, suggesting descent from a single ancestor. Rubinsztein et al. (1994) investigated the evolution of HD by typing CAG alleles from 5 different human populations and 10 different species of primates. Using computer simulations, they found that human alleles have expanded from a shorter primate ancestor and exhibit unusual asymmetric length distributions. Suggesting that the key element in HD evolution is a simple length-dependent mutational bias toward longer alleles, they predicted that, in the absence of interference, expansion of trinucleotide repeats will continue and accelerate, leading to an ever-increasing incidence of HD. Masuda et al. (1995) demonstrated that the size of the CAG repeat in Japanese HD patients ranges from 37 to 95 repeats, as compared with a range from 7 to 29 in normal controls. Whereas HD chromosomes in the west are strongly associated with the (CCG)7 repeat, immediately 3-prime adjacent to the CAG repeat, Japanese HD chromosomes were found to be in strong linkage disequilibrium with the (CCG)10 repeat. The frequency of HD in Japan is less than one-tenth of the prevalence in western countries. It had been suggested that the low frequency reflected western European origin with spread to Japan by immigration. The haplotype findings concerning the association of the CAG repeat and the CCG repeat suggest a separate origin with founder effect in the Japanese cases. Morrison et al. (1995) achieved virtually complete ascertainment of HD in Northern Ireland which, with a population of 1.5 million, showed a 1991 prevalence rate of 6.4/100,000. Estimates of heterozygote frequency gave values between 10 and 11 x 10(-5). The direct and indirect mutation rates were 0.32 x 10(-6) and 1.05 x 10(-6), respectively. Genetic fitness was increased in the affected HD population but decreased in the at-risk population. Fertility in HD was not reduced, but it appeared that at-risk persons had actively limited their family size. Factors responsible for this included, among others, the fear of developing HD and genetic counseling of families. Scrimgeour et al. (1995) described a case of apparently typical HD in a 40-year-old Sudanese man from Khartoum, in whom the HD gene showed 51 CAG repeats. It was suspected that his mother and his deceased 16-year-old son were also affected. Silber et al. (1998) described Huntington disease with proven expansions of the HD gene in 5 black South African families of different ethnic origins. Falush et al. (2001) described a new approach for analysis of the epidemiology of progressive genetic disorders that quantifies the rate of progression of the disease in the population by measuring mutational flow. They applied the method to HD. The disease is 100% penetrant in individuals with 42 or more repeats of the CAG trinucleotide sequence. Measurement of the flow from disease alleles provided a minimum estimate of the flow in the whole population and implied that the new mutation rate for HD in each generation is 10% or more of currently known cases (95% confidence limits 6-14%). Analysis of the pattern of flow demonstrated systematic underascertainment for repeat lengths less than 44. Ascertainment fell to less than 50% for individuals with 40 repeats and to less than 5% for individuals with 36 to 38 repeats. Falush et al. (2001) stated that clinicians should not assume that HD is rare outside of known pedigrees or that most cases have onset at less than 50 years of age. In a study of Huntington disease in British Columbia based on referrals for testing the CAG expansion, Almqvist et al. (2001) found that of the 141 subjects with a CAG expansion of at least 36, almost one-quarter did not have a family history of HD. An extensive chart review revealed that 11 patients had reliable information on both parents (who lived well into old age) and therefore could possibly represent new mutations for HD. This indicated a new mutation rate 3 to 4 times higher than previously reported. The findings also showed that the yearly incidence rate for HD was 6.9 per million, which was 2 times higher than previous incidence studies performed before identification of the HD mutation. They identified 5 persons with a clinical presentation of HD but without CAG expansion, i.e., genocopies. Garcia-Planells et al. (2005) analyzed the genetic history of the HD mutation in 115 HD patients from 83 families from the Valencia region of eastern Spain. They identified a haplotype H1 (based on allele A of marker dbSNP rs1313770, allele 7 of the CCG triplet, and allele A of marker dbSNP rs82334) that was found in 47 of 48 phase-known mutant chromosomes and in 120 of 166 chromosomes constructed using the PHASE program. By constructing extended haplotypes, Garcia-Planells et al. (2005) determined that the H1-associated CAG expansion originated between 4,700 and 10,000 years ago. They also observed a nonhomogeneous distribution in different geographic regions associated with the different extended haplotypes of the ancestral haplotype H1, suggesting that local founder effects had occurred. In a population-based study of 1,772 chromosomes covering all regions of Portugal, do Carmo Costa et al. (2006) found that the most frequent HTT allele was 17 CAG repeats (37.9%), intermediate class 2 alleles (27 to 35 repeats) represented 3.0% of the population, and there were 2 expanded alleles (36 and 40 repeats, 0.11%). There was no evidence for geographic clustering. Among 140 Portuguese HD families, there were 3 different founder haplotypes associated with 7-, 9-, or 10-CCG repeats, suggesting different origins for the HD mutation. The haplotype carrying the 7-CCG repeat was the most frequent. Warby et al. (2009) identified a haplogroup, haplogroup A, comprising 22 SNPs in the HTT region on chromosome 4p that was significantly associated with HD disease chromosomes (greater than 35 CAG repeats) among 65 European HD patients but not in controls. The data were confirmed in a replication cohort of 203 HD patients. The same SNPs were significantly associated with the disease chromosome, but some were not, arguing against a founder effect. In addition, chromosomes with increased CAG repeats of 27 to 35 were also associated with haplogroup A. Chromosomes with a haplotype subgroup, haplogroup A1 comprising 10 SNPs, were 6.5 times more likely to carry a CAG expansion. The specific haplogroup A variants at risk for CAG expansion were not present in the general population in China, Japan, and Nigeria, where the prevalence of HD is much lower than in Europe. The data supported a stepwise model for CAG expansion and suggested that CAG expansions occur on haplotypes that are predisposed for CAG instability, likely resulting from cis-acting elements. Warby et al. (2009) noted that the strong association between specific SNP alleles and CAG expansion may provide an opportunity for personalized therapeutics by using allele-specific gene silencing. In a response to the report by Warby et al. (2009), Falush (2009) presented evolutionary modeling of the HD CAG repeat length distribution within populations and argued that the distribution of CAG repeat length and disease incidence in different haplotypes can be explained by founder events. Each haplotype examined involved expansion of repeats to lengths that are classified as normal by HD investigators (less than 28 repeats). The results were based on the assumptions that the HD CAG repeat is upwardly based (increases in length are more common than decreases) and length-dependent (longer repeats mutate more frequently than short ones), and that there is natural selection against longer disease alleles. Falush (2009) argued against a cis element having a role in the evolution of HD chromosomes. In a reply, Warby et al. (2009) found fault with some aspects of the modeling presented by Falush (2009), and asserted that cis elements do play a role in the instability of CAG repeats at the HD locus.