Inverse relationship between age at onset of Huntington disease and paternal age suggests involvement of genetic imprinting.

It is well recognized that age at onset of Huntington disease (HD) is strongly influenced by the sex of the affected parent, and this has lead to suggestions that genetic imprinting or maternal specific factors may play a role in the expression of the disease. This study evaluated maternal and paternal ages, birth order, parental age at onset, and sex of the affected parent and grandparent in 1,764 patients in the National HD Roster by using linear-regression techniques which incorporated a weighted least-squares approach to accommodate the correlation among siblings. It was found that paternal age is negatively associated with age at onset of HD, particularly among subjects who inherit the mutant gene from grandfathers. Apparent associations between age at onset and birth order and between age at onset and maternal age were not significant after adjustment for paternal age. The paternal age effect is strongest among juvenile-onset cases and individuals with anticipation of greater than or equal to 10 years, although it is detectable across the entire age-at-onset distribution. The tendency for older fathers, including those not transmitting the HD gene, to have affected offspring with early-onset disease may be consistent with a gene imprinting mechanism involving DNA methylation. Because paternal age in unaffected fathers is also a significant determinant of age at onset, methylation in this context might involve HD modifier genes or the normal HD allele.     

Anticipation and Instability of IT-15 (CAG)N Repeats in Parent-Offspring Pairs with Huntington Disease

Huntington disease (HD) is an autosomal dominant degenerative disorder caused by an expanded and unstable trinucleotide repeat (CAG)n in a gene (IT-15) on chromosome 4. HD exhibits genetic anticipation—earlier onset in successive generations within a pedigree. From a population-based clinical sample, we ascertained parent-offspring pairs with expanded alleles, to examine the intergenerational behavior of the trinucleotide repeat and its relationship to anticipation. We find that the change in repeat length with paternal transmission is significantly correlated with the change in age at onset between the father and offspring. When expanded triplet repeats of affected parents are separated by median repeat length, we find that the longer paternal and maternal repeats are both more unstable on transmission. However, unlike in paternal transmission, in which longer expanded repeats display greater net expansion than do shorter expanded repeats, in maternal transmission there is no mean change in repeat length for either longer or shorter expanded repeats. We also confirmed the 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. Stepwise multiple regression indicates that, in addition to repeat length of offspring, age at onset of affected parent and sex of affected parent contribute significantly to the variance in age at onset of the offspring. Thus, in addition to triplet repeat length, other factors, which could act as environmental factors, genetic factors, or both, contribute to age at onset. Our data establish that further expansion of paternal repeats within the affected range provides a biological basis of anticipation in HD.     

A test of the hypothesis that age at onset in Huntington disease is controlled by an X-linked recessive modifier.

Data from the Research Roster for Huntington Disease Patients and Families were used to assess the hypothesis that juvenile onset in Huntington disease is determined by an X-linked recessive modifying gene in the affected parent. The observed proportion of affected fathers to affected mothers who had such offspring was not compatible with this hypothesis. Furthermore, neither the excess of affected grandfathers nor the existence of juvenile-onset and adult-onset cases within a sibship would be predicted by this model. We also rejected a more general hypothesis that a major change in gene expression across generations, measured by the presence of juvenile onset and/or major anticipation, is determined by an X-linked modifier. However, the inheritance of a propensity toward juvenile onset via the affected male line could be due to an abnormal pattern of paternal genomic imprinting.     

Factors related to onset age of Huntington disease.

One prominent feature of Huntington disease (HD) is the variable age at which the characteristic neurological or psychiatric symptoms appear. Ages of manifestation varying from 4 to 65 years are found in a sample of 95 HD pedigrees compiled since 1968 from the Southeastern United States. Significant parent-child correlations of age of onset indicate consistency of onset age within nuclear families. However, an average intrafamily range of 9 years and an average intrapedigree range of 12 years reveal substantial variability of onset age within these groups. Of the nine cases of juvenile-onset HD identified in this sample, seven were of paternal descent. The preponderance of juvenile patients inheriting the HD gene from a father confirms similar findings from other studies. In addition, a trend toward earlier onset in all offspring of paternal transmission suggests that the juvenile-onset phenomenon is only the tail of a shift in the curve of onset ages for this group. A trend toward earlier onset in successive generations was noted. This "anticipation" may reflect the finding that persons of early onset in prior generations are selectively nonreproductive as a result of manifestation of the disorder. By identifying familial factors influencing onset age of HD, it may be possible to more effectively evaluate environmental factors that influence the onset of the disorder.     

Maternal factors in onset of Huntington disease.

Analyses of father-offspring and mother-offspring similarity in onset age suggest that nuclear genes account for a significant portion of the modification of onset age in Huntington disease. The effects of non-nuclear modifiers are supported by the finding that the offspring of affected women have significantly older mean ages of onset than offspring of affected men irrespective of the onset age in the parent. The absence of increased father-daughter similarity indicates that modification is not X-linked. The absence of reproductive advantage for late-onset individuals and the absence of a multigenerational maternal-lineage effect suggest that the modifying effect of the sex of the affected parent occurs in a single parental generation. Offspring of affected women with onset between ages 35 and 49 had a significantly older mean onset age than their mothers. This suggests that a protective effect may be conferred upon the offspring of affected women.     

Size of the unstable CTG repeat sequence in relation to phenotype and parental transmission in myotonic dystrophy.

A clinical and molecular analysis of 439 individuals affected with myotonic dystrophy, from 101 kindreds, has shown that the size of the unstable CTG repeat detected in nearly all cases of myotonic dystrophy is related both to age at onset of the disorder and to the severity of the phenotype. The largest repeat sizes (1.5-6.0 kb) are seen in patients with congenital myotonic dystrophy, while the minimally affected patients have repeat sizes of < 0.5 kb. Comparison of parent-child pairs has shown that most offspring have an earlier age at onset and a larger repeat size than their parents, with only 4 of 182 showing a definite decrease in repeat size, accompanied by a later age at onset or less severe phenotype. Increase in repeat size from parent to child is similar for both paternal and maternal transmissions when the increase is expressed as a proportion of the parental repeat size. Analysis of congenitally affected cases shows not only that they have, on average, the largest repeat sizes but also that their mothers have larger mean repeat sizes, supporting previous suggestions that a maternal effect is involved in the pathogenesis of this form of the disorder.     

A genetic model for age at onset in Huntington disease.

Although numerous investigators have confirmed excess paternal transmission among juvenile-onset cases of Huntington disease (HD), there are conflicting reports that the late-onset form is inherited more often from the mother than from the father. Results from a survey of age at onset and age at death in 569 patients corroborate earlier findings of delayed onset of HD among offspring of affected mothers at both ends of the onset-age spectrum: 23 of 28 juvenile-onset offspring had affected fathers, and there were 1.6 times more late-onset offspring born to affected mothers than to affected fathers. These patterns, together with data that link age-at-onset variability to familial longevity trends, suggest a model where age at onset is governed, generally, by a set of independently inherited aging genes, but expression of the HD gene may be significantly delayed in individuals who possess a particular maternally transmitted factor.     

Huntington disease in Georgia: age at onset.

Age at onset of motor symptoms was collected on 611 persons affected with Huntington disease (HD) among 3,201 persons "at risk" in 108 kindreds. Life-table estimates correcting for truncated intervals of observation (censoring) produced a median age at onset 5 years older than the observed mean. Risk estimates of HD onset for persons at risk, as calculated by life-table methods, were significantly higher for older ages than were estimates based on the observed distribution of onsets. Age-specific incidence was found to be highest at age 35-64 years, a considerably older age interval than suggested by previous estimates. The offspring of affected males had significantly younger onset than did offspring of affected females, and a trend suggesting and excess of paternal descent among juvenile-onset cases was present. Life-table analysis is contrasted with analyses of (a) the observed distribution of age at onset and (b) remote cohorts age 63 or older at the time of data collection. The implications for risk prediction, genetic counseling, and genetic analysis of HD are discussed.     

Covariate-dependent age-at-onset distributions for Huntington disease.

A combined logistic regression and life-table analysis is presented on age-at-onset data for Huntington disease. Covariates included in the analysis were sex of the at-risk individual, parental age at onset, and sex of transmitting parent. Parental age at onset and parental sex were found to be significant covariates for age at onset in the offspring, and the appropriate logistic regression functions are calculated by maximum likelihood methods. These regression functions permit a more precise evaluation of carrier risks and likelihoods than hitherto was possible by simple computational means. We further introduce a novel method to account for sibship correlations in the significance assessment, using log-likelihood differences between different models.     

A database of germline p53 mutations in cancer-prone families.

We created a comprehensive database covering all published cases of germline p53 mutations. The current version lists 580 tumours in 448 individuals belonging to 122 independent pedigrees. The database describes each p53 mutation (type of the mutation, exon and codon affected by the mutation, nucleotide and amino acid change), each family (family history of cancer, diagnosis of Li-Fraumeni syndrome), each affected individual (sex, generation, p53 status, from which parent the mutation was inherited) and each tumour (type, age of onset, p53 status-loss of heterozygosity, immunostaining). Each entry contains the original reference(s). The database is freely available and can be obtained from http://www.lf2.cuni.cz     

Huntington's disease: a clinical review

Huntington disease (HD) is a rare neurodegenerative disorder of the central nervous system characterized by unwanted choreatic movements, behavioral and psychiatric disturbances and dementia. Prevalence in the Caucasian population is estimated at 1/10,000-1/20,000. Mean age at onset of symptoms is 30-50 years. In some cases symptoms start before the age of 20 years with behavior disturbances and learning difficulties at school (Juvenile Huntington's disease; JHD). The classic sign is chorea that gradually spreads to all muscles. All psychomotor processes become severely retarded. Patients experience psychiatric symptoms and cognitive decline. HD is an autosomal dominant inherited disease caused by an elongated CAG repeat (36 repeats or more) on the short arm of chromosome 4p16.3 in the Huntingtine gene. The longer the CAG repeat, the earlier the onset of disease. In cases of JHD the repeat often exceeds 55. Diagnosis is based on clinical symptoms and signs in an individual with a parent with proven HD, and is confirmed by DNA determination. Pre-manifest diagnosis should only be performed by multidisciplinary teams in healthy at-risk adult individuals who want to know whether they carry the mutation or not. Differential diagnoses include other causes of chorea including general internal disorders or iatrogenic disorders. Phenocopies (clinically diagnosed cases of HD without the genetic mutation) are observed. Prenatal diagnosis is possible by chorionic villus sampling or amniocentesis. Preimplantation diagnosis with in vitro fertilization is offered in several countries. There is no cure. Management should be multidisciplinary and is based on treating symptoms with a view to improving quality of life. Chorea is treated with dopamine receptor blocking or depleting agents. Medication and non-medical care for depression and aggressive behavior may be required. The progression of the disease leads to a complete dependency in daily life, which results in patients requiring full-time care, and finally death. The most common cause of death is pneumonia, followed by suicide.     

HLA haplotype segregation in families of type 1 diabetics

The hypothesis of linkage between HLA and a disease susceptibility (DS) locus (or loci) for type 1 diabetes was tested. HLA segregation was random among 57 non-diabetic sibs but not among 39 diabetic sibs, suggesting that susceptibility to type 1 diabetes may be due to an HLA-linked gene(s). The data did not fit a genetic model involving either a single recessive or dominant gene. The excess of HLA-identical diabetic sibs and the reduced number who were HLA-discordant compared to expected numbers indicated that factors from both paternal and maternal haplotypes were necessary for DS. In 1 of the 3 families with a diabetic parent and more than one diabetic sib, the diabetic sibs inherited different haplotypes from the affected parent, suggesting that either of these haplotypes conferred DS. HLAB 8, B 18 and B 40 were increased in frequency among 97 unrelated type 1 diabetics compared with 238 controls, especially among those with onset age less than 10 years. This early onset group may represent a subtype of type 1 diabetes.     

The normal Huntington disease (HD) allele, or a closely linked gene, influences age at onset of HD.

We evaluated the hypothesis that Huntington disease (HD) is influenced by the normal HD allele by comparing transmission patterns of genetically linked markers at the D4S10 locus in the normal parent against age at onset in the affected offspring. Analysis of information from 21 sibships in 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. These findings suggest that the expression of HD is modulated by the normal HD allele or by a closely linked locus.     

Sex-dependent mechanisms for expansions and contractions of the CAG repeat on affected Huntington disease chromosomes.

A total of 254 affected parent-child pairs with Huntington disease (HD) and 440 parent-child pairs with CAG size in the normal range were assessed to determine the nature and frequency of intergenerational CAG changes in the HD gene. Intergenerational CAG changes are extremely rare (3/440 [0.68%]) on normal chromosomes. In contrast, on HD chromosomes, changes in CAG size occur in approximately 70% of meioses on HD chromosomes, with expansions accounting for 73% of these changes. These intergenerational CAG changes make a significant but minor contribution to changes in age at onset (r2 = .19). The size of the CAG repeat influenced larger intergenerational expansions (> 7 CAG repeats), but the likelihood of smaller expansions or contractions was not influenced by CAG size. Large expansions (> 7 CAG repeats) occur almost exclusively through paternal transmission (0.96%; P < 10(-7)), while offspring of affected mothers are more likely to show no change (P = .01) or contractions in CAG size (P = .002). This study demonstrates that sex of the transmitting parent is the major determinant for CAG intergenerational changes in the HD gene. Similar paternal sex effects are seen in the evolution of new mutations for HD from intermediate alleles and for large expansions on affected chromosomes. Affected mothers almost never transmit a significantly expanded CAG repeat, despite the fact that many have similar large-sized alleles, compared with affected fathers. The sex-dependent effects of major expansion and contractions of the CAG repeat in the HD gene implicate different effects of gametogenesis, in males versus females, on intergenerational CAG repeat stability.     

Huntington disease and Tourette syndrome. I. Electron spin resonance of bed ghosts.

Abnormalities in the electron spin resonance (ESR) of nitroxide-labeled red blood cell membranes have been reported in Huntington disease (HD). Because of the importance of verifying a general membrane defect in this disease, we have examined 13 unmedicated HD patients of all grades of severity, with a duration of symptoms from 3 to 20 years and including juvenile and rigid cases. No significance differences in the ESR of controls, HD patients, and three Tourette syndrome patients were found.     

Genetic and family study of the Apert syndrome

Of 119 patients with the Apert syndrome, 94 pedigrees are available for study. Selected family histories and recorded events during pregnancy are also reported. The sex ratio is 1:1 (60 males, 59 females). All 94 pedigrees except one (an affected father and daughter) represent sporadic instances. Combining our cases with those available in the literature, only nine familial instances are known to date. The familial cases, the equal number of affected males and females, and the increased paternal age in sporadic cases strongly suggest autosomal dominant inheritance. The rarity of familial instances can be explained by reduced genetic fitness of affected individuals because severe malformations and the presence of mental deficiency, found in many cases, diminish desirability as mates. The variability of the syndrome has been defined mainly on the basis of sporadic cases. High resolution banding was normal in five recently studied cases.     

The study of the association between genotype and phenotypic manifestations of the Huntington’s chorea pathogenesis

Direct molecular-genetic analysis of the region containing CAG and CCG repeats of the IT15 gene from 37 patients with the clinical diagnosis of Huntington’s chorea was carried out. The allele with the expansion of CAG repeats in the state of heterozygosity was found in 33 patients; DNA analysis did not confirm a clinical diagnosis in four cases. Twenty probable asymptomatic carriers were examined; 11 of them inherited a mutant chromosome. A disequilibrium in the linkage between the (CGG)₁₀ allele and the alleles with the expansion of CAG repeats in the IT15 gene in a group of patients from Ukraine was found. Significant differences in character of instability of CAG repeats that depends on paternal or maternal inheritance were revealed. The genetic factors that are associated with age variability of onset of the disease were studied.     

Reduced recombination and paternal age effect in Klinefelter syndrome

Summary The parental origin of the additional sex chromosome was studied in 47 cases with an XXY sex chromosome consitution. In 23 cases (49%), the error occurred during the first paternal meiotic division. Maternal origin of the additional chromosome was found in the remaining 24 cases (51%). Centromeric homo- versus heterozygosity could be determined in 18 out of the 24 maternally derived cases. According to the centromeric status and recombination rate, the nondisjunction was attributable in 9 cases (50%) to an error at the first maternal meiotic division, in 7 cases (39%) to an error at the second maternal meiotic division and in 2 cases (11%) to a nullo-chiasmata nondisjunction at meiosis II or to postzygotic mitotic error. No recombination, and in particular none in the pericentromeric region, was found in any of the 9 cases due to nondisjunction at the first maternal meiotic division. Significantly increased paternal age was found in the paternally derived cases. Maternal age was significantly higher in the maternally derived cases due to a meiotic I error compared with those due to a meiotic II error. There were no significant clinical differences between patients with respect to the origin of the additional X chromosome.     

A genome scan for modifiers of age at onset in Huntington disease: The HD MAPS study

Huntington disease (HD) is caused by the expansion of a CAG repeat within the coding region of a novel gene on 4p16.3. Although the variation in age at onset is partly explained by the size of the expanded repeat, the unexplained variation in age at onset is strongly heritable (h²=0.56), which suggests that other genes modify the age at onset of HD. To identify these modifier loci, we performed a 10-cM density genomewide scan in 629 affected sibling pairs (295 pedigrees and 695 individuals), using ages at onset adjusted for the expanded and normal CAG repeat sizes. Because all those studied were HD affected, 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), 6p21–23 (LOD=2.29), and 6q24–26 (LOD=2.28), which may be useful for investigation of genes that modify age at onset of HD.     

Häufige Erkrankungen mit Repeatexpansionen

Expansions of unstable DNA repeats are causes of a growing number of human developmental and degenerative disorders. The repetitive sequences vary in copy number even in normal individuals. In affected individuals the repeat is expanded beyond a disease-specific threshold. There is some relationship between the copy number of the repeat and the severity and/or age at onset of symptoms. An earlier age of onset and a more severe clinical phenotype in subsequent generations (anticipation) is usually correlated with larger repeat size. Expanded alleles show both somatic and germ-line instability and, usually, expand rather than contract upon transmission from parent to offspring. In doing so, the sex of the transmitting parent can influence the size of the disease allele in the affected child. The unstable repeat may be located in non-coding regions or within the open reading frame of the disease gene. Depending on the intragenic location and the mode of inheritance the pathogenetic mechanisms involve loss of protein function as well as gain of function at protein or RNA level.