Age of onset in Huntington''s disease: lack of parental age effect.

In a recent publication Brackenridge and Teltscher (1975) concluded that the age of onset of Huntington's disease was in part a function of the age of the transmitting parent at the time of birth of a subsequently affected child. Their analysis suggested that the younger the parent was at the time of birth of the subsequently affected child, the later in life symptoms of disease would appear in the child. The data of Brackenridge and Teltscher have been statistically reevaluated here, and this analysis fails to support their conclusion. Consequently it would be irresponsible to counsel persons at risk for Huntington's disease to plan families early in life.     

Relation of parental age to rigidity in Huntington''s disease

The birth ranks and parental ages at birth of subjects affected with Huntington's disease were ascertained from the literature and examined in relation to the neurological sign displayed (muscular rigidity or choreo-athetosis). With respect to the sex of the affected parent, the percentage of rigid cases was found to decrease linearly with advancing paternal age and to increase linearly with advancing maternal age. In contrast, no significant relation was found for birth rank or for age of the unaffected parent.

The results could be explained in terms of the somatic gene-mutation theory of Burch by invoking a `switching mechanism' which converts a predisposing autosomal allele for rigidity in the germ cell of affected fathers into one which is expressed as chorea. The converse mechanism is postulated to occur in affected mothers. Calculation showed that the hypothetical mutation rates were of the same magnitude in affected parents of each sex.

     

Huntington''s disease in Grampian region: correlation of the CAG repeat number and the age of onset of the disease.

The identification of an unstable trinucleotide repeat as the mutation responsible for Huntington's disease (HD) has given the hope that additional information can be provided about age of onset and mode of action of the mutated gene. We present in this paper results of a clinical and molecular study of 82 patients affected with HD from 46 pedigrees within the Grampian region, Scotland. Our results show a correlation between age of onset and size of the CAG expansion. This study has produced no overlap in mutation size between affected and unaffected alleles. The sex of the parent transmitting the mutated allele and the size of the normal allele have no significant effect on the clinical features of the disease. In the three juvenile cases the affected parent was the father but the number of cases is too small to produce statistical significance. An increase in the CAG repeat size is shown in the transmission of the gene in five cases, accompanied by an earlier age of onset in four; in three of these cases, the affected parent was the father. Eleven sib pairs were studied and there is a negative correlation between the difference in age at onset and the difference in repeat size. Thus there is some evidence of a relationship, but this is not statistically significant because of the small numbers involved. The presence of the same or different normal allele had no effect on age of onset in this small group. We suggest that additional factors, as yet unrecognised, influence the age of onset and clinical presentation of HD.     

Mutation size and age at onset in Huntington''s disease.

The mutation responsible for Huntington's disease is a polymorphic (CAG)n repeat sequence which is expanded on affected chromosomes. The number of repeat units observed on 229 affected chromosomes varied from 27 to 102, while the control chromosomes showed a range of 7 to 34 repeats. There was a highly significant relationship between the size of the expanded region and age at onset, larger mutations being associated with earlier onset. This association was strongest in those with onset before 25 years of age but less clear cut with later onset, and is therefore unlikely to be useful for predicting age at onset in the context of presymptomatic testing.     

The relation of some features of Huntington''s disease to the age at onset of symptoms in parents

To determine whether the parental age at onset of Huntington's disease plays a significant role in defining the clinical picture in affected offspring, a statistical study was made of cases drawn from the literature. The relation of parental onset age to the predominant neurological sign (chorea or rigidity), order of appearance of neurological and psychiatric symptoms, sex and onset age of offspring was calculated by analysis of variance and partial correlation. Sex of parent and of offspring were not important, but the remaining factors exerted significant effects. It was concluded that parental onset age is a significant factor in the order of appearance and age at onset of symptoms in offspring, but that neurological sign is intrinsically related to the onset age of the subject.     

The relation of the sex of choreic and rigid subjects to the age at onset of Huntington''s disease

In a series of non-adult cases of Huntington's disease largely ascertained from the literature, the male sex-ratio increased linearly with onset age from 0.5 in the 0–5 years age-group to 1.15 in the 16–20 years age-group. When cases were separated according to the presence or absence of muscular rigidity, the same effect was observed among rigid subjects; the mean onset age for males significantly exceeded that for females.
In the absence of rigidity, typically choreic cases showed a different type of sex variation with age of onset. The crescent-shaped curve found was accentuated in those who inherited the disorder from their fathers so that females exceeded males over most of the reproductive period. The converse tended to apply to cases of maternal descent. A later onset age of maternal than paternal cases was found to be associated with this parental difference. It was speculated that hormonal factors may play a part in determining the sex differences observed.     

The relation of type of initial symptoms and line of transmission to ages at onset and death in Huntington''s disease

To determine whether the age at onset and age at death were related to the type of initial symptoms of Huntington's disease, analyses of variance with respect to (A) order of appearance of neurological and psychiatric symptoms, (B) type of muscular disorder (chorea or rigidity), (C) sex of affcctcd subject, (D) sex of transmitting parent, and (E) sex of transmitting grandparent were calculated. Agc at onset and age at death were each significantly affected by order of symptoms, neurological sign, sex of subject, and sex of affected parent. The duration of illness depended only on the order of neurological and psychiatric symptoms.
Fathcrs exceeded mothers as transmitting parents of sibships with one or more affected subjects. The proportions of the four parental-grandparental lines of transmission differed significantly among subjects grouped according to type of first symptoms but not according to muscular signs. The ratio of choreic to rigid cases varied significantly with the order of symptoms and sex of the subject.
The earlier ages at onset and death of subjects with Westphal (rigid-hypokinetic) symptoms than those with typical choreic movements confirm the validity of distinguishing between these variants of the disorder.     

Non-Mendelian transmission at the Machado-Joseph disease locus in normal females: preferential transmission of alleles with smaller CAG repeats.

Machado-Joseph disease (MJD), also known as spinocerebellar ataxia type 3, is a neurodegenerative disorder which is associated with a CAG repeat expansion in the MJD1 gene on chromosome 14q32.1. A recent study reported an excess of transmission of disease chromosomes relative to normal chromosomes from affected fathers, while this phenomenon was not observed in female meioses. These data were compatible with meiotic drive. We investigated the transmission of alleles with larger versus smaller CAG repeat numbers in the MJD1 gene in normal heterozygotes from the 40 CEPH families. Our data suggest that there was no segregation distortion in male meioses, while the smaller CAG allele was inherited in 57% of female meioses (p < 0.016). The pattern of inheritance of smaller versus larger CAG alleles at this locus was significantly different when male and female meioses were compared (p = 0.0139). While previous data suggest that meiotic drive may be a feature of certain human diseases, including the trinucleotide diseases MJD, myotonic dystrophy, and dentatorubral-pallidoluysian atrophy, these data are compatible with meiotic drive also occurring among non-disease associated CAG sizes.     

Molecular analysis of late onset Huntington''s disease.

Late onset Huntington's disease is characterised by onset of symptoms after the age of 50 and is usually associated with a milder course. We have analysed the CAG trinucleotide repeat within the HD gene in 133 late onset patients from 107 extended families. The median upper allele size for the CAG repeat was 42 with a range of 38 to 48 repeats. A significant negative correlation (r = -0.29, p = 0.001) was found between the length of repeat and age of onset for the total cohort. However, for persons with age of onset greater than 60, no significant correlation was found. In addition, no significant correlation was found between age of onset and size of the lower allele and the sex of the affected parent or grandparent. There was no preponderance of maternal descent for late onset cases in this series. This study shows that variation in repeat length only accounts for approximately 7% of the variation in age of onset for persons beyond the age of 50 and clearly shows how with increasing onset age the effect of the repeat length on this onset age seems to diminish.     

Validation and aplication of an interval factor in estimating age at onset of Huntington''s disease.

The time interval between the first appearance of signs in the transmitting parent and the birth of the subsequently affected child has been shown by Brackenridge and Telscher (1975) to influence the age at onset of Huntington's disease. The cirticism by Burke (1976) that the interval factor offers no predictive advantage over parental onset age is refuted. The advantage of small sibship sizes in familial correlation studies is noted and an equation to estimate onset age is derived to control for ascertainment bias. The interval factor is shown to surpass parental onset age as a determinant of offspring onset age. When applied to Queensland material, reasonable agreement is obtained between predicted and reported onset ages. Evidence for the desirability for parents at risk who intend to have families to plan them early is discussed.     

Gametic but not somatic instability of CAG repeat length in Huntington''s disease.

Instability of a CAG repeat in 4p16.3 has been found in Huntington's disease (HD) chromosomes. Unlike a similar repeat in the fragile X syndrome, the expanded HD repeat showed no evidence of somatic instability in a comparison of blood, lymphoblast, and brain DNA from the same persons. Four pairs of monozygotic HD twins displayed identical CAG repeat lengths suggesting that repeat size is determined in gametogenesis. In contrast with the fragile X syndrome and with HD somatic tissue, mosaicism was readily detected as a diffuse spread of repeat lengths in DNA from HD sperm samples. Typically, the modal repeat size was larger in the sperm DNA than in corresponding lymphoblast DNA, with the greatest degree of gametic mosaicism coinciding with the longest somatic CAG repeats. These data indicate that the developmental timing of repeat instability appears to differ between HD and fragile X syndrome, and that the fundamental mechanisms leading to repeat expansion may therefore be distinct.     

Very early onset Huntington''s disease: genetic mechanism and risk to siblings

A study of very early onset Huntington's disease (VEOHD) has shown that at least 38% of gene-carrying sibs also develop symptoms before the age of 10, thus improving the genetic risk for those sibs who remain healthy. The prevalence of VEOHD among sibs shows that mutation during spermatogenesis is most unlikely to account for these uncommon cases. The data suggest that two mechanisms contribute to VEOHD: modification by many genes (individually of small effect), and an epigenetic mechanism occurring when transmission is through a series of males.     

Instability of expanded CAG/CAA repeats in spinocerebellar ataxia type 17

Trinucleotide repeat expansions are dynamic mutations causing many neurological disorders, and their instability is influenced by multiple factors. Repeat configuration seems particularly important, and pure repeats are thought to be more unstable than interrupted repeats. But direct evidence is still lacking. Here, we presented strong support for this hypothesis from our studies on spinocerebellar ataxia type 17 (SCA17). SCA17 is a typical polyglutamine disease caused by CAG repeat expansion in TBP (TATA binding protein), and is unique in that the pure expanded polyglutamine tract is coded by either a simple configuration with long stretches of pure CAGs or a complex configuration containing CAA interruptions. By small pool PCR (SP-PCR) analysis of blood DNA from SCA17 patients of distinct racial backgrounds, we quantitatively assessed the instability of these two types of expanded alleles coding similar length of polyglutamine expansion. Mutation frequency in patients harboring pure CAG repeats is 2-3 folds of those with CAA interruptions. Interestingly, the pure CAG repeats showed both expansion and deletion while the interrupted repeats exhibited mostly deletion at a significantly lower frequency. These data strongly suggest that repeat configuration is a critical determinant for instability, and CAA interruptions might serve as a limiting element for further expansion of CAG repeats in SCA17 locus, suggesting a molecular basis for lack of anticipation in SCA17 families with interrupted CAG expansion.     

Estimation of the age at onset of Huntington''s disease from factors associated with the affected parent.

In an attempt to relate the age at onset of Huntington's disease to parental factors, the effects of parental onset-age (Po) and the age of the transmitting parent at the birth of a subsequently affected child (Pc) have been examined in a sample of cases ascertained from Victorian kindreds. There was a significant positive linear regression of onset-age on the variable Po-Pc; the result was independent of the sex of affected parent or child. It is suggested that the pathogenetic process is activated in individuals at a fixed time before their genetically determined onset-ages and need not commence at birth. Somatic gene mutations accumulating with age may interact with modifiers activated at initiation of pathogenesis and favour the transmission of genes determining early onset. An important conclusion for genetic counselling is the desirability of parents at risk who intend to have children to plan their families early in life so that the illness will tend to appear in late adulthood in their affected children. The regression equation may also be applied to estimate the risk of inheritance of the disorder and, by taking interfamilial variation into account, appears to have an advantage over the esisting method based on the distribution of onsettages.     

Transmissible and non-transmissible neurodegenerative disease: similarities in age of onset and genetics in relation to aetiology

In only a few cases is transmissible dementia known to have been acquired by infection from a source outside the individual; the remaining cases can be classified as sporadic, loosely familial, or autosomal dominant. Each group has a characteristic mean age of onset. A range of neurodegenerative diseases (including Alzheimer-type dementia and amyotrophic lateral sclerosis) can also be classified in this way, with similar characteristic mean ages of onset. The emergence of these diseases in later middle age, and the interdependence of age of onset and the type of familial occurrence suggest that these pathological processes are related to those genetic mechanisms which determine senescence. It is argued that the majority of cases of transmissible dementia arise, not from infection, but from the expression of endogenous virogene sequences as part of the aging processes.     

Age at onset in Huntington''s disease: effect of line of inheritance and patient''s sex.

The Leiden Roster for Huntington's disease (HD) contained data on 2617 cases up to July 1988. The age at onset (AO) was known in 1084 cases and in 1020 of these both their AO and the sex of the affected parent was known. The mean AO was higher for females than for males and higher for maternal than for paternal cases. However, in the group born before 1925 only females with maternal inheritance had a higher mean AO. Data on influence of sex and line of inheritance were present for the grandparents as well as for the great grandparents. Influence of the line of inheritance from the grandparents was particularly present for the grandmother-father (MP) lineage; regarding the great grandparents a significant difference was found between the MPM and PMP lineage. The results obtained for juvenile HD cases were comparable to those previously published. In late onset cases (over 50 years) no maternal preponderance in inheritance was found.     

Interaction of normal and expanded CAG repeat sizes influences age at onset of Huntington disease

Huntington disease (HD) is a neurodegenerative disorder caused by the abnormal expansion of CAG repeats in the HD gene on chromosome 4p16.3. Past studies have shown that the size of expanded CAG repeat is inversely associated with age at onset (AO) of HD. It is not known whether the normal Huntington allele size influences the relation between the expanded repeat and AO of HD. Data collected from two independent cohorts were used to test the hypothesis that the unexpanded CAG repeat interacts with the expanded CAG repeat to influence AO of HD. In the New England Huntington Disease Center Without Walls (NEHD) cohort of 221 HD affected persons and in the HD-MAPS cohort of 533 HD affected persons, we found evidence supporting an interaction between the expanded and unexpanded CAG repeat sizes which influences AO of HD (P = 0.08 and 0.07, respectively). The association was statistically significant when both cohorts were combined (P = 0.012). The estimated heritability of the AO residual was 0.56 after adjustment for normal and expanded repeats and their interaction. An analysis of tertiles of repeats sizes revealed that the effect of the normal allele is seen among persons with large HD repeat sizes (47-83). These findings suggest that an increase in the size of the normal repeat may mitigate the expression of the disease among HD affected persons with large expanded CAG repeats.     

CAG repeats in Restless Legs syndrome.

Recent reports established an association of restless legs syndrome (RLS) and spinocerebellar ataxia (SCA) type 1, 2, and 3. To evaluate the contribution of SCA alleles to idiopathic RLS we investigated the CAG repeat length at the SCA1, SCA2, SCA3, SCA6, SCA7, and SCA17 loci in 215 patients who fulfilled the clinical criteria of RLS and presented periodic leg movements in sleep (PLMS) in polysomnographic recording. Fifty percent of patients had a positive family history of RLS. We found one intermediate (CAG)(43) allele for SCA17 in a 44-year-old female with RLS starting at the age of 43. Neurologic examination and family history were unremarkable in this patient. Otherwise, allele distribution did not differ between RLS patients and healthy controls. Stratification for age, age of onset, sex, peripheral neuropathy, and sporadic or familial RLS revealed no effect. Thus, CAG repeat length in the investigated genes is not a major determinant of idiopathic or familial RLS.     

New mutation to Huntington''s disease.

We report a large family with an isolated case of Huntington's disease (HD), which is probably the result of a new mutation. The patient developed clinical signs typical of HD at the age of 36. The clinical course of the patient's disease is documented by several clinical admissions over a period of 14 years at present. The family history is strikingly negative with the parents having been clearly unaffected into their 80s and with 13 older and two younger, living, healthy sibs. Extensive testing of polymorphic markers (blood groups, red cell and serum proteins, HLA antigens) showed no indication of non-paternity, but rather gave strong support to the hypothesis that the proband is a full sib. In addition, DNA typing for several RFLPs known to be closely linked to the HD gene locus indicated that several clearly unaffected sibs share one or the other or both of the patient's haplotypes. This is further evidence in favour of the hypothesis of a new mutation at the HD locus. The posterior probability of a new mutation to HD in the patient exceeds 99%, even if an a priori probability of non-paternity of 10% and a mutation rate of HD of 10(-7) is assumed.