Polymorphism analysis of the huntingtin gene in Italian families affected with Huntington disease

Two sources of variation in the huntingtin gene, the lengthof the CCG-rich segment downstream to the (CAG)_n stretch undergoingexpansion in Huntington disease (HD) and the deletion of 3 bpat codon positions 2642–2645(     

Huntington''s disease in two New Britain families.

In East New Britain, Papua New Guinea, two Melanesian families were studied in which the typical features of Hungtington's disease were observed in clinically affected members. Mendelian autosomal dominant inheritance was indicated by the respective family trees.     

Study of the Huntington''s disease (HD) gene CAG repeats in schizophrenic patients shows overlap of the normal and HD affected ranges but absence of correlation with schizophrenia.

The CAG repeats in the Huntington's disease gene were investigated in chromosomes from 71 unrelated schizophrenic persons and 18 patients with schizoaffective disorder in order to determine if any of these patients had abnormal expansions. All of the probands had repeat sizes in the normal range (< 35 repeats) and there was no significant difference between the allele distributions of these patients and the normal controls. The families of two patients with 32 repeats and one patient with 34 repeats were investigated further and showed no uniform segregation of the disease with the large repeat alleles. The proband with 34 repeats inherited a chromosome that originally had 36 repeats in her father. The presence of 36 CAG repeats in members of her family and in HD patients suggests that there is an overlap between the normal and Huntington's disease CAG repeat size ranges. The more recently described CCG polymorphism in this gene was also examined in the schizophrenic and schizoaffective persons. All patients had alleles in the normal range.     

The sex-ratio of children born to parents affected with Huntington''s disease

To examine a Pennsylvanian report that children born to mothers a decade before or after the onset of Huntington's disease tend to be girls, a study was made of sibships ascertained from the Victorian population. Although a trend was observed in the direction described, no significant result was obtained. When the effect of parental age on the sex-ratio was tested, the proportion of boys increased linearly with the age of the affected mother. The effect occurred for all children and for those to whom the disease was transmitted. Some possible mechanisms were discussed.     

Analysis of the trinucleotide repeat expansion in Italian families affected with Huntington disease

150 subjects affected with HD and 45 at high risk for the diseasewere typed for the CAG trinucleotide repeat at the 5‘end of IT15. In all of them we find expanded segments showingmarked instability upon transmission. Their length distributionmatches those previously reported and inversely correlates (–0.686)with age at onset. Two at risk sibs from a large HD pedigreeshow expanded segments that overlap the normal distributionand can represent reductions from the HD to the normal range.A case of instability on a normal chromosome is also reported.Finally, an analysis of the CAG repeat as a function of threepolymorphic DNA markers at D4S127 and D4S95 loci shows no significantdifference in the average repeat length on HD chromosomes groupedaccording to the cosegregating allele of each marker or to thecorresponding haplotype. Despite the marked heterogeneity inrepeat length among HD families, haplotypes are not associatedwith different values around which the repeat length fluctuates.     

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.     

Huntington''s disease in Tanzania.

Huntington's disease was studied in a Bantu community in northern Tanzania. Although there is evidence to suggest that the disease has been present here for over one hundred years, this is the first report of the condition in Tanzania. A survey of published reports indicates that the disease is infrequently reported in persons of Negro ancestry.     

Predictive testing for Huntington''s disease: after the gene. The United Kingdom Huntington''s Disease Prediction Consortium.

The discovery of a mutation responsible for Huntington's disease (HD) offers the possibility of accurate predictive testing, as well as hope for treatment or prevention of this disease. We urge caution in the use of this new test as considerable ethical and counselling problems still exist, and new issues have arisen. The current guidelines for predictive testing should still apply, since it remains vital that subjects and their families have time to come to terms with the diagnosis of HD, and the implications of testing. Mutation analysis may allow the diagnosis of HD in isolated cases, or reverse a test result produced using linkage. Problems will arise as those at 25% risk may now receive a result despite the lack of support of their parent at 50% risk who may not wish to have their own status defined. In addition, couples who seek the exclusion test in pregnancy may find it difficult to investigate the pregnancy without producing information on themselves. Different centres should cooperate in maintaining the confidentiality of family members, ensuring that adequate counselling is given before results are produced which may affect the wider family.     

Instability of CAG repeats in Huntington''s disease: relation to parental transmission and age of onset.

Huntington's disease (HD) has recently been found to be caused by expansion of a trinucleotide (CAG) repeat within the putative coding region of a gene with an unknown function. We report here an analysis of HD mutation and the characteristics of its transmission in 36 HD families. CAG repeats on HD chromosomes were unstable when transmitted from parent to offspring. Instability appeared more frequent and stronger upon transmission from a male than from a female, with a clear tendency towards increased size. We have also found a significant inverse correlation (p = 0.0001) between the age of onset and the CAG repeat length. The observed scatter would, however, not allow an accurate individual prediction of age of onset. Three juvenile onset cases analysed had an HD mutation of paternal origin. In at least two of these cases a large expansion of the HD allele upon paternal transmission may explain the major anticipation observed. Our results suggest that several features of the expansion mutation in HD are similar to those previously observed for mutations of similar size in spinobulbar muscular atrophy and in myotonic dystrophy, and to those observed more recently in spinocerebellar ataxia type 1 and in dentatorubropallidoluysian atrophy, four diseases also caused by expansion of CAG repeats.     

Genetic linkage between Huntington''s disease and the DNA polymorphism G8 in South Wales families.

Analysis of the polymorphism shown by the DNA probe G8 in eight South Wales families with Huntington's disease has confirmed close genetic linkage between this marker and the disorder, the most likely genetic distance being two centimorgans (cM). The closeness of the linkage suggests that G8 may have clinical applications in genetic prediction for this condition.     

Linkage disequilibrium in Huntington''s disease: an improved localisation for the gene.

The search for the Huntington's disease gene has recently concentrated on the telomere of the short arm of chromosome 4. The evidence suggesting this position has been based on single crossover events, but there is conflicting evidence regarding the position of the gene relative to the most terminal markers. We have found significant linkage disequilibrium between the markers D4S98 (probe BS731B-C) and D4S95 (probe BS674E-D) and HD, which supports a localisation for the gene proximal to D4S90 and makes a telomeric localisation unlikely. This disequilibrium may also prove to be important in the future in allowing modification of risk estimates based on genetic linkage.     

Onset symptoms in 510 patients with Huntington''s disease.

The onset of Huntington's disease (HD) is preceded or accompanied by events and symptoms which contribute to the natural history of the disease. Data obtained from the first 510 completed 'Questionnaires for Affected Individuals', recorded by the National Huntington's Disease Research Roster (NHDRR) were analysed. The following features were evaluated: (1) neurological and psychiatric onset symptoms; (2) the precipitating effect of stressful events and drugs; (3) the modification after onset of smoking and alcohol consumption. The most frequent psychiatric onset symptom was depression. Stressful events in the year before onset occurred in 43% of patients. However, onset age was the same in patients with and without previous stressful events. Smoking and especially alcohol consumption showed a decreasing trend after onset.     

Parental factors associated with rigidity in Huntington''s disease.

The discriminatory power of ten factors has been explored in relation to the presence or absence of muscular rigidity in patients with Huntington's disease. The sex and neurological sign of an affected parent were the only two significant determinants of rigidity or choreoathetosis in offspring. It was shown, using the Mantel-Haenszel method of adjusting for confounding variables that the risk of a patient displaying rigidity (and thereby having a graver prognosis) is five times as great for those with rigid parents as it is for those with non-rigid parents. Additionally, the risk of a patient displaying rigidity is more than three times as great for those with affected fathers as it is for those with affected mothers. Some implications of these findings are discussed.     

Suicide risk in Huntington''s disease.

In order to evaluate the relevance of suicide risk in families affected by Huntington's disease (HD), 2793 subjects registered with the National Huntington's Disease Research Roster were studied. Suicide was the reported cause of death in 205 subjects (7.3%). This group included affected and possibly affected subjects, subjects at 50% and 25% risk, possibly at risk subjects, and normal relatives. In all categories suicide was more frequent than in the general US population. The data suggest that suicide is quite frequent in some families with HD. This increased suicide risk must be carefully considered in planning genetic counselling for predictive testing in HD.     

Exclusion mapping of the hereditary dentatorubropallidoluysian atrophy gene from the Huntington''s disease locus.

Hereditary dentatorubropallidoluysian atrophy (DRPLA) is an autosomal dominant neurodegenerative disorder. Clinical and genetic findings in hereditary DRPLA are very similar to those of Huntington's disease (HD). However, it can be differentiated from HD by the pathological findings of dentatorubral and pallidoluysian atrophies and by a lack of prominent atrophy of the striatum at necropsy. The hereditary DRPLA gene has not been localised and the possibility that the two disease loci are allelic has been suggested. We have searched for linkage between the locus for hereditary DRPLA and D4S10 using the G8 probe, which is a genetic marker linked to HD. In four families, there were negative scores at all recombination fractions and the lod score was -2.215 at recombination fraction theta = 0.15. These data indicate that the locus for hereditary DRPLA is not closely linked to D4S10 and that hereditary DRPLA is a distinct disease from HD.     

Four novel mutations of the connexin 32 gene in four Japanese families with Charcot-Marie-Tooth disease type 1

DNA-based mutation analysis on the connexin 32 gene was performed in 49 families with Charcot-Marie-Tooth disease (CMT) type 1 but without duplication involving the chromosomal region, 17p12-p11.2. Mutations were identified in five of the 49 families, and four of the five mutations were hitherto undescribed: Val37Met, Glu57His, Arg142Glu, Val177Ala. X-linked CMT sometimes lacks evidence for X-linked transmission and cannot be differentiated from CMT type 2, especially in females with mildly decreased nerve conduction velocity. Therefore, molecular analysis is useful for molecular pathology of their disease. Am. J. Med. Genet. 80:352–355, 1998. © 1998 Wiley-Liss, Inc.     

Cognitive performance in UK sample of presymptomatic people carrying the gene for Huntington''s disease.

This paper presents an investigation of cognitive ability in 30 subjects at risk for Huntington's disease. Those shown to be at high or low risk for this disease are compared on a wide range of neuropsychological measures. Results indicate only one significant difference between the two groups; those who carry the gene show a higher level of performance on the Corsi Supraspan task. It is suggested, however, that minimal deficits are apparent in the at risk gene carrying group but that current measures of assessment are not sensitive enough to identify them.     

Four mutations of the spastin gene in Japanese families with spastic paraplegia

Hereditary spastic paraplegia (HSP) is a group of genetically heterogeneous neurodegenerative disorders characterized by slowly progressive spasticity and weakness of the lower limbs. HSP is caused by failure of development or selective degeneration of the corticospinal tracts, which contain the longest axons in humans. The most common form of HSP is caused by mutations of the spastin gene (SPAST), located on chromosome 2p21-p22, which encodes spastin, one of the ATPases associated with diverse cellular activities (AAA). In this study, we detected four causative mutations of SPAST among 14 unrelated patients with spastic paraplegia. Two missense mutations (1447A→G, 1207C→G) and two deletion mutations (1465delT, 1475-1476delAA) were located in the AAA cassette region. Three of these four mutations were novel. Previous reports and our results suggest that the frequency of SPAST mutations is higher among Japanese patients with autosomal dominant HSP, although SPAST mutations are also observed in patients with sporadic spastic paraplegia.Rehana Basri, Ichiro Yabe and Hiroyuki Soma have contributed equally to this work.