| 1. |
- Chong, S S, et al.
(författare)
-
Contribution of DNA sequence and CAG size to mutation frequencies of intermediate alleles for Huntington disease : evidence from single sperm analyses.
- 1997
-
Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 6:2, s. 301-9
-
Tidskriftsartikel (refereegranskat)abstract
- New mutations for Huntington disease (HD) arise from intermediate alleles (IAs) with between 29 and 35 CAG repeats that expand on transmission through the paternal germline to 36 CAGs or greater. Using single sperm analysis, we have assessed CAG mutation frequencies for four IAs in families with sporadic HD (IANM) and IAs ascertained from the general population (IAGP) by analyzing 1161 single sperm from three persons. We show that IANM are more unstable than IAGP with identical size and sequence. Furthermore, comparison of different sized IAs and IAs with different sequences between the CAG and the adjacent CCG tracts indicates that DNA sequence is a major influence on CAG stability. These studies provide estimates of the likelihood of expansion of IANM and IAGP to > or = 36 CAG repeats for these individuals. For an IA with a CAG of 35 in this family with sporadic HD, the likelihood for siblings to inherit a recurrent mutation > or = 36 CAG is approximately 10%. For IAGP of a similar size, the risk of inheriting an expanded allele of > or = 36 CAG through the paternal germline is approximately 6%. These risk estimates are higher than previously reported and provide additional information for counselling in these families. Further studies on persons with IAs will be needed to determine whether these results can be generalized to other families.
|
|
| 2. |
- Kremer, B, et al.
(författare)
-
Influence of lamotrigine on progression of early Huntington disease : a randomized clinical trial.
- 1999
-
Ingår i: Neurology. - 0028-3878 .- 1526-632X. ; 53:5, s. 1000-11
-
Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To assess the efficacy of lamotrigine, a novel antiepileptic drug that inhibits glutamate release, to retard disease progression in Huntington disease (HD).BACKGROUND: Excitatory amino acids may cause selective neuronal death in HD, and lamotrigine may inhibit glutamate release in vivo.METHODS: A double-blinded, placebo-controlled study was conducted of 64 patients with motor signs of less than 5 years' duration who were randomly assigned to either placebo or lamotrigine and assessed at 0 (baseline), 12, 24, and 30 months. The primary response variable was total functional capacity (TFC) score. Secondary response variables included the quantified neurological examination and a set of cognitive and motor tests. Repeated fluorodeoxyglucose measurements of regional cerebral metabolism using PET also were included.RESULTS: Fifty-five patients (28 on lamotrigine, 27 on placebo) completed the study. Neither the primary response variable nor any of the secondary response variables differed significantly between the treatment groups. Both the lamotrigine and the placebo group deteriorated significantly on the TFC, in the lamotrigine group by 1.89 and the placebo group by 2.11 points. No effect of CAG size on the rate of deterioration could be detected.CONCLUSIONS: There was no clear evidence that lamotrigine retarded the progression of early Huntington disease over a period of 30 months. However, more patients on lamotrigine reported symptomatic improvement (53.6 versus 14.8%; p = 0.006), and a trend toward decreased chorea was evident in the treated group (p = 0.08). The study also identified various indices of disease progression, including motor tests and PET studies, that were sensitive to deterioration over time.
|
|
| 3. |
|
|
| 4. |
- Kremer, B, et al.
(författare)
-
Sex-dependent mechanisms for expansions and contractions of the CAG repeat on affected Huntington disease chromosomes.
- 1995
-
Ingår i: American Journal of Human Genetics. - 0002-9297 .- 1537-6605. ; 57:2, s. 343-50
-
Tidskriftsartikel (refereegranskat)abstract
- 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.
|
|
| 5. |
|
|
| 6. |
|
|
| 7. |
|
|
