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Biomedical subjects

A Brice

Publications and source records attributed to A Brice.

At least 199 records · Page 11Linked to original sources
PubMed1996

Autosomal dominant cerebellar ataxia type I in Martinique (French West Indies): genetic analysis of three unrelated SCA2 families.

Autosomal dominant cerebellar ataxias (ADCAs) are a group of neurodegenerative disorders that are clinically and genetically heterogeneous. We report here a genetic linkage study, with five chromosome 12q markers, of three Martinican families with ADCA type 1, for which the spinocerebellar ataxia 1 (SCA1) locus was excluded. Linkage to the SCA2 locus was demonstrated with a maximal lead score of 6.64 at theta = 0.00 with marker D12S354. Recombinational events observed by haplotype reconstruction demonstrated that the SCA2 locus is located in an approximately 7-cM interval flanked by D12S105 and D12S79. Using the z(max)-1 method, multipoint analysis further reduced the candidate interval for SCA2 to a region of 5 cM. Two families shared a common haplotype at loci spanning 7 cM, which suggests a founder effect, whereas a different haplotype segregated with the disease in the third family. Finally, a mean anticipation of 12+/-14 years was found in parent-child couples, with no parental sex effect, suggesting that the disease might be caused by an expanded and unstable triplet repeat.

Adolescent↗
PubMed1996

[Genetics of Alzheimer's disease].

This review reports the different genetic factors that have been identified either as risk factor for Alzheimer's disease (AD) or directly causing the disease. First are reviewed epidemiological data and biological mechanisms about the apoplipoprotein E gene allele epsilon 4 that is a major risk factor for Alzheimer's disease. The second part describes the mutations responsible for early-onset autosomal dominant AD found in three different genes. The gene located on chromosome 21 encodes the amyloid precusor protein (APP). The presenilin 1 and presenilin 2 genes, located on chromosome 14 and 1 respectively, encode not yet known membrane proteins.

Alzheimer Disease↗
PubMed1996

Cloning of the gene for spinocerebellar ataxia 2 reveals a locus with high sensitivity to expanded CAG/glutamine repeats.

Two forms of the neurodegenerative disorder spinocerebellar ataxia are known to be caused by the expansion of a CAG (polyglutamine) trinucleotide repeat. By screening cDNA expression libraries, using an antibody specific for polyglutamine repeats, we identified six novel genes containing CAG stretches. One of them is mutated in patients with spinocerebellar ataxia linked to chromosome 12q (SCA2). This gene shows ubiquitous expression and encodes a protein of unknown function. Normal SCA2 alleles (17 to 29 CAG repeats) contain one to three CAAs in the repeat. Mutated alleles (37 to 50 repeats) appear particularly unstable, upon both paternal and maternal transmissions. The sequence of three of them revealed pure CAG stretches. The steep inverse correlation between age of onset and CAG number suggests a higher sensitivity to polyglutamine length than in the other polyglutamine expansion diseases.

Adolescent↗
PubMed1996

Phenotype of autosomal dominant spastic paraplegia linked to chromosome 2.

We report the clinical features of 12 families with autosomal dominant spastic paraplegia (ADSP) linked to the SPG4 locus on chromosome 2p, the major locus for this disorder that accounts for approximately 40% of the families. Among 93 gene carriers, 32 (34%) were unaware of symptoms but were clinically affected. Haplotype reconstruction showed that 90% of the asymptomatic gene carriers presented increased reflexes and/or extensor plantar responses independent of age at examination. The mean age at onset was 29 years, ranging from 1 to 63 years. Intra- as well as inter-familial variability of age at onset was important, but did not result from anticipation. Phenotype-genotype correlations and comparison with SPG3 and SPG5 families indicated that despite the variability of age at onset, SPG4 is a single genetic entity but no clinical features distinguish individual SPG4 patients from those with SPG3 or SPG5 mutations.

Adolescent↗
PubMed1996

Autosomal dominant cerebellar ataxia type I clinical features and MRI in families with SCA1, SCA2 and SCA3.

Sixty-five patients suffering from autosomal dominant cerebellar ataxia-I(ADCA-1) were subjected genotype phenotype correlation analysis using molecular genetic assignment to the spinocerebellar ataxia type 1, 2 or 3 (SCA1, -2 or -3) locus, clinical examination, eye movement recording and morphometric analysis of MRIs. Pyramidal tract signs, pale discs and dysphagia were more frequent in SCA1 compared SCA2 and SCA3 patients. Saccade velocity was reduced in 56% of SCA1 and all SCA2, but only in 30% of SCA3 patients. MRIs of SCA2 patients showed atrophy changes typical of severe olivopontocerebellar atrophy (OPCA). The morphological changes in SCA1 were similar but less pronounced. In contrast, SCA3 patients had only mild cerebellar and brain stem atrophy distinct from typical OPCA. The principal finding of this study is that mutations of the SCA2 and SCA3 gene cause phenotypes which can be distinguished in vivo by recording of eye movements and morphometric MRI analysis. Correlative plotting of saccade velocity and diameter of the middle cerebellar peduncle yields a clear separation of SCA2 and SCA3. Spinocerebellar ataxia type I falls into an intermediate range that overlaps with both SCA2 and SCA3. However, the clinical syndrome observed in SCA1 patients is different from that in SCA2 and SCA3.

Adult↗
PubMed1996

A de novo case of hereditary neuropathy with liability to pressure palsies (HNPP) of maternal origin: a new mechanism for deletion in 17p11.2?

Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant neuropathy, most often associated with a deletion of the 17p11.2 region, which is duplicated in 70% of patients with Charcot-Marie-Tooth type 1 (CMT1A). Most de novo CMT1A and HNPP cases have been of paternal origin. A rare case of de novo HNPP of maternal origin was analysed to determine the underlying mechanism. Affected individuals in the family carried a deletion corresponding to the CMT1A/HNPP monomer unit associated with a rearrangement of the CMT1A-REP sequences. Segregation analysis of 17p11-p12 markers in the family indicated that the deletion was not generated by unequal crossing over between homologous 17 chromosomes, as in de novo cases from paternal origin, but rather by an intrachromosomal rearrangement. Two distinct mechanisms can therefore lead to the same 17p11.2 deletion. This result suggests that intrachromosomal rearrangement may be specific to maternal transmissions.

Adult↗
PubMed1996

Homozygosity mapping of an autosomal recessive form of demyelinating Charcot-Marie-Tooth disease to chromosome 5q23-q33.

Charcot-Marie-Tooth (CMT) disease is the most frequent inherited peripheral motor and sensory neuropathy characterised by chronic distal weakness with progressive muscular atrophy and sensory loss of the distal extremities. The dominant form of the disease is genetically heterogeneous but only one locus has been identified on chromosome 8q13-q21.1 for autosomal recessive CMT. By homozygosity mapping in a large Algerian kindred, we have assigned a second locus for autosomal recessive CMT to chromosome 5q23-33. Linkage analysis demonstrated that the same locus is involved in a second Algerian family with a demyelinating CMT. Haplotype reconstruction and determination of the minimal region of homozygosity restricts the candidate region to a 4 cM interval.

Charcot-Marie-Tooth Disease↗
PubMed1996

Screening for proteins with polyglutamine expansions in autosomal dominant cerebellar ataxias.

Expansion of trinucleotide CAG repeats coding for polyglutamine has been implicated in five neurodegenerative disorders, including spinocerebellar ataxia (SCA) 1 and SCA3 or Machado-Joseph disease (SCA3/MJD), two forms of type I autosomal dominant cerebellar ataxias (ADCA). Using the 1C2 antibody which specifically recognizes large polyglutamine tracts, particularly those that are expanded, we recently reported the detection of proteins with pathological glutamine expansions in lymphoblasts from another form of ADCA type I, SCA2, as well as from patients presenting with the distinct phenotype of ADCA type II. We now have screened a large series of patients with ADCA or isolated cases with cerebellar ataxia, for the presence of proteins with polyglutamine expansions. A 150 kDa SCA2 protein was detected in 16 out of 40 families with ADCA type I. This corresponds to 24% of all ADCA type I families, which is much more frequent than SCA1 in this series of patients (13%). The signal intensity of the SCA2 protein was negatively correlated to age at onset, as expected for an expanded and unstable trinucleotide repeat mutation. The disease segregated with markers closely linked to the SCA2 locus in all identified SCA2 families. In addition, a specific 130 kDa protein, which segregated with the disease, was detected in lymphoblasts of patients from nine families with ADCA type II. It was also visualized in the cerebral cortex of one of the patients, demonstrating its translation in the nervous system. Finally, no new disease-related proteins containing expanded polyglutamine tracts could be detected in lymphoblasts from the remaining patients with ADCA or isolated cases with cerebellar ataxia.

Cerebellar Ataxia↗
PubMed1996

Intergenerational instability of the CAG repeat of the gene for Machado-Joseph disease (MJD1) is affected by the genotype of the normal chromosome: implications for the molecular mechanisms of the instability of the CAG repeat.

Machado-Joseph disease (MJD) is an autosomal dominant neurodegenerative disorder caused by unstable expansion of a CAG repeat in the MJD1 gene at 14q32.1. To identify elements affecting the intergenerational instability of the CAG repeat, we investigated whether the CGG/GGG polymorphism at the 3' end of the CAG repeat affects intergenerational instability of the CAG repeat. The [expanded (CAG)n-CGG]/[normal (CAG)n-GGG] haplotypes were found to result in significantly greater instability of the CAG repeat compared to the [expanded (CAG)n-CGG]/[normal (CAG)n-CGG] or [expanded (CAG)nGGG]/[normal (CAG)n-GGG] haplotypes. Multiple stepwise logistic regression analysis revealed that the relative risk for a large intergenerational change in the number of CAG repeat units (< -2 or > 2) is 7.7-fold (95% CI: 2.5-23.9) higher in the case of paternal transmission than in that of maternal transmission and 7.4-fold (95% CI: 2.4-23.3) higher in the case of transmission from a parent with the [expanded (CAG)n-CGG]/[normal (CAG)n-GGG] haplotypes than in that of transmission from a parent with the [expanded (CAG)n-CGG]/[normal (CAG)n-CGG] or [expanded (CAG)n-GGG]/[normal (CAG)n-GGG] haplotypes. The combination of paternal transmission and the [expanded (CAG)n-CGG]/[normal (CAG)n-GGG] haplotypes resulted in a 75.2-fold (95% CI: 9.0-625.0) increase in the relative risk compared with that of maternal transmission and the [expanded (CAG)n-CGG]/[normal (CAG)n-CGG] or [expanded (CAG)n-GGG]/[normal (CAG)n-GGG] haplotypes. The results suggest that an inter-allelic interaction is involved in the intergenerational instability of the expanded CAG repeat.

Chromosomes, Human, Pair 14↗
PubMed1996

Alzheimer's disease associated with mutations in presenilin 2 is rare and variably penetrant.

Missense mutations in the presenilin 2 (PS-2) gene on chromosome 1 were sought by direct nucleotide sequence analysis of the open reading frame of 60 pedigrees with familial Alzheimer's disease (FAD). In the majority of these pedigrees, PS-1 and beta-amyloid precursor protein (beta APP) gene mutations had been excluded. While no additional PS-2 pathogenic mutations were detected, four silent nucleotide substitutions and alternative splicing of nucleotides 1338-1340 (Glu325) were observed. Analysis of additional members of a pedigree known to segregate a Met239Val mutation in PS-2 revealed that the age of onset of symptoms is highly variable (range 45-88 years). This variability is not attributable to differences in ApoE genotypes. These results suggest (i) that, in contrast to mutations in PS-1, mutations in PS-2 are a relatively rare cause of FAD; (ii) that other genetic or environmental factor modify the AD phenotype associated with PS-2 mutations; and (iii) that still other FAD susceptibility genes remain to be identified.

Age of Onset↗
PubMed1996

Genetics of movement disorders.

Trinucleotide repeat expansions or unstable mutations are the cause of a growing number of hereditary movement disorders, especially inherited ataxias. Diagnostic practice as well as disease classifications have altered accordingly. Genes responsible for "Parkinsonian plus' syndromes and episodic movement disorders have also been recently mapped.

Chromosome Aberrations↗
PubMed1996

An expanded CAG repeat sequence in spinocerebellar ataxia type 7.

Expanded CAG repeat sequences have been identified in the coding region of genes mutated in several neurodegenerative disorders, including spinocerebellar ataxia type 1 and Machado-Joseph disease. In all disorders described to date the CAG expansion codes for an elongated polyglutamine chain. An increased polyglutamine chain size leads to a more severe disease, thus correlating with the genetic anticipation seen in repeat expansion disorders. Spinocerebellar ataxia type 7 (SCA7) is an autosomal dominant spinocerebellar ataxia with anticipation and a progressive degeneration of the cerebellar cortex. Using repeat expansion detection (RED), a method in which a thermostable ligase is used to detect repeat expansions directly from genomic DNA, we have analyzed 8 SCA7 families for the presence of CAG repeat expansions. RED products of 150-240 bp were found in all affected individuals and found to cosegregate with the disease (P < 0.000001, n = 66), indicating strongly that a CAG expansion is the cause of SCA7. On the basis of a previously established correlation between RED product sizes and actual repeat sizes in Machado-Joseph disease, we were able to estimate the average expansion size in SCA7 to be 64 CAG copies.

Chromosome Mapping↗
PubMed1996

Genetic fitness in Huntington's Disease and Spinocerebellar Ataxia 1: a population genetics model for CAG repeat expansions.

An analysis of genetic fitness was performed in Huntington's Disease (HD) and Spinocerebellar Ataxia 1 (SCA1) families. Two partially overlapping samples were used: clinically defined HD and SCA1 patients from families ascertained in definite geographical areas, and molecularly typed carriers of HD and SCA1 mutations (CAG trinucleotide expansions). In both cases, a control group of normal relatives was used. HD and SCA1 patients born before 1915-20 had more children than normal controls. Carriers of HD and SCA1 mutations, all in the low/medium expansion range (37-49 and 47-54 CAG repeats respectively), had a higher number of children than controls up to more recent times (1935-1950). The reproduction of heterozygotes for large expansions could be analysed only in subjects born after 1950 and provided indirect evidence of a lower than normal number of children. The above results fit a model based on a differential fitness according to the degree of expansion. Such a model predicts that 1) up to relatively recently the frequency of alleles in the low/medium range has been maintained or even increased by the increased fitness of their carriers, as well as by new mutations, and 2) the frequency of large expansions, part of which are lost at each generation, is maintained through further expansions of alleles in the low/medium expansion range. The implications of such a model on linkage disequilibrium and the possible spread of these diseases in future generations are discussed.

Age of Onset↗
PubMed1996

No founder effect in three novel Alzheimer's disease families with APP 717 Val-->Ile mutation. Clerget-darpoux. French Alzheimer's Disease Study Group.

We sequenced exons 16 and 17 of the APP (amyloid precursor protein) gene in 18 unrelated French Alzheimer's disease (AD) patients. These patients had an onset before the age of 60 and belonged to families with autosomal dominant transmission of the disease. We detected the APP 717 Val-->Ile mutation in three out of 18 (16.6%) families. In these three families, all affected subjects had the APOE 3/3 genotype, but their ages of onset ranged from 38 to 60 years, indicating that factors other than the APOE genotype influence age of onset. Analysis of two polymorphic loci adjacent to the APP gene showed that at least two independent mutational events had occurred within these pedigrees, in spite of their origin in the same region of France.

Adult↗
PubMed1996

Microsatellite mapping of the deletion in patients with hereditary neuropathy with liability to pressure palsies (HNPP): new molecular tools for the study of the region 17p12 --> p11 and for diagnosis.

Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant peripheral neuropathy characterized by recurrent episodes of nerve palsies. We have analyzed 11 microsatellite markers from chromosome 17p12 --> p11 in nine French families with HNPP. The three microsatellites D17S839 (afm200yb12), D17S955 (afm317ygl), and D17S921 (afm191xh12) were localized in the deleted region. In allele segregation analyses, the microsatellite D17S793 (afm165zd4) detected two chromosome 17-linked loci, one of which was deleted in HNPP patients. Using these STR markers, we found that the deletion coincided with the CMT1A/HNPP monomer unit in eight of the nine families. In the remaining pedigree, the deletion lay between the centromeric microsatellite D17S805 (afm234tal) and the telomeric marker D17S922 (afm197xh6), which flank the CMT1A monomer unit. Comparison of these data with the available genetic and physical maps of 17p12 --> p11 shows that this region, which is frequently subject to rearrangement-inducing diseases, such as Smith-Magenis syndrome, Charcot-Marie-Tooth type 1A, and HNPP, presents recombination hot spots. Finally, this study demonstrates the usefulness of the D17S122 (RM11GT) and D17S921 (afm191xh12) microsatellites as tools for the molecular diagnosis of HNPP.

Chromosome Aberrations↗
PubMed1996

Estimation of the mutation frequencies in Charcot-Marie-Tooth disease type 1 and hereditary neuropathy with liability to pressure palsies: a European collaborative study.

A European collaboration on Charcot-Marie-Tooth type 1 (CMT1) disease and hereditary neuropathy with liability to pressure palsies (HNPP) was established to estimate the duplication and deletion frequency, respectively, on chromosome 17p11.2 and to make an inventory of mutations in the myelin genes, peripheral myelin protein 22 (PMP22), myelin protein zero (MPZ) and connexin 32 (Cx32) located on chromosomes 17p11.2, 1q21-q23 and Xq13.1, respectively. In 70.7% of 819 unrelated CMT1 patients, the 17p11.2 duplication was present. In 84.0% of 156 unrelated HNPP patients, the 17p11.2 deletion was present. In the nonduplicated CMT1 patients, several different mutations were identified in the myelin genes PMP22, MPZ and Cx32.

Charcot-Marie-Tooth Disease↗
PubMed1996

Recombination hot spot in a 3.2-kb region of the Charcot-Marie-Tooth type 1A repeat sequences: new tools for molecular diagnosis of hereditary neuropathy with liability to pressure palsies and of Charcot-Marie-Tooth type 1A. French CMT Collaborative Research Group.

Charcot-Marie-Tooth type 1A (CMT1A) disease and hereditary neuropathy with liability to pressure palsies (HNPP) are autosomal dominant neuropathies, associated, respectively, with duplications and deletions of the same 1.5-Mb region on 17p11.2-p12. These two rearrangements are the reciprocal products of an unequal meiotic crossover between the two chromosome 17 homologues, caused by the misalignment of the CMT1A repeat sequences (CMT1A-REPs), the homologous sequences flanking the 1.5-Mb CMT1A/HNPP monomer unit. In order to map recombination breakpoints within the CMT1A-REPs, a 12.9-kb restriction map was constructed from cloned EcoRI fragments of the proximal and distal CMT1A-REPs. Only 3 of the 17 tested restriction sites were present in the proximal CMT1A-REP but absent in the distal CMT1A-REP, indicating a high degree of homology between these sequences. The rearrangements were mapped in four regions of the CMT1A-REPs by analysis of 76 CMT1A index cases and 38 HNPP patients, who where unrelated. A hot spot of crossover breakpoints, located in a 3.2-kb region, accounted for three-quarters of the rearrangements, detected after EcoRI/SacI digestion, by the presence of 3.2-kb and 7.8-kb junction fragments in CMT1A and HNPP patients, respectively. These junction fragments, which can be detected on classical Southern blots, permit molecular diagnosis. Other rearrangements can also be detected by gene dosage on the same Southern blots.

Charcot-Marie-Tooth Disease↗