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Biomedical subjects

A Brice

Publications and source records attributed to A Brice.

At least 73 records · Page 4Linked to original sources
PubMed2001

The frequency of 17p11.2 duplication and Connexin 32 mutations in 282 Charcot-Marie-Tooth families in relation to the mode of inheritance and motor nerve conduction velocity.

The 17p11.2 duplication and Connexin 32 (Cx32) mutations are the most frequent gene mutations responsible for Charcot-Marie-Tooth diseases. We classified 282 Charcot-Marie-Tooth families according to the median motor nerve conduction velocity of the index patient and the mode of inheritance, and screened them for 17p11.2 duplication and Cx32 mutations. Forty-seven percent of the Charcot-Marie-Tooth families had median motor nerve conduction velocity under 30 m/s (group 1), 15% between 30 and 40 m/s (group 2), and 28% over 40 m/s (group 3). Spinal Charcot-Marie-Tooth (group 4) was observed in 7% of the families. Modes of inheritance were not similarly represented among the different groups. The 17p11.2 duplication was detected in index patients of group 1 only, and accounted for 83% of the familial cases and 36% of the isolated cases. In contrast, 21 Cx32 mutations were detected to variable degrees in groups 1-3, but were most numerous by far in dominant families of group 2 (44%). This systematic approach was taken to estimate the frequency of 17p11.2 duplication and Cx32 mutations in the different Charcot-Marie-Tooth subgroups, in order to propose a practical strategy for molecular analysis.

Adult↗
PubMed2001

First genetic evidence of GABA(A) receptor dysfunction in epilepsy: a mutation in the gamma2-subunit gene.

Major advances in the identification of genes implicated in idiopathic epilepsy have been made. Generalized epilepsy with febrile seizures plus (GEFS+), benign familial neonatal convulsions and nocturnal frontal lobe epilepsy, three autosomal dominant idiopathic epilepsies, result from mutations affecting voltage-gated sodium and potassium channels, and nicotinic acetylcholine receptors, respectively. Disruption of GABAergic neurotransmission mediated by gamma-aminobutyric acid (GABA) has been implicated in epilepsy for many decades. We now report a K289M mutation in the GABA(A) receptor gamma2-subunit gene (GABRG2) that segregates in a family with a phenotype closely related to GEFS+ (ref. 8), an autosomal dominant disorder associating febrile seizures and generalized epilepsy previously linked to mutations in sodium channel genes. The K289M mutation affects a highly conserved residue located in the extracellular loop between transmembrane segments M2 and M3. Analysis of the mutated and wild-type alleles in Xenopus laevis oocytes confirmed the predicted effect of the mutation, a decrease in the amplitude of GABA-activated currents. We thus provide the first genetic evidence that a GABA(A) receptor is directly involved in human idiopathic epilepsy.

Amino Acid Sequence↗
PubMed2001

Use of haplotype information to test involvement of the LRP gene in Alzheimer's disease in the French population.

The low density lipoprotein receptor-related protein gene (LRP) is a good candidate gene for Alzheimer's Disease (AD). Its protein is involved in the physiopathology of AD and has been found in senile plaques; on the other hand, LRP is located in 12q, a region in which genetic linkage to AD was reported. Two common polymorphisms, a tetranucleotide repeat in the 5' untranslated region and a single nucleotide polymorphism at position 766 in exon 3, were found to be associated with AD, but contradictory results were obtained in subsequent association studies. In the absence of clear hypotheses concerning the association of these polymorphisms with AD and their functional role, our objective was to test the association between AD and the two LRP polymorphisms in a large French case-control sample (274 Caucasian AD patients and 290 matched controls) using haplotype analysis. First, the separate study of each polymorphism showed no significant difference in genotype and allele frequencies between AD cases and controls. Second, strong linkage disequilibrium was found between alleles of the two polymorphisms in controls and in cases and the linkage disequilibrium between the 91 bp and C alleles were opposite in cases and in controls. Third, we found that the frequency of the 91-C haplotype was higher in cases than in controls, but the type I error was 0.061, slightly higher than the conventional one of 5%. The haplotype frequencies did not vary significantly as a function of age and APOE epsilon4 status. One interest in this study is the use of the haplotype analysis, which can be used to combine information from several polymorphisms, taking into account their dependence.

Adult↗
PubMed2001

CAG repeat expansion in the TATA box-binding protein gene causes autosomal dominant cerebellar ataxia.

At least 13 loci responsible for autosomal dominant cerebellar ataxia (ADCA) have been identified. Spinocerebellar ataxia 1, 2, 3, 6 and 7 are caused by translated CAG repeat expansions. However, in France, >30% of ADCAs are not explained by the known genes. Recently, analysis of the TATA box-binding protein (TBP) gene, one of the transcription factors known to contain a CAG/CAA repeat, in patients with progressive cerebellar ataxia revealed one sporadic case with 63 repeats. We examined this gene in 162 index cases with ADCA. An expanded repeat with 46 repeat units was detected in a single index case from Belgium. In this family, two affected members and six unaffected, but at-risk, individuals carried expanded alleles. Interestingly, the expanded repeat was stable during transmission. The main clinical features in six patients were cerebellar ataxia, dementia and behavioural disturbances with onset in their fourth to sixth decade. The main neuropathological finding was severe neuronal loss and gliosis in the Purkinje cell layer. Immunohistochemical analysis showed neuronal intranuclear inclusions containing expanded polyglutamine, indicating that this disease shares several features with other polyglutamine diseases. This study demonstrates that CAG/CAA repeat expansion in the TBP gene causes ADCA with dementia and/or psychiatric manifestations.

Adult↗
PubMed2001

Clinical, electrophysiological and molecular genetic characteristics of 93 patients with X-linked Charcot-Marie-Tooth disease.

X-linked dominant Charcot-Marie-Tooth (CMTX) disease is a motor and sensory neuropathy caused by mutations in the connexin 32 (CX32) gene. In this study we report the clinical, electrophysiological and genetic features of 93 patients (41 males, 52 females) from 37 unrelated families with CMTX. Age at onset was 15.4 +/- 9.6 years in males (range 1-40 years) and 18.7 +/- 13.1 years in females (range 1-56 years) (P = 0.22) and the duration of disease at the time of examination was 18.3 +/- 14.6 years in males and 23.9 +/- 13.7 years in females (P = 0.11). Males were more severely affected than females, with significantly more frequent muscle weakness, amyotrophy, proprioception loss, upper limb areflexia and pes cavus. Females were more frequently asymptomatic, whereas high functional disability scores were more frequently encountered in males. The electrophysiological studies showed that motor nerve conduction velocities in CMTX females, but not males, were heterogeneous between nerves compared with Charcot-Marie-Tooth type 1A (CMT1A) patients and controls. The terminal latency index (TLI) for the median nerve was 0.37 +/- 0.08; it was similar in men and in women and a little higher than those observed in CMT1A and controls. The range of values for median TLI was wider in both male and female CMTX patients than in controls, but was similar to that of CMT1A patients, suggesting that motor conduction was relatively homogeneous within a given nerve. Twenty-seven different CX32 mutations, including missense (n = 23), nonsense (n = 2) and frameshift mutations (n = 1) and one entire deletion of the CX32 coding sequence, were observed in the 37 families. Four of these mutations are described for the first time. The phenotype of the patients, especially age at onset, is discussed in relation to the functional consequences of CX32 mutations, analysed in vitro in Xenopus oocytes and mammalian cells. CMTX patients with age at onset in the first decade mostly presented non-functional mutations, suggesting that the physiological consequences of the mutations affect age at onset in CMTX.

Adolescent↗
PubMed2001

Recent advances in hereditary spastic paraplegia.

The hereditary spastic paraplegias are a group of rare disorders that are characterized by great clinical and genetic heterogeneity. There has been an exponential increase in the number of HSP loci mapped in recent years, with nine out of the 17 loci reported during the past 2 years. Eight loci have now been identified for the autosomal-dominant form, and seven of these are associated with pure HSP. Spastic paraplegia-4 remains the most frequent locus, and is usually associated with a pure phenotype. Although the corresponding spastin gene was only recently identified, over 50 mutations have been described to date, which renders molecular diagnosis difficult. Five loci are known for autosomal-recessive HSP, and four of these are associated with complex forms, all with different phenotypes. Two genes have been identified: paraplegin and sacsin. Finally, three loci have been identified in X-linked HSP, two of which are complex forms. The genes that encode L1 and PLP were the first to be identified in HSP disorders. Surprisingly, the five genes encode proteins of different families, making understanding and diagnosis of HSP even more difficult. The discovery of new genes should hopefully help to clarify the pathophysiology of these disorders.

Chromosome Aberrations↗
PubMed2001

Three parkin gene mutations in a sibship with autosomal recessive early onset parkinsonism.

The objective was to describe a family with autosomal recessive, early onset parkinsonism, with affected siblings carrying three different exon rearrangements in the parkin gene. The living affected siblings were personally examined. Molecular genetic analyses included exon dosage of the parkin gene using a semiquantitative multiplex polymerase chain reaction (PCR) protocol and haplotype analysis. The index case was a compound heterozygote with a deletion of exon 5 and a duplication of exon 3. His affected sister was a compound heterozygote for a deletion of exon 5 and a deletion of exons 3-9. Haplotype analysis confirmed the presence of three mutant alleles at the parkin locus. The phenotype was early onset parkinsonism with marked response to levodopa, and a very slow, prolonged course. In conclusion, the frequency of mutations in the parkin gene in certain populations might be high enough to cause allelic heterogeneity in the same sibship.

Aged↗
PubMed2001

SCA12 is a rare locus for autosomal dominant cerebellar ataxia: a study of an Indian family.

Spinocerebellar ataxia 12 (SCA12) is an autosomal dominant cerebellar ataxia (ADCA) described in a single family with a CAG repeat expansion in the PPP2R2B gene. We screened 247 index cases, including 145 families with ADCA, for this expansion. An expanded repeat ranging from 55 to 61 triplets was detected in 6 affected and 3 unaffected individuals at risk in a single family from India. The association of the PPP2R2B CAG repeat expansion with disease in this new family provides additional evidence that the mutation is causative.

Adult↗
PubMed2000

Ancestral origins of the Machado-Joseph disease mutation: a worldwide haplotype study.

Machado-Joseph disease (MJD) is an autosomal dominant neurodegenerative disorder originally described in families of Portuguese-Azorean ancestry. The cloning of the MJD1 gene allowed identification of the disease in many other populations, and MJD is now known to be the most common cause of dominant spinocerebellar ataxia. The hypothesis that its present world distribution could result from the spread of an original founder mutation has been raised, both at historical and molecular levels. In the present study, we tested this hypothesis by linkage-disequilibrium analysis of tightly linked polymorphisms and by haplotype comparison, in 249 families from different countries. We typed five microsatellite markers surrounding the MJD1 locus (D14S1015, D14S995, D14S973, D14S1016, and D14S977), and three intragenic single-base-pair polymorphisms (A(669)TG/G(669)TG, C(987)GG/G(987)GG, and TAA(1118)/TAC(1118)). The results show two different haplotypes, specific to the island of origin, in families of Azorean extraction. In families from mainland Portugal, both Azorean haplotypes can be found. The majority of the non-Portuguese families also share the same intragenic haplotype seen in the families coming from the island of Flores, but at least three other haplotypes were seen. These findings suggest two introductions of the mutation into the Portuguese population. Worldwide, the sharing of one intragenic haplotype by the majority of the families studied implies a founder mutation in MJD.

Alleles↗
PubMed2000

Dementia with prominent frontotemporal features associated with L113P presenilin 1 mutation.

The authors report a presenilin 1 (PSEN1) mutation (L113P) in a family with six cases of dementia. The patients had personality changes and behavioral disorders, whereas spatial orientation and praxis were preserved late in the course of the illness. Neuroimaging features were consistent with the diagnosis of frontotemporal dementia. The authors conclude that PSEN1 mutations can be associated with clinical features of frontotemporal dementia.

Adult↗
PubMed2000

Association between early-onset Parkinson's disease and mutations in the parkin gene.

BACKGROUND: Mutations in the parkin gene have recently been identified in patients with early-onset Parkinson's disease, but the frequency of the mutations and the associated phenotype have not been assessed in a large series of patients. METHODS: We studied 73 families in which at least one of the affected family members was affected at or before the age of 45 years and had parents who were not affected, as well as 100 patients with isolated Parkinson's disease that began at or before the age of 45 years. All subjects were screened for mutations in the parkin gene with use of a semiquantitative polymerase-chain-reaction assay that simultaneously amplified several exons. We sequenced the coding exons in a subgroup of patients. We also compared the clinical features of patients with parkin mutations and those without mutations. RESULTS: Among the families with early-onset Parkinson's disease, 36 (49 percent) had parkin mutations. The age at onset ranged from 7 to 58 years. Among the patients with isolated Parkinson's disease, mutations were detected in 10 of 13 patients (77 percent) with an age at onset of 20 years or younger, but in only 2 of 64 patients (3 percent) with an age at onset of more than 30 years. The mean (+/-SD) age at onset in the patients with parkin mutations was younger than that in those without mutations (32+/-11 vs. 42+/-11 years, P<0.001), and they were more likely to have symmetric involvement and dystonia at onset, to have hyperreflexia at onset or later, to have a good response to levodopa therapy, and to have levodopa-induced dyskinesias during treatment. Nineteen different rearrangements of exons (deletions and multiplications) and 16 different point mutations were detected. CONCLUSIONS: Mutations in the parkin gene are a major cause of early-onset autosomal recessive familial Parkinson's disease and isolated juvenile-onset Parkinson's disease (at or before the age of 20 years). Accurate diagnosis of these cases cannot be based only on the clinical manifestations of the disease.

Adolescent↗
PubMed2000

Mapping of spinocerebellar ataxia 13 to chromosome 19q13.3-q13.4 in a family with autosomal dominant cerebellar ataxia and mental retardation.

We examined a large French family with autosomal dominant cerebellar ataxia (ADCA) that was excluded from all previously identified spinocerebellar ataxia genes and loci. The patients-seven women and a 4-year-old boy-exhibited slowly progressive childhood-onset cerebellar gait ataxia associated with cerebellar dysarthria, moderate mental retardation (IQ 62-76), and mild developmental delays in motor acquisition. Nystagmus and pyramidal signs were also observed in some cases. This unique association of clinical features clearly distinguishes this new entity from other previously described ADCA. Cerebral magnetic-resonance imaging showed moderate cerebellar and pontine atrophy in two patients. We performed a genomewide search and found significant evidence for linkage to chromosome 19q13.3-q13.4, in an approximately 8-cM interval between markers D19S219 and D19S553.

Adult↗
PubMed2000

Spectrum of SPG4 mutations in autosomal dominant spastic paraplegia.

Autosomal dominant hereditary spastic paraplegia (AD-HSP) is a group of genetically heterogeneous neurodegenerative disorders characterized by pro- gressive spasticity of the lower limbs. Five AD-HSP loci have been mapped to chromosomes 14q, 2p, 15q, 8q and 12q. The SPG4 locus at 2p21-p22 has been shown to account for approximately 40% of all AD-HSP families. SPG4 encoding spastin, a putative nuclear AAA protein, has recently been identified. Here, sequence analysis of the 17 exons of SPG4 in 87 unrelated AD-HSP patients has resulted in the detection of 34 novel mutations. These SPG4 mutations are scattered along the coding region of the gene and include all types of DNA modification including missense (28%), nonsense (15%) and splice site point (26.5%) mutations as well as deletions (23%) and insertions (7.5%). The clinical analysis of the 238 mutation carriers revealed a high proportion of both asymptomatic carriers (14/238) and patients unaware of symptoms (45/238), and permitted the redefinition of this frequent form of AD-HSP.

Adenosine Triphosphatases↗
PubMed2000

No evidence for long CAG/CTG repeats in families with spastic paraplegia linked to chromosome 2p21-24.

Autosomal dominant familial spastic paraplegia (AD-FSP) is a genetically heterogeneous, neurodegenerative disorder characterized by spasticity and progressive weakness in the lower limbs. Anticipation has been suggested to occur and an association between expanded CAG/CTG repeats and AD-FSP linked to the SPG4 locus (2p21-p24) has been described. In this study, 42 affected individuals from six SPG4 families were screened for expanded CAG/CTG repeats using the repeat expansion detection (RED) method. Large RED products (range 180-240 nucleotides) corresponding in size to repeats at the ERDA1 locus were detected in eight patients and at the CTG 18.1 locus in one patient. The large ERDA1 repeats did not segregate with the disorder within families. Mean age at onset and index of severity were not significantly different between patients with or without expanded RED products. Furthermore, no abnormal proteins were found by Western blot in 15 selected patient samples as compared with controls, using the 1C2 antibody, which detects long polyglutamine stretches. Thus, in contrast to previous reports, our study provides evidence against the hypothesis that a large translated CAG repeat expansion is the basis of SPG4. We propose that mechanisms other than large pathogenic CAG/CTG repeats may account for the disease in the SPG4 families tested here.

Adolescent↗
PubMed2000

Frequency of the DYT1 mutation in primary torsion dystonia without family history.

BACKGROUND: Idiopathic torsion dystonia is a clinically and genetically heterogeneous movement disorder. A GAG deletion at position 946 of the DYT1 gene was the first mutation found, in early-onset dystonia, with an autosomal dominant transmission and reduced penetrance. OBJECTIVE: To evaluate the frequency of the DYT1 mutation in patients with idiopathic torsion dystonia but without a family history. DESIGN: Prospective cohort study. SETTING: Four botulinum toxin clinics in the Paris, France, area. PATIENTS: A French population of 100 patients with dystonia. MAIN OUTCOME: Frequency of the DYT1 mutation tested by polymerase chain reaction and enzyme restriction analysis for the 946 GAG deletion, and genotype-to-phenotype correlation. RESULTS: Only 5 mutation carriers were identified, 4 of whom were part of a group of 10 patients with generalized dystonia. Onset was between ages 5 and 12 years as in typical early-onset dystonia. All 4 patients had cranial muscle involvement, which is atypical for DYT1 mutation carriers. One had segmental dystonia. Molecular analysis of relatives in 2 families demonstrated that the lack of family history was due to reduced penetrance. CONCLUSIONS: For accurate diagnosis and genetic counseling, screening for the DYT1 deletion is of great interest in cases with generalized dystonia without a family history. In other cases, positive results are rare.

Adult↗
PubMed2000

Phenotypic and genetic study of a family with hereditary sensory neuropathy and prominent weakness.

We report the clinical and electrophysiological features of six members of a French family with a dominantly inherited motor and sensory neuropathy. Mean age at onset was 33.6 +/- 9.1 years. Mean age at examination was 55.5 +/- 13.3 years. Clinical presentation combined symptoms of hereditary sensory and autonomic neuropathy type I (HSAN-I) with prominent distal muscle weakness. Five male patients presented with sensory symptoms involving the distal part of the limbs, especially the legs. All but one had histories of trophic alterations, consisting of poorly healing foot ulcers. Muscle weakness and wasting were always present, often severe, and mainly affected dorsiflexion of the toes and feet. One obligate female carrier aged 65 was clinically asymptomatic. Electrophysiological findings were consistent with a distal axonal motor and sensory neuropathy. Results of linkage analysis excluded the Charcot-Marie-Tooth 2A (CMT2A) and CMT2B loci and suggested the possibility of a linkage to HSAN-I locus on 9q22.1-q22.3.

Adult↗