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G Stevanin

Publications and source records attributed to G Stevanin.

At least 19 recordsLinked to original sources
PubMed2006

Predominant dystonia with marked cerebellar atrophy: a rare phenotype in familial dystonia.

BACKGROUND: Dystonia syndromes constitute a heterogeneous group of phenotypes that may be caused by different heredodegenerative, metabolic, or genetic diseases. OBJECTIVE: To describe the characteristics of an unusual dystonia-plus phenotype associated with cerebellar atrophy. METHODS: We selected patients with predominant dystonia and cerebellar atrophy among the 861 families referred to us for genetic testing from 1992 to 2003. The main secondary heredodegenerative causes and the major genes responsible for hereditary dystonias and autosomal dominant or recessive ataxias were excluded. RESULTS: We identified 12 patients in 8 families with an unusual dystonia-plus phenotype characterized by dystonia and cerebellar atrophy on brain MRI. The mean age at onset was 27.3 +/- 11.5 years (range: 9 to 42 years) and the mean disease duration 14.7 +/- 7.7 years (range: 4 to 30). At onset, dystonia was focal or multifocal, mainly affecting vocal cords (n = 8) and upper limbs (n = 2). During the disease course spasmodic dysphonia became severe in five patients, leading to complete aphonia in two. Dystonia became generalized in five. Cerebellar ataxia was limited to unsteadiness in most patients and progressed very slowly. The paucity of clinical cerebellar signs contrasted with the marked cerebellar atrophy on brain MRI in most patients. Four families with two affected sibs support the hypothesis of an autosomal recessive disorder. However, X-linked inheritance is possible since only men were affected. CONCLUSION: We have characterized an unusual familial phenotype associating dystonia and cerebellar atrophy in 12 male patients.

Adult↗
PubMed2006

Mutation analysis of the paraplegin gene (SPG7) in patients with hereditary spastic paraplegia.

BACKGROUND: Mutations in the SPG7 gene, which encodes paraplegin, are responsible for an autosomal recessive hereditary spastic paraplegia (HSP). OBJECTIVE: To screen the SPG7 gene in a large population of HSP families compatible with autosomal recessive transmission. METHODS: The authors analyzed 136 probands with pure or complex HSP for mutations in the SPG7 using denaturation high-performance liquid chromatography and direct sequencing. RESULTS: The authors identified 47 variants including 6 mutations, 27 polymorphisms, and 14 changes with unknown effects. In one family from Morocco, compound c.850_851delTTinsC and c.1742_1744delTGG heterozygous mutations were shown to be causative. This family had complex HSP with cerebellar impairment. Progression of the disease was rapid, resulting in a severe disease after 8 years of duration. Also detected were 20 families with one heterozygous mutation that was not found in a large control population. The mutations produced highly defective proteins in four of these families, suggesting that they were probably causative. Direct sequencing of all exons and reverse transcription PCR experiments demonstrated the absence of a second mutation. However, the p.Ala510Val missense substitution previously described as a polymorphism was shown to be significantly associated with HSP, suggesting that it had a functional effect. CONCLUSION: SPG7 mutations account for less than 5% of hereditary spastic paraplegia (HSP) families compatible with autosomal recessive inheritance. Cerebellar signs or cerebellar atrophy on brain imaging were the most frequent additional features in patients with SPG7 HSP. Rare nucleotide variants in SPG7 are frequent, complicating routine diagnosis.

ATPases Associated with Diverse Cellular Activitie↗
PubMed2006

SPG3A is the most frequent cause of hereditary spastic paraplegia with onset before age 10 years.

Seven families with six different SPG3A mutations were identified among 106 with autosomal dominant hereditary spastic paraplegia (HSP). Two mutations were novel (T162P, C375R). SPG3A was twice as frequent as SPG4 in patients with onset before age 10 years (31.8%). Later onset was not observed. The phenotype was pure HSP, but disease duration was longer than in non-SPG3A/SPG4 patients, leading ultimately to greater handicap.

Adolescent↗
PubMed2002

CAG/CTG repeat expansions at the Huntington's disease-like 2 locus are rare in Huntington's disease patients.

The authors report a large series of patients with Huntington disease (HD)-like phenotype without CAG repeat expansions in the IT15 gene that were screened for the newly identified CAG/CTG expansion in the gene encoding junctophilin-3. Normal alleles in controls had from 8 to 28 repeats. A single patient of North African origin with typical HD carried an allele with 50 uninterrupted repeats, representing approximately 2% of the non-IT15 HD patients tested. Therefore, further genetic heterogeneity is expected in HD.

Adolescent↗
PubMed2001

Similarities between spinocerebellar ataxia type 7 (SCA7) cell models and human brain: proteins recruited in inclusions and activation of caspase-3.

Spinocerebellar ataxia type 7 (SCA7) is an autosomal dominant polyglutamine disorder presenting with progressive cerebellar ataxia and blindness. The molecular mechanisms underlying the selective neuronal death typical of SCA7 are unknown. We have established SCA7 cell culture models in HEK293 and SH-SY5Y cells, in order to analyse the effects of overexpression of the mutant ataxin-7 protein. The cells readily formed anti-ataxin-7 positive, fibrillar inclusions and small, nuclear electron dense structures. We have compared the inclusions in cells expressing mutant ataxin-7 and in human SCA7 brain tissue. There were consistent signs of ongoing abnormal protein folding, including the recruitment of heat-shock proteins and proteasome subunits. Occasionally, sequestered transcription factors were found. Activated caspase-3 was recruited into the inclusions in both the cell models and human SCA7 brain and its expression was upregulated in cortical neurones, suggesting that it may play a role in the disease process. Finally, on the ultrastructural level, there were signs of autophagy and nuclear indentations, indicative of a major stress response in cells expressing mutant ataxin-7.

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↗
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

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

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

Clinical and molecular advances in autosomal dominant cerebellar ataxias: from genotype to phenotype and physiopathology.

Major advances have been made in the understanding of autosomal dominant cerebellar ataxias since genetic markers came into use in the 1980s. The subsequent mapping of nine genes, six of which have been identified, involved in this clinically diverse group of disorders highlighted their great genetic heterogeneity. Evidence is now accumulating that, except for SCA8, the same molecular and physiopathological processes underlie these diseases and other neurodegenerative disorders sharing the same mutational basis, the expansion of a (CAG)n-polyglutamine coding sequence. The clinical overlap among the different genetic entities makes prediction of the molecular origin impossible in a single patient so that molecular characterisation is necessary. However, extended clinical and neuropathological comparisons have shown that each genetic entity has a characteristic constellation of signs and symptoms that are related to CAG repeat size and disease duration. The combined genetic and clinical information form the basis of a new classification that will aid better understanding of disease evolution, assure follow up and permit genetic counselling by the clinician.

Anticipation, Genetic↗
PubMed1999

Clinical and MRI findings in spinocerebellar ataxia type 5.

Spinocerebellar ataxia type 5 (SCA5), one of the genetically heterogeneous autosomal dominant cerebellar ataxias, was assigned to chromosome 11 in a single family descending from the grandparents of President Abraham Lincoln. We report a second, apparently unrelated, SCA5 family of French origin. The overall clinical picture was a slowly progressive cerebellar syndrome beginning mostly in the third decade (27+/-10 years, range 14 to 40). MRI showed a marked global cerebellar atrophy similar to SCA6.

Female↗
PubMed1999

Spinocerebellar ataxia type 6: evidence for a strong founder effect among German families.

The authors found a strong geographic cluster of spinocerebellar ataxia type 6 (SCA6) families in the Northrhine-Westfalia area, suggesting a founder effect in the German SCA6 population. Genotyping with DNA markers linked to the CACNL1A4 gene on chromosome 19p13 revealed a common haplotype and shared allelic characteristics in the majority of German families. The observed founder effect may be related to the relative meiotic stability of CAG repeats in this type of autosomal dominant cerebellar ataxia.

Alleles↗
PubMed1999

Multiple origins of the spinocerebellar ataxia 7 (SCA7) mutation revealed by linkage disequilibrium studies with closely flanking markers, including an intragenic polymorphism (G3145TG/A3145TG).

Spinocerebellar ataxia 7 (SCA7) is a neurodegenerative disease characterised by the association of cerebellar ataxia and, in most patients, progressive macular degeneration leading to loss of autonomy and blindness. The patients die after 5-30 years of evolution. The cause of the disease has been identified as a (CAG)n repeat expansion in the coding sequence of the SCA7 gene on chromosome 3p. De novo mutations occur on intermediate-sized alleles carrying from 28 to 35 CAG repeats. Neomutations explain the persistence of the disease in spite of the great instability of the repeat sequence which results in the appearance of juvenile onset patients and the extinction of the disease within families. This rare disorder has been reported in a wide variety of countries and ethnic groups. In a large number of SCA7 families (n = 41) of different origins, we have determined the haplotypes segregating with the mutation of several microsatellite markers close to the SCA7 gene and of a new intragenic polymorphism (G3145TG/A3145TG). Four different haplotypes were found for centromeric markers (G3145TG/A3145TG-D3S1287-D3S3635) in the majority of the kindreds from four different geographic regions: A-2-4 in Korea; A-3-6 in North Africa, B-3-6 in continental Europe and A-4-6 in the UK and USA. The haplotypes in the Jamaican, Filipino, Brazilian and German families were different, suggesting that independent regional founders are at the origin of the SCA7 mutation in each population. Two different haplotypes were observed, however, in two families from the same rural area in central Italy in which de novo SCA7 mutations on intermediate alleles have been observed, suggesting the existence of different pools of at-risk chromosomes in this population.

Alleles↗
PubMed1999

Molecular and clinical study of 18 families with ADCA type II: evidence for genetic heterogeneity and de novo mutation.

The SCA7 mutation has been found in 54 patients and 7 at-risk subjects from 17 families who have autosomal dominant cerebellar ataxia (ADCA) II with progressive pigmentary maculopathy. In one isolated case, haplotype reconstruction through three generations confirmed a de novo mutation owing to paternal meiotic instability. Different disease-associated haplotypes segregated among the SCA7-positive kindreds, which indicated a multiple origin of the mutation. One family with the clinical phenotype of ADCA type II did not have the CAG expansion that indicated locus heterogeneity. The distribution of the repeat size in 944 independent normal chromosomes from controls, unaffected at-risk subjects, and one affected individual fell into two ranges. The majority of the alleles were in the first range of 7-19 CAG repeats. A second range could be identified with 28-35 repeats, and we provide evidence that these repeats represent intermediate alleles that are prone to further expansion. The repeat size of the pathological allele, the widest reported for all CAG-repeat disorders, ranged from 37 to approximately 220. The repeat size showed significant negative correlation with both age at onset and age at death. Analysis of the clinical features in the patients with SCA7 confirmed that the most frequently associated features are pigmentary maculopathy, pyramidal tract involvement, and slow saccades. The subjects with <49 repeats tended to have a less complicated neurological phenotype and a longer disease duration, whereas the converse applied to subjects with >/=49 repeats. The degree of instability during meiotic transmission was greater than in all other CAG-repeat disorders and was particularly striking in paternal transmission, in which a median increase in repeat size of 6 and an interquartile range of 12 were observed, versus a median increase of 3 and interquartile range of 3.5 in maternal transmission.

Age of Onset↗