Is the locus for Costello syndrome on 11p?
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Abnormalities, Multiple↗
Biomedical subjects
M A Voelckel
Publications and source records attributed to M A Voelckel.
Fragile X syndrome and 22q11.2 microdeletion in the same sibship.
We present a family with an unusual association of two frequent genetic disorders, 22q11.2 microdeletion and fragile X syndrome, originating from the same parent. Our observation confirms the wide intrafamilial clinical variability of the 22q11.2 microdeletion and illustrates the difficulty of the clinical diagnosis for the fragile X syndrome in affected females.
Child, Preschool↗
Genetic homogeneity of the urofacial (Ochoa) syndrome confirmed in a new French family.
The urofacial syndrome (UFS) or Ochoa syndrome has been reported as a rare autosomal recessive disorder comprising a uropathy and facial abnormalities. The gene was mapped on chromosome region 10q23-q24. We report the first European cases of UFS. Haplotype analyses in our French family were compared with those previously described in patients from Columbia and America (literature data). The results are compatible with the same localization of the critical region and favor the hypothesis of genetic homogeneity.
Adolescent↗
A first molecular approach towards CGG repeat expansion in FMR1 gene in systemic lupus erythematosus and in Sjögren's syndrome: a preliminary report.
Co-occurrent autoimmune disease and fragile X syndrome has been reported in the literature and we have therefore studied the expansion of Cytosine-Guanine-Guanine (CGG) repeat in FMR1 gene in a series of females with autoimmune diseases such as systemic lupus erythematosus and Sjögren's syndrome, with PCR and Southern blot methods. The average length of trinucleotide repeat was not increased in these female patients as compared with controls. These preliminary data on a short series of patients suggest a possible absence of trinucleotide repeat expansion abnormality associated with autoimmune diseases such as systemic lupus erythematosus and Sjögren's syndrome.
Adult↗
Angelman syndrome resulting from UBE3A mutations in 14 patients from eight families: clinical manifestations and genetic counselling.
Angelman syndrome (AS) is a neurological disorder with a heterogeneous genetic aetiology. It most frequently results from a de novo interstitial deletion in the 15q11-q13 region, but in a few cases it is caused by paternal uniparental disomy (UPD) or an imprinting mutation. The remaining 20 to 30% of AS patients exhibit biparental inheritance and a normal pattern of allelic methylation in the 15q11-q13 region. In this latter group, mutations in the UBE3A gene have recently been shown to be a cause of AS. Here we describe the phenotypic expression in 14 AS cases involving eight UBE3A mutations. These comprise 11 familial cases from five families and three sporadic cases. Subtle differences from the typical phenotype of AS were found. Consistent manifestations were psychomotor delay, a happy disposition, a hyperexcitable personality, EEG abnormalities, and mental retardation with severe speech impairment. The other main manifestations of AS, ataxia, epilepsy, and microcephaly, were either milder or absent in various combinations among the patients. In addition, myoclonus of cortical origin was frequently observed with severe fits inducing myoclonic seizures. The majority of the patients were overweight. This study showed that ataxia, myoclonus, EEG abnormalities, speech impairment, characteristic behavioural phenotype, and abnormal head circumference are attributable to a deficiency in the maternally inherited UBE3A allele. Furthermore, analysis of mutation transmission showed an unexpectedly high rate of somatic mosaicism in normal carriers. These data have important consequences for genetic counselling.
Adolescent↗
Atypical molecular findings identify limits of technical screening tests for Prader-Willi and Angelman syndrome diagnoses.
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Angelman Syndrome↗
Exertional rhabdomyolysis and exercise intolerance revealing dystrophinopathies.
Exercise intolerance associated with myalgias, muscle cramps or myoglobinuria may be associated with a dystrophinopathy. A search for abnormal dystrophin expression (using immunohistochemistry, immunoblot and DNA analysis) was carried out in a series of 15 patients. They were selected because they presented exercise intolerance, negative biochemical tests (lipid, glycogen and mitochondrial metabolism) and abnormal immunohistochemistry with at least one anti-dystrophin antibody (anti-Dys 1, rod domain; anti-Dys 2, C terminus; anti-Dys 3, N terminus). Lack of anti-Dys 1 immunoreactivity was seen in three patients and abnormal immunoreactivity with all three anti-dystrophin antibodies in two. Immunoblot confirmed the dystrophinopathy in these five patients only, and multiplex polymerase chain reaction DNA analysis revealed a deletion in the dystrophin gene in two of these patients, affecting the proximal part of the rod domain in one and the distal part of this domain in the other. The clinical, biological and histopathological features of the five patients reported here, together with the previous cases reported in the literature, are described and reveal that exercise intolerance associated with dystrophinopathy displays characteristic clinical, biological and immunohistochemical features and defines a new dystrophinopathy phenotype. The absence of staining in the rod domain provides a secure diagnosis of this syndrome. Dystrophinopathy is one etiology of idiopathic myoglobinuria, requiring genetic counseling.
Adolescent↗
Unexpected inheritance of the (CGG)n trinucleotide expansion in a fragile X syndrome family.
The fragile X syndrome is the most frequent cause of inherited mental retardation. CGG repeat alleles are usually classified as normal, premutation, or full mutation based on the length of this triplet in the 5' untranslated region of the FMR1 gene. The pattern of inheritance follows a two-stage intergenerational process in which the premutation evolves into the full mutation. Some reverse mutations have been described, but they appear to be very rare. We describe a family in which a mother of two affected males herself carried a full mutation. Surprisingly, her clinically normal daughter, initially considered to be a carrier by linkage analysis, carried a very short premutation. Findings from our family study corroborate the hypothesis that the expansion during female transmission could be a postzygotic event and raise the problem of mosaicism.
Blotting, Southern↗
[Angelman syndrome].
The Angelman syndrome is a neurological disorder characterized by constant features: severe mental retardation, easily provoked laughter, ataxia, absent speech, seizures. Most cases are sporadic but familial cases have been reported. About 60 to 70% of cases are due to an interstitial deletion on the maternally inherited chromosome 15 in the region q11-q13. Rare cases result from paternal disomy. In 30% of patients, neither maternal by inherited deletion, nor paternal disomy, can be found. In this category of patients recurrence risk for sibs is high and molecular mechanisms are not completely known. They appear to be more complex than previously suggested. It is clear that this syndrome is a genetically heterogeneous group. The main example of genomic imprinting in human pathology, Angelman syndrome is now a model in research for understanding molecular mechanisms underlying imprinting.
Angelman Syndrome↗
Triplet repeat expansion at the FRAXE locus and X-linked mild mental handicap.
We have recently shown that the expression of the FRAXE fragile site in Xq28 is associated with the expansion of a GCC trinucleotide repeat. In the families studied, FRAXE expression is also associated with mild mental handicap. Here we present data on families that previously had been diagnosed as having the fragile X syndrome but that later were found to be negative for trinucleotide repeat expansion at the FRAXA locus. In these families we demonstrate the presence of a GCC trinucleotide repeat expansion at the FRAXE locus. Studies of the FRAXE locus of normal individuals show that they have 6-25 copies of the repeat, whereas affected individuals have > 200 copies. As in the fragile X syndrome, the amplified CpG residues are methylated in affected males.
DNA↗
Characterization of cAMP dependent CFTR-chloride channels in human tracheal gland cells.
Human tracheal gland cells are believed to be a major site at the origin of cystic fibrosis. Since this disease is due to mutations in a protein called CFTR, we looked for the activity of CFTR in human tracheal gland cells in culture. We have identified CFTR-like chloride-selective channels as having a linear current voltage relationship and unitary conductance of 7 pS in these cells. In cell-attached patches, theophylline (1 mM), IBMX (1 mM), or a cocktail of dibutyryl cAMP (1 mM) and IBMX (0.1 mM) promoted the opening of channels. The unitary current had a reversal potential close to the cell resting potential. Replacement of choline by K+ or Na+ in the pipette solution was without effect on the current-voltage relationship, the reversal potential or the unitary conductance, which is consistent with the chloride selectivity of the channel. Channels were always found clustered and their opening probability was not noticeably dependent on membrane potential. This work therefore represents the first observation of a CFTR-like channel activity in submucosal gland cells.
Base Sequence↗
[Molecular biology in genetic counseling of Duchenne and Becker myopathy].
From 1985-1991, molecular biology studies were carried out in 115 families affected with X-linked muscular dystrophy (DMD/BMD), including 59 prenatal diagnoses. The approach has changed over the last 6 years when new intragenic markers and cDNA probes became available. The polymerase chain reaction technique allows a rapid detection of dystrophin deletions, but classical Southern blot technique remains useful for restriction length polymorphism analysis. Fifty percent (42/85) of patients with DMD/BMD exhibited deletions of the dystrophin gene. In affected families with a detectable deletion, carrier detection is possible by gene dosage analysis and prenatal diagnosis is reliable. When no deletion is found, carrier detection and prenatal diagnosis depends on linkage analysis using polymorphic probes. Due to the high recombination rate, several markers need to be used. The information provided by linkage analysis must be interpreted given the proper family structure.
Female↗
[Fragile X syndrome: current knowledge].
Fragile X syndromes is a disease characterized by the association of mental retardation and dysmorphic features to a fragile site on Xq27-3. It is a frequent genetic disorder (1 in 1,500 males) recognized only 20 years ago but remaining difficult to understand, because its transmission among generations does not correspond to the classical model of recessivity linked to chromosome X. In fact, carrier females can express the disease and transmitting males can be normal. With DNA probes, molecular biology has contributed to genetic counselling and prenatal diagnosis. Restriction polymorphisms have long been used to study the inheritance of fragile X syndrome and DNA markers' analysis improved risk estimates for carriers. From a clinical viewpoint, there was a need for more closely linked probes to help in prenatal diagnosis and to assess carrier status and hence reduce risk of recombination. In 1991, new probes allowed direct diagnosis of the Fra (X) mutation and a gene was sequenced. Nevertheless the understanding of the mechanism involved in the underlying mutation is still unknown. Geneticists, cytogeneticists and biologists must collaborate further to elucidate the fragile site mystery.
Chromosome Mapping↗
Linkage homogeneity near the fragile X locus in normal and fragile X families.
The fragile X syndrome locus, FRAXA, is located at Xq27. Until recently, few polymorphic loci had been genetically mapped close to FRAXA. This has been attributed to an increased frequency of recombination at Xq27, possibly associated with the fragile X mutation. In addition, the frequency of recombination around FRAXA has been reported to vary among fragile X families. These observations suggested that the genetic map at Xq27 in normal populations was different from that in fragile X populations and that the genetic map also varied within the fragile X population. Such variability would reduce the reliability of carrier risk estimates based on DNA studies in fragile X families. Five polymorphic loci have now been mapped to within 4 cM of FRAXA--DXS369, DXS297, DXS296, IDS, and DXS304. The frequency of recombination at Xq26-q28 was evaluated using data at these loci and at more distant loci from 112 families with the fragile X syndrome. Two-point and multipoint linkage analyses failed to detect any difference in the recombination fractions in fragile X versus normal families. Two-point and multipoint tests of linkage homogeneity failed to detect any evidence of linkage heterogeneity in the fragile X families. On the basis of this analysis, genetic maps derived from large samples of normal families and those derived from fragile X families are equally valid as the basis for calculating carrier risk estimates in a particular family.
Fragile X Syndrome↗
Genetic mapping of new DNA probes at Xq27 defines a strategy for DNA studies in the fragile X syndrome.
The fragile X syndrome is the most common cause of familial mental retardation and is characterized by a fragile site at the end of the long arm of the X chromosome. The unusual genetics and cytogenetics of this X-linked condition make genetic counseling difficult. DNA studies were of limited value in genetic counseling, because the nearest polymorphic DNA loci had recombination fractions of 12% or more with the fragile X mutation, FRAXA. Five polymorphic loci have recently been described in this region of the X chromosome. The positions of these loci in relation to FRAXA were defined in a genetic linkage study of 112 affected families. The five loci--DXS369, DXS297, DXS296, IDS, and DXS304--had recombination fractions of 4% or less with FRAXA. The closest locus, DXS296, was distal to FRAXA and had a recombination fraction of 2%. The polymorphisms at these loci can be detected in DNA enzymatically digested with a limited number of restriction endonucleases. A strategy for DNA studies which is based on three restriction endonucleases and on five probes will detect one or more of these polymorphisms in 94% of women. This strategy greatly increases the utility of DNA studies in providing genetic advice to families with the fragile X syndrome.
Chromosome Mapping↗
Study of a family with a fragile site of the X chromosome at Xq27-28 without mental retardation.
The fragile site Xq27-28 was observed in several individuals of a large family. It is expressed at a high frequency among the carrier females, even as adults, and in one clinically normal male. None of the members of this family is affected with the mental retardation normally linked to this fragile site. Cytogenetic and flanking DNA marker polymorphism studies suggest a possible dissociation between the fragile site and clinical expression of the disease.
Adult↗
[Linkage studies in Emery-Dreifuss muscular dystrophy].
We report linkage studies between Emery-Dreifuss muscular dystrophy (EDMD) and polymorphic probes from the long arm of chromosome X in two pedigrees. The results don't show significant linkage but are consistent with previous localisation of EDMD in Xq28. Further studies will be necessary to apply molecular biology to genetic counselling and prenatal diagnosis of this disease.
DNA Probes↗
Dissociation between mental retardation and fragile site expression in a family with fragile X-linked mental retardation.
We report an extended family in which two brothers with a fragile X chromosome are mentally retarded while a third brother with the fragile site is both phenotypically and mentally normal. The study of six probes detecting restriction fragment length polymorphisms on either sides of the fragile site Xq27 confirmed that the fragile X regions inherited by these three brothers were identical from DXS102 to the telomere. These data highlight the heterogeneity of the fragile X syndrome, which is discussed in the framework of the different hypotheses previously proposed.
Child↗