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Cockayne syndrome is an autosomal recessive multisystem disorder characterized principally by neurological and sensory impairment, cachectic dwarfism, and photosensitivity. This rare disease is linked to mutations in the CSB/ERCC6 and CSA/ERCC8 genes encoding proteins involved in the transcription-coupled DNA repair pathway. The clinical spectrum of Cockayne syndrome encompasses a wide range of severity from severe prenatal forms to mild and late-onset presentations. We have reviewed the 45 published mutations in CSA and CSB to date and we report 43 new mutations in these genes together with the corresponding clinical data. Among the 84 reported kindreds, 52 (62%) have mutations in the CSB gene. Many types of mutations are scattered along the whole coding sequence of both genes, but clusters of missense mutations can be recognized and highlight the role of particular motifs in the proteins. Genotype-phenotype correlation hypotheses are considered with regard to these new molecular and clinical data. Additional cases of molecular prenatal diagnosis are reported and the strategy for prenatal testing is discussed. Two web-based locus-specific databases have been created to list all identified variants and to allow the inclusion of future reports ( and ). Hum Mutat 31:113-126, 2010. © 2009 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Cockayne syndrome is a multi-systemic, autosomal recessive disease characterised by postnatal growth failure and progressive multi-organ dysfunction. The main clinical features are severe dwarfism (<-2 SD), microcephaly (<-3 SD), psychomotor delay, sensorial loss (cataracts, pigmentary retinopathy, and deafness), and cutaneous photosensitivity. Here, 13 new cases of Cockayne syndrome are reported, which have been clinically diagnosed and confirmed using a biochemical transcription assay. The wide clinical variability, ranging from prenatal features to normal psychomotor development, is emphasised. When cardinal features are lacking, the diagnosis of Cockayne syndrome should be considered when presented with growth retardation, microcephaly, and one of the suggesting features such as enophthalmia, limb ataxia, abnormal auditory evoked responses, or increased ventricular size on cerebral imaging. [ABSTRACT FROM AUTHOR]

Cockayne syndrome is a multi-systemic, autosomal recessive disease characterised by postnatal growth failure and progressive multi-organ dysfunction. The main clinical features are severe dwarfism (<-2 SD), microcephaly (<-3 SD), psychomotor delay, sensorial loss (cataracts, pigmentary retinopathy, and deafness), and cutaneous photosensitivity. Here, 13 new cases of Cockayne syndrome are reported, which have been clinically diagnosed and confirmed using a biochemical transcription assay. The wide clinical variability, ranging from prenatal features to normal psychomotor development, is emphasised. When cardinal features are lacking, the diagnosis of Cockayne syndrome should be considered when presented with growth retardation, microcephaly, and one of the suggesting features such as enophthalmia, limb ataxia, abnormal auditory evoked responses, or increased ventricular size on cerebral imaging. [ABSTRACT FROM AUTHOR]

Blons H, Feldmann D, Duval V, Messaz O, Denoyelle F, Loundon N, Sergout-Allaoui A, Houang M, Duriez F, Lacombe D, Delobel B, Leman J, Catros H, Journel H, Drouin-Garraud V, Obstoy M-F, Toutain A, Odent S, Toublanc JE, Couderc R, Petit C, Garabédian E-N, Marlin S. Screening ofSLC26A4(PDS) gene in Pendred's syndrome: a large spectrum of mutations in France and phenotypic heterogeneity.Sensorineural hearing defect and goiter are common features of Pendred's syndrome. The clinical diagnosis of Pendred's syndrome remains difficult because of the lack of sensitivity and specificity of the thyroid signs. The identification ofPDSas the causative gene allowed molecular screening and enabled a re-evaluation of the syndrome to identify potential diagnostic characteristics. This report presents the clinical and genotypic findings of 30 French families, for whom a diagnosis of Pendred's syndrome had been made. Twenty-seven families had at least one mutated allele. Twenty-eight different mutations were identified, 11 of which had never been previously reported. The main clinical characteristics were: early hearing loss, fluctuation in terms of during deafness evolution, and the presence of an enlarged vestibular aqueduct. [ABSTRACT FROM AUTHOR]

Introduction--Congenital disorders of glycosylation (CDG), or carbohydrate deficient glycoprotein syndromes, form a new group of multisystem disorders characterised by defective glycoprotein biosynthesis, ascribed to various biochemical mechanisms. Methods--We report the clinical, biological, and molecular analysis of 26 CDG I patients, including 20 CDG la, two CDG Ib, one CDG Ic, and three CDG Ix, detected by western blotting and isoelectric focusing of serum transferrin. Results--Based on the clinical features, CDG Ia could be split into two subtypes: a neurological form with psychomotor retardation, strabismus, cerebellar hypoplasia, and retinitis pigmentosa (n=11), and a multivisceral form with neurological and extraneurological manifestations including liver, cardiac, renal, or gastrointestinal involvement (n=9). Interestingly, dysmorphic features, inverted nipples, cerebellar hypoplasia, and abnormal subcutaneous fat distribution were not consistently observed in CDG Ia. By contrast, the two CDG Ib patients had severe liver disease, enteropathy, and hyperinsulinaemic hypoglycaemia but no neurological involvement. Finally, the CDG Ic patient and one of the CDG Ix patients had psychomotor retardation and seizures. The other CDG Ix patients had severe proximal tubulopathy, bilateral cataract, and white matter abnormalities (one patient), or multiorgan failure and multiple birth defects (one patient). Conclusions--Owing to the remarkable clinical variability of CDG, this novel disease probably remains largely underdiagnosed. The successful treatment of CDG Ib patients with oral mannose emphasises the paramount importance of early diagnosis of PMI deficiency. [ABSTRACT FROM AUTHOR]

Unlabelled: The Smith-Lemli-Opitz syndrome (SLO) is an autosomal recessive disorder characterized by dysmorphic facial features with abnormal limbs and genitalia. Two forms have been recognized based on clinical course and severity: the classical SLO (type I) and the lethal acrodysgenital syndrome (type II). Type I SLO has been recently ascribed to a defect in cholesterol synthesis. Taking advantage of a series of seven patients including five type I and two type II SLO, we describe micrognathia, severe microcephaly, major ante and post natal growth retardation and feeding difficulties as consistent features in the disease. In addition, we give support to the presence of abnormal cholesterol levels in the lethal acrodysgenital syndrome but find no correlation between plasma sterol levels and the clinical severity of the disease.Conclusion: The identification of the same biochemical defect in both types of Smith-Lemli-Opitz Syndrome suggests that despite major discrepancies in clinical course and severity, type I and type II SLo are probably allelic disorders. [ABSTRACT FROM AUTHOR]

The Kabuki (Niikawa-Kuroki) syndrome was reported in 1981 by Niikawa et al. and Kuroki et al. in a total of ten unrelated Japanese children with a characteristic array of multiple congenital anomalies and mental retardation. The syndrome is characterized by a distinct face, mild to moderate mental retardation, postnatal growth retardation, dermatoglyphic and skeletal abnormalities. In Japan, the syndrome appears to have an incidence of about 1:32,000 newborns. Outside of Japan, a growing number of patients have been recognized. Clinical data are presented on 29 Caucasian patients; the patients were diagnosed over a relatively short period of time, indicating that the incidence outside of Japan is probably not lower than in Japan. A literature review of 89 patients (60 Japanese and 29 non-Japanese) is given. In 66% of the non-Japanese patients serious neurological problems were present, most notably hypotonia and feeding problems (which were not only related to the cleft palate); this was not reported in the Japanese patients. Inheritance is not clear. Most patients are isolated, sex-ratio is equal. The syndrome can be recognized in patients with cleft (lip/)palate, with mild to moderate developmental delay and in young children with hypotonia and/or feeding problems. In counselling parents, the designation "Kabuki" syndrome seems to be more appropriate than "Kabuki make-up" syndrome. [ABSTRACT FROM AUTHOR]

X linked retinoschisis (RS) is a vitreoretinal disease resulting from microcystic degeneration of the macula associated with peripheral lesions. The disease gene has already been assigned to the distal short arm of the X chromosome (Xp22.2) by linkage studies. In order to contribute both to a better localisation of the RS locus and to genetic counselling in RS families, we have carried out a clinical and genetic analysis in seven pedigrees. We show, first, that in contrast with previous reports, heterozygote carriers frequently express the disease, and display peripheral retinal alterations similar to those found in affected males. Second, while distal markers DXS16, DXS207, and DXS43 are closely linked to the disease locus, a high level of recombination events was found with centromeric markers, namely DXS274, DXS41, and DXS164. These findings must be taken into account for both carrier detection and prenatal diagnosis in X linked RS. [ABSTRACT FROM PUBLISHER]

We have evaluated a two-tier neonatal cystic fibrosis (CF) screening of immunoreactive trypsinogen (IRT) followed by CFTR gene mutation analysis using a systematic scanning of exons 7, 10, and 11, and, if necessary, by direct DNA sequencing. Over an 18-month period we screened 32,300 neonates born in the western part of Britanny. The first tier, involving IRT screening at 3 days of age, utilizes a low elevation of the trypsinogen level (600 ng/ml), which is highly sensitive. The second tier, which corresponds to the exhaustive screening for mutations in three exons of the gene, is highly specific for this population (Britanny). The false positive rate is very low, and no false negatives have been reported to date. This strategy has allowed the identification of five novel alleles (V322A, V317A, 1806 del A, R553G, G544S). Moreover the test can be adapted to other countries in which the distribution of mutations is established. [ABSTRACT FROM AUTHOR]

Autosomal dominant optic atrophy (OPA, MIM 165500) is an eye disease causing a variable reduction of visual acuity with an insidious onset in the first six years of life. It is associated with a central scotoma and an acquired blue-yellow dyschromatopsia. A gene for dominant optic atrophy (OPA1) has recently been mapped to chromosome 3q in three large Danish pedigrees. Here, we confirm the mapping of OPA1 to chromosome 3q28-qter by showing close linkage of the disease locus to three recently reported microsatellite DNA markers in the interval defined by loci D3S1314 and D3S1265 in four French families (Zmax = 5.13 at theta = 0 for probe AFM 308yf1 at locus D3S1601). Multipoint analysis supports the mapping of the disease gene to the genetic interval defined by loci D3S1314 and D3S1265. The present study provides three new markers closely linked to the disease gene for future genetic studies in OPA. [ABSTRACT FROM PUBLISHER]

Pelizaeus-Merzbacher's disease is a progressive encephalopathy with demyelination of the cerebral white matter. The diagnosis can not be made on clinical or biological grounds: pathological investigation is necessary to confirm tigroid demyelination. CT scanning failed to visualize this type of anomaly but detection is now possible with the advent of magnetic resonance imaging (MRI). The authors studied the case of a boy who, at the age of 8 presented with symptoms characteristic of the disease: rotatory nystagmus, progressive encephalopathy, and inherited X-linked recessive traits. Magnetic resonance imaging revealed a high signal in the supra-tentorial white matter and the usual contrast was inverted. The authors believe that MRI can make an important contribution to the diagnosis of the disease. [ABSTRACT FROM AUTHOR]

The cystic fibrosis (CF) gene has been cloned and a major mutation identified (ΔF508). This 3-bp deletion has been found in approximately 70% of CF chromosomes. We have used the strategy of denaturing gradient gel electrophoresis followed by direct sequencing of the polymerase chain reaction products, in order to detect other mutations in exons 10, 11 and 20 of the CF transmembrane conductance regulator gene. A new mutation, F1286-S, was found in exon 20. It involves a nucleotide change of T→C at nucleotide 3989 and changes a phenylalanine into serine at position 1286 of the protein. [ABSTRACT FROM AUTHOR]

Background Over the last few years, array-comparative genomic hybridisation (CGH) has considerably improved our ability to detect cryptic unbalanced rearrangements in patients with syndromic mental retardation. Method Molecular karyotyping of six patients with syndromic mental retardation was carried out using whole-genome oligonucleotide array-CGH. Results 5q14.3 microdeletions ranging from 216 kb to 8.8 Mb were detected in five unrelated patients with the following phenotypic similarities: severe mental retardation with absent speech, hypotonia and stereotypic movements. Facial dysmorphic features, epilepsy and/or cerebral malformations were also present in most of these patients. The minimal common deleted region of these 5q14 microdeletions encompassed only MEF2C, the gene for a protein known to act in brain as a neurogenesis effector, which regulates excitatory synapse number. In a patient with a similar phenotype, an MEF2C nonsense mutation was subsequently identified. Conclusion Taken together, these results strongly suggest that haploinsufficiency of MEF2C is responsible for severe mental retardation with stereotypic movements, seizures and/or cerebral malformations. [ABSTRACT FROM AUTHOR]