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 (www.umd.be/ CSA/ and www.umd.be/CSB/). Hum Mutat 31:113-126,

The abnormal retinal neurotransmission observed in Duchenne muscular dystrophy (DMD) patients and in some genotypes of mice lacking dystrophin has been attributed to altered expression of short products of the dystrophin gene. We have investigated the potential role of Dp71, the most abundant C-terminal dystrophin gene product, in retinal electrophysiology. Comparison of the scotopic electroretinograms (ERG) between Dp71-null mice and wild-type (wt) littermates revealed a normal ERG in Dp71-null mice with no significant changes of the b-wave amplitude and kinetics. Analysis of DMD gene products, utrophin and dystrophin-associated proteins (DAPs), showed that Dp71 and utrophin were localized around the blood vessels, in the ganglion cell layer (GCL), and the inner limiting membrane (ILM). Dp71 deficiency was accompanied by an increased level of utrophin and decreased level of beta-dystroglycan localized in the ILM, without any apparent effect on the other DAPs. Dp71 deficiency was also associated with an impaired clustering of two Müller glial cell proteins-the inwardly rectifying potassium channel Kir4.1 and the water pore aquaporin 4 (AQP4). Immunostaining of both proteins decreased around blood vessels and in the ILM of Dp71-null mice, suggesting that Dp71 plays a role in the clustering and/or stabilization of the two proteins. AQP4 and Kir4.1 may also be involved in the regulation of the ischemic process. We found that a transient ischemia resulted in a greater damage in the GCL of mice lacking Dp71 than in wt mice. This finding points at a crucial role played by Dp71 in retinal function.

SUMMARY:CS is an autosomal recessive multisystem disorder, which is mainly characterized by neurologic and sensory impairment, cachectic dwarfism, and photosensitivity. We describe the neuroimaging features (MR imaging, 1 H-MR spectroscopy, and CT) in the various clinical subtypes of CS from a cohort of genetically and biochemically proved cases. Hypomyelination, calcifications, and brain atrophy were the main imaging features. Calcifications were typically found in the putamen and less often in the cortex and dentate nuclei. Severe progressive atrophy was seen in the supratentorial white matter, the cerebellum, the corpus callosum, and the brain stem. Patients with early-onset disease displayed more severe hypomyelination and prominent calcifications in the sulcal depth of the cerebral cortex, but atrophy was less severe in late-onset patients. On proton MR spectroscopy, lactate was detected and Cho and NAA values were decreased. These combined neuroradiologic findings can help in the differential diagnosis of CS, distinguishing it from other leukoencephalopathies and/or cerebral calcifications in childhood., ABBREVIATIONS: Cho ϭ choline; Cr ϭ creatine; CS ϭ Cockayne syndrome; COFS ϭ cerebro-oculofacio-skeletal syndrome; FLAIR ϭ fluid-attenuated inversion recovery; NAA ϭ N-acetylaspartate

Our data indicate that COFS syndrome represents the most severe end of the Cockayne spectrum. New diagnostic criteria for COFS syndrome are proposed, based on our findings and on the few genetically proven COFS cases from the literature.