Update on the genetics of X-linked mental retardation

Mutations in X-linked genes are likely to account for the observation that more males than females are affected with mental retardation. Causative mutations have been identified in both syndromic XLMR and in the genetically heterogeneous non-syndromic forms of XLMR, without a clear clinical phenotype other than cognitive deficit. Progress in genome analysis and the establishment of large collaborations between clinical and molecular research teams, especially the European XLMR consortium, have led to the identification of 20 non-syndromic XLMR genes and 25 syndromic XLMR genes. Given the extensive heterogeneity of non syndromic XLMR, different strategies are used for the identification of new genes: linkage analysis, studies of balanced chromosomal rearrangements (X-autosome translocations, microdeletions) and candidate genes strategies by mutation screening in regions of the X chromosome known to be involved in neuronal development and function. Delineating the monogenic causes of XLMR and their molecular and cellular consequences will provide insight into the mechanisms that are required for normal development of cognitive function in humans. Non syndromic XLMR proteins include 5 distinct classes: transmembrane receptors, small GTPases effectors or regulators, enzymes and translational regulators.     

A FOXG1 mutation in a boy with congenital variant of Rett syndrome

Mutations in the FOXG1 gene have been shown to cause congenital variant of Rett syndrome. To date, point mutations have been reported only in female patients. We screened the entire coding region of the gene for mutations in 50 boys with congenital encephalopathy, postnatal microcephaly, and complex movement disorders, a clinical picture very similar to that described in girls with FOXG1 mutations. We found one boy carrying the de novo c.256_257dupC frameshift mutation. He presented the association of postnatal microcephaly, severe axial dystonia with severe feeding difficulties with protruding tongue movements during the first year of life that subsequently evolved into dyskinetic movement disorders with hand stereotypies. In contrast to his severe motor impairment, he developed nonverbal communication skills and relative good eye contact. Brain MRI showed frontal gyral simplification with dramatic myelination delay most prominent in both frontal lobes. Altogether the presentation in this male patient is highly reminiscent of that observed in FOXG1-mutated females with the congenital variant of Rett syndrome. This new case confirms the prediction that congenital variant of Rett syndrome should be found also in males, with the characteristic hallmarks consisting of postnatal microcephaly, dyskinetic movement disorder with Rett-like features, i.e., hand stereotypies, and frontal gyral simplification with myelination delay. FOXG1 screening should be considered in individuals with these clinical features.     

Cost variation in a laparoscopic cholecystectomy and the association with outcomes across a single health system: implications for standardization and improved resource utilization

BackgroundPayers and regulatory bodies are increasingly placing emphasis on cost containment, quality/outcome measurement and transparent reporting. Significant cost variation occurs in many operative procedures without a clear relationship with outcomes. Clear cost‐benefit associations will be necessary to justify expenditures in the era of bundled payment structures.MethodsAll laparoscopic cholecystectomies (LCCKs) performed within a single health system over a 1‐year period were analysed for operating room (OR) supply cost. The cost was correlated with American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) outcomes.ResultsFrom July 2013 to June 2014, 2178 LCCKs were performed by 55 surgeons at seven hospitals. The median case OR supply cost was $513 ± 156. There was variation in cost between individual surgeons and within an individual surgeon's practice. There was no correlation between cost and ACS NSQIP outcomes. The majority of cost variation was explained by selection of trocar and clip applier constructs.ConclusionsSignificant case OR cost variation is present in LCCK across a single health system, and there is no clear association between increased cost and NSQIP outcomes. Placed within the larger context of overall cost, the opportunity exists for improved resource utilization with no obvious risk for a reduction in the quality of care.     

Linkage of X-linked myopathy with excessive autophagy (XMEA) to Xq28

X-linked myopathy with excessive autophagy (XMEA, MIM 310440) is a rare inherited mild myopathy. We have used 32 polymorphic markers spanning the entire X chromosome to exclude most of the chromosome except the Xq28 region in a large XMEA family. Using three additional families for linkage analysis, we have obtained a significant two-point lod score with marker DXS1183 (Z = 2.69 at theta = 0). Multipoint linkage analysis confirmed the assignment of the disease locus with a maximal lod score of 2.74 obtained at recombination fraction zero. Linkage of XMEA to the Xq28 region is thus firmly established. In addition, we have ruled out the Emery-Dreifuss muscular dystrophy to be allelic with XMEA by direct sequencing of the emerin gene in three of our families.