A new missense <Emphasis Type="Italic">GDAP1</Emphasis> mutation disturbing targeting to the mitochondrial membrane causes a severe form of AR-CMT2C disease

Charcot–Marie–Tooth disease (CMT) caused by mutations in the ganglioside-induced differentiation-associated protein 1 (GDAP1) gene is characterized by a spectrum of phenotypes. Recurrent nonsense mutations (Q163X and S194X) showing regional distribution segregate with an early onset, severe course of recessive CMT disease with early loss of ambulancy. Missense mutations in GDAP1 have been reported in sporadic CMT cases with variable course of disease, among them the recurrent L239F missense GDAP1 mutation occurring in the European population. Finally, some GDAP1 mutations are associated with a mild form of CMT inherited as an autosomal dominant trait. In this study, we characterize the CMT phenotype in one Polish family with recessive trait of inheritance at the clinical, electrophysiological, morphological, cellular, and genetic level associated with a new Gly327Asp mutation in the GDAP1 gene. In spite of the nature of Gly327Asp mutation (missense), the CMT phenotype associated with this variant may be characterized as an early onset, severe axonal neuropathy, with severe skeletal deformities. The mutation lies within the transmembrane domain of GDAP1 and interferes with the mitochondrial targeting of the protein, similar to the loss of the domain in the previously reported Q163X and S194X mutations. We conclude that the loss of mitochondrial targeting is associated with a severe course of disease. Our study shows that clinical outcome of CMT disease caused by mutations in the GDAP1 gene cannot be predicted solely on the basis of genetic results (missense/nonsense mutations).     

Risk factors for executive dysfunction after subthalamic nucleus stimulation in Parkinson's disease

A slight decline in cognitive functions and especially in executive functioning after deep brain stimulation (DBS) of the nucleus subthalamicus (STN) in patients with Parkinson's disease (PD) has been described. This study evaluated baseline parameters that contribute to a deterioration of cognitive functioning after DBS. We analyzed data from the neuropsychological protocol in a randomized controlled study comparing DBS with best medical treatment (BMT). Change scores were calculated for the cognitive domains “global cognitive functioning,” “memory,” “working memory,” “attention,” and “executive function.” These domain‐specific change scores were correlated with previously defined preoperative parameters. Compared with the BMT group (63 patients), the STN‐DBS group (60 patients) showed a significant decline only in the domain executive function 6 months after DBS, which was significantly correlated with age, levodopa‐equivalence dosage (LED) and axial subscore of the UPDRS in the off‐medication state at baseline. Multiple regression analysis showed that these three factors explained, however, only about 23% of the variance. Patients with higher age, higher baseline LED, and/or higher axial subscore of the UPDRS at baseline have an increased risk for worsening of executive function after STN‐DBS. High scores of these factors might reflect an advanced stage of disease progression. As these baseline factors explained the variance of the change score executive function only to a minor proportion, other factors including the surgical procedure, the exact placement of the electrode or postsurgical management might be more relevant for a decline in executive functioning after STN‐DBS. © 2010 Movement Disorder Society     

Development of novel metaphor and metonymy comprehension in typically developing children and Williams syndrome

This study investigated the development of novel metaphor and metonymy comprehension in both typically developing (TD) children and individuals with Williams syndrome (WS). Thirty-one TD children between the ages of 3;09 and 17;01 and thirty-four individuals with WS between the ages of 7;01 and 44 years old were administered a newly developed task examining novel metaphor and metonymy comprehension, as well as a range of standardised tests that assess semantic knowledge. This age range and the background measures allowed construction of developmental trajectories to investigate whether chronological age or mental age, represented by word knowledge, relate to novel metaphor and metonymy comprehension. The results showed that comprehension of figurative language did not increase with chronological age in WS, in contrast to TD. Although there was no difference for the different types of metaphors, certain metonymy expressions were found to be easier than others in the TD group. In addition, semantic knowledge was a reliable predictor for novel metaphor and metonymy comprehension in the TD but only for metonymy in the WS group. In sum, development of novel metonymy in the WS group is only delayed while comprehension of novel metaphor is both delayed and atypical. However, future research should further investigate differences between sub-types, as well as what cognitive factors relate to novel metaphor comprehension in individuals with Williams syndrome.     

Effect of Alkylureas on the Polymerization of Hemoglobin S

Alkylureas (methyl-, ethyl-, propyl-, and butyl-) can inhibit both the gelation of deoxyhemoglobin S and red cell sickling without denaturation of the hemoglobin or intrinsic alteration of its oxygen affinity. This effect is directly proportional to the length of the alkyl chain and substantiates the importance of hydrophobic interactions in the polymerization of hemoglobin S. In addition, it opens the possibility that further systematic investigations with these compounds will help quantitate the role of hydrophobic interactions in this system so as to further our understanding of the polymerization of deoxyhemoglobin S.     

Navigating the niche. Three markets respond to the influx of specialty facilities--Indianapolis,Phoenix, Columbus

Specialty centers that focus on lucrative services such as cardiology and orthopedics pose a challenge to full-service hospitals in already crowded health care markets. We examine how hospitals in three markets have responded, from aggressively working to keep niche facilities from gaining a foothold to partnering with physicians on their own centers.     

Dueling priorities

The Institute of Medicine report on medical errors and the resulting attention from the public and health care purchasers pushed patients safety to the forefront of providers' quality initiatives. Now, some health care leaders say the preoccupation with safety is wrongheaded and could detract from broad efforts to improve care.     

Progress in molecular chorea diagnosis. McLeod syndrome and chorea acanthocytosis

McLeod syndrome and chorea-acanthocytosis are classified with the so-called neuroacanthocytosis group of syndromes. Both lead to progressive basal ganglia degeneration and were not easily distinguished in the past. With the discovery of their molecular bases, mutations of the X-linked gene XK and autosomal recessive mutations of the gene coding for chorein, respectively, the two phenotypes can now be differentiated and extend the diagnostic spectrum in patients presenting with chorea. The present review compares the two conditions and proposes a practical approach to diagnosis and treatment. Better-defined disease concepts should eventually replace the umbrella term of "neuroacanthocytosis." Animal models are needed to understand the underlying mechanisms. A final common pathway is likely for the pathogenesis of these conditions and is most probably shared with Huntington's disease.