Autosomal dominant SCA5 and autosomal recessive infantile SCA are allelic conditions resulting from SPTBN2 mutations

Although many genes have been identified for the autosomal recessive cerebellar ataxias (ARCAs), several patients are unlinked to the respective loci, suggesting further genetic heterogeneity. We combined homozygosity mapping and exome sequencing in a consanguineous Egyptian family with congenital ARCA, mental retardation and pyramidal signs. A homozygous 5-bp deletion in SPTBN2, the gene whose in-frame mutations cause autosomal dominant spinocerebellar ataxia type 5, was shown to segregate with ataxia in the family. Our findings are compatible with the concept of truncating SPTBN2 mutations acting recessively, which is supported by disease expression in homozygous, but not heterozygous, knockout mice, ataxia in Beagle dogs with a homozygous frameshift mutation and, very recently, a homozygous SPTBN2 nonsense mutation underlying infantile ataxia and psychomotor delay in a human family. As there was no evidence for mutations in 23 additional consanguineous families, SPTBN2-related ARCA is probably rare.     

TET2 mutations in cytogenetically normal acute myeloid leukemia: Clinical implications and evolutionary patterns

Mutations of the Ten‐Eleven‐Translocation 2 (TET2) gene have been identified in patients with various myeloid neoplasms, but the clinical relevance of these mutations and their timing during disease development in cytogenetically normal acute myeloid leukemia (CN‐AML) remain unclear. The total coding region of TET2 was analyzed by direct sequencing in 215 CN‐AML patients younger than 60 years from multicenter treatment trials AML‐SHG 0199 (ClinicalTrials Identifier NCT00209833) and 0295. Associations were analyzed in the context of other molecular markers, such as CEBPA, DNMT3A, NMP1, FLT3, IDH1/2, RAS, and WT1. To investigate the order of appearance of TET2 and concomitant mutations, targeted deep resequencing was performed in six patients. At least one sequence variation with impact on TET2 protein sequence was found in 13 of the 215 CN‐AML patients (6%). Patients with TET2 mutations tended to be older (P = 0.078) and had higher platelet counts (P = 0.041). TET2‐mutated patients were more likely to have concomitant NPM1 (11 of 13; P = 0.047) and DNMT3A (10 of 13; P = 0.001) mutations but were mutually exclusive to partial tandem duplication of the MLL gene (MLL‐PTD) and IDH1/2 mutations. TET2 mutations were identified as subclones in four of the six investigated patients by deep sequencing. Progenitor‐derived colony assays suggest a stepwise acquisition of mutations during disease development, TET2 mutation being later than NPM1 and DNMT3A. The TET2 mutation status did not influence overall or relapse‐free survival. © 2014 Wiley Periodicals, Inc.     

Mutation of POC1B in a Severe Syndromic Retinal Ciliopathy

We describe a consanguineous Iraqi family with Leber congenital amaurosis (LCA), Joubert syndrome (JBTS), and polycystic kidney disease (PKD). Targeted next‐generation sequencing for excluding mutations in known LCA and JBTS genes, homozygosity mapping, and whole‐exome sequencing identified a homozygous missense variant, c.317G>C (p.Arg106Pro), in POC1B, a gene essential for ciliogenesis, basal body, and centrosome integrity. In silico modeling suggested a requirement of p.Arg106 for the formation of the third WD40 repeat and a protein interaction interface. In human and mouse retina, POC1B localized to the basal body and centriole adjacent to the connecting cilium of photoreceptors and in synapses of the outer plexiform layer. Knockdown of Poc1b in zebrafish caused cystic kidneys and retinal degeneration with shortened and reduced photoreceptor connecting cilia, compatible with the human syndromic ciliopathy. A recent study describes homozygosity for p.Arg106Pro_POC1B in a family with nonsyndromic cone‐rod dystrophy. The phenotype associated with homozygous p.Arg106Pro_POC1B may thus be highly variable, analogous to homozygous p.Leu710Ser in WDR19 causing either isolated retinitis pigmentosa or Jeune syndrome. Our study indicates that POC1B is required for retinal integrity, and we propose POC1B mutations as a probable cause for JBTS with severe PKD.     

Partner choice and fidelity stabilize coevolution in a Cretaceous-age defensive symbiosis

Many insects rely on symbiotic microbes for survival, growth, or reproduction. Over evolutionary timescales, the association with intracellular symbionts is stabilized by partner fidelity through strictly vertical symbiont transmission, resulting in congruent host and symbiont phylogenies. However, little is known about how symbioses with extracellular symbionts, representing the majority of insect-associated microorganisms, evolve and remain stable despite opportunities for horizontal exchange and de novo acquisition of symbionts from the environment. Here we demonstrate that host control over symbiont transmission (partner choice) reinforces partner fidelity between solitary wasps and antibiotic-producing bacteria and thereby stabilizes this Cretaceous-age defensive mutualism. Phylogenetic analyses show that three genera of beewolf wasps (Philanthus, Trachypus, and Philanthinus) cultivate a distinct clade of Streptomyces bacteria for protection against pathogenic fungi. The symbionts were acquired from a soil-dwelling ancestor at least 68 million years ago, and vertical transmission via the brood cell and the cocoon surface resulted in host–symbiont codiversification. However, the external mode of transmission also provides opportunities for horizontal transfer, and beewolf species have indeed exchanged symbiont strains, possibly through predation or nest reuse. Experimental infection with nonnative bacteria reveals that—despite successful colonization of the antennal gland reservoirs—transmission to the cocoon is selectively blocked. Thus, partner choice can play an important role even in predominantly vertically transmitted symbioses by stabilizing the cooperative association over evolutionary timescales.Cooperation is ubiquitous in nature, yet it presents a conundrum to evolutionary biology because acts that are beneficial to the receiver but costly to the actor should not be favored by natural selection (1). In interspecific associations (i.e., symbioses), the two most important models to explain the maintenance of cooperation are partner fidelity and partner choice (2, 3). In partner-fidelity associations, host and symbiont interact repeatedly and reward cooperating individuals while punishing cheaters, thereby reinforcing mutually beneficial interactions (2, 4). In partner-choice associations, individuals may interact only once, but one member can select its partner in advance of any possible exploitation (2, 4). Partner choice appears to select for cooperative strains among environmentally acquired microbial symbionts, e.g., the bioluminescent Vibrio fischeri bacteria of squids (5), the nitrogen-fixing rhizobia of legumes (6), and mycorrhizal fungi of plants (7). By contrast, partner fidelity is generally assumed to be the major stabilizing force in the widespread and ecologically important vertically transmitted symbioses of insects (4).However, localization and transmission routes of mutualistic bacteria in insects are diverse, and the differences across symbiotic systems have important implications for the evolutionary trajectory of the associations. Symbionts with an obligate intracellular lifestyle are usually tightly integrated into the host’s metabolism (e.g., ref. 8) and development (9), and the mutual interdependence of both partners coincides with perfect vertical symbiont transmission. Over evolutionary timescales, the high degree of partner fidelity results in host–symbiont cocladogenesis, and, concordantly, phylogenies of hosts and their intracellular symbionts are often found to be congruent (10–13). Although such a pattern is also observed for some extracellular symbioses with especially tight host–symbiont integration (14, 15), the ability of many extracellularly transmitted symbionts to spend part of their life cycle outside of the host’s body is often reflected in more or less extensive horizontal transmission or de novo acquisition of symbionts from the environment (16, 17). In these cases, partner choice mechanisms are expected to ensure specificity in the establishment and maintenance of the association (18). The nature of such control mechanisms, however, remains poorly understood.Although many of the well-studied mutualistic associations in insects have a nutritional basis (19, 20), an increasing number of symbioses for the defense of the host against predators (21), parasitoids (22), or pathogens (23–25) have recently been discovered. Among defensive symbionts, Actinobacteria are particularly prevalent, probably due to their ubiquity in the soil and their ability to produce secondary metabolites with antibiotic properties (23). Antibiotic-producing actinobacterial symbionts have been discovered on the cuticle of leaf-cutting ants (26), in the fungal galleries of a bark beetle (27), and in the antennae and on cocoons of beewolf wasps (28). While in the former two cases the symbionts have been implicated in the defense of the hosts’ nutritional resources against competing fungi (26, 27), the beewolves’ bacteria protect the offspring in the cocoon against pathogenic microorganisms (28, 29).Beewolves are solitary wasps in the genera Philanthus, Trachypus, and Philanthinus (Hymenoptera, Crabronidae, Philanthini). They engage in a defensive alliance with the Actinobacterium ‘Candidatus Streptomyces philanthi’ (CaSP) (28, 30, 31), which is cultivated by female beewolves in specialized antennal gland reservoirs (32). The uniqueness and complexity of the glands suggest a long history of host adaptation towards cultivating its actinobacterial symbionts (32). From the antennae, the streptomycetes are secreted into the brood cell, taken up by the larva, and incorporated into its cocoon (33), where they provide protection against pathogenic fungi and bacteria (28) by producing at least nine different antimicrobial compounds (29). Weeks or months later, eclosing adult females acquire the bacteria from the cocoon surface (33), thus completing the vertical transmission of CaSP. However, this mode of transmission provides opportunities for the horizontal transfer of symbionts among beewolf species or the de novo uptake of bacteria from the environment. Despite these opportunities, a monophyletic clade of CaSP strains has previously been found in 31 species of beewolves, suggesting an ancient and highly coevolved relationship (30, 31, 34).Here we combine cophylogenetic analyses of beewolves and their vertically transmitted defensive symbionts with experimental manipulation of symbiont infection status and subsequent observations of transmission from female antennal gland reservoirs into the brood cell to (i) reconstruct the coevolutionary history of the symbiosis, (ii) estimate the age of the symbiosis, (iii) elucidate the ancestral lifestyle of the symbionts, and (iv) assess the importance of partner fidelity and partner choice for the long-term stability of the association.     

Neurocognitive outcome in patients with hypertyrosinemia type I after long-term treatment with NTBC

Objective  

The implementation of NTBC into treatment of hypertyrosinemia type I (HT I) greatly improved survival by prevention of acute liver failure and hepatocellular carcinoma. However, there are first reports of cognitive impairment in patients with elevated plasma tyrosine concentrations.     

Morbidity related to defunctioning loop ileostomy in low anterior resection

Aim

A defunctioning loop ileostomy in low anterior resection reduces the incidence and morbidity of an anastomotic leakage, but complications related to the stoma may occur. We explored stoma-associated complications during the stoma period and after stoma reversal.

Methods

A retrospective analysis of rectal cancer patients operated with low anterior resection and a defunctioning loop ileostomy at Helsingborg Hospital and Malm? University Hospital from January 2007 to June 2009 was undertaken.

Results

Ninety-two patients were included, of whom 82 (89?%) underwent stoma reversal. The median stoma period was 6.2?±?3.2?months. Sixty-six percent of the patients suffered from minor or major stoma-associated morbidity. The complication rate was significantly related to the stoma time (p?<?0.01). Twenty-nine percent (27/92) had at least one episode of dehydration, leading to readmittance in half of the cases. Elderly patients were more prone to develop dehydration. Dehydration most commonly occurred early in the postoperative period (mean, 5.8?weeks). The mean hospital stay for stoma reversal was 6.5?±?4.0?days. Forty percent (33/82) had some complication associated with the reversal.

Conclusion

This study indicates high morbidity associated with defunctioning loop ileostomy. Our data suggest that the stoma time should be limited to reduce complications. Monitoring and early stoma reversal should be considered in elderly patients. Furthermore, stoma reversal is not uneventful, and more studies are needed to address how to minimize complications.     

Dysfunction of a Structurally Normal Motor Pathway in a Brain Injury Patient as Revealed by Multimodal Integrated Techniques

We report on a patient with left hemiparesis and peripersonal neglect after post-traumatic left frontal hemorrhage, who underwent fMRI, TMS and TCD to identify the functional abnormalities that account for his neurological symptoms, in the absence of any detectable lesion affecting right motor areas.     

Developmental outcomes of children with congenital diaphragmatic hernia: A multicenter prospective study

Purpose

To determine developmental outcomes and associated factors in patients with congenital diaphragmatic hernia (CDH) at 2 years of age.

Methods

This is a multicenter prospective study of a CDH birth cohort. Clinical and socioeconomic data were collected. Bayley Scales of Infant Development (BSID-III) and Vineland Adaptive Behavior Scales (VABS-II) were performed at 2 years of age.

Results

BSID-III and VABS-II assessments were completed on 48 and 49 children, respectively. The BSID-III mean cognitive, language, and motor scores were significantly below the norm mean with average scores of 93 ± 15, 95 ± 16, and 95 ± 11. Ten percent (5/47) scored more than 2 standard deviations below the norm on one or more domains. VABS-II scores were similar to BSID-III scores with mean communication, daily living skills, social, motor, adaptive behavior scores of 97 ± 14, 94 ± 16, 93 ± 13, 97 ± 10, and 94 ± 14. For the BSID-III, supplemental oxygen at 28 days, a prenatal diagnosis, need for extracorporeal membrane oxygenation (ECMO) and exclusive tube feeds at time of discharge were associated with lower scores. At 2 years of age, history of hospital readmission and need for tube feeds were associated with lower scores. Lower socioeconomic status correlated with lower developmental scores when adjusted for significant health factors.

Conclusion

CDH patients on average have lower developmental scores at 2 years of age compared to the norm. A need for ECMO, oxygen at 28 days of life, ongoing health issues and lower socioeconomic status are factors associated with developmental delays.