Intrafamilial phenotypic variability in four families with Anderson‐Fabry disease

We analysed the clinical history of 16 hemizygous males affected by Anderson‐Fabry Disease, from four families, to verify their intrafamilial phenotypic variability. Seven male patients, ranging from 26 to 61 years of age, died, whereas nine (age range 23–55) are alive. Eleven patients have undergone enzyme replacement therapy (ERT) for a period of 5–10 years. We have found a wide range of intrafamilial phenotypic variability in these families, both in terms of target‐organs and severity of the disease. Overall, our findings confirm previous data from the literature showing a high degree of intrafamilial phenotypic variability in patients carrying the same mutation. Furthermore, our results underscore the difficulty in giving accurate prognostic information to patients during genetic counselling, both in terms of rate of disease progression and involvement of different organs, when such prognosis is solely based on the patient's family history.     

A perception-based ERP reveals that the magnitude of delay matters for memory-guided reaching

Delayed action research has suggested that perceptual information about a visual stimulus decays over several seconds. With event-related potential (ERP) methodology, one should be able to track the time course of the electrophysiological processes associated with this decay. Recently, Cruikshank et al. (J Vis 12:29, 2012) found that the N170 ERP component reflected ventral stream processes linked to motor planning and perception for action. Specifically, the N170 was larger for actions that relied on perceptual-based information. However, the delay interval was very short (tens of ms). Behavioral and neuroimaging studies suggest that when longer delays are employed, reactivation of ventral areas is necessary in order to access a stored representation of the target’s characteristics. Therefore, the N170 may reflect not only the perception-for-action processes, but also the accuracy of the representation. In order to test this, we traced the time course of the N170 in memory-guided reaching when 1-, 2-, and 3-s delays separated target occlusion and response initiation. During reach initiation, the N170 was more negative and peaked earlier for the 1 s than the 2- and 3-s delays and correlated significantly with performance at the longest delay. These results suggest that the neural mechanisms involved in movement planning change for delays beyond 1 s. The smaller N170 may reflect an impoverished visual perceptual representation in the ventral stream. To our knowledge, these are the first electrophysiological results to suggest that there is decay of visual perceptual information that occurs with increasing time.     

Endodermal/ectodermal interfaces during pharyngeal segmentation in vertebrates

A key event in the formation of the pharyngeal arches is the outpocketing of the endodermal pharyngeal pouches and the establishment of contact with the overlying ectoderm. However, relatively little is known about how the endoderm and ectoderm relate to each other at these points of contact and the extent to which this differs between the pouches. We have therefore detailed the interactions between the pharyngeal pouches and ectoderm in the chick embryo. Unlike the other pouches, the first pouch does not sustain direct contact with the ectoderm but separates after initial contact. Contrastingly, a perforation is formed between the second pouch and cleft that creates an external opening into the pharynx. Finally, the third and fourth pouch endoderm can be seen to bulge outwards through the ectoderm, although external openings to the pharyngeal lumen are not established. To understand whether these behaviours represent derived or ancestral features, we characterised the pharyngeal ectodermal–endodermal interfaces in the shark embryo. We found that the pouches of the posterior gill-bearing arches in this species also displayed the outward bulging of the endoderm into the ectoderm, although openings were established. We further used genetic tools to detail unambiguously the relationship between the endoderm and ectoderm in zebrafish and mouse embryos and again found that the posterior pouches break through the ectoderm. Thus different pharyngeal pouches establish different topological relationships with the overlying ectoderm and the posterior pouches initiate the developmental programme for the formation of gills, be they amniotes or anamniotes.     

Anandamide produced by Ca2+-insensitive enzymes induces excitation in primary sensory neurons

The endogenous lipid agent N-arachidonoylethanolamine (anandamide), among other effects, has been shown to be involved in nociceptive processing both in the central and peripheral nervous systems. Anandamide is thought to be synthesised by several enzymatic pathways both in a Ca²⁺-sensitive and Ca²⁺-insensitive manner, and rat primary sensory neurons produce anandamide. Here, we show for the first time, that cultured rat primary sensory neurons express at least four of the five known Ca²⁺-insensitive enzymes implicated in the synthesis of anandamide, and that application of 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-arachidonoyl, the common substrate of the anandamide-synthesising pathways, results in anandamide production which is not changed by the removal of extracellular Ca²⁺. We also show that anandamide, which has been synthesised in primary sensory neurons following the application of 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-arachidonoyl induces a transient receptor potential vanilloid type 1 ion channel-mediated excitatory effect that is not inhibited by concomitant activation of the cannabinoid type 1 receptor. Finally, we show that sub-populations of transient receptor potential vanilloid type 1 ion channel-expressing primary sensory neurons also express some of the putative Ca²⁺-insensitive anandamide-synthesising enzymes. Together, these findings indicate that anandamide synthesised by primary sensory neuron via a Ca²⁺-insensitive manner has an excitatory rather than an inhibitory role in primary sensory neurons and that excitation is mediated predominantly through autocrine signalling. Regulation of the activity of the Ca²⁺-insensitive anandamide-synthesising enzymes in these neurons may be capable of regulating the activity of these cells, with potential relevance to controlling nociceptive processing.     

Microcephaly with or without chorioretinopathy,lymphoedema, or mental retardation (MCLMR): review of phenotype associated with KIF11 mutations

Microcephaly with or without chorioretinopathy, lymphoedema, or mental retardation (MCLMR) (MIM No.152950) is a rare autosomal dominant condition for which a causative gene has recently been identified. Mutations in the kinesin family member 11 (KIF11) gene have now been described in 16 families worldwide. This is a review of the condition based on the clinical features of 37 individuals from 22 families. This report includes nine previously unreported families and additional information for some of those reported previously. The condition arose de novo in 8/20 families (40%). The parental results were not available for two probands. The mutations were varied and include missense, nonsense, frameshift, and splice site and are distributed evenly throughout the KIF11 gene. In our cohort, 86% had microcephaly, 78% had an ocular abnormality consistent with the diagnosis, 46% had lymphoedema, 73% had mild-moderate learning difficulties, 8% had epilepsy, and 8% had a cardiac anomaly. We identified three individuals with KIF11 mutations but no clinical features of MCLMR demonstrating reduced penetrance. The variable expression of the phenotype and the presence of mildly affected individuals indicates that the prevalence may be higher than expected, and we would therefore recommend a low threshold for genetic testing.     

Replication of the effect of SLC2A9 genetic variation on serum uric acid levels in American Indians

Increased serum uric acid (SUA) or hyperuricemia, a risk factor for gout, renal and cardiovascular diseases, is caused by either increased production or decreased excretion of uric acid or a mix of both. The solute carrier protein 2 family, member 9 (SLC2A9) gene encodes a transporter that mediates urate flux across the renal proximal tubule. Genome-wide association studies have consistently shown the association of single-nucleotide polymorphisms in this gene with SUA in majority populations. American Indian participants of the Strong Heart Family Study, belonging to multigenerational families, have high prevalence of hyperuricemia. We conducted measured genotype analyses, based on variance components decomposition method and accounting for family relationships, to assess whether the association between SUA and SLC2A9 gene polymorphisms generalized to American Indians (n=3604) of this study. Seven polymorphisms were selected for genotyping based on their association with SUA levels in other populations. A strong association was found between SLC2A9 gene polymorphisms and SUA in all centers combined (P-values: 1.3 × 10⁻³¹–5.1 × 10⁻²³) and also when stratified by recruitment center; P-values: 1.2 × 10⁻¹⁴–1.0 × 10⁻⁵. These polymorphisms were also associated with the estimated glomerular filtration rate and serum creatinine but not albumin–creatinine ratio. In summary, the association of polymorphisms in the uric acid transporter gene with SUA levels extends to a new population of American Indians.     

Tumor genetics and survival of thymic neuroendocrine neoplasms: A multi‐institutional clinicopathologic study

Thymic neuroendocrine tumors (TNET) are rare primary epithelial neoplasms of the thymus. This study aimed to determine clinically relevant parameters for their classification and for therapeutic decisions. We performed a comprehensive histological, clinical, and genetic study of 73 TNET cases (13 thymic typical carcinoids [TTC], 40 thymic atypical carcinoids [TAC], and 20 high‐grade neuroendocrine carcinomas [HGNEC] of the thymus), contributed by multiple institutions. The mean number of chromosomal imbalances per tumor was 0.8 in TTC (31% aberrant cases) versus 1.1 in TAC (44% aberrant cases) versus 4.7 in HGNEC (75% aberrant cases). Gains of 8q24 (MYC gene locus) were the most frequent alteration and one of the overlapping features between carcinoids and HGNEC. The 5‐year survival rates for TTC, TAC, and HGNEC were 100, 60, and 30%. The 10‐year survival rates for TTC and TAC were 50 and 30% (P = 0.002). Predictive mitotic cut‐off values for TTC versus TAC were 2.5 per 10 high‐power fields (HPF; indicating a higher death rate, P = 0.062) and 15 per 10 HPF (indicating higher risk of recurrence, P = 0.036) for separating HGNEC from TAC. We conclude that the current histopathologic classifications of TNET reflect tumor biology and provide important information for therapeutic management. © 2014 Wiley Periodicals, Inc.     

Malignant gastric outlet obstruction: Which is the best therapeutic option?

Malignant gastric outlet obstruction(MGOO) is a clinical condition characterized by the mechanical obstruction of the pylorus or the duodenum due to tumor compression/infiltration, with consequent reduction or impossibility of an adequate oral intake. MGOO is mainly secondary to advanced pancreatic or gastric cancers, and significantly impacts on patients' survival and quality of life.Patients suffering from this condition often present with intractable vomiting and severe malnutrition, which further compromise therapeutic chances. Currently,palliative strategies are based primarily on surgical gastrojejunostomy and endoscopic enteral stenting with self-expanding metal stents. Several studies have shown that surgical approach has the advantage of a more durable relief of symptoms and the need of fewer re-interventions, at the cost of higher procedure-related risks and longer hospital stay. On the other hand, enteral stenting provides rapid clinical improvement, but have the limit of higher stent dysfunction rate due to tumor ingrowth and a subsequent need of frequent reinterventions. Recently, a third way has come from interventional endoscopic ultrasound, through the development of endoscopic ultrasound-guided gastroenterostomy technique with lumen-apposing metal stent. This new technique may ideally encompass the minimal invasiveness of an endoscopic procedure and the long-lasting effect of the surgical gastrojejunostomy, and brought encouraging results so far, even if prospective comparative trial are still lacking. In this Review, we described technical aspects and clinical outcomes of the above-cited therapeutic approaches, and discussed the open questions about the current management of MGOO.     

Bowel endometriosis: Colorectal surgeon’s perspective in a multidisciplinary surgical team

Endometriosis is a gynecological condition that presents as endometrial-like tissue outside the uterus and induces a chronic inflammatory reaction. Up to 15% of women in their reproductive period are affected by this condition. Deep endometriosis is defined as endometriosis located more than 5 mm beneath the peritoneal surface. This type of endometriosis is mostly found on the uterosacral ligaments, inside the rectovaginal septum or vagina, in the rectosigmoid area, ovarian fossa, pelvic peritoneum, ureters, and bladder, causing a distortion of the pelvic anatomy. The frequency of bowel endometriosis is unknown, but in cases of bowel infiltration, about 90% are localized on the sigmoid colon or the rectum. Colorectal involvement results in alterations of bowel habits such as constipation, diarrhea, tenesmus, dyschezia, and, rarely, rectal bleeding. Differential diagnosis must be made in case of irritable bowel syndrome, solitary rectal ulcer syndrome, and a rectal tumor. A precise diagnosis about the presence, location, and extent of endometriosis is necessary to plan surgical treatment. Multidisciplinary laparoscopic treatment has become the standard of care. Depending on the size of the lesion and site of involvement, full-thickness disc excision or bowel resection needs to be performed by an experienced colorectal surgeon. Long-term outcomes, following bowel resection for severe endometriosis, regarding pain and recurrence rate are good with a pregnancy rate of 50%.