Molecular study of Pompe disease in Egyptian infants

Background Pompe disease (PD) is a serious genetic disorder caused by deficiency of acid α-glucosidase (GAA) and subsequent glycogen accumulation inside lysosomes. This study included a cohort of 5 Egyptian infants (1–8 months old) with far lower than average normal GAA activity and clinical signs of PD in 4 of the 5 cases. The fifth case was discovered by newborn screening (NBS). Molecular analysis of the GAA gene was performed to confirm the diagnosis and identify the underlying mutation. Results The study identified the causative mutations [c.1193T > C (p.Leu398Pro), c.1134C > G (p.Tyr378*) & c.1431del (p.Ile477Metfs*43)] in 4 cases. However, molecular analysis reversed the expected pathologic state in the fifth infant, where his reduced enzymatic activity was related to the presence of pseudodeficiency allele c.868A > G (p.Asn290Asp) in addition to heterozygous disease-causing mutation c.2238G > C (p.Trp746Cys). Conclusion This study presents the first molecular analysis of GAA gene in Egypt and has thrown some light on the importance of PD molecular diagnosis to provide precise diagnosis and enable therapeutic commencement in affected subjects.

Green notes: The rhythms of cyanobacteria exoelectrogenesis as de-composed by the Hilbert-Huang transform

Electrons from cyanobacteria photosynthetic and respiratory systems are implicated in current generated in biophotovoltaic (BPV) devices. However, the pathway that electrons follow to electrodes remains largely unknown, limiting progress of applied research. Here we use Hilbert-Huang transforms to decompose Synechococcus elongatus sp. PCC7942 BPV current density profiles into physically meaningful oscillatory components, and compute their instantaneous frequencies. We develop hypotheses for the genesis of the oscillations via repeat experiments with iron-depleted and 20% CO2 enriched biofilms. The oscillations exhibit rhythms that are consistent with the state of the art cyanobacteria circadian model, and putative exoelectrogenic pathways. In particular, we observe oscillations consistent with: rhythmic D1:1 (photosystem II core) expression; circadian-controlled glycogen accumulation; circadian phase shifts under modified intracellular %ATP; and circadian period shortening in the absence of the iron-sulphur protein LdpA. We suggest that the extracted oscillations may be used to reverse-identify proteins and/or metabolites responsible for cyanobacteria exoelectrogenesis.

Diagnostic Yield of Chilaiditi’s Sign in Advanced-Phase Late-Onset Pompe Disease

Purpose: Chilaiditi’s sign (CS), hepatodiaphragmatic interposition of the intestine, was caused by morphological abnormalities such as diaphragmatic atrophy, intestinal dilation, and liver atrophy. The sign is potentially important due to associations with clinically recurrent abdominal pain or even colonic volvulus. In general, neuromuscular disease (NMD) could have the high prevalence of CS because of widened hepatodiaphragmatic space, following diaphragmatic atrophy. Particularly, in late-onset Pompe disease (LOPD), glycogen accumulation in smooth muscle of intestine could lead to the abnormal dilation of intestine. Though the prevalence of CS in LOPD could be high because of developing two main factors of CS, no studies have evaluated the prevalence of CS in LOPD. Our aim was to investigate the prevalence of CS in LOPD, and to identify the risk factors of CS in LOPD patients. Methods: Medical records of genetically confirmed patients of Pompe disease at the National Center Hospital, National Center of Neurology and Psychiatry were retrospectively reviewed. We evaluated CS using chest X-ray (CXR) and abdominal CT and assessed the prevalence of CS in LOPD patients. We also divided the patients into two groups, CS and non-CS group, and evaluated the factor associated with CS compared to clinical variables between groups. Results: Three of seven (43%) were detected in CS. CS group (P5-7) and non-CS group (P1-4) were obtained. In comparison of clinical variables, the severity of atrophy in right diaphragms was significantly higher in CS than non-CS groups (p =0.029). Also, the frequency of abnormal position of right diaphragm and liver, and abnormally dilated bowel was seen in all of CS patients, but none of non-CS patient (p = 0.029, each). Conclusion: In LOPD patients, the prevalence of CS was much higher of 43%, compared to healthy groups, or even in similarly respiratory muscle impaired neuromuscular diseases such as Duchenne muscular dystrophy (DMD) or Myotonic dystrophy type 1 (DM1). The anatomically abnormal position of diaphragm and liver, atrophy and fat infiltration of diaphragms, and abnormally dilated bowel were significantly associated with CS in LOPD. Since CS can cause intestinal symptoms or even contribute to sudden-death of intestinal volvulus, we should pay more attention to CXR or abdominal CT as follow up in LOPD patients.

Effects of Bile Acids Supplement in High Plant Protein Diet on Common Carp (Cyprinus Carpio) Bile Acids Profile and Hepatopancreas Health

BackgroundBile acids (BAs) have considerable importance in the metabolism of glycolipid and cholesterol. BAs profile in mammals has been widely reported, but lacking in fishes. The purpose of the present study is to clarify BAs profiles of common carp and how exogenous additions of BAs could alleviate hepatopancreas injured of common carp under a high plant protein diet. A 11-week feeding trial was conducted with high plant protein diet (18%) (HP) and high plant protein diet (18%) added 600 mg/kg BAs (HP+BAs) for Common carp, and then the UHPLC-MS/MS technology was used to analyze the BAs in the bile and plasma of two groups. ResultsHP could induce vacuolation of hepatocytes and accumulation of glycogen in Common carp, while these phenotypes were significantly improved in HP+BAs group. In addition, BAs profile of HP group and HP+BAs group were described in detail, for Common carp bile with treatment by exogenous BAs, TCA, CA, T β MCA and T ω MCA were the main components. Furthermore, in HP+BAs group plasma, CDCA, CA, LCA, and GCDCA increased significantly, they could activate TGR5, the activation of hepatopancreas TGR5 might regulate glucose metabolism to relieve hepatopancreas glycogen accumulation. ConclusionsHP could induce glycogen accumulation in common carp hepatopancreas while supplemented BAs to HP could mitigate this symptom. And we determined that the reduction of common carp hepatopancreas glycogen accumulation in the HP+BAs group is importantly related to the change in the endogenous BAs profile after the addition of BAs in HP through an integrated bile acids profile determination by UHPLC-MS/MS . This study has important guiding significance for aquaculture.

Loss of Autophagy Causes Increased Apoptosis of Tibial Plateau Chondrocytes in Guinea Pigs with Spontaneous Osteoarthritis

Objective The goal of the present study was to observe the effect of autophagy in tibial plateau chondrocytes on apoptosis in spontaneous knee osteoarthritis (OA) in guinea pigs. Design Fifty 2-month-old female Hartley guinea pigs were divided into a normal group (10 animals, all euthanized after 7 months) and an OA group (40 animals, 10 of which were euthanized after 10 months). Immunohistochemistry, RT-qPCR and Western blotting were used to evaluate autophagy levels, intracellular glycogen accumulation and apoptosis in tibial plateau chondrocytes in vivo and in vitro. The remaining 30 guinea pigs in the OA group were divided into 3 groups: a rapamycin group, a normal saline group, and a 3-methyladenine (3-MA) group. Intracellular glycogen accumulation and chondrocyte apoptosis were assessed by altering the level of autophagy in chondrocytes in vivo. Results When spontaneous OA occurred in guinea pigs, autophagy levels in tibial plateau chondrocytes decreased, while intracellular glycogen accumulation and the rate of chondrocyte apoptosis increased. After enhancing the level of autophagy in tibial plateau chondrocytes in guinea pigs with OA, intracellular glycogen accumulation and the rate of chondrocyte apoptosis decreased, while inhibiting autophagy had the opposite effects. Conclusion The results indicate that the function of autophagy in chondrocytes may at least partly involve the catabolism of glycogen. In guinea pigs with OA, the level of autophagy in tibial plateau chondrocytes decreased, and chondrocytes were unable to degrade intracellular glycogen into glucose, leading to less energy for chondrocytes and increased apoptosis.

Endometrial Glucose Transporters in Health and Disease

Pregnancy loss is a frequent occurrence during the peri-implantation period, when there is high glucose demand for embryonic development and endometrial decidualization. Glucose is among the most essential uterine fluid components required for those processes. Numerous studies associate abnormal glucose metabolism in the endometrium with a higher risk of adverse pregnancy outcomes. The endometrium is incapable of synthesizing glucose, which thus must be delivered into the uterine lumen by glucose transporters (GLUTs) and/or the sodium-dependent glucose transporter 1 (SGLT1). Among the 26 glucose transporters (14 GLUTs and 12 SGLTs) described, 10 (9 GLUTs and SGLT1) are expressed in rodents and 8 (7 GLUTs and SGLT1) in the human uterus. This review summarizes present knowledge on the most studied glucose transporters in the uterine endometrium (GLUT1, GLUT3, GLUT4, and GLUT8), whose data regarding function and regulation are still lacking. We present the recently discovered SGLT1 in the mouse and human endometrium, responsible for controlling glycogen accumulation essential for embryo implantation. Moreover, we describe the epigenetic regulation of endometrial GLUTs, as well as signaling pathways included in uterine GLUT’s expression. Further investigation of the GLUTs function in different endometrial cells is of high importance, as numerous glucose transporters are associated with infertility, polycystic ovary syndrome, and gestational diabetes.

New Insights into Gastrointestinal Involvement in Late-Onset Pompe Disease: Lessons Learned from Bench and Bedside

Background: There are new emerging phenotypes in Pompe disease, and studies on smooth muscle pathology are limited. Gastrointestinal (GI) manifestations are poorly understood and underreported in Pompe disease. Methods: To understand the extent and the effects of enzyme replacement therapy (ERT; alglucosidase alfa) in Pompe disease, we studied the histopathology (entire GI tract) in Pompe mice (GAAKO 6neo/6neo). To determine the disease burden in patients with late-onset Pompe disease (LOPD), we used Patient-Reported Outcomes Measurements Information System (PROMIS)-GI symptom scales and a GI-focused medical history. Results: Pompe mice showed early, extensive, and progressive glycogen accumulation throughout the GI tract. Long-term ERT (6 months) was more effective to clear the glycogen accumulation than short-term ERT (5 weeks). GI manifestations were highly prevalent and severe, presented early in life, and were not fully amenable to ERT in patients with LOPD (n = 58; age range: 18–79 years, median age: 51.55 years; 35 females; 53 on ERT). Conclusion: GI manifestations cause a significant disease burden on adults with LOPD, and should be evaluated during routine clinical visits, using quantitative tools (PROMIS-GI measures). The study also highlights the need for next generation therapies for Pompe disease that target the smooth muscles.