Increased Number of Cerebellar Granule Cells and Astrocytes in the Internal Granule Layer in Sheep Following Prenatal Intra-amniotic Injection of Lipopolysaccharide

Chorioamnionitis is an important problem in perinatology today, leading to brain injury and neurological handicaps. However, there are almost no data available regarding chorioamnionitis and a specific damage of the cerebellum. Therefore, this study aimed at determining if chorioamnionitis causes cerebellar morphological alterations. Chorioamnionitis was induced in sheep by the intra-amniotic injection of lipopolysaccharide (LPS) at a gestational age (GA) of 110 days. At a GA of 140 days, we assessed the mean total and layer-specific volume and the mean total granule cell (GCs) and Purkinje cell (PC) number in the cerebelli of LPS-exposed and control animals using high-precision design-based stereology. Astrogliosis was assessed in the gray and white matter (WM) using a glial fibrillary acidic protein staining combined with gray value image analysis. The present study showed an unchanged volume of the total cerebellum as well as the molecular layer, outer and inner granular cell layers (OGL and IGL, respectively), and WM. Interestingly, compared with controls, the LPS-exposed brains showed a statistically significant increase (+20.4%) in the mean total number of GCs, whereas the number of PCs did not show any difference between the two groups. In addition, LPS-exposed animals showed signs of astrogliosis specifically affecting the IGL. Intra-amniotic injection of LPS causes morphological changes in the cerebellum of fetal sheep still detectable at full-term birth. In this study, changes were restricted to the inner granule layer. These cerebellar changes might correspond to some of the motor or non-motor deficits seen in neonates from compromised pregnancies

Autism: Neuropathology, Alterations of the GABAergic System, and Animal Models

This chapter discusses autism neuropathology, the role of GABAergic system, the system in which neurons produce gamma-aminobutyric acid (GABA) as their output, in this disorder, and the relevance of rodent models with autistic features. With respect to the neuropathology of autism, consistent findings have emerged for the limbic system, cerebellum, and cerebral cortex. The neuropathologic data of the limbic system show increased cell packing density and smaller neurons. These observations might be explained by an arrest of normal development. As with the cholinergic system, several studies have reported a reduction in GABA function, availability, and activity in autism. A decrease in GABA receptor binding has also been shown in autism. Evidence indicates that GABA plays a role in several developmental processes, including cell migration, proliferation, and differentiation. Although the neuropathologic results in autistic subjects are revealing, animal models are essential for a better understanding of the pathophysiology, cause, and treatment of autism. The recent linkages of neuroligin (NLGN), DLX, and engrailed 2 (En2) to autism offer possibilities for animal models, particularly if introducing the relevant, specific mutations (as opposed to simple knockouts [Kos]) and can cause interesting pathology and behavior

Are Anti-rhGAA Antibodies a Determinant of Treatment Outcome in Adults with Late-Onset Pompe Disease? A Systematic Review

Background: Pompe disease is a lysosomal storage disease characterised by skeletal and respiratory muscle weakness. Since 2006, enzyme replacement therapy (ERT) with alglucosidase alfa has been available. ERT significantly improves the prognosis of patients with Pompe disease. The effect of high antibody titres on treatment response in adults with late-onset Pompe disease (LOPD) remains unclear but may contribute to interpatient variation. We therefore conducted a systematic review on this subject. Methods: A systematic search was performed in Embase, Medline Ovid, Web of Science, Psych Info Ovid, Cochrane (Clinical Trials only), and Google Scholar (random top-200). Articles were included if they involved adults with LOPD treated with alglucosidase alfa and mentioned anti-rhGAA antibodies or antibody titres. In addition, articles mentioning dosages different from the standard recommended dosage were included. Results: Our literature search retrieved 2562 publications, and 17 fulfilled our selection criteria, describing 443 cases. Seven publications reported on anti-rhGAA antibody titres on a group level, with the percentage of patients with a high titre as defined in the included articles ranging from 0–33%. Six publications reported on the effect of anti-rhGAA antibody titre on clinical course, and four found no correlation. Two studies reported a negative effect on treatment. The first study found a greater improvement in Medical Research Council (MRC) score in patients with no detectable antibody titre. In the second study, a patient discontinued ERT due to a declining neuromuscular state as a result of high anti-rhGAA antibody titres. Seven publications reported on 17 individual patients with a high antibody titre (range 1:12,800–1:3,906,250). In only two cases were high-sustained neutralising antibodies reported to interfere with treatment efficacy. Conclusions: No clear effect of anti-rhGAA IgG antibodies on treatment response could be established for the majority of LOPD patients with a high antibody titre. In a minority of patients, a clinical decline related to (possible) interference of anti-rhGAA antibodies was described

Antibodies against recombinant human alpha-glucosidase do not seem to affect clinical outcome in childhood onset Pompe disease

Background: Enzyme replacement therapy (ERT) with recombinant human alpha-glucosidase (rhGAA, alglucosidase alfa) has improved survival, motor outcomes, daily life activity and quality of life in Pompe patients. However, ERT in Pompe disease often induces formation of antibodies, which may reduce the efficacy of treatment and can lead to adverse events. In this study antibody formation and their effect on clinical outcome in patients with childhood onset Pompe disease treated with enzyme replacement therapy (ERT) with recombinant human alpha-glucosidase (rhGAA) are analyzed. Methods: Enzyme-linked immunosorbent assay (ELISA) was used to determine anti-rhGAA antibody titers at predefined time points. The effect of antibodies on rhGAA activity (neutralizing effects) was measured in vitro. Clinical effects were evaluated by assessing muscle strength (MRC score) and function (QMFT-score), pulmonary function and infusion associated reactions (IARs). Results: Twenty-two patients were included (age at start ERT 1.1–16.4 years, median treatment duration 12.4 years). Peak antibody titers were low (< 1:1250) in 9%, intermediate (1:1250–1:31,250) in 68% and high (≥ 1:31250) in 23% of patients; three patients (14%) had more than one titer of ≥ 1:31,250. Four patients (18%) experienced IARs; two patients from the high titer group had 86% of all IARs. Inhibition of intracellular GAA activity (58%) in vitro was found in one sample. The clinical course did not appear to be influenced by antibody titers. Conclusions: Ninety-one percent of childhood onset Pompe patients developed anti-rhGAA antibodies (above background level), a minority of whom had high antibody titers at repeated time points, which do not seem to interfere with clinical outcome. High antibody titers may be associated with the occurrence of IARs. Although the majority of patients does not develop high titers; antibody titers should be determined in case of clinical deterioration

Home-Based Infusion of Alglucosidase Alfa Can Safely be Implemented in Adults with Late-Onset Pompe Disease: Lessons Learned from 18,380 Infusions

Background: Enzyme replacement therapy (ERT) with alglucosidase alfa is the treatment for patients with Pompe disease, a hereditary metabolic myopathy. Home-based ERT is unavailable in many countries because of the boxed warning alglucosidase alfa received due to the risk of infusion-associated reactions (IARs). Since 2008, home infusions have been provided in The Netherlands. Objectives: This study aimed to provide an overview of our experience with home-based infusions with alglucosidase alfa in adult Pompe patients, focusing on safety, including management of IARs. Method: We analysed infusion data and IARs from adult patients starting ERT between 1999 and 2018. ERT was initially given in the hospital during the first year. Patients were eligible for home treatment if they were without IARs for multiple consecutive infusions and if a trained home nurse, with on-call back-up by a doctor, was available. The healthcare providers graded IARs. Results: We analysed data on 18,380 infusions with alglucosidase alfa in 121 adult patients; 4961 infusions (27.0%) were given in hospital and 13,419 (73.0%) were given at home. IARs occurred in 144 (2.9%) hospital infusions and 113 (0.8%) home infusions; 115 (79.9% of 144) IARs in hospital and 104 (92.0% of 113) IARs at home were mild, 25 IARs (17.4%) in hospital and 8 IARs (7.1%) at home were moderate, and very few severe IARs occurred (4 IARs in hospital [2.8%] and 1 IAR at home [0.9%]). Only one IAR in the home situation required immediate clinical evaluation in the hospital. Conclusion: Given the small numbers of IARs that occurred with the home infusions, of which only one was severe, we conclude that alglucosidase alfa can be administered safely in the home situation, provided the appropriate infrastructure is present