Genes, Vol. 9, Pages 63: Alternative Splicing of Alpha- and Beta-Synuclein Genes Plays Differential Roles in Synucleinopathies

Genes, Vol. 9, Pages 63: Alternative Splicing of Alpha- and Beta-Synuclein Genes Plays Differential Roles in Synucleinopathies

Genes doi: 10.3390/genes9020063

Authors: Ana Gámez-Valero Katrin Beyer

The synuclein family is composed of three members, two of which, α- and β-synuclein, play a major role in the development of synucleinopathies, including Parkinson’s disease (PD) as most important movement disorder, dementia with Lewy bodies (DLB) as the second most frequent cause of dementia after Alzheimer’s disease and multiple system atrophy. Whereas abnormal oligomerization and fibrillation of α-synuclein are now well recognized as initial steps in the development of synucleinopathies, β-synuclein is thought to be a natural α-synuclein anti-aggregant. α-synuclein is encoded by the SNCA gene, and β-synuclein by SNCB. Both genes are homologous and undergo complex splicing events. On one hand, in-frame splicing of coding exons gives rise to at least three shorter transcripts, and the functional properties of the corresponding protein isoforms are different. Another type of alternative splicing is the alternative inclusion of at least four initial exons in the case of SNCA, and two in the case of SNCB. Finally, different lengths of 3’ untranslated regions have been also reported for both genes. SNCB only expresses in the brain, but some of the numerous SNCA transcripts are also brain-specific. With the present article, we aim to provide a systematic review of disease related changes in the differential expression of the various SNCA and SNCB transcript variants in brain, blood, and non-neuronal tissue of synucleinopathies, but especially PD and DLB as major neurodegenerative disorders.

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Comparison of a loading dose of dexmedetomidine combined with propofol or sevoflurane for hemodynamic changes during anesthesia maintenance: a prospective, randomized, double-blind, controlled clinical trial

There may be great individual variability in the hemodynamic effects of this dexmedetomidine. For this reason, the dose must be carefully adjusted to achieve the desired clinical effect. Whether a loading dose...

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Utilization trends and safety of intravenous iron replacement in pediatric specialty care: A large retrospective cohort study

Abstract

Background

Iron deficiency is a common and clinically diverse hematologic disorder in childhood for which oral iron is often an infeasible or ineffective treatment option. Intravenous (IV) iron can be an efficient and highly successful means of iron replacement but its use has not been well-characterized on a large scale in pediatrics.

Procedure

All IV iron doses administered to patients for iron replacement therapy at a tertiary pediatric hospital from January 2010 through October 2016 were evaluated. Analyses included patient demographics, underlying medical conditions, and detailed information for each dose. Individual chart review was performed to identify infusion-related reactions. Nephrology patients as well as those patients 21 years or older at the time of the first infusion were excluded.

Results

A total of 1,088 doses of IV iron administered to 194 patients met inclusion criteria. A wide variety of specialties prescribed IV iron, with gastroenterology, hematology, and hospital medicine being the highest users in this cohort. A majority of patients (68%) required multiple infusions and dosing was highly variable, ranging from 1.3–1,030 mg per infusion. Premedication use was infrequent (10.3% of doses) and no severe infusion-associated reactions occurred.

Conclusions

IV iron is commonly prescribed by certain pediatric specialties but there is little standardization in the indications, formulations, or dosing. These data suggest that IV iron should be considered a safe alternative for iron deficiency treatment in pediatrics when oral iron is either unsuccessful or contraindicated.

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Targeted therapy for infants with diencephalic syndrome: A case report and review of management strategies

Abstract

Young children with emaciation caused by a hypothalamic glioma are considered to have diencephalic syndrome (DS), which is often poorly controlled with conventional treatment. We describe an infant with DS whose tumor progressed following chemotherapy. Biopsy was performed for molecular testing and demonstrated a BRAF fusion. Treatment with the MEK inhibitor trametinib for 18 months resulted in reduction of tumor size, normalization of his weight curve, and marked neurodevelopmental improvement. Our results build on earlier reports of using targeted agents for low-grade glioma, and we review the evolving management strategy for such patients in the era of precision medicine.

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Reirradiation in patients with diffuse intrinsic pontine gliomas: The Canadian experience

Abstract

Objective

Clinical trials have failed to demonstrate a survival benefit of adjuvant chemotherapy in diffuse intrinsic pontine gliomas (DIPG). Radiation therapy (RT) is the only effective treatment thus far and reirradiation (rRT) has become an option at the time of progression. The aim of this study was to review the Canadian experience of DIPG rRT with a focus on the safety and possible efficacy of this approach.

Method

We retrospectively reviewed the demographic, clinical, and RT data of patients with DIPG treated in Canada with rRT.

Results

Since January 2011, we identified 16 patients with progressive DIPG who received rRT. Median time from diagnosis to progression was 10.5 months (range, 4–37 months). rRT was given focally in 14 patients at a dose ranging from 21.6 to 36 Gy. rRT was well tolerated by all children but one. All but three patients showed neurological improvement. With a median follow-up from original diagnosis of 19.2 months, all patients died, with a median time from rRT to death of 6.48 months (range, 3.83–13.26 months). When compared to a historic cohort of 46 consecutive patients, the median time from progression to death was 92 days in the non-reirradiated patients versus 218 days in the reirradiated ones (P = 0.0001).

Conclusion

In this limited experience, rRT was safe and feasible in patients with progressive DIPG, providing neurological improvement and a prolonged life span in most patients. Prospective Canadian rRT protocols are ongoing to further assess the benefit of this approach, including quality of life assessment.

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Sources of parental hope in pediatric oncology

Abstract

Background

Hope is a multidimensional concept that is important for all parents of children with cancer. However, most work has focused on advanced cancer and poor prognoses. We examined hopes of all parents of children with cancer longitudinally during the first year of treatment.

Procedure

Prospective, longitudinal, questionnaire-based cohort study of parents and physicians of children with cancer at two academic pediatric hospitals. Parents reported on general sense of hopefulness and specific hopes at time of diagnosis (N = 374); a subset of parents (N = 164) were followed longitudinally at 4 and 12 months.

Results

Fifty-five percent of parents (N = 206/374) reported being extremely hopeful in general at baseline. Hopefulness did not significantly change over time, and most parents (51–58%) reported being extremely hopeful regardless of prognosis (P = 0.66). Most parents (N = 327/356) considered hope for cure to be an extremely important source of hope; most also reported hope that the child would feel loved (N = 328/356), that the child would have the best possible quality of life (N = 316/356), and that they would always do all they could for the child (N = 300/356). Hope for cure was slightly lower among parents of children with less than a 50% chance of cure at baseline (N = 53/63) when compared to those with better prognoses (moderately likely cure, N = 76/78; very likely cure, N = 198/215) (P = 0.02).

Conclusions

Many hopes contribute to parental hopefulness, not just hope for cure. This hopefulness persists over time, even when the prognosis is poor. Clinicians should focus on supporting the myriad hopes that contribute to overall hopefulness.

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Characteristics and management of ganglioneuroma and ganglioneuroblastoma-intermixed in children and adolescents

Abstract

Background

Ganglioneuromas (GNs) usually demonstrate favorable histological and clinical features. Surgery is often performed due to clinical symptoms and/or theoretical concerns that GN may transform into neuroblastoma (NB); however, several studies have identified significant GN-surgical morbidities.

Objectives

We compared the natural history, biological and clinical features of GN and ganglioneuroblastoma-intermixed (GNB-I) managed by surgery or observation to inform management and surveillance.

Procedures

This retrospective study includes patients (n = 67) with histological diagnosis of GN (50/67) and GNB-I (17/67) at the Hospital for Sick Children between 1990 and 2014. Clinical, pathological features, tumor dimensions, and management were recorded.

Results

Median age and maximal tumor diameter were 6 years (1.3–17.8) and 6.3 cm (1.4–16.9), respectively. Of the 67 patients, 46 (69%) had upfront surgery and 21 (31%) were observed. Of the 21 observed patients 4 later underwent resection. There were post-operative complications in 15 of the 50 (30%) surgical patients. The presence of imaging-defined risk factors correlated with complications (P = 0.005). Observed patients were older (median 8.4 vs. 5.3 years) and diagnosed more recently. Median growth was 0.3 cm/year and 6 of 21 had progressive disease (PD). At median follow-up of 2.2 years (0.2–14.3), all patients were alive and for those with evaluable imaging there were 27 complete and 10 partial responses, 19 stable and 6 PD. Pathology classification changed at resection for three cases, but no GN was reclassified to NB.

Conclusions

GN and GNB-I have a slow growth rate and resection can be associated with significant morbidity. Watch and wait approaches should be considered for some GN and GNB-I.

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