A novel splice site mutation in ERLIN2 causes hereditary spastic paraplegia in a Saudi family

Hereditary Spastic Paraplegias (HSP) encompass a clinically and genetically heterogeneous group of neurodegenerative disorders characterized by insidiously progressive weakness and spasticity of the lower extremities. We describe a consanguineous Saudi family segregating a complicated form of HSP in an autosomal recessive pattern. The two affected siblings had early onset, cognitive, speech and motor involvement with spasticity of the lower extremities. Their upper extremities were mildly hypertonic. An intronic splice acceptor site mutation in ERLIN2 was found to be responsible for causing this disorder found in this family. ERLIN2 is a mediator of endoplasmic reticulum degradation pathway (ERAD) which helps to remove the aberrant proteins. Our results, in concurrence with previous studies suggest that alteration in ERLIN2 is one of the causes of complicated HSP, thereby increasing the spectrum of known mutations in SPG18.     

The effect of definitions of activities of daily living on estimates of changing ability among older people

Physical functioning status is often assessed using scales of activities of daily living and instrumental activities of daily living. Different ways of defining change in adequacy of performance of both activities of daily living and instrumental activities of daily living tasks may be used, including increasing difficulty in performance, the need for assistance and inability to do tasks. In this prospective study, we investigated the effect of different definitions of decline on estimates of physical function, and explored the relationships between decline in each activity of daily living individually and potential predictors. The study was based on a sample of 999 individuals aged 65 years or more who participated in a national survey of quality of life, of whom 531 (68% of those eligible for follow up) responded 12-18 months later. Different definitions of decline were used and the prevalence of decline was, depending on the individual activities of daily living item, used as an outcome in logistic regression models. The results showed that the strength of association with chronic diseases, demographic, psychological and environmental factors varied by altering the activities of daily living item used. Decline in ability to walk 400 yards was strongly associated with respiratory problems (odds ratio 3.5 [95% confidence interval 1.3-9.0]) while decline in ability to get on a bus was associated with musculoskeletal problems (odds ratio 2.8 [95% confidence interval 1.4-5.6]). In conclusion, the prevalence of decline varies by definition, and summary measures which are customarily used to describe disability, may be inadequate for the assessment and identification of predictors of decline in functional ability.     

The Target for Statins,HMG-CoA Reductase,Is Expressed in Ductal Carcinoma-In Situ and May Predict Patient Response to Radiotherapy

Background

Patients with ductal carcinoma-in-situ (DCIS) are currently not prescribed adjuvant systemic treatment after surgery and radiotherapy. Prediction of DCIS patients who would benefit from radiotherapy is warranted. Statins have been suggested to exert radio-sensitizing effects. The target for cholesterol-lowering statins is HMG-CoA reductase (HMGCR), the rate-limiting enzyme in the mevalonate pathway. The aim of this study was to examine HMGCR expression in DCIS and study its treatment predictive value.

Methods

A population-based cohort including 458 women diagnosed with primary DCIS between 1986 and 2004 were followed until November 2011 to study long-term survival. Tumor tissue microarrays were constructed, and immunohistochemical analyses were performed to detect cytoplasmic protein expression of HMGCR. The association between DCIS HMGCR expression and invasive breast cancer recurrence-free survival (RFS_inv) and overall survival (OS) was analyzed by Kaplan–Meier curves, log rank test, and Cox proportional hazard analysis.

Results

HMGCR was strongly expressed in 24 % of the assessed DCIS samples, moderately expressed in 46 %, and weakly expressed in 23 %; no expression was detected in 7 % of the samples. During the follow-up time (median 13.8 years), 61 patients were diagnosed with an invasive breast cancer recurrence, and 80 patients died. A crude analysis showed no survival benefit from radiotherapy. However, patients with strong HMGCR expression showed an improved RFS_inv (log rank, p = 0.03) and OS (log rank, p = 0.04) after radiotherapy. No statistically significant interaction was observed for HMGCR and radiotherapy (RFS_inv p = 0.69 and OS p = 0.29).

Conclusions

This study demonstrates HMGCR expression in DCIS and suggests HMGCR as a predictive marker of response to postoperative radiotherapy in DCIS, although the test for interaction was nonsignificant. Future DCIS studies addressing the potential of statin treatment targeting HMGCR are warranted.     

IgG Against Dengue Virus in Healthy Blood Donors,Zanzibar, Tanzania

We conducted a seroprevalence survey among 500 healthy adult donors at Zanzibar National Blood Transfusion Services. Dengue virus IgG seroprevalence was 50.6% and independently associated with age and urban residence. These data will aid in building a surveillance, preparedness, and response plan for dengue virus infections in the Zanzibar Archipelago.Key words: dengue, seroprevalence, Zanzibar, viruses, vector-borne infections     

The mutational spectrum of the NF1 gene in neurofibromatosis type I patients from UAE

Introduction

Germline heterozygous mutations in the tumor suppresser NF1 gene cause a cancer predisposition syndrome known as neurofibromatosis type 1 (NF1). This disease is one of the most common multisystem disorders with an estimated incidence of 1 in 3,000 to 1 in 4,000 births. Clinically, NF1 patients are prone to develop “café au lait” spots, neurofibromas, Lisch nodules, freckling of the axillary, or inguinal region and optic nerve gliomas.

Materials and methods

In the present study, we report clinical and molecular findings of five unrelated patients and seven cases from four families with NF1 from UAE. To reveal the genetic defects underlying NF1 in our cohort of patients, we screened the whole coding and splice site regions of the NF1 gene. In addition, MLPA or CGH array has been used to screen for structural variations including deletions, indels, and complex rearrangements.

Results

This resulted in the identification of five distinct novel mutations and two previously reported ones. These variations included three missense and one nonsense mutations, one single base, one dinucleotide, and one large deletion.

Conclusion

Four mutations were inherited, and the remaining were absent from both parents and therefore are “de novo” mutations. This analysis represents the spectrum of NF1 mutations in UAE and supports the premise of absence of hotspot mutations in the NF1 gene. Moreover, no obvious genotype-phenotype correlations were observed in our patients.     

Evaluation of immune responses to an oral typhoid vaccine,Ty21a,in children from 2 to 5 years of age in Bangladesh

Young children are very susceptible to typhoid fever, emphasizing the need for vaccination in under five age groups. The parenteral Vi polysaccharide vaccine is not immunogenic in children under 2 years and the oral Ty21a vaccine (Vivotif) available in capsular formulation is only recommended for those over 5 years.     

Primary ciliary dyskinesia gene contribution in Tunisia: Identification of a major Mediterranean allele

Primary ciliary dyskinesia (PCD) is a genetically heterogeneous disease of motile cilia. Even though PCD is widely studied, North‐African patients have been rarely explored. In this study, we aim at confirming the clinical diagnosis and explore the genetic spectrum of PCD in a cohort of Tunisian patients. Forty clinically diagnosed patients with PCD belonging to 34 families were recruited from Tunisian pediatric departments. In each proband, targeted capture PCD panel sequencing of the 40 PCD genes was performed. PCD panel sequencing identified bi‐allelic mutations in 82% of the families in eight PCD genes. Remarkably, 23.5% of patients carried the same c.2190del CCDC39 mutation. Single nucleotide polymorphism profiling in six unrelated patients carrying this mutation has revealed a founder effect in North‐African patients. This mutation is estimated to date back at least 1,400–1,750 years ago. The identification of this major allele allowed us to suggest a cost‐effective genetic diagnostic strategy in North‐African patients with PCD.