scholarly journals Molecular Biomarkers for Adrenoleukodystrophy: An Unmet Need

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3427
Author(s):  
Madison I. J. Honey ◽  
Yorrick R. J. Jaspers ◽  
Marc Engelen ◽  
Stephan Kemp ◽  
Irene C. Huffnagel

X-linked adrenoleukodystrophy (ALD) is an inherited progressive neurometabolic disease caused by mutations in the ABCD1 gene and the accumulation of very long-chain fatty acids in plasma and tissues. Patients present with heterogeneous clinical manifestations which can include adrenal insufficiency, myelopathy, and/or cerebral demyelination. In the absence of a genotype-phenotype correlation, the clinical outcome of an individual cannot be predicted and currently there are no molecular markers available to quantify disease severity. Therefore, there is an unmet clinical need for sensitive biomarkers to monitor and/or predict disease progression and evaluate therapy efficacy. The increasing amount of biological sample repositories (‘biobanking’) as well as the introduction of newborn screening creates a unique opportunity for identification and evaluation of new or existing biomarkers. Here we summarize and review the many studies that have been performed to identify and improve knowledge surrounding candidate molecular biomarkers for ALD. We also highlight several shortcomings of ALD biomarker studies, which often include a limited sample size, no collection of longitudinal data, and no validation of findings in an external cohort. Nonetheless, these studies have generated a list of interesting biomarker candidates and this review aspires to direct future biomarker research.

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii410-iii410
Author(s):  
Christopher Bennett ◽  
Sarah Kohe ◽  
Florence Burte ◽  
Heather Rose ◽  
Debbie Hicks ◽  
...  

Abstract SHH medulloblastoma patients have a variable prognosis. Infants (<3–5 years at diagnosis) are associated with a good prognosis, while disease-course in childhood is associated with specific prognostic biomarkers (MYCN amplification, TP53 mutation, LCA histology; all high-risk). There is an unmet need to identify prognostic subgroups of SHH tumours rapidly in the clinical setting, to aid in real-time risk stratification and disease management. Metabolite profiling is a powerful technique for characterising tumours. High resolution magic angle spinning NMR spectroscopy (HR-MAS) can be performed on frozen tissue samples and provides high quality metabolite information. We therefore assessed whether metabolite profiles could identify subsets of SHH tumours with prognostic potential. Metabolite concentrations of 22 SHH tumours were acquired by HR-MAS and analysed using unsupervised hierarchical clustering. Methylation profiling assigned the infant and childhood SHH subtypes, and clinical and molecular features were compared between clusters. Two clusters were observed. A significantly higher concentration of lipids was observed in Cluster 1 (t-test, p=0.012). Cluster 1 consisted entirely of childhood-SHH whilst Cluster 2 included both childhood-SHH and infant-SHH subtypes. Cluster 1 was enriched for high-risk markers - LCA histology (3/7 v. 0/5), MYCN amplification (2/7 v. 0/5), TP53 mutations (3/7 v. 1/5) and metastatic disease - whilst having a lower proportion of TERT mutations (0/7 v. 2/5) than Cluster 2. These pilot results suggest that (i) it is possible to identify childhood-SHH patients linked to high-risk clinical and molecular biomarkers using metabolite profiles and (ii) these may be detected non-invasively in vivo using magnetic-resonance spectroscopy.


2021 ◽  
Vol 10 (2) ◽  
pp. 243
Author(s):  
Matteo Piga ◽  
Laurent Arnaud

Systemic lupus erythematosus (SLE) is an immune-mediated multi-systemic disease characterized by a wide variability of clinical manifestations and a course frequently subject to unpredictable flares. Despite significant advances in the understanding of the pathophysiology and optimization of medical care, patients with SLE still have significant mortality and carry a risk of progressive organ damage accrual and reduced health-related quality of life. New tools allow earlier classification of SLE, whereas tailored early intervention and treatment strategies targeted to clinical remission or low disease activity could offer the opportunity to reduce damage, thus improving long-term outcomes. Nevertheless, the early diagnosis of SLE is still an unmet need for many patients. Further disentangling the SLE susceptibility and complex pathogenesis will allow to identify more accurate biomarkers and implement new ways to measure disease activity. This could represent a major step forward to find new trials modalities for developing new drugs, optimizing the use of currently available therapeutics and minimizing glucocorticoids. Preventing and treating comorbidities in SLE, improving the management of hard-to-treat manifestations including management of SLE during pregnancy are among the remaining major unmet needs. This review provides insights and a research agenda for the main challenges in SLE.


2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Xi Luo ◽  
Xiang-mei Zhang ◽  
Liu-song Wu ◽  
Jindong Chen ◽  
Yan Chen

Abstract Background α-thalassemia is relatively endemic in Guizhou province of southwestern China. To predict the clinical manifestations of α-globin gene aberration for genetic counseling, we examined the prevalence of the α-globin triplication and the genotype–phenotype correlation in this subpopulation Methods A cohort of 7644 subjects was selected from nine ethnicities covering four regions in Guizhou province of China. Peripheral blood was collected from each participant for routine blood testing and hemoglobin electrophoresis. PCR-DNA sequencing and Gap-PCR were used to identify the thalassemia gene mutations. Chi-square tests and one-way analysis of variance (ANOVA) were used to statistically analyze the data. Results We found that the frequency of α-globin triplication in Guizhou province was 0.772% (59/7644). Genotypically, the αααanti4.2/αα accounted for 0.523% (40/7644), the αααanti3.7/αα for 0.235% (18/7644), and the αααanti3.7/–SEA for 0.013% (1/7644). The αααanti4.2/αα is more prevalent than the αααanti3.7/αα in Guizhou. In addition, the frequency of the HKαα/αα (that by GAP-PCR is like αααanti4.2/-α3.7) was 0.235% (18/7644). Ethnically, the Tujia group presented the highest prevalence (2.47%) of α-globin triplication. Geographically, the highest frequency of the α-globin triplication was identified in Qiannan region (2.23%). Of the triplicated α-globin cases, 5 coinherited with heterozygote β-thalassemia and presented various clinical manifestations of anemia. Conclusions These data will be used to update the Chinese triplicated α-globin thalassemia database and provide insights into the pathogenesis of thalassemia. These findings will be helpful for the diagnosis of thalassemia and future genetic counseling in those regions.


PEDIATRICS ◽  
1975 ◽  
Vol 55 (6) ◽  
pp. 826-835 ◽  
Author(s):  
Frank M. Anderson

The subject of occult spinal dysraphism or myelodysplasia is reviewed from standpoints of embryology, clinical manifestations, and treatment, and the management of 73 cases summarized. In general, these concealed lesions arise from developmental variants in the most distal part of the neural tube, a situation which may cause distortion or partial absence of neural tissues and also lead to damage from compression or traction. Lipomyelomeningocele and congenital dermal sinus are two examples of the many types of such lesions, but some are more complicated, and borderline myelomeningocele-like forms occur. Incontinence, deformity or weakness of the feet, impaired gait, and other difficulties may appear late and increase with growth. Surgical treatment is advised to reduce chances of delayed or progressive loss of function.


2019 ◽  
Vol 2019 ◽  
pp. 1-17 ◽  
Author(s):  
Dominik Samotij ◽  
Adam Reich

Systemic lupus erythematosus (SLE) is a chronic autoimmune inflammatory disease affecting multiple organ systems that runs an unpredictable course and may present with a wide variety of clinical manifestations. Advances in treatment over the last decades, such as use of corticosteroids and conventional immunosuppressive drugs, have improved life expectancy of SLE sufferers. Unfortunately, in many cases effective management of SLE is still related to severe drug-induced toxicity and contributes to organ function deterioration and infective complications, particularly among patients with refractory disease and/or lupus nephritis. Consequently, there is an unmet need for drugs with a better efficacy and safety profile. A range of different biologic agents have been proposed and subjected to clinical trials, particularly dedicated to this subset of patients whose disease is inadequately controlled by conventional treatment regimes. Unfortunately, most of these trials have given unsatisfactory results, with belimumab being the only targeted therapy approved for the treatment of SLE so far. Despite these pitfalls, several novel biologic agents targeting B cells, T cells, or cytokines are constantly being evaluated in clinical trials. It seems that they may enhance the therapeutic efficacy when combined with standard therapies. These efforts raise the hope that novel drugs for patients with refractory SLE may be available in the near future. This article reviews the current biological therapies being tested in the treatment of SLE.


2014 ◽  
Vol 2014 ◽  
pp. 1-5
Author(s):  
Yu-Hua Chao ◽  
Kang-Hsi Wu ◽  
Han-Ping Wu ◽  
Su-Ching Liu ◽  
Ching-Tien Peng ◽  
...  

Thalassemia is highly prevalent in Taiwan, but limited data are available about the association between genotypes and clinical manifestations in Taiwanese patients with Hb H disease. Here, we studied α-globin gene abnormalities and clinical features in Taiwanese patients with Hb H disease. Of the 90 patients, sixty-four (71.1%) were deletional and twenty-six (28.9%) were nondeletional Hb H disease. The (- -SEA) type ofα0-thalassemia mutation was detected in the majority of patients (>95%). The most common genotype was (- -SEA/-α3.7), followed by (- -SEA/αcsα). After further investigation of the genotype-phenotype correlation in 68 patients, we found that patients with nondeletional Hb H disease had more severe clinical features than those with deletional Hb H disease, including younger age at diagnosis, more requirement of blood transfusions, and larger proportion of patients with splenomegaly, hepatomegaly or jaundice. This is probably a consequence of the lower hemoglobin levels and the higher Hb H levels. The clinical severity was highly variable even among patients with an identical genotype, and the diversity was much more profound among patients with (- -/αcsα) genotype. Therefore, predicting the phenotype directly from the genotype in Hb H disease remains relatively difficult in Taiwan.


Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3845-3845
Author(s):  
Anupam Sachdeva ◽  
Aditya Raina ◽  
Varinder Kumar Khanna ◽  
Subhash Chander Arya ◽  
Satya Prakash Yadav ◽  
...  

Abstract Among the inherited disorders of blood, thalassemia constitutes a major bulk of genetic diseases in India. It causes a high degree of morbidity. In a study conducted in India it has been estimated that there is a frequency of 1:2700 at the time of birth. Thus on an average 9000 new thalassemics are born every year in India.. The present study has been aimed at investigating the clinical and hematological spectrum in the above syndrome. It also assessed the prevalence of Xmn -1 polymorphism its relationship with various mutations and its role in modifying the clinical manifestations. The study was conducted on fifty patients representing 49 families and consisting of 33 males and 17 females who were homozygous for beta thalassemia and ranged in age from 3 months to 32 years. The patients were screened for common Indian mutations and their Xmn polymorphism status and this was correlated with their clinical parameters. Apositive correlation in presence of Xmn-1 polymorphism and IVS1-1 mutation was noted. There was also a correlation between age at diagnosis and also the age at first transfusion. There was a correlation between Xmn polymorphism and IVS1-1 mutation. This was found most commonly in the Punjabi Khatri community. None of the patients with blood group O had positivity of Xmn polymorphism. There was no correlation between Xmn and hemoglobin at diagnosis, HbF at diagnosis, MCV at diagnosis, amount of blood in mL/Kg/year and sex and religion.


2015 ◽  
Vol 43 (5) ◽  
pp. 937-942 ◽  
Author(s):  
Viktor Hlaváč ◽  
Pavel Souček

ATP-binding cassette (ABC) transporters, belonging to the family D, are expressed in peroxisomes, endoplasmic reticulum or lysosomes. ABCD transporters play a role in transport of lipids, bile acids and vitamin B12 and associate with peroxisomal disorders. ABCD1 performs transport of coenzyme A esters of very-long-chain fatty acids (VLCFA) in peroxisomes and a number of mutations in ABCD1 gene were linked to an X-linked adrenoleucodystrophy (X-ALD). The role of ABCD transporters in tumour growth has not been studied in detail, but there is some evidence that ABCDs levels differ between undifferentiated stem or tumour cells and differentiated cells suggesting a possible link to tumorigenesis. In this mini-review, we discuss the available information about the role of ABCD transporters in cancer.


2019 ◽  
Vol 1 ◽  
pp. 1-2
Author(s):  
Kenneth Field

<p><strong>Abstract.</strong> Cartographic education is seemingly in limbo. Courses are closing, professionally trained cartographers are dwindling in numbers and mapping is often not much more than a self-service activity. And all this against a backdrop of the massive increase in map use, the democratization of mapping and a plethora of online materials to aid the novice map-maker. We see many more maps and there’s no doubt that amongst the few gems we see many more very poorly designed maps. But what of the expertise? And what of core competencies in cartography? In a world that now uses Google and Wikipedia as the go-to sage, what of the cartographic textbook? And what of core training? In this presentation I assert that the death of cartographic expertise needs to be staunched. I’ll discuss two new mechanisms to approach the problem. First, a new book designed to re-imagine the dissemination of cartographic knowledge; a cartographic text book with a difference. Secondly, a Massive Open Online Course that, to date, has been taught to over 80,000 registrants worldwide.</p><p> In planning the book, over a number of years, it became obvious that there was a massive unmet need for a new book about thinking about cartography. A book that veers markedly from a traditional textbook yet delivers core concepts and cartographic principles in a new and engaging way. A book whose content is not tied to chapters but is immediately accessible through a unique structure and which keeps the often mystical cartographic vocabulary to a minimum. A book that supports new map-makers in a visually compelling way yet is mature enough to support practiced cartographers as a go-to companion. “Cartography.” is that book. Published in July 2018, this major new publication is designed to engage with a modern audience keen to learn how to make better maps (Figure 1). In this presentation I will explore the need for a new book and demonstrate the void that it fills in cartographic education. I’ll explain its structure as one that mirrors the map-making process - which is never one that linearly considers projections, colour, typography and so on - but one which supports the interplay of the many simultaneous decisions made in the map-making process. I’ll go into detail about the book’s design, format and content and link it clearly to modern praxis and learning environments.</p><p> Running at 550 pages with contributions from over 20 acknowledged cartographic experts and over 300 maps and illustrations, it is bold in scope and the intent is to make this a one-stop-shop for cartography, delivering the essentials in a way that makes sense to those who have never studied cartography but which will enable them to take advantage of the many ideas and approaches that define the discipline of cartography; and for those experienced cartographers that seek a companion in their everyday work. I will explain how the book differs from what has gone before and how it supports cartographic education and practice going forward.</p><p> Turning attention to other learning realms, I will also discuss the book’s companion, a Massive Open Online Course (MOOC). To date the course has run three times to over 80,000 people. It’s free and spans a 6 week period during which time students get access to videos, software, data and exercises, quizzes and access to cartographic experts via a discussion forum. Each week requires around 3&amp;ndash;4&amp;thinsp;hrs of work per week. The idea is simply to expose people to some fundamental cartographic ideas as an antidote to the simple notion that ‘anyone can make a map’. While that is true, the ability to think about the map and better understand how to make decisions to make the map better are crucial. While not the first MOOC or online course in cartography, this was developed to be a bit larger in scope than those that have gone before. Figure 2 also demonstrates the international reach of the global classroom and how it has captured the imagination.</p><p> It’s important to note that this is not a talk designed to sell anything other than the idea that we need to rethink cartographic education going forward and for cartographers to reassert their relevance as key players. The two initiatives I present her are one attempt at contributing to repositioning cartographic expertise. Going beyond the cartographic field into data visualisation, visual journalism and democratised mapping is crucial to ensure that people make maps of worth. To do that, we, as a cartographic community must find new and engaging ways, beyond our traditional approaches, to help them see that our ideas resonate and we can add value to their work.</p>


Diagnostics ◽  
2021 ◽  
Vol 11 (11) ◽  
pp. 2118
Author(s):  
Alexandra Maria Burlui ◽  
Anca Cardoneanu ◽  
Luana Andreea Macovei ◽  
Ciprian Rezus ◽  
Lucian Vasile Boiculese ◽  
...  

Systemic sclerosis (SSc) patients exhibit a plethora of risk factors for nutritional decline, including the presence of chronic inflammation and the progressive nature of disease-related multisystem involvement. The prevalence and consequences of nutritional decline in scleroderma are frequently underestimated, its management currently remaining a subject of debate. The main objective of the present study was to perform a detailed assessment of scleroderma patients’ diet as well as their eating habits and to describe the relationships with weight loss and malnutrition risk in the absence of professional nutritional counseling. Methods: We used a translated and validated version of the EPIC-Norfolk FFQ (European Prospective Investigation into Cancer and Nutrition Norfolk Food Frequency Questionnaire) to evaluate the patients’ diet and MUST (Malnutrition Universal Screening Tool) to investigate the risk of malnutrition. Disease activity was estimated using the EUSTAR-AI (European Scleroderma Trials and Research group Activity Index). Results: We included 69 patients with SSc, of which 42 underwent a detailed dietary assessment. Dietary factors were connected to body composition and digestive symptoms. We found high sodium intake and frequent suboptimal energy consumption in our study group, including patients with cardiopulmonary involvement. Liver transaminases were inversely correlated with the consumption of nuts and seeds. Malnutrition and weight loss were significantly associated with pulmonary hypertension, heart failure, albumin levels, and the extent of skin fibrosis, but not advanced age. Although the patients with EUSTAR-AI ≥ 2.5 were more frequently included in the moderate and high malnutrition risk categories, these results did not reach statistical significance. Conclusions: Currently, there is an unmet need for longitudinal and interventional research focusing on the long-term significance, ramifications, and management of nutritional impairment in SSc patients with various clinical manifestations. Our results indicate that scleroderma patients could benefit from personalized nutritional counseling in an interdisciplinary setting.


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