Soluble M6P/IGFIIR in the Circulation
2015-08-24 09:51:19 AM
Publication date: Available online 15 August 2015
Source:Best Practice & Research Clinical Endocrinology & Metabolism
Author(s): Carolyn D. Scott, Wieland Kiess
Soluble M6P/IGFIIR has the potential to be a significant carrier of IGF-II and mannose 6-P proteins in the circulation and play an important role as an antagonist to the cellular receptor. Evidence suggests that soluble receptor plays a role in fetal and childhood growth by opposing the growth stimulatory effects of IGF-II. Maternal serum levels of M6P/IGFIIR are elevated in late pregnancy and the IGF-II:soluble M6P/IGFIIR ratio in cord blood correlates strongly with weight at birth and placental weight suggesting an important role in fetal growth and development. However, elevated soluble receptor levels may also be indicative of disease in later life, such as liver cirrhosis and some tumour types and may be a useful marker for monitoring treatment and progression of the disease. Further investigation of the regulation of this soluble receptor in health and disease is required to fully elucidate its role in the circulation.Preface
2015-08-24 09:51:19 AM
Publication date: August 2015
Source:Best Practice & Research Clinical Endocrinology & Metabolism, Volume 29, Issue 4
Author(s): Paolo Beck-PeccozClassical nuclear hormone receptor activity as a mediator of complex biological responses: A look at health and disease
2015-08-24 09:51:19 AM
Publication date: August 2015
Source:Best Practice & Research Clinical Endocrinology & Metabolism, Volume 29, Issue 4
Author(s): Paul Michael Yen
Nuclear hormone receptors are a large family of receptors that bind a wide range of lipolic hormones and intracellular ligands. They act as ligand-inducible transcription factors to regulate the expression of target genes and play important roles in normal development, reproduction, and metabolism. NRs bind to hormones steroids, thyroid hormone, and vitamin D as well as metabolites of fatty acids, cholesterol, and bild acids. Orphan receptors are another group of NRs for which no known ligands have been identified yet but appear to have major roles in regulating intracellular metabolism. Targeting NRs has been a major source for the development of new drugs, particularly selective agonists and antagonists for cancer and metabolic diseases. Additionally, hormone resistance syndromes in man have enlarged our understanding of the functions of specific NRs and their isoforms as well as genetic mechanisms for phenotype expression.Noncoding RNAs and the control of signalling via nuclear receptor regulation in health and disease
2015-08-24 09:51:19 AM
Publication date: August 2015
Source:Best Practice & Research Clinical Endocrinology & Metabolism, Volume 29, Issue 4
Author(s): Paul Cathcart, Walter Lucchesi, Silvia Ottaviani, Alex De Giorgio, Jonathan Krell, Justin Stebbing, Leandro Castellano
Nuclear receptors belong to a superfamily of proteins that play central roles in human biology, orchestrating a large variety of biological functions in both health and disease. Understanding the interactions and regulatory pathways of NRs will allow development of potential therapeutic interventions for a multitude of disease processes. Non-coding RNAs have recently been discovered to have significant interactions with NR signalling pathways via a variety of biological connections. This review summarises the known interactions between ncRNAs and the NR superfamily in health, embryogenesis and a plethora of human diseases.Specificity and sensitivity of glucocorticoid signaling in health and disease
2015-08-24 09:51:19 AM
Publication date: August 2015
Source:Best Practice & Research Clinical Endocrinology & Metabolism, Volume 29, Issue 4
Author(s): Derek W. Cain, John A. Cidlowski
Endogenous glucocorticoids regulate a variety of physiologic processes and are crucial to the systemic stress response. Glucocorticoid receptors are expressed throughout the body, but there is considerable heterogeneity in glucocorticoid sensitivity and induced biological responses across tissues. The immunoregulatory properties of glucocorticoids are exploited in the clinic for the treatment of inflammatory and autoimmune disorders as well as certain hematological malignancies, but adverse side effects hamper prolonged use. Fully understanding the molecular events that shape the physiologic effects of glucocorticoid treatment will provide insight into optimal glucocorticoid therapies, reliable assessment of glucocorticoid sensitivity in patients, and may advance the development of novel GR agonists that exert immunosuppressive effects while avoiding harmful side effects. In this review, we provide an overview of mechanisms that affect glucocorticoid specificity and sensitivity in health and disease, focusing on the distinct isoforms of the glucocorticoid receptor and their unique regulatory and functional properties.Estrogen receptor alpha and beta in health and disease
2015-08-24 09:51:19 AM
Publication date: August 2015
Source:Best Practice & Research Clinical Endocrinology & Metabolism, Volume 29, Issue 4
Author(s): Min Jia, Karin Dahlman-Wright, Jan-Åke Gustafsson
Estrogen receptors alpha (ERα) and beta (ERβ) are transcription factors that are involved in the regulation of many complex physiological processes in humans. Abnormal ER signaling leads to development of a variety of diseases, such as cancer, metabolic and cardiovascular disease, neurodegeneration, inflammation, and osteoporosis. This review provides an overview and update on ERα and ERβ in health and disease with focus on their role in cancer and metabolic disease and in the context of recent years' success in providing genome wide data on ER function. Furthermore, potential clinical applications and challenges are also discussed.Androgen insensitivity syndrome
2015-08-24 09:51:19 AM
Publication date: August 2015
Source:Best Practice & Research Clinical Endocrinology & Metabolism, Volume 29, Issue 4
Author(s): Nigel P. Mongan, Rieko Tadokoro-Cuccaro, Trevor Bunch, Ieuan A. Hughes
Androgen insensitivity syndrome (AIS) results from androgen receptor dysfunction and is a common cause of disorder of sex development. The AIS phenotype largely depends on the degree of residual androgen receptor (AR) activity. This review describes the molecular action of androgens and the range of androgen receptor gene mutations, essential knowledge to understand the pathogenesis of the complete and partial forms of this syndrome. A multidisciplinary approach is recommended for clinical management from infancy through to adulthood. Hormone replacement therapy is needed following gonadectomy. Patients who choose to retain the gonads are at risk of developing germ cell tumors for which sensitive circulating tumor markers may soon become available. Whilst the contribution of AR dysfunction to complete AIS is well understood, the involvement of the AR and associated proteins as contributors to partial AIS is an area of active research. Disorders of sex development such as AIS which are related to AR dysfunction offer a breadth of manifestations for the clinician to manage and opportunities for further research on the mechanism of androgen action.Overlapping nongenomic and genomic actions of thyroid hormone and steroids
2015-08-24 09:51:19 AM
Publication date: August 2015
Source:Best Practice & Research Clinical Endocrinology & Metabolism, Volume 29, Issue 4
Author(s): Stephen R. Hammes, Paul J. Davis
The genomic actions of thyroid hormone and steroids depend upon primary interactions of the hormones with their specific nuclear receptor proteins. Formation of nuclear co-activator or co-repressor complexes involving the liganded receptors subsequently result in transcriptional events—either activation or suppression—at genes that are specific targets of thyroid hormone or steroids. Nongenomic actions of thyroid hormone and steroids are in contrast initiated at binding sites on the plasma membrane or in cytoplasm or organelles and do not primarily require formation of intranuclear receptor protein-hormone complexes. Importantly, hormonal actions that begin nongenomically outside the nucleus often culminate in changes in nuclear transcriptional events that are regulated by both traditional intranuclear receptors as well as other nuclear transcription factors. In the case of thyroid hormone, the extranuclear receptor can be the classical "nuclear" thyroid receptor (TR), a TR isoform, or integrin αvβ3. In the case of steroid hormones, the membrane receptor is usually, but not always, the classical "nuclear" steroid receptor. This concept defines the paradigm of overlapping nongenomic and genomic hormone mechanisms of action. Here we review some examples of how extranuclear signaling by thyroid hormone and by estrogens and androgens modulates intranuclear hormone signaling to regulate a number of vital biological processes both in normal physiology and in cancer progression. We also point out that nongenomic actions of thyroid hormone may mimic effects of estrogen in certain tumors.Androgen receptor roles in spermatogenesis and infertility
2015-08-24 09:51:19 AM
Publication date: August 2015
Source:Best Practice & Research Clinical Endocrinology & Metabolism, Volume 29, Issue 4
Author(s): Laura O'Hara, Lee B. Smith
Androgens such as testosterone are steroid hormones essential for normal male reproductive development and function. Mutations of androgen receptors (AR) are often found in patients with disorders of male reproductive development, and milder mutations may be responsible for some cases of male infertility. Androgens exert their action through AR and its signalling in the testis is essential for spermatogenesis. AR is not expressed in the developing germ cell lineage so is thought to exert its effects through testicular Sertoli and peri-tubular myoid (PTM) cells. AR signalling in spermatogenesis has been investigated in rodent models where testosterone levels are chemically supressed or models with transgenic disruption of AR. These models have pinpointed the steps of spermatogenesis that require AR signalling, specifically maintenance of spermatogonial numbers, blood-testis barrier integrity, completion of meiosis, adhesion of spermatids and spermiation, together these studies detail the essential nature of androgens in the promotion of male fertility.DAX-1 (NR0B1) and steroidogenic factor-1 (SF-1, NR5A1) in human disease
2015-08-24 09:51:19 AM
Publication date: August 2015
Source:Best Practice & Research Clinical Endocrinology & Metabolism, Volume 29, Issue 4
Author(s): Jenifer P. Suntharalingham, Federica Buonocore, Andrew J. Duncan, John C. Achermann
DAX-1 (NR0B1) and SF-1 (NR5A1) are two nuclear receptor transcription factors that play a key role in human adrenal and reproductive development. Loss of DAX-1 function is classically associated with X-linked adrenal hypoplasia congenita. This condition typically affects boys and presents as primary adrenal insufficiency in early infancy or childhood, hypogonadotropic hypogonadism at puberty and impaired spermatogenesis. Late onset forms of this condition and variant phenotypes are increasingly recognized. In contrast, disruption of SF-1 only rarely causes adrenal insufficiency, usually in combination with testicular dysgenesis. Variants in SF-1/NR5A1more commonly cause a spectrum of reproductive phenotypes ranging from 46,XY DSD (partial testicular dysgenesis or reduced androgen production) and hypospadias to male factor infertility or primary ovarian insufficiency. Making a specific diagnosis of DAX-1 or SF-1 associated conditions is important for long-term monitoring of endocrine and reproductive function, appropriate genetic counselling for family members, and for providing appropriate informed support for young people.Vitamin D signaling in calcium and bone homeostasis: A delicate balance
2015-08-24 09:51:19 AM
Publication date: August 2015
Source:Best Practice & Research Clinical Endocrinology & Metabolism, Volume 29, Issue 4
Author(s): Geert Carmeliet, Veronique Dermauw, Roger Bouillon
Loss-of-function mutations in genes involved in the vitamin D/vitamin D receptor system have clearly evidenced its critical role for mineral and skeletal homeostasis. Adequate levels of 1,25-dihydroxyvitamin D [1,25(OH)2D], the active form of vitamin D are therefore required and depend on sufficient sunlight exposure or dietary intake. Intestinal calcium absorption is a primary target of 1,25(OH)2D action and this pathway indirectly promotes calcium incorporation in bone. Severe vitamin D deficiency may thus decrease bone quality and leads to osteomalacia, whereas less severe deficiency increases the risk of osteoporosis and bone fractures. On the other hand, high vitamin D levels together with low dietary calcium intake will increase bone resorption and decrease bone mineralization in order to maintain normal serum calcium levels. Appropriate dietary calcium intake and sufficient serum vitamin D levels are thus important for skeletal health. Dosing of calcium and vitamin D supplements is still debated and requires further investigation.Inherited forms of mineralocorticoid hypertension
2015-08-24 09:51:19 AM
Publication date: August 2015
Source:Best Practice & Research Clinical Endocrinology & Metabolism, Volume 29, Issue 4
Author(s): Maria-Christina Zennaro, Sheerazed Boulkroun, Fabio Fernandes-Rosa
Aldosterone plays an essential role in the maintenance of fluid and electrolyte homeostasis in the distal nephron. Monogenic forms of mineralocorticoid hypertension result from genetic defects leading to excessive production of aldosterone (or other mineralocorticoids) from the adrenal cortex or to illegitimate mineralocorticoid effects in the kidney. They are characterized in the majority of cases by early onset, severe or resistant hypertension and associated with suppressed renin levels. Depending on their causes, these diseases are distinguished at the clinical and biochemical level and differently affect aldosterone levels and kalemia. The diagnosis is confirmed by genetic testing, which allows in many cases targeted treatment to prevent severe cardiovascular consequences of high blood pressure or aldosterone excess. In this review we describe the different forms of inherited mineralocorticoid hypertension, providing an overview of their clinical and biochemical features, their underlying genetic defects and specific therapeutic options.Resistance to thyroid hormone due to defective thyroid receptor alpha
2015-08-24 09:51:19 AM
Publication date: August 2015
Source:Best Practice & Research Clinical Endocrinology & Metabolism, Volume 29, Issue 4
Author(s): Carla Moran, Krishna Chatterjee
Thyroid hormones act via nuclear receptors (TRα1, TRβ1, TRβ2) with differing tissue distribution; the role of α2 protein, derived from the same gene locus as TRα1, is unclear. Resistance to thyroid hormone alpha (RTHα) is characterised by tissue-specific hypothyroidism associated with near-normal thyroid function tests. Clinical features include dysmorphic facies, skeletal dysplasia (macrocephaly, epiphyseal dysgenesis), growth retardation, constipation, dyspraxia and intellectual deficit. Biochemical abnormalities include low/low-normal T4 and high/high-normal T3 concentrations, a subnormal T4/T3 ratio, variably reduced reverse T3, raised muscle creatine kinase and mild anaemia. The disorder is mediated by heterozygous, loss-of-function, mutations involving either TRα1 alone or both TRα1 and α2, with no discernible phenotype attributable to defective α2. Whole exome sequencing and diagnostic biomarkers may enable greater ascertainment of RTHα, which is important as thyroxine therapy reverses some metabolic abnormalities and improves growth, constipation, dyspraxia and wellbeing. The genetic and phenotypic heterogeneity of RTHα and its optimal management remain to be elucidated.Keyword index
2015-08-24 09:51:19 AM
Publication date: August 2015
Source:Best Practice & Research Clinical Endocrinology & Metabolism, Volume 29, Issue 4The soluble interleukin-6 receptor and related proteins
2015-08-24 09:51:19 AM
Publication date: Available online 8 July 2015
Source:Best Practice & Research Clinical Endocrinology & Metabolism
Author(s): Stefan Rose-John
Interleukin-6 is a cytokine involved in the regulation of the immune system and the central nervous system. Interleukin-6 binds to an interleukin-6 receptor, and then associates with a dimer of the ubiquitously expressed gp130 receptor subunit, which initiates intracellular signaling. The interleukin-6 receptor is found in a soluble form, which is generated by proteolytic cleavage and also to a minor extent by translation from an alternatively spliced mRNA. The complex of interleukin-6 bound to the interleukin-6 receptor can stimulate cells, which only express gp130. Such cells are not responsive to interleukin-6 alone. We have for the first time identified the molecular basis of pro-and anti-inflammatory properties of interleukin-6 and we have defined the generation of the soluble IL-6R as a crucial point in the regulation between these two properties. Furthermore, we have deduced a therapeutic principle, which enables us to exclusively block the pro-inflammatory activities of this important cytokine.Physiology and pathophysiology of IGFBP-1 and IGFBP-2 – Consensus and dissent on metabolic control and malignant potential
2015-08-24 09:51:19 AM
Publication date: Available online 8 July 2015
Source:Best Practice & Research Clinical Endocrinology & Metabolism
Author(s): Andreas Hoeflich, Vincenzo C. Russo
IGFBP-1 and IGFBP-2 are suppressed by growth hormone and therefore represent less prominent members of the IGFBP family when compared to IGFBP-3 that carries most of the IGFs during circulation under normal conditions in humans in vivo. As soon as the GH signal is decreased expression of IGF-I and IGFBP-3 is reduced. Under conditions of lowered suppression by GH the time seems come for IGFBP-1 and IGFBP-2. Both IGFBPs are potent effectors of growth and metabolism. Secretion of IGFBP-1 and IGFBP-2 is further suppressed by insulin and diminished with increasing obesity. Both IGFBP family members share the RGD sequence motif that mediates binding to integrins and is linked to PTEN/PI3K signalling. In mice, IGFBP-2 prevents age- and diet-dependent glucose insensitivity and blocks differentiation of preadipocytes. The latter function is modulated by two distinct heparin-binding domains of IGFBP-2 which are lacking in IGFBP-1. IGFBP-2 is further regulated by leptin and has been demonstrated to affect insulin sensitivity and glucose tolerance, further supporting a particular role of IGFBP-2 in glucose and fat metabolism. Since IGFBP-2 is controlled by sex steroids as well, we devised a scheme to compare IGFBP effects in breast, ovarian and prostate cancer. While a positive association does not seem to exist with IGFBP-1 and risk of cancers within these reproductive tissues, a relationship between IGFBP-2 and breast cancer, ovarian cancer and prostate cancer does indeed appear to be present. To date, the specific roles of IGFBP-2 in estrogen signalling are unclear, though there is accumulating evidence for an effect of IGFBP-2 on PI3K signalling via PTEN, particularly in breast cancer.Behind the scenes of vitamin D binding protein: More than vitamin D binding
2015-08-24 09:51:19 AM
Publication date: Available online 2 July 2015
Source:Best Practice & Research Clinical Endocrinology & Metabolism
Author(s): Joris R. Delanghe, Reinhart Speeckaert, Marijn M. Speeckaert
Although being discovered in 1959, the number of published papers in recent years reveals that vitamin D binding protein (DBP), a member of the albuminoid superfamily, is a hot research topic. Besides the three major phenotypes (DBP1F, DBP1S and DBP2), more than 120 unique variants have been described of this polymorphic protein. The presence of DBP has been demonstrated in different body fluids (serum, urine, breast milk, ascitic fluid, cerebrospinal fluid, saliva and seminal fluid) and organs (brain, heart, lungs, kidneys, placenta, spleen, testes and uterus). Although the major function is binding, solubilization and transport of vitamin D and its metabolites, the name of this glycoprotein hides numerous other important biological functions. In this review, we will focus on the analytical aspects of the determination of DBP and discuss in detail the multifunctional capacity [actin scavenging, binding of fatty acids, chemotaxis, binding of endotoxins, influence on T cell response and influence of vitamin D binding protein-macrophage activating factor (DBP-MAF) on bone metabolism and cancer] of this abundant plasma protein.The biomarker sex hormone-binding globulin – From established applications to emerging trends in clinical medicine
2015-08-24 09:51:19 AM
Publication date: Available online 30 June 2015
Source:Best Practice & Research Clinical Endocrinology & Metabolism
Author(s): Markus A. Thaler, Vanadin Seifert-Klauss, Peter B. Luppa
Sex hormone-binding globulin (SHBG) is a serum glycoprotein exhibiting the unique feature of binding sex steroids with high affinity and specificity. Its serum levels are regulated not only by androgens and estrogens but also by thyroid hormones and other metabolic factors. Several disease conditions are accompanied by altered SHBG levels such as hyper- and hypoandrogenism, thyroid disorders, pituitary diseases, liver disorders, and breast as well as prostate cancer. Additionally, several drugs and alcohol consumption influence serum concentrations of SHBG. In some cases, altered SHBG levels are a specific result of the underlying pathology. In others, they merely constitute an epiphenomenon, which still might offer the possibility of using serum measurements of SHBG as surrogate marker. This review article portrays the different disorders associated with altered SHBG levels and discusses the usefulness of SHBG as disease biomarker from a clinicians as well as from an endocrinological researchers point of view.Insulin-like growth factor binding proteins 4-6
2015-08-24 09:51:19 AM
Publication date: Available online 27 June 2015
Source:Best Practice & Research Clinical Endocrinology & Metabolism
Author(s): Leon A. Bach
Insulin-like growth factor binding proteins (IGFBPs) 4-6 have important roles as modulators of IGF actions. IGFBP-4 and IGFBP-6 predominantly inhibit IGF actions, whereas IGFBP-5 may enhance these actions under some circumstances. IGFBP-6 is unique among the IGFBPs for its marked IGF-II binding preference. IGFBPs 4-6 are found in the circulation as binary complexes with IGFs that can enter tissues. Additionally, about half of the circulating IGFBP-5 is found in ternary complexes with IGFs and an acid labile subunit; this high molecular complex cannot leave the circulation and acts as an IGF reservoir. IGFBPs 4-6 also have IGF-independent actions. These IGFBPs are regulated in a cell-specific manner and their dysregulation may play a role in a range of diseases including cancer. However, there is no clear clinical indication for measuring serum levels of these IGFBPs at present.Insulin-like growth factor binding-protein-3 (IGFBP–3)
2015-08-24 09:51:19 AM
Publication date: Available online 27 June 2015
Source:Best Practice & Research Clinical Endocrinology & Metabolism
Author(s): Michael B. Ranke
The IGF system comprises two IGFs (IGF-1, IGF-2), two IGF-receptors (IGF-R1, IGF-R2), and six IGF binding proteins (IGFBPs) with a high affinity for IGFs. The IGFBPs, of which IGFBP-3 is the most abundant in postnatal blood, link with IGFs and prevent them from being degraded; they also facilitate IGF transport through body compartments. The interaction between IGFs and their specific receptors is partly regulated by structural modifications inherent to the IGFBPs. IGFBPs also have IGF-independent biological effects. Since serum IGFBP-3 is GH-dependent and correlates quantitatively with GH secretion, its measurement is useful in tests of abnormal GH secretion. Particularly during childhood, IGFBP-3 values play an important role in ascertaining alterations in GH secretion and action (i.e., primary IGF deficiency states). A new role for IGFBP-3 and other IGFBPs with natural or altered structures is likely to be established through current studies investigating their application in promoting apoptotic processes in malignancies.Growth hormone binding protein – Physiological and analytical aspects
2015-08-24 09:51:19 AM
Publication date: Available online 27 June 2015
Source:Best Practice & Research Clinical Endocrinology & Metabolism
Author(s): Katharina Schilbach, Martin Bidlingmaier
A significant proportion of total circulating growth hormone (GH) is bound to a high affinity growth hormone binding protein (GHBP). Several low affinity binding proteins have also been described. Significant differences between species exist with respect to origin and regulation of GHBP, but generally it resembles the extracellular domain of the GH receptor. Concentrations are associated with GH status, body composition and other factors. Although the clinical relevance of GHBP is not fully understood it is suggested that concentrations indirectly reflect GH receptor status. This is supported by cases of Laron's syndrome where a molecular defect in the extracellular domain of the GH receptor is associated with low or unmeasurable GHBP concentrations. Methods to measure GHBP have evolved from chromatographic, activity based procedures to direct immunoassays. In clinical practice, measurement of GHBP can be helpful to differentiate between GH deficiency and GH insensitivity, particularly if GHBP is absent.Preface
2015-08-24 09:51:19 AM
Publication date: June 2015
Source:Best Practice & Research Clinical Endocrinology & Metabolism, Volume 29, Issue 3
Author(s): Wieland Kiess, George WertherClosed loop insulin delivery in diabetes
2015-08-24 09:51:19 AM
Publication date: June 2015
Source:Best Practice & Research Clinical Endocrinology & Metabolism, Volume 29, Issue 3
Author(s): Tadej Battelino, Jasna Šuput Omladič, Moshe Phillip
The primary goal of type 1 diabetes treatment is attaining near-normal glucose values. This currently remains out of reach for most people with type 1 diabetes despite intensified insulin treatment in the form of insulin analogues, educational interventions, continuous glucose monitoring, and sensor augmented insulin pump. The main remaining problem is risk of hypoglycaemia, which cannot be sufficiently reduced in all patient groups. Additionally, patients' burn-out often develops with years of tedious day-to-day diabetes management, rendering available diabetes-related technology less efficient. Over the past 40 years, several attempts have been made towards computer-programmed insulin delivery in the form of closed loop, with faster developments especially in the past decade. Automated insulin delivery has reduced human error in glycaemic control and considerably lessened the burden of routine self-management. In this chapter, data from randomized controlled trials with closed-loop insulin delivery that included type 1 diabetes population are summarized, and an evidence-based vision for possible routine utilization of closed loop is provided.Childhood obesity: Current and novel approaches
2015-08-24 09:51:19 AM
Publication date: June 2015
Source:Best Practice & Research Clinical Endocrinology & Metabolism, Volume 29, Issue 3
Author(s): Matthew A. Sabin, Wieland Kiess
The prevalence of childhood obesity has increased over the last fifty years by approximately 5% per decade, and approximately a quarter of all children are now either overweight or obese. These children have a significantly increased risk of many future health problems including adult obesity, type 2 diabetes and heart disease. Despite this relentless increase, common-sense approaches aimed at prevention and treatment have failed to solve the problem. Current approaches at prevention have faced major challenges with some progress in implementing smaller scale programs and social marketing, but little action on broad public policy approaches which often appears unpalatable to society or individual governments. Meanwhile, treatment approaches have mainly focused on lifestyle change, and novel approaches are urgently needed. Prevention needs to shift to improving maternal health prior to conception, with more research focussed on the impact of early years in programming offspring to future overweight/obesity. Likewise, treatment paradigms need to move from simply thinking that obesity can be solved by readdressing diet and activity levels. Novel approaches are needed which take into consideration the complex physiology which regulates early childhood growth and the development of obesity in susceptible individuals.Hormone replacement therapy in children: The use of growth hormone and IGF-I
2015-08-24 09:51:19 AM
Publication date: June 2015
Source:Best Practice & Research Clinical Endocrinology & Metabolism, Volume 29, Issue 3
Author(s): Roland Pfäffle
Recombinant human GH (rhGH) has been available since 1985. This article gives an overview, what has been achieved over the past 30 years in respect to optimization of rhGH treatment for the individual child with GH deficiency and what are the safety issues concerned with this treatment. In the last twenty years significant scientific progress has been made in the diagnosis of GH deficiency, the genetic disorders that are associated with pituitary GH deficiency and the genetics that influence growth in general. On the other hand rhGH is not only used in states of GH deficiency but also various conditions without a proven GH deficiency by classical standards. Clinical studies that investigated both the genetics of growth and the individual responses to rhGH therapy in these patient populations were able to refine our concept about the physiology of normal growth. In most patients under rhGH treatment there is a considerable short-term effect, however the overall gain in growth obtained by a long-term treatment until final height still remains a matter of debate in some of the conditions treated. Also first studies on the long-term safety risks of rhGH treatment have raised the question whether this treatment is similarly safe for all the patient groups eligible for such a treatment. Therefore even in the face of a longstanding safety record of this drug replacement therapy the discussion about the right cost and risk to benefit ratio is continuing. Consequently there is still a need for carefully conducted long-term studies that use modern anthropometric, genetic, and laboratory techniques in order to provide the necessary information for clinicians to select the patients that will benefit best from this valuable treatment without any long term risk.Novel approaches to short stature therapy
2015-08-24 09:51:19 AM
Publication date: June 2015
Source:Best Practice & Research Clinical Endocrinology & Metabolism, Volume 29, Issue 3
Author(s): Jan M. Wit, Wilma Oostdijk
Besides growth hormone, several pharmaceutical products have been investigated for efficacy and safety in increasing short term growth or adult height. Short-term treatment with testosterone esters in boys with constitutional delay of growth and puberty is efficacious in generating secondary sex characteristics and growth acceleration. The addition of oxandrolone to growth hormone (GH) in Turner syndrome has an additive effect on adult height gain. Treatment with GnRH analogs is the established treatment of central precocious puberty, and its addition to GH therapy appears effective in increasing adult height in GH deficient children, and possibly short children born SGA or with SHOX deficiency, who are still short at pubertal onset. Aromatase inhibitors appear effective in several rare disorders, but their value in increasing adult height in early pubertal boys with GH deficiency or idiopathic short stature is uncertain. A trial with a C-natriuretic peptide analog offers hope for children with achondroplasia.Pubertal induction in hypogonadism: Current approaches including use of gonadotrophins
2015-08-24 09:51:19 AM
Publication date: June 2015
Source:Best Practice & Research Clinical Endocrinology & Metabolism, Volume 29, Issue 3
Author(s): Margaret Zacharin
Primary disorders of the gonad or those secondary to abnormalities of the hypothalamic pituitary axis result in hypogonadism. The range of health problems of childhood and adolescence that affect this axis has increased, as most children now survive chronic illness, but many have persisting deficits in gonadal function as a result of their underlying condition or its treatment. An integrated approach to hormone replacement is needed to optimize adult hormonal and bone health, and to offer opportunities for fertility induction and preservation that were not considered possible in the past. Timing of presentation ranges from birth, with disorders of sexual development, through adolescent pubertal failure, to adult fertility problems. This review addresses diagnosis and management of hypogonadism and focuses on new management strategies to address current concerns with fertility preservation. These include Turner syndrome, and fertility presevation prior to childhood cancer treatment. New strategies for male hormone replacement therapy that may impinge upon future fertility are emphasized.Complications of vitamin D deficiency from the foetus to the infant: One cause, one prevention, but who's responsibility?
2015-08-24 09:51:19 AM
Publication date: June 2015
Source:Best Practice & Research Clinical Endocrinology & Metabolism, Volume 29, Issue 3
Author(s): Wolfgang Högler
Calcium and phosphorus represent building material for bones. The supplier of these bone minerals is the hormone calcitriol, which originates from vitamin D, itself made by sunshine in human skin. Requirement for bone minerals is highest during phases of rapid growth, and no one grows faster than the foetus and the infant, making them particularly vulnerable. Deprivation of calcium, whether through low calcium intake or low vitamin D, leads to serious health consequences throughout life, such as hypocalcaemic seizures, dilated cardiomyopathy, skeletal myopathy, congenital and infantile rickets, and osteomalacia. These 5 conditions are often summarised as 'symptomatic vitamin D deficiency', are fully reversible but also fully preventable. However, the increasing prevalence of rickets and osteomalacia, and the deaths from hypocalcaemic cardiomyopathy, demand action from global health care providers. Clarification of medical and parental responsibilities is a prerequisite to deliver successful prevention programmes. The foetus and infant have the human right to be protected against harm, and vitamin D supplementation has the same public health priority as vaccinations.Treatment of congenital thyroid dysfunction: Achievements and challenges
2015-08-24 09:51:19 AM
Publication date: June 2015
Source:Best Practice & Research Clinical Endocrinology & Metabolism, Volume 29, Issue 3
Author(s): Heiko Krude, Peter Kühnen, Heike Biebermann
The active thyroid hormone tri-iodothyronine (T3) is essential for a normal development of children. Especially within the first years of life, thyroid hormone is pivotal in enabling maturation of complex brain function and somatic growth. The most compelling example for a life without thyroid hormone are those historical cases of children who came to birth without a thyroid gland – as shown in autopsy-studies- and who suffered from untreated hypothyroidism, at that time initially called "sporadic congenital hypothyroidism" (CH). In the last decades huge achievements resulted in a normal development of these children based on newborn screening programs that enable an early onset of a high dose LT4-treatment. Further progress will be necessary to further tailor an individualized thyroid hormone substitution approach and to identify those more complex patients with congenital hypothyroidism and associated defects, who will not benefit from an even optimized LT4 therapy.Besides the primary production of thyroid hormone a variety of further mechanisms are necessary to mediate the function of T3 on normal development that are located downstream of thyroid hormone production. Abnormalities of these mechanisms include the MCT8-transport defect, deiodinase-insufficiency and thyroid hormone receptor alpha-and beta defects. These thyroid hormone resistant diseases can not be treated with classical LT4 substitution alone. The development of new treatment options for those rare cases of thyroid hormone resistance is one of the most challenging tasks in the field of congenital thyroid diseases today.Management of diabetes insipidus and adipsia in the child
2015-08-24 09:51:19 AM
Publication date: June 2015
Source:Best Practice & Research Clinical Endocrinology & Metabolism, Volume 29, Issue 3
Author(s): Natascia Di Iorgi, Giovanni Morana, Flavia Napoli, Anna Elsa Maria Allegri, Andrea Rossi, Mohamad Maghnie
Central diabetes insipidus (CDI) is a complex and heterogeneous clinical syndrome affecting the hypothalamic-neurohypophyseal network and water balance. A recent national surveillance in Denmark showed a prevalence rate of twenty-three CDI patients per 100 000 inhabitants in five years. The differential diagnosis between several presenting conditions with polyuria and polydipsia is puzzling, and the etiological diagnosis of CDI remains a challenge before the identification of an underlying cause. For clinical practice, a timely diagnosis for initiating specific treatment in order to avoid central nervous system damage, additional pituitary defects and the risk of dissemination of germ cell tumor is advisable. Proper etiological diagnosis can be achieved via a series of steps that start with careful clinical observation of several signs and endocrine symptoms and then progress to more sophisticated imaging tools. This review summarizes the best practice and approach for the diagnosis and treatment of patients with CDI.Hormone replacement in disorders of sex development: Current thinking
2015-08-24 09:51:19 AM
Publication date: June 2015
Source:Best Practice & Research Clinical Endocrinology & Metabolism, Volume 29, Issue 3
Author(s): Jacqueline Hewitt, Margaret Zacharin
Congenital disruptions of sex hormone production lead to wide-ranging developmental and physiological effects in individuals who have atypical chromosomal, gonadal or anatomic sex. Aberrant developmental sex hormone exposure causes disorders of genital anatomy, attainment of secondary sexual characteristics and has long-term effects on metabolism, fertility and psychological functioning. Principles in the management of disorders of sex development (DSD) aim to improve physiological health and long-term outcome, as well as development of male or female sexual anatomy. Concerns raised by DSD patient advocacy groups about beneficence and autonomy with respect to prescribed hormone treatments and avoidance of unnecessary genital and gonadal surgery have demanded greater informed consent and attention to long-term outcome. Hormone treatment is influenced by underlying clinical diagnosis and by factors such as sex of rearing and gender identity of the affected individual. We describe diagnostic criteria for different DSDs, clinical considerations in management protocols, together with current concepts and detailed practical hormone treatments for male and female individuals with DSD. Gender identity issues requiring multidisciplinary consensus, ethical consideration and informed consent or assent from the young person are also addressed.Current and novel approaches to children and young people with congenital adrenal hyperplasia and adrenal insufficiency
2015-08-24 09:51:19 AM
Publication date: June 2015
Source:Best Practice & Research Clinical Endocrinology & Metabolism, Volume 29, Issue 3
Author(s): Emma A. Webb, Nils Krone
Congenital adrenal hyperplasia (CAH) represents a group of autosomal recessive conditions leading to glucocorticoid deficiency. CAH is the most common cause of adrenal insufficiency (AI) in the paediatric population. The majority of the other forms of primary and secondary adrenal insufficiency are rare conditions. It is critical to establish the underlying aetiology of each specific condition as a wide range of additional health problems specific to the underlying disorder can be found. Following the introduction of life-saving glucocorticoid replacement sixty years ago, steroid hormone replacement regimes have been refined leading to significant reductions in glucocorticoid doses over the last two decades. These adjustments are made with the aim both of improving the current management of children and young persons and of reducing future health problems in adult life. However despite optimisation of existing glucocorticoid replacement regimens fail to mimic the physiologic circadian rhythm of glucocorticoid secretion, current efforts therefore focus on optimising replacement strategies. In addition, in recent years novel experimental therapies have been developed which target adrenal sex steroid synthesis in patients with CAH aiming to reduce co-morbidities associated with sex steroid excess. These developments will hopefully improve the health status and long-term outcomes in patients with congenital adrenal hyperplasia and adrenal insufficiency.Fetal endocrine therapy for congenital adrenal hyperplasia should not be done
2015-08-24 09:51:19 AM
Publication date: June 2015
Source:Best Practice & Research Clinical Endocrinology & Metabolism, Volume 29, Issue 3
Author(s): Walter L. Miller
Prenatal treatment of congenital adrenal hyperplasia by administering dexamethasone to a woman presumed to be carrying an at-risk fetus remains a controversial experimental treatment. Review of data from animal experimentation and human trials indicates that dexamethasone cannot be considered safe for the fetus. In animals, prenatal dexamethasone decreases birth weight, affects renal, pancreatic beta cell and brain development, increases anxiety and predisposes to adult hypertension and hyperglycemia. In human studies, prenatal dexamethasone is associated with orofacial clefts, decreased birth weight, poorer verbal working memory, and poorer self-perception of scholastic and social competence. Numerous medical societies have cautioned that prenatal treatment of adrenal hyperplasia with dexamethasone is not appropriate for routine clinical practice and should only be done in Institutional Review Board approved, prospective clinical research settings with written informed consent. The data indicate that this treatment is inconsistent with the classic medical ethical maxim to 'first do no harm'.Adolescents with gender dysphoria
2015-08-24 09:51:19 AM
Publication date: June 2015
Source:Best Practice & Research Clinical Endocrinology & Metabolism, Volume 29, Issue 3
Author(s): Peggy T. Cohen-Kettenis, Daniel Klink
Young people with gender dysphoria are increasingly seen by pediatric endocrinologists. Mental health child specialists assess the adolescent and give advice about psychological or medical treatment. Provided they fulfill eligibility and readiness criteria, adolescents may receive pubertal suspension, consisting of using gonadotrophin-releasing hormone analogs, later followed by cross-sex hormones (sex steroids of the experienced gender). If they fulfill additional criteria, they may have various types of gender affirming surgery. Current issues involve safety aspects. Although generally considered safe in the short-term, the long-term effects regarding bone health and cardiovascular risks are still unknown. Therefore, vigilance is warranted during and long after completion of the last gender affirming surgeries. The timing of the various treatment steps is also under debate: instead of fixed age limits, the cognitive and emotional maturation, along with the physical development, are now often considered as more relevant.Transition to adult endocrine services: What is achievable? The diabetes perspective
2015-08-24 09:51:19 AM
Publication date: June 2015
Source:Best Practice & Research Clinical Endocrinology & Metabolism, Volume 29, Issue 3
Author(s): Mary White, Michele A. O'Connell, Fergus J. Cameron
Transition is defined as the 'purposeful, planned movement of adolescents and young adults with chronic physical and medical conditions from child-centred to adult-oriented health care systems' by Blum RW, (2002). The primary goal of transition is to ensure an uninterrupted process in healthcare delivery between the paediatric and adult settings; however, losses to follow up and decreased engagement with specialist services are common during this time. The current transition literature specifically pertaining to type 1 diabetes mellitus (T1DM) is often limited by incomplete data, the absence of control data and lack of follow up data spanning both the paediatric and adult years. This paper serves to review the current transition literature base, highlighting areas which warrant further study.Transition of adolescents and young adults with endocrine diseases to adult health care
2015-08-24 09:51:19 AM
Publication date: June 2015
Source:Best Practice & Research Clinical Endocrinology & Metabolism, Volume 29, Issue 3
Author(s): Thomas M. Kapellen, Wieland Kiess
The transition of adolescents with chronic endocrine diseases to adult care remains a major challenge for all those participating in the process. In paediatric endocrinology, a variety of diseases pose different challenges in the transitional process. The outcome of this transitional process is often judged by what happens after transfer. The young patient needs to be educated early on about continuing treatment into adulthood, resulting in full autonomy over their health care in early adulthood. Therefore, to optimize transition, paediatric and adult endocrinologists must work together to achieve continuity and to meet the needs of young patients.Keyword index
2015-08-24 09:51:19 AM
Publication date: June 2015
Source:Best Practice & Research Clinical Endocrinology & Metabolism, Volume 29, Issue 3Preface
2015-08-24 09:51:19 AM
Publication date: March 2015
Source:Best Practice & Research Clinical Endocrinology & Metabolism, Volume 29, Issue 2Bridging the age spectrum of neurodegenerative storage diseases
2015-08-24 09:51:19 AM
Publication date: March 2015
Source:Best Practice & Research Clinical Endocrinology & Metabolism, Volume 29, Issue 2
Author(s): Barry Boland, Frances M. Platt
For over a century, researchers have observed similar neurodegenerative hallmarks in brains of people affected by rare early-onset lysosomal storage diseases and late-onset neurodegenerative diseases such as Alzheimer's and Parkinson's disease. Increasing evidence suggests these apparently disparate diseases share a common underlying feature, namely, a dysfunctional clearance of cellular cargo through the secretory-endosomal-autophagic-lysosomal-exocytic (SEALE) network. By providing examples of rare and common neurodegenerative diseases known to have pathologically altered cargo flux through the SEALE network, we explore the unifying hypothesis that impaired catabolism or exocytosis of SEALE cargo, places a burden of stress on neurons that initiates pathogenesis. We also describe how a growing understanding of genetic, epigenetic and age-related modifications of the SEALE network, has inspired a number of novel disease-modifying therapeutic approaches aimed at alleviating SEALE storage and providing therapeutic benefit to people affected by these devastating diseases across the age spectrum.Epidemiology and diagnosis of lysosomal storage disorders; challenges of screening
2015-08-24 09:51:19 AM
Publication date: March 2015
Source:Best Practice & Research Clinical Endocrinology & Metabolism, Volume 29, Issue 2
Author(s): Sandra D.K. Kingma, Olaf A. Bodamer, Frits A. Wijburg
The lysosomal storage disorders (LSDs) are a group of genetic disorders resulting from defective lysosomal metabolism and subsequent accumulation of substrates. Patients present with a large phenotypic spectrum of disease manifestations that are generally not specific for LSDs, leading to considerable diagnostic delay and missed cases. Introduction of new disease modifying therapies for LSDs has made early diagnosis a priority. Increased awareness, but particularly the introduction of screening programs allow for early diagnosis and timely initiation of treatment. This review will provide insight into the epidemiology and diagnostic process for LSDs. In addition, challenges for carrier screening, high-risk screening and newborn population screening for LSDs are discussed.Neuronopathic lysosomal storage disorders: Approaches to treat the central nervous system
2015-08-24 09:51:19 AM
Publication date: March 2015
Source:Best Practice & Research Clinical Endocrinology & Metabolism, Volume 29, Issue 2
Author(s): Maurizio Scarpa, Cinzia Maria Bellettato, Christina Lampe, David J. Begley
Pharmacological research has always focused on developing new therapeutic strategies capable of modifying a disease's natural history and improving patients' quality of life. Despite recent advances within the fields of medicine and biology, some diseases still represent a major challenge for successful therapy. Neuronopathic lysosomal storage disorders, in particular, have high rates of morbidity and mortality and a devastating socio-economic effect. Many of the available therapies, such as enzyme replacement therapy, can reverse the natural history of the disease in peripheral organs but, unfortunately, are still unable to reach the central nervous system effectively because they cannot cross the blood–brain barrier that surrounds and protects the brain. Moreover, many lysosomal storage disorders are characterized by a number of blood–brain barrier dysfunctions, which may further contribute to disease neuropathology and accelerate neuronal cell death. These issues, and their context in the development of new therapeutic strategies, will be discussed in detail in this chapter.Non-neuronopathic lysosomal storage disorders: Disease spectrum and treatments
2015-08-24 09:51:19 AM
Publication date: March 2015
Source:Best Practice & Research Clinical Endocrinology & Metabolism, Volume 29, Issue 2
Author(s): Gregory M. Pastores, Derralynn A. Hughes
Distinctive facial features, hepatosplenomegaly or cardiomyopathy with or without associated skeletal dysplasia are clinical manifestations that may be suggestive of an underlying lysosomal storage disorder (LSD), However, these features may not be evident in certain subtypes associated primarily with central nervous system involvement. Age at onset can be broad, ranging from infancy to adulthood. Diagnosis may be delayed, as manifestations may be slow to evolve (taking months to years), particularly in those with later (adult-)onset, and in isolated cases (i.e., those without a prior family history). Diagnosis of individual subtypes can be confirmed using a combination of biochemical and molecular assays. In a few LSDs, treatment with hematopoietic stem cell transplantation, enzyme replacement or substrate reduction therapy is available. Symptomatic and palliative measure may enhance quality of life for both treatable and currently untreatable cases. Genetic counseling is important, so patients and their families can be informed of reproductive risks, disease prognosis and therapeutic options. Investigations of underlying disease mechanisms are enhancing knowledge about rare diseases, but also other more common medical conditions, on account of potential convergent disease pathways.The role of antibodies in enzyme treatments and therapeutic strategies
2015-08-24 09:51:19 AM
Publication date: March 2015
Source:Best Practice & Research Clinical Endocrinology & Metabolism, Volume 29, Issue 2
Author(s): Brian W. Bigger, Muhammad Saif, Gabor E. Linthorst
Substitution of the defective lysosomal enzyme in lysosomal storage disorders (LSDs) often elicits antibody formation towards the infused protein. Aside from Gaucher disease, antibodies often lead to infusion associated reactions and a reduced biochemical response. In Pompe disease, antibody titer is predictive of clinical outcome, but this is less apparent in other LSDs and warrants further study. Few laboratories are capable of enzyme-antibody determination: often physicians need to rely on the enzyme manufacturer for analysis. Currently, laboratories employ different antibody assays which hamper comparisons between cohorts or treatment regimens. Assay standardisation, including measurement of antibody-related enzyme inhibition, is therefore urgently needed. Successful immunomodulation has been reported in Pompe and in Gaucher disease, with variable success. Immunomodulation regimens that contain temporary depletion of B-cells (anti-CD20) are most used. Bone marrow transplantation in MPS-I results in disappearance of antibodies. No other clinical studies have been conducted in humans with immunomodulation in other LSDs.Fabry disease and the heart
2015-08-24 09:51:19 AM
Publication date: March 2015
Source:Best Practice & Research Clinical Endocrinology & Metabolism, Volume 29, Issue 2
Author(s): Nora Seydelmann, Christoph Wanner, Stefan Störk, Georg Ertl, Frank Weidemann
Fabry disease is induced by a mutation in the alpha-galactosidase A gene, causing a deficiency of the enzyme alpha-galactosidase A. (1) The enzyme defect leads to progressive intracellular accumulation of globotriaosylceramide in lysosomes of various tissues and organs, including heart, kidney and nerve system. Cardiac involvement is common and is presenting as concentric left ventricular hypertrophy. Myocardial replacement fibrosis is a typical feature of more advanced stages of Fabry cardiomyopathy, first limited to the mid-myocardial layers of the basal postero-lateral wall, then spreading to transmural fibrosis. Since 2001, enzyme replacement therapy is available. If therapy is started early, before myocardial fibrosis has developed, a long-term improvement of myocardial morphology, function and exercise capacity can be achieved. In end-stage cardiomyopathy enzyme replacement therapy might prevent further progression of the disease. This review provides an overview of Fabry disease, with a focus on cardiac involvement with its characteristic features, clinical presentation and possible treatment.The attenuated/late onset lysosomal storage disorders: Therapeutic goals and indications for enzyme replacement treatment in Gaucher and Fabry disease
2015-08-24 09:51:19 AM
Publication date: March 2015
Source:Best Practice & Research Clinical Endocrinology & Metabolism, Volume 29, Issue 2
Author(s): Carla E.M. Hollak, Neal J. Weinreb
Enzyme replacement therapies have been developed and authorized for commercial use for six different lysosomal storage disorders. For Gaucher disease, Fabry disease and mucopolysaccharidosis type 1, disease-specific treatments have been available for more than a decade. Although long term follow-up data are still sparse, therapeutic goals for patients with Gaucher disease and Fabry disease have been formulated and published for both adults and children. Without adaptation or modification, these goals are often applied in clinical research and in routine patient care across the entire phenotypic spectrum of disease, although in practice, patients commonly manifest high variability in clinical presentation and course of the illness. In this context, establishing goals for the follow-up and treatment of late onset/attenuated phenotypes is particularly challenging. In this chapter, we review current therapeutic goals for Gaucher disease and Fabry disease and discuss approaches for those with attenuated disease manifestations.The clinical spectrum and pathophysiology of skeletal complications in lysosomal storage disorders
2015-08-24 09:51:19 AM
Publication date: March 2015
Source:Best Practice & Research Clinical Endocrinology & Metabolism, Volume 29, Issue 2
Author(s): Lorne A. Clarke, Carla E.M. Hollak
Lysosomal storage disorders affect multiple organs including the skeleton. Disorders with prominent skeletal symptoms are type 1 and 3 Gaucher disease, the mucopolysaccharidoses, the glycoproteinoses and pycnodysostosis. Clinical manifestations range from asymptomatic radiographical evidence of bone pathology to overt bone crises (Gaucher), short stature with typical imaging features known as dysostosis multiplex (MPS), with spine and joint deformities (mucopolysaccharidoses, mucolipidosis), or osteopetrosis with pathological fractures (pynodysostosis). The pathophysiology of skeletal disease is only partially understood and involves direct substrate storage, inflammation and other complex alterations of cartilage and bone metabolism. Current treatments are enzyme replacement therapy, substrate reduction therapy and hematopoietic stem cell transplantation. However, effects of these interventions on skeletal disease manifestations are less well established and outcomes are highly dependent on disease burden at treatment initiation. It is now clear that adjunctive treatments that target skeletal disease are needed and should be part of future research agenda.Types A and B Niemann-Pick disease
2015-08-24 09:51:19 AM
Publication date: March 2015
Source:Best Practice & Research Clinical Endocrinology & Metabolism, Volume 29, Issue 2
Author(s): Edward H. Schuchman, Melissa P. Wasserstein
Two distinct metabolic abnormalities are encompassed under the eponym Niemann-Pick disease (NPD). The first is due to the deficient activity of the enzyme acid sphingomyelinase (ASM). Patients with ASM deficiency are classified as having types A and B Niemann-Pick disease (NPD). Type A NPD patients exhibit hepatosplenomegaly in infancy and profound central nervous system involvement. They rarely survive beyond two years of age. Type B patients also have hepatosplenomegaly and pathologic alterations of their lungs, but there are usually no central nervous system signs. The age of onset and rate of disease progression varies greatly among type B patients, and they frequently live into adulthood. Recently, patients with phenotypes intermediate between types A and B NPD also have been identified. These individuals represent the expected continuum caused by inheriting different mutations in the ASM gene (SMPD1). Patients in the second NPD category are designated as having types C and D NPD. These patients may have mild hepatosplenomegaly, but the central nervous system is profoundly affected. Impaired intracellular trafficking of cholesterol causes types C and D NPD, and two distinct gene defects have been found. In this chapter only types A and B NPD will be discussed.The emergence of Parkinson disease among patients with Gaucher disease
2015-08-24 09:51:19 AM
Publication date: March 2015
Source:Best Practice & Research Clinical Endocrinology & Metabolism, Volume 29, Issue 2
Author(s): Deborah Elstein, Roy Alcalay, Ari Zimran
In the last decade, several lines of evidence have been presented that document the clinical manifestations, genetic associations, and sub-cellular mechanisms of the inter-relatedness of β-glucocerebrosidase mutations and the emergence of Parkinson disease among carriers and patients with Gaucher disease. This review is an attempt to apprise the reader of the recent literature with the caveat that this is an area of intensive exploration that is constantly being updated because of the immediate clinical ramifications but also because of the impact on our understanding of Parkinson disease, and finally because of the unexpected inter-reactions between these entities on the molecular level. It has been an unexpected happenstance that it has been discovered that a rare monogenetic disease has an interface at many points with a neurological disorder of the elderly that has both familial and sporadic forms: to date there is no cure for either of these disorders.Metachromatic leukodystrophy: Disease spectrum and approaches for treatment
2015-08-24 09:51:19 AM
Publication date: March 2015
Source:Best Practice & Research Clinical Endocrinology & Metabolism, Volume 29, Issue 2
Author(s): Diane F. van Rappard, Jaap Jan Boelens, Nicole I. Wolf
Metachromatic leukodystrophy is an inherited lysosomal disorder caused by recessive mutations in ARSAencoding arylsulfatase A. Low activity of arylsulfatase A results in the accumulation of sulfatides in the central and peripheral nervous system leading to demyelination. The disease is classified in a late-infantile, juvenile and adult onset type based on the age of onset, all characterized by a variety of neurological symptoms, which eventually lead to death if untreated. There is no curative treatment for all types and stages. This review discusses diagnostic process and efficacy of current and possible future therapies such as hematopoietic stem cell transplantation, enzyme replacement therapy and gene therapy. A systematic evaluation regarding the efficacy of hematopoietic stem cell transplantation and a longer follow up period for gene therapy are needed to come to a general conclusion and improve treatment options for metachromatic leukodystrophy.Innovative Treatments for Lysosomal Diseases
2015-08-24 09:51:19 AM
Publication date: March 2015
Source:, Volume 29, Issue 2
Author(s): Timothy M. Cox
Striking therapeutic advances for lysosomal diseases have harnessed the biology of this organelle and illustrate its central rôle in the dynamic economy of the cell. Further Innovation will require improved protein-targetting or realization of therapeutic gene- and cell transfer stratagems. Rescuing function before irreversible injury, mandates a deep knowledge of clinical behaviour as well as molecular pathology – and frequently requires an understanding of neuropathology. Whether addressing primary causes, or rebalancing the effects of disordered cell function, true therapeutic innovation depends on continuing scientific exploration of the lysosome. Genuine partnerships between biotech and the patients affected by this extraordinary family of disorders continue to drive productive pharmaceutical discovery.
Κυριακή 23 Αυγούστου 2015
Best Practice & Research Clinical Endocrinology & Metabolism
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