[Show abstract][Hide abstract] ABSTRACT: Introduction:
Despite being reported for the first time almost one century ago, only in the last few decades effective have treatments become available for the mucopolysaccharidoses (MPSs), a group of 11 inherited metabolic diseases that affect lysosomal function. These diseases are progressive, usually severe, and, in a significant number of cases, involve cognitive impairment. Areas covered: This review will not cover established treatments such as bone marrow/hematopoietic stem cell transplantation and classic intravenous enzyme replacement therapy (ERT), whose long-term outcomes have already been published (MPS I, MPS II, and MPS VI), but it instead focuses on emerging therapies for MPSs. That includes intravenous ERT for MPS IVA and VII, intrathecal ERT, ERT with fusion proteins, substrate reduction therapy, gene therapy, and other novel approaches. Expert opinion: The available treatments have resulted in improvements for several disease manifestations, but they still do not represent a cure for these diseases; thus, it is important to develop alternative methods to approach the unmet needs (i.e. bone disease, heart valve disease, corneal opacity, and central nervous system (CNS) involvement). The work in progress with novel approaches makes us confident that in 2017, when MPS will commemorate 100 years of its first report, we will be much closer to an effective cure for these challenging conditions.
Full-text · Article · Jan 2016 · Expert Opinion on Emerging Drugs
[Show abstract][Hide abstract] ABSTRACT: and Aims
. The use of bone marrow cells has been suggested as an alternative treatment for acute liver failure. In this study, we investigate the effect of encapsulated whole bone marrow cells in a liver failure model.
. Encapsulated cells or empty capsules were implanted in rats submitted to 90% partial hepatectomy. The survival rate was assessed. Another group was euthanized at 6, 12, 24, 48, and 72 hours after hepatectomy to study expression of cytokines and growth factors.
. Whole bone marrow group showed a higher than 10 days survival rate compared to empty capsules group. Gene expression related to early phase of liver regeneration at 6 hours after hepatectomy was decreased in encapsulated cells group, whereas genes related to regeneration were increased at 12, 24, and 48 hours. Whole bone marrow group showed lower regeneration rate at 72 hours and higher expression and activity of caspase 3. In contrast, lysosomal-
-glucuronidase activity was elevated in empty capsules group.
. The results show that encapsulated whole bone marrow cells reduce the expression of genes involved in liver regeneration and increase those responsible for ending hepatocyte division. In addition, these cells favor apoptotic cell death and decrease necrosis, thus increasing survival.
Preview · Article · Jan 2016 · Stem cell International
[Show abstract][Hide abstract] ABSTRACT: Purpose:
CDKN2A is the main high-risk melanoma-susceptibility gene, but it has been poorly assessed in Latin America. We sought to analyze CDKN2A and MC1R in patients from Latin America with familial and sporadic multiple primary melanoma (SMP) and compare the data with those for patients from Spain to establish bases for melanoma genetic counseling in Latin America.
CDKN2A and MC1R were sequenced in 186 Latin American patients from Argentina, Brazil, Chile, Mexico, and Uruguay, and in 904 Spanish patients. Clinical and phenotypic data were obtained.
Overall, 24 and 14% of melanoma-prone families in Latin America and Spain, respectively, had mutations in CDKN2A. Latin American families had CDKN2A mutations more frequently (P = 0.014) than Spanish ones. Of patients with SMP, 10% of those from Latin America and 8.5% of those from Spain had mutations in CDKN2A (P = 0.623). The most recurrent CDKN2A mutations were c.-34G>T and p.G101W. Latin American patients had fairer hair (P = 0.016) and skin (P < 0.001) and a higher prevalence of MC1R variants (P = 0.003) compared with Spanish patients.
The inclusion criteria for genetic counseling of melanoma in Latin America may be the same criteria used in Spain, as suggested in areas with low to medium incidence, SMP with at least two melanomas, or families with at least two cases among first- or second-degree relatives.Genet Med advance online publication 17 December 2015Genetics in Medicine (2015); doi:10.1038/gim.2015.160.
Full-text · Article · Dec 2015 · Genetics in medicine: official journal of the American College of Medical Genetics
[Show abstract][Hide abstract] ABSTRACT: This study aimed to compare flexible fiberoptic laryngoscopy (FFL) and polysomnography (PSG) findings in patients with mucopolysaccharidosis (MPS) type VI and to describe upper airway anatomical findings and abnormal PSG results in these patients. In this cross-sectional study, all MPS VI patients followed up at the genetic division of a hospital in southern Brazil were included. Overnight PSG was performed, and the results were classified as normal or mildly, moderately, or severely abnormal. FFL was performed between 7 days before and 7 days after PSG. FFL findings were classified as (1) no obstruction, (2) mild obstruction, (3) moderate obstruction, or (4) severe obstruction of the airways, using the highest score obtained in all the regions.Eleven patients with MPS VI were included. FFL detected severe airway obstruction in eight (72.7%) patients, moderate obstruction in two (18.2%), and mild obstruction in one (9.1%). PSG revealed obstructive sleep apnea syndrome (OSAS) in nine (81.8%) patients. Among these, mild OSAS was observed in five (45.5%) patients, moderate OSAS in three (27.2%), and severe OSAS in one (9.1%). Moderate to severe hypertrophy of the nasal turbinates was found in 81.8% of the patients, and 64% had severe infiltration in the supraglottic region. There was no association between FFL and PSG findings (p = 0.454; κ = -0.09; 95%CI = -0.34 to 0.17), indicating no agreement between the two methods. In the present study, all patients with MPS showed some degree of airway obstruction. We suggest performing PSG in MPS patients to determine disease severity.
[Show abstract][Hide abstract] ABSTRACT: Lysosomal storage disorders (LSDs) are a group of almost 50 monogenic diseases characterized by mutations causing deficiency of lysosomal enzymes or non-enzyme proteins involved in transport across the lysosomal membrane, protein maturation or lysosomal biogenesis. Usually, affected patients are normal at birth and have a progressive and severe disease with high morbidity and reduced life expectancy. The overall incidence of LSDs is usually estimated as 1:5000, but newborn screening studies are indicating that it could be much higher. Specific therapies were already developed for selected LSDs, making the timely and correct diagnosis very important for successful treatment and also for genetic counseling. In most LSD cases the biochemical techniques provide a reliable diagnosis. However, the identification of pathogenic mutations by genetic analysis is being increasingly recommended to provide additional information. In this paper we discuss the conventional methods for genetic analysis used in the LSDs (restriction fragment length polymorphism [RFLP], amplification-refractory mutation system [ARMS], single strand conformation polymorphism [SSCP], denaturing high performance liquid chromatography [dHPLC], real-time polymerase chain reaction [RT-PCR], high resolution melting [HRM], multiplex ligation-dependent probe amplification [MLPA], Sanger sequencing) and also the newer approaches (massive parallel sequencing, array comparative genomic hybridization [CGH]).
No preview · Article · Nov 2015 · Expert Review of Molecular Diagnostics
[Show abstract][Hide abstract] ABSTRACT: The mucopolysaccharidoses (MPSs) are a group of rare genetic diseases caused by a deficiency of specific enzymes involved in catabolism of glycosaminoglycans, which causes multisystem abnormalities. Quality of life (QoL) is directly associated with physical, mental, and psychological well-being and with social relationships, including family and friends.
[Show abstract][Hide abstract] ABSTRACT: Mucopolysaccharidosis VI (MPS VI) is a very rare autosomal recessive disorder caused by mutations in the ARSB gene, which lead to deficient activity of the lysosomal enzyme ASB. This enzyme is important for the breakdown of the glycosaminoglycans (GAGs) dermatan sulfate and chondroitin sulfate, which accumulate in body tissues and organs of MPS VI patients. The storage of GAGs (especially dermatan sulfate) causes bone dysplasia, joint restriction, organomegaly, heart disease, and corneal clouding, among several other problems, and reduced life span. Despite the fact that most cases are severe, there is a spectrum of severity and some cases are so attenuated that diagnosis is made late in life. Although the analysis of urinary GAGs and/or the measurement of enzyme activity in dried blood spots are useful screening methods, the diagnosis is based in the demonstration of the enzyme deficiency in leucocytes or fibroblasts, and/or in the identification of pathogenic mutations in the ARSB gene. Specific treatment with enzyme replacement has been available since 2005. It is safe and effective, bringing measurable benefits and increased survival to patients. As several evidences indicate that early initiation of therapy may lead to a better outcome, newborn screening is being considered for this condition, and it is already in place in selected areas where the incidence of MPS VI is increased. However, as enzyme replacement therapy is not curative, associated therapies should be considered, and research on innovative therapies continues. The management of affected patients by a multidisciplinary team with experience in MPS diseases is highly recommended.
Full-text · Article · Oct 2015 · The Application of Clinical Genetics
[Show abstract][Hide abstract] ABSTRACT: The mucopolysaccharidoses (MPS) are a group of 11 inborn errors of metabolism (IEM) which are part of the lysosomal storage diseases (LSDs). The MPS are multisystemic conditions that affect the entire body, with variations in the clinical presentation, having specific treatments available depending on the type of MPS. Nearly all MPS disorders compromise the osteoarticular system in different ways, and virtually all patients have abnormal urinary excretion of glycosaminoglycans (GAGs). MPS are rare diseases that are underdiagnosed due to health-care professionals' lack of awareness, to poor access to screening and diagnostic methods, and to their extensive clinical heterogeneity. Attenuated forms may occur, which can make diagnosis of MPS even more difficult.
This study was conducted prospectively from March 2012 to January 2014 and included 55 patients at rheumatology and/or orthopedic services in Porto Alegre, Brazil. The screened patients presented with articular manifestations with no defined etiology. These patients were screened by quantitative and qualitative assessment of urinary GAGs.
Among the 55 cases investigated, one 15-year-old patient exhibited increased urinary GAG excretion; this patient was subsequently diagnosed with an attenuated form of MPS II, which was previously undetected.
Although the proportion of patients with MPS identified in the study sample was small (1/55), this study shows that these diseases are underdiagnosed and that systematic screening can help identify patients who may benefit from specific treatments already available for several MPS types.
[Show abstract][Hide abstract] ABSTRACT: The Latin American Network of Human Genetics (RELAGH) created the Latin American School of Human and Medical Genetics (ELAG) to prepare young researchers and professionals of Latin America to deal with the growing challenge of the genomic medicine. ELAG promotes an annually course since 2005, which received 838 students from 17 Latin American countries over these 10 years. ELAG plays an important role to provide education in genetics applied to health sciences to fellows who live in countries with a less favorable economic situation. Influenced, among others, by the humanitarian perspective of José Maria Cantú, one of its founders, ELAG has always favored the discussion of ethical and social issues related to genetics in Latin America. Few initiatives in Latin America lasted 10 consecutive years. One of the factors responsible for the ELAG's success has been its group of faculty members, who contribute to a friendly environment prone to facilitating the exchange of their own experiences with young researchers.
No preview · Article · May 2015 · Journal of community genetics
[Show abstract][Hide abstract] ABSTRACT: Patients with mucopolysaccharidosis IVA (MPS IVA) can present with systemic skeletal dysplasia, leading to a need for multiple orthopedic surgical procedures, and often become wheelchair bound in their teenage years. Studies on patients with MPS IVA treated by enzyme replacement therapy (ERT) showed a sharp reduction on urinary keratan sulfate, but only modest improvement based on a 6-minute walk test and no significant improvement on a 3-minute climb-up test and lung function test compared with the placebo group, at least in the short-term. Surgical remnants from ERT-treated patients did not show reduction of storage materials in chondrocytes. The impact of ERT on bone lesions in patients with MPS IVA remains limited. ERT seems to be enhanced in a mouse model of MPS IVA by a novel form of the enzyme tagged with a bone-targeting moiety. The tagged enzyme remained in the circulation much longer than untagged native enzyme and was delivered to and retained in bone. Three-month-old MPS IVA mice treated wi
Full-text · Article · Apr 2015 · Drug Design, Development and Therapy
[Show abstract][Hide abstract] ABSTRACT: The recent progress in genome editing technology using the engineered zinc finger nucleases (ZFN), transcriptional activator-like effector nucleases (TALEN), and more recently, clustered regularly interspaced short palindromic repeat-CRISPR-associated protein 9 (CRISPR-Cas9) system have enabled the possibility of precisely modifying target sites in the genome. This technology brings hope of a cure for many genetic diseases. With this review, our goal is to discuss how targeted genome editing can be combined with hematopoietic stem cell transplantation and other approaches to be used for the treatment of a particular group of genetic diseases, the lysosomal storage disorders. We also highlight which diseases within this group would potentially benefit from this treatment and what are the main problems to be addressed to transform this promising technology into reality.
[Show abstract][Hide abstract] ABSTRACT: Outcomes from 5 years of treatment with agalsidase alfa enzyme replacement therapy (ERT) for Fabry disease in patients enrolled in the Fabry Outcome Survey (FOS) were compared with published findings for untreated patients with Fabry disease. Data were extracted from FOS, a Shire-sponsored database, for comparison with data from three published studies. Outcomes evaluated were the annualized rate of change in estimated glomerular filtration rate (eGFR) and left ventricular mass indexed to height (LVMI) as well as time to and ages at a composite morbidity endpoint and at death. FOS data were extracted for 740 treated patients who were followed for a median of ~ 5 years. Compared with no treatment, patients treated with agalsidase alfa demonstrated slower decline in renal function and slower progression of left ventricular hypertrophy. Treated male patients with baseline eGFR < 60 mL/min/1.73 m2 had a mean (standard error of the mean [SEM]) annualized change in eGFR of − 2.86 (0.53) mL/min/1.73 m2/y compared with − 6.8 (1.5) in the published untreated cohort. The mean (SEM) rate of LVMI increase with treatment was 0.33 (0.10) g/m2.7/y in males and 0.48 (0.09) in females, compared with 4.07 (1.03) in untreated males and 2.31 (0.81) in untreated females. Morbidity occurred later in treated patients, with ~ 16% risk of a composite morbidity event (26% in males) after 24 months with ERT versus ~ 45% without treatment, with first events and deaths also occurring at older ages in patients administered ERT (e.g., estimated median survival in treated males was 77.5 years versus 60 years in untreated males). Findings from these retrospective comparisons of observational data and published literature support the long-term benefits of ERT with agalsidase alfa for Fabry disease in slowing the progression of renal impairment and cardiomyopathy. Treatment also appeared to delay the onset of morbidity and mortality. Interpretation of these findings should take into account that they are based on retrospective comparisons with previously published data.
Full-text · Article · Feb 2015 · Molecular Genetics and Metabolism