Premature termination codon (PTC) mutations account for approximately 10% of pathogenic variants in monogenic diseases. Stimulation of translational readthrough, also known as stop codon suppression, using translational readthrough-inducing drugs (TRIDs) may serve as a possible therapeutic strategy for the treatment of genetic PTC diseases. One important parameter governing readthrough is the stop codon context (SCC)-the stop codon itself and the nucleotides in the vicinity of the stop codon on the mRNA. However, the quantitative influence of the SCC on treatment outcome and on appropriate drug concentrations are largely unknown. Here, we analyze the readthrough-stimulatory effect of various readthrough-inducing drugs on the SCCs of five common premature termination codon mutations of PEX5 in a sensitive dual reporter system. Mutations in PEX5, encoding the peroxisomal targeting signal 1 receptor, can cause peroxisomal biogenesis disorders of the Zellweger spectrum. We show that the stop context has a strong influence on the levels of readthrough stimulation and impacts the choice of the most effective drug and its concentration. These results highlight potential advantages and the personalized medicine nature of an SCC-based strategy in the therapy of rare diseases.
Codon, Nonsense , Peroxisomal Disorders/genetics , Peroxisomal Disorders/metabolism , Peroxisome-Targeting Signal 1 Receptor , Protein Biosynthesis , RNA, Messenger , HeLa Cells , Humans , Peroxisomal Disorders/therapy , Peroxisome-Targeting Signal 1 Receptor/biosynthesis , Peroxisome-Targeting Signal 1 Receptor/genetics , RNA, Messenger/genetics , RNA, Messenger/metabolism
Inherited metabolism disorders are serious childhood diseases that lead to significant cognitive impairment and regression of psychomotor development. The pathophysiology of the neural progressive deterioration is usually associated with severe neuroinflammation and demyelination, and as a consequence, neurodegeneration. At the moment they have no adequate treatment and require early and aggressive therapeutic approaches, which entail high mortality rates and, very frequently, low degrees of functional improvement and survival. Bone marrow transplantation and bone marrow mesenchymal cells grafts are therapeutic and experimental therapies that improve the course of these diseases through different mechanisms of action: enzyme replacement, membrane exchange and regulation of the inflammatory process.
Los trastornos heredados del metabolismo son enfermedades graves de la infancia que cursan con un gran deterioro cognitivo y del desarrollo psicomotor. La fisiopatología del progresivo deterioro del sistema nervioso suele estar asociada a una severa neuroinflamación y desmielinización, y como consecuencia, neurodegeneración. Por el momento no tienen cura y precisan de actitudes terapéuticas precoces y agresivas, que conllevan altas tasas de mortalidad y, muy frecuentemente, escasos grados de mejoría funcional y supervivencia. El trasplante de médula ósea y de células mesenquimales de médula ósea son terapias de elección y experimentales que consiguen mejorar el curso de estas enfermedades mediante diferentes mecanismos de acción: remplazo de enzima deficiente, intercambio de membranas y regulación del proceso inflamatorio.
Bone Marrow Transplantation/methods , Lysosomal Storage Diseases/therapy , Peroxisomal Disorders/therapy , Humans , Lysosomal Storage Diseases/physiopathology , Mesenchymal Stem Cell Transplantation/methods , Peroxisomal Disorders/physiopathology
Los trastornos heredados del metabolismo son enfermedades graves de la infancia que cursan con un gran deterioro cognitivo y del desarrollo psicomotor. La fisiopatología del progresivo deterioro del sistema nervioso suele estar asociada a una severa neuroinflamación y desmielinización, y como consecuencia, neurodegeneración. Por el momento no tienen cura y precisan de actitudes terapéuticas precoces y agresivas, que conllevan altas tasas de mortalidad y, muy frecuentemente, escasos grados de mejoría funcional y supervivencia. El trasplante de médula ósea y de células mesenquimales de médula ósea son terapias de elección y experimentales que consiguen mejorar el curso de estas enfermedades mediante diferentes mecanismos de acción: remplazo de enzima deficiente, intercambio de membranas y regulación del proceso inflamatorio.
Inherited metabolism disorders are serious childhood diseases that lead to significant cognitive impairment and regression of psychomotor development. The pathophysiology of the neural progressive deterioration is usually associated with severe neuroinflammation and demyelination, and as a consequence, neurodegeneration. At the moment they have no adequate treatment and require early and aggressive therapeutic approaches, which entail high mortality rates and, very frequently, low degrees of functional improvement and survival. Bone marrow transplantation and bone marrow mesenchymal cells grafts are therapeutic and experimental therapies that improve the course of these diseases through different mechanisms of action: enzyme replacement, membrane exchange and regulation of the inflammatory process.
Humans , Bone Marrow Transplantation/methods , Lysosomal Storage Diseases/therapy , Peroxisomal Disorders/therapy , Lysosomal Storage Diseases/physiopathology , Peroxisomal Disorders/physiopathology , Mesenchymal Stem Cell Transplantation/methods
PURPOSE OF REVIEW: Adrenoleukodystrophy (ALD) is a peroxisomal disorder with varying clinical presentations, including adrenal insufficiency, neurologic disease, and testicular dysfunction. The present review is intended to describe the current knowledge of the pathophysiology of ALD and provide an update regarding newborn screening, diagnosis, monitoring, and treatment. RECENT FINDINGS: New York State initiated newborn screening for ALD on December 30, 2013. Successful ALD newborn screening has led to its addition on other state newborn screens and recommendations for universal screening. Initial incidence reports, based on newborn screening, suggest ALD may be more common than previously described. The Pediatric Endocrine Society has published guidance for monitoring newborn males with ALD and case reports suggest biochemical adrenal insufficiency can be present during early infancy. Allogeneic hematopoietic stem cell transplant and gene therapy have been effective at halting the progression of cerebral ALD. SUMMARY: Early diagnosis and monitoring for progression of ALD can prevent adrenal crisis and treat the cerebral form of the disease. Initial guidelines for surveillance are likely to evolve as newborn screening not only aids in early detection and therapeutic interventions for ALD, but also expands our knowledge of the natural history of ALD.
Adrenoleukodystrophy/diagnosis , Neonatal Screening , Adrenal Insufficiency/diagnosis , Adrenal Insufficiency/genetics , Adrenal Insufficiency/therapy , Adrenoleukodystrophy/epidemiology , Adrenoleukodystrophy/genetics , Adrenoleukodystrophy/therapy , Child , Diagnosis, Differential , Disease Progression , Genetic Therapy , Hematopoietic Stem Cell Transplantation , Humans , Infant, Newborn , Male , Neonatal Screening/methods , Neonatal Screening/trends , Peroxisomal Disorders/diagnosis , Peroxisomal Disorders/epidemiology , Peroxisomal Disorders/genetics , Peroxisomal Disorders/therapy
Gene therapies for lysosomal storage diseases (LSD) and peroxisomal diseases (PD) are rapidly advancing. Most LSDs and PDs are characterized by brain involvement, prompting the development of therapies targeting the brain. There are two types of gene therapy for brain involvement in LSD and PD, i.e., the direct transfer of a therapeutic gene into brain cells and hematopoietic stem cell-targeted gene therapy. The rationale for the latter approach is that brain microglia are derived from hematopoietic cells. Thus, gene-corrected hematopoietic cells migrate into the brain and differentiate into microglial cells. These gene-corrected microglial cells correct the metabolic defects associated with LSD and reduce inflammation in PD and LSD, leading to a clinical benefit. Gene editing technology has recently been applied in this area and a trial focused on LSD is currently ongoing. Although these approaches are still under investigation, very encouraging results have been obtained. This review provides an overview of recently developed gene therapies for various LSDs and PDs, including the results of clinical trials, with an emphasis on the benefits of this approach for these diseases.
Enzyme Replacement Therapy , Genetic Therapy , Lysosomal Storage Diseases/therapy , Peroxisomal Disorders/therapy , Animals , Humans , Lysosomal Storage Diseases/genetics , Peroxisomal Disorders/genetics
Defects in the peroxisomes biogenesis and/or function result in peroxisomal disorders. In this study, we describe the largest Arab cohort to date (72 families) of clinically, biochemically and molecularly characterized patients with peroxisomal disorders. At the molecular level, we identified 43 disease-causing variants, half of which are novel. The founder nature of many of the variants allowed us to calculate the minimum disease burden for these disorders in our population ~1:30 000, which is much higher than previous estimates in other populations. Clinically, we found an interesting trend toward genotype/phenotype correlation in terms of long-term survival. Nearly half (40/75) of our peroxisomal disorders patients had documented survival beyond 1 year of age. Most unusual among the long-term survivors was a multiplex family in which the affected members presented as adults with non-specific intellectual disability and epilepsy. Other unusual presentations included the very recently described peroxisomal fatty acyl-CoA reductase 1 disorder as well as CRD, spastic paraparesis, white matter (CRSPW) syndrome. We conclude that peroxisomal disorders are highly heterogeneous in their clinical presentation. Our data also confirm the demonstration that milder forms of Zellweger spectrum disorders cannot be ruled out by the "gold standard" very long chain fatty acids assay, which highlights the value of a genomics-first approach in these cases.
Arabs , Peroxisomal Disorders/epidemiology , Peroxisomal Disorders/etiology , Arabs/genetics , Biomarkers , Brain/abnormalities , Brain/diagnostic imaging , Cohort Studies , Consanguinity , Cost of Illness , Disease Management , Disease Susceptibility , Facies , Female , Genetic Association Studies , Genetic Predisposition to Disease , Humans , Magnetic Resonance Imaging , Male , Mutation , Pedigree , Peroxisomal Disorders/diagnosis , Peroxisomal Disorders/therapy , Phenotype , Population Surveillance , Prognosis
Peroxisomes and lysosomes are distinct subcellular compartments that underlie several pediatric metabolic disorders. Knowledge of their function and cell biology leads to understanding how the disorders result from genetic defects. Diagnostic and therapeutic approaches for the disorders take advantage of the cell biology mechanisms. Whereas peroxisomal disorders are characterized by enzymatic defects in peroxisomal pathways leading to metabolic and lipid changes, lysosomal storage disorders are marked by accumulation of substrates of lysosomal pathways inside the lysosome. The human diseases related to these two organelles are reviewed, focusing on general disease patterns and underlying diagnosis and treatment principles.
Lysosomal Storage Diseases/diagnosis , Peroxisomal Disorders/diagnosis , Humans , Infant , Infant, Newborn , Lysosomal Storage Diseases/therapy , Lysosomes/metabolism , Lysosomes/pathology , Peroxisomal Disorders/therapy , Peroxisomes/metabolism , Peroxisomes/pathology
Peroxisomes catalyze a number of essential metabolic functions of which fatty acid alpha- and beta-oxidation, ether phospholipid biosynthesis, glyoxylate detoxification and bile acid synthesis are the most important. The key role of peroxisomes in humans is exemplified by the existence of a group of peroxisomal disorders, caused by mutations inâ¯>â¯30 different genes which code for proteins with a role in either peroxisome biogenesis or one of the metabolic pathways in peroxisomes. Technological advances in laboratory methods at the metabolite-, enzyme-, and molecular level have not only allowed the identification of new peroxisomal disorders but also new phenotypes associated with already identified genetic defects thus extending the clinical spectrum. Unfortunately, progress in the field of pathogenesis and treatment has lagged behind although there are certainly new and hopeful developments with respect to X-linked adrenoleukodystrophy and hyperoxaluria type 1.
Peroxisomal Disorders/diagnosis , Peroxisomal Disorders/therapy , Biomarkers/metabolism , Humans , Models, Biological , Organelle Biogenesis
Introducción. Las enfermedades neurometabólicas son individualmente ultrarraras, pero algunas de ellas tienen un tratamiento eficaz. Desarrollo. Se revisan algunas novedades terapéuticas. Las enfermedades lisosomales tienen actualmente mejores posibilidades de tratamiento. En los últimos años se ha extendido el uso de la terapia enzimática sustitutiva a la mucopolisacaridosis tipo IVA (Morquio A), a la mucopolisacaridosis tipo VII (enfermedad de Sly), al déficit de lipasa ácida lisosomal y a la alfa-manosidosis. Se ha constatado que un tratamiento muy precoz de las mucopolisacaridosis puede cambiar su historia natural. Se está probando la terapia enzimática sustitutiva intratecal en algunas mucopolisacaridosis con afectación cognitiva, en el intento de frenar la neurodegeneración. Se han obtenido resultados muy positivos con autotrasplante modificado genéticamente en leucodistrofia metacromática infantil tardía y se está trabajando en otras patologías (mucopolisacaridosis tipo III, adrenoleucodistrofia ligada a X). También hay novedades en la terapia de algunas encefalopatías sensibles a vitaminas o cofactores: la triple terapia en la dependencia de piridoxina, el tratamiento con tiamina de algunas encefalopatías subagudas con afectación de ganglios basales, el tratamiento con ácido folínico de niños con deficiencia de folato cerebral, o el tratamiento con monofosfato de piranopterina cíclico en los defectos de cofactor de molibdeno de tipo A. Conclusiones. Los neuropediatras debemos actualizar nuestro conocimiento especialmente en aquellas patologías neurometabólicas tratables, dado que una terapia precoz puede cambiar de forma significativa su pronóstico (AU)
Introduction. Individually, neurometabolic diseases are ultra rare, but for some of them there is an effective treatment. Development. Several recent therapeutic advances are reviewed. Today, the possibilities of treatment for lysosomal diseases have improved. In recent years the use of enzyme replacement therapy has become more widely extended to treat mucopolysaccharidosis type IVA (Morquio A), mucopolysaccharidosis type VII (Sly syndrome), lysosomal acid lipase deficiency and alpha-mannosidosis. It has been proven that very early treatment of mucopolysaccharidoses can change their natural course. Intrathecal enzyme replacement therapy is being tried in some mucopolysaccharidoses with cognitive involvement, in an attempt to halt neurodegeneration. Very positive results have been obtained with genetically modified autotransplants in late-onset infantile metachromatic leukodystrophy and research is being conducted on other pathologies (mucopolysaccharidosis type III, X-linked adrenoleukodystrophy). Novel outcomes are also being achieved in the treatment of some encephalopathies that are sensitive to vitamins or cofactors: triple therapy in pyridoxine dependency, treatment with thiamine for some subacute encephalopathies with involvement of the basal ganglia, treatment with folinic acid for children with cerebral folate deficiency, or treatment with cyclic pyranopterin monophosphate in molybdenum cofactor deficiency type A. Conclusions. As neuropaediatricians we must update our knowledge, especially in the case of treatable neurometabolic pathologies, since early treatment can change their prognosis significantly (AU)
Humans , Child , Brain Diseases, Metabolic/diagnosis , Brain Diseases, Metabolic/therapy , Metabolic Diseases/complications , Metabolic Diseases/therapy , Early Diagnosis , Mucopolysaccharidosis VII/therapy , Treatment Outcome , Enzyme Replacement Therapy , Enzyme Therapy , Vitamins/therapeutic use , Peroxisomal Disorders/therapy , Pyridoxine/therapeutic use
No disponible
Humans , Male , Female , Infant , Citrulline , Citrulline/pharmacokinetics , Arginine , Arginine/pharmacokinetics , Prognosis , Critical Care/methods , Critical Illness/therapy , Glutamine/pharmacokinetics , Glutamine/therapeutic use , Critical Care/methods , /methods , Peroxisomal Disorders/complications , Peroxisomal Disorders/therapy
Peroxisomes are small intracellular organelles that catalyse key metabolic reactions such as the beta-oxidation of some straight-chain or branched-chain fatty acids and the alpha-oxidation of phytanic acid. These enzyme reactions produce hydrogen peroxide, which is subsequently neutralized by the peroxisomal catalase. Peroxisomes also metabolize glyoxylate to glycine, and catalyze the first steps of plasmalogen biosynthesis. There are more than a dozen inherited peroxisomal disorders in humans. These metabolic diseases are due to monogenic defects that affect either a single function (such as enzyme or a transporter) or more than two distinct functions because of the impairment of several aspects of peroxisome biogenesis. With the notable exception of X-linked adrenoleucodystrophy, these inborn disorders are transmitted as autosomal recessive traits. Their clinical presentation can be very heterogeneous, and include neonatal, infantile or adult forms. The present review describes the symptomatology of these genetic diseases, the underlying genetic and biochemical alterations, and summarizes their diagnostic approach.
Peroxisomal Disorders/genetics , Adolescent , Adult , Age of Onset , Bone Marrow Transplantation , Brain/pathology , Cataract/congenital , Cataract/genetics , Child , Decision Trees , Dietary Fats/administration & dosage , Dietary Fats/adverse effects , Fatty Acids/metabolism , Female , Genes, Recessive , Humans , Hydrogen Peroxide/metabolism , Infant , Infant, Newborn , Male , Myocardium/pathology , Organelle Biogenesis , Peroxisomal Disorders/diagnosis , Peroxisomal Disorders/epidemiology , Peroxisomal Disorders/pathology , Peroxisomal Disorders/therapy , Peroxisomes/enzymology , Peroxisomes/physiology , Phenotype , Phytanic Acid/metabolism
Peroxisome biogenesis disorders in the Zellweger spectrum (PBD-ZSD) are a heterogeneous group of genetic disorders caused by mutations in PEX genes responsible for normal peroxisome assembly and functions. As a result of impaired peroxisomal activities, individuals with PBD-ZSD can manifest a complex spectrum of clinical phenotypes that typically result in shortened life spans. The extreme variability in disease manifestation ranging from onset of profound neurologic symptoms in newborns to progressive degenerative disease in adults presents practical challenges in disease diagnosis and medical management. Recent advances in biochemical methods for newborn screening and genetic testing have provided unprecedented opportunities for identifying patients at the earliest possible time and defining the molecular bases for their diseases. Here, we provide an overview of current clinical approaches for the diagnosis of PBD-ZSD and provide broad guidelines for the treatment of disease in its wide variety of forms. Although we anticipate future progress in the development of more effective targeted interventions, the current guidelines are meant to provide a starting point for the management of these complex conditions in the context of personalized health care.
Mutation , Peroxisomal Disorders/diagnosis , Peroxisomal Disorders/therapy , Zellweger Syndrome/diagnosis , Zellweger Syndrome/therapy , Adult , Genetic Testing , Hearing Loss, Sensorineural/etiology , Hearing Loss, Sensorineural/physiopathology , Humans , Membrane Proteins/genetics , PHEX Phosphate Regulating Neutral Endopeptidase/genetics , Peroxisomes/genetics , Phenotype , Practice Guidelines as Topic , Precision Medicine , Retinal Dystrophies/etiology , Retinal Dystrophies/physiopathology
Following a propofol anesthetic, a 5-year-old girl with lower extremity spasticity seized and developed hypertriglyceridemia, hyperkalemia, and metabolic acidosis. A presumed diagnosis of propofol infusion syndrome (PRIS) was made, but further investigation revealed neonatal adrenoleukodystrophy. PRIS should be considered with this constellation of symptoms, but other neurometabolic disorders must always be ruled out.
Anesthetics, Intravenous/adverse effects , Mitochondrial Diseases/diagnosis , Peroxisomal Disorders/diagnosis , Propofol/adverse effects , Acidosis/complications , Blood Gas Analysis , Cerebral Palsy/complications , Child, Preschool , Female , Humans , Liver Function Tests , Magnetic Resonance Imaging , Mitochondrial Diseases/therapy , Peroxisomal Disorders/therapy
Metabolism, Inborn Errors/therapy , Adult , Amino Acid Metabolism, Inborn Errors/genetics , Amino Acid Metabolism, Inborn Errors/therapy , Clinical Competence , Female , Humans , Infant, Newborn , Lysosomal Storage Diseases/genetics , Lysosomal Storage Diseases/therapy , Metabolism, Inborn Errors/diagnosis , Metabolism, Inborn Errors/genetics , Mitochondrial Diseases/genetics , Mitochondrial Diseases/therapy , Patient Care Team , Patient-Centered Care , Peroxisomal Disorders/genetics , Peroxisomal Disorders/therapy , Phenylketonurias/diet therapy , Phenylketonurias/genetics , Pregnancy , Pregnancy Complications/therapy , Risk Factors , Urea Cycle Disorders, Inborn/genetics , Urea Cycle Disorders, Inborn/therapy
BACKGROUND: Docosahexaenoic acid (DHA, 22:6ω3) is a fundamental component of cell membranes, especially in the brain and retina. In the experimental animal, DHA deficiency leads to suboptimal neurological performance and visual deficiencies. Children with the Zellweger syndrome (ZS) have a profound DHA deficiency and symptoms that can be attributed to their extremely low DHA levels. These children seem to have a metabolic defect in DHA biosynthesis, which has never been totally elucidated. Treatment with DHA ethyl ester greatly improves these patients, but if we could normalize their endogenous DHA production we could get additional benefits. We examined whether DHA biosynthesis by Δ4-desaturation could be enhanced in the human species by transfecting the enzyme, and if this could normalize the DHA levels in cells from ZS patients. RESULTS: We showed that the Δ4-desaturase gene (Fad4) from Thraustochytrium sp, which can be expressed by heterologous transfection in other plant and yeast cells, can also be transfected into human lymphocytes, and that it expresses the enzyme (FAD4, Δ4-desaturase) by producing DHA from direct Δ4-desaturation of 22:5ω3. We also found that the other substrate for Δ4-desaturase, 22:4ω6, was parallely desaturated to 22:5ω6. CONCLUSIONS: The present "in vitro" study demonstrates that Δ4-desaturase can be transfected into human cells and synthesize DHA (as well as 22:5ω6, DPA) from 22:5ω3 and 22:4ω6, respectively, by putative Δ4-desaturation. Even if this pathway may not be the physiological route for DHA biosynthesis "in vivo", the present study opens new perspectives for the treatment of patients within the ZS spectrum.
Docosahexaenoic Acids/metabolism , Fatty Acid Desaturases/genetics , Fatty Acid Desaturases/metabolism , Zellweger Syndrome/metabolism , Cell Line, Transformed , Cell Transformation, Viral , Fatty Acids/metabolism , Fatty Acids, Essential/deficiency , Fatty Acids, Essential/metabolism , Fatty Acids, Omega-6/metabolism , Fungi/genetics , Gene Library , Genes, Fungal , Genetic Therapy , Humans , Infant , Lymphocytes/cytology , Lymphocytes/metabolism , Peroxisomal Disorders/therapy , Recombinant Fusion Proteins/biosynthesis , Refsum Disease, Infantile/therapy , Substrate Specificity , Transfection , Zellweger Syndrome/genetics , Zellweger Syndrome/therapy
The importance of peroxisomes for human health is highlighted by the number of peroxisomal disorders (PDs), diseases associated to peroxisome biogenesis disorders and peroxisomal enzyme/transporter deficiencies. Currently, many physiological/biosynthetic mechanisms involved in these illnesses have been elucidated, but PDs remain incurable. This review examines the most important aspects concerning peroxisomes (i.e. peroxisome proliferation, peroxisome biogenesis, metabolic functions of mammalian peroxisomes) and presents the most significant trends and advances in the study of peroxisomal disorders.
Peroxisomal Disorders/etiology , Peroxisomes/physiology , Bile Acids and Salts/metabolism , Cell Proliferation , Cholesterol/biosynthesis , Fatty Acids/metabolism , Humans , Membrane Proteins/metabolism , Oxidation-Reduction , Oxidative Stress , Peroxisomal Disorders/diagnosis , Peroxisomal Disorders/therapy , Protein Transport
OBJECTIVE: To describe the current state of treatment for disorders of intermediate metabolism (primarily of amino acids, urea cycle and organic acids) and for diseases related to two subcellular organelles (lysosomes and peroxisomes). SOURCES: In covering the treatment of disorders of intermediate metabolism, priority was given to the most important methods for managing intoxication, in view of the importance for pediatricians to treat acute and life-threatening cases. The article also provides a general overview of the treatment for lysosomal and peroxisomal diseases, with emphasis on enzyme replacement therapy, which is a treatment modality that is growing in use and with which pediatricians should make themselves familiar. SUMMARY OF THE FINDINGS: The most important measures used to manage the intoxication present in many inborn errors of intermediate metabolism were presented (restriction of substrate build-up by means of diet or enzymatic inhibition, removal of toxic products, stimulation of residual enzyme activity, replacement of the deficient product). The section on treatment for lysosomal and peroxisomal diseases includes tables providing information on the treatments available. CONCLUSIONS: Treating inborn errors of metabolism is a complex task that should be performed by a multidisciplinary team of which the pediatrician is the key member. This article provides practical information relating to the management of some inborn errors of metabolism and provides pediatricians with a general overview of recent developments in this area of medicine.
Metabolism, Inborn Errors/therapy , Amino Acid Metabolism, Inborn Errors/diet therapy , Amino Acid Metabolism, Inborn Errors/drug therapy , Enzyme Therapy , Humans , Lysosomal Storage Diseases/therapy , Peroxisomal Disorders/therapy
We evaluated the feasibility of UCBT from unrelated donors and a myeloablative preparative regimen that did not involve anti-thymocyte globulin in five children with lysosomal and peroxisomal diseases. Patients with MPS II (n = 1), adrenoleukodystrophy (n = 1), metachromatic leukodystrophy (n = 2), and Krabbe disease (n = 1) received UCBT between December 2001 and September 2005. All patients received oral Bu (600 mg/m2), CY (200 mg/kg IV), and fludarabine (180 mg/m2 IV). Prophylaxis for GVHD consisted of a combination of tacrolimus and a short methotrexate course. Neutrophil engraftment occurred a median of 24 days (range, 21-25) after transplantation. None had graft rejection. One patient developed grade III acute GVHD and the other four patients had grade I acute GVHD; none had extensive chronic GVHD. One patient developed hemorrhagic cystitis. There were no treatment-related deaths. Although one child with MPS II died of PTLD 10 months after the UCBT, four of the five children are alive 14, 20, 31, and 55 months after transplantation with complete donor chimerism. These results suggest the feasibility of the UCBT with Bu, fludarabine, and CY-preparative regimen for patients with inherited metabolic diseases.
Cord Blood Stem Cell Transplantation/methods , Lysosomal Storage Diseases/therapy , Peroxisomal Disorders/therapy , Administration, Oral , Busulfan/adverse effects , Child, Preschool , Cyclophosphamide/adverse effects , Female , Graft vs Host Disease , Humans , Immunosuppressive Agents/adverse effects , Infant , Male , Methotrexate/adverse effects , Vidarabine/adverse effects , Vidarabine/analogs & derivatives
OBJETIVO: Esta revisão teve por objetivo abordar a situação atual do tratamento dos distúrbios do metabolismo intermediário (principalmente dos aminoácidos, ciclo da uréia e ácidos orgânicos) e das doenças relacionadas a duas organelas subcelulares (lisossomos e peroxissomos). FONTES DOS DADOS: Na abordagem do tratamento dos distúrbios do metabolismo intermediário, foi dada prioridade às principais formas de manejo da intoxicação, em virtude da importância para o pediatra do tratamento de quadros agudos e com risco de vida. O artigo apresenta também uma visão geral do tratamento das doenças lisossômicas e peroxissômicas, com ênfase na terapia de reposição enzimática, uma modalidade de tratamento de uso crescente com a qual o pediatra deve se familiarizar. SÍNTESE DOS DADOS: As principais medidas para manejo da intoxicação presente em muitos erros inatos do metabolismo intermediário foram apresentadas (restrição de aporte de substrato através da dieta ou através de inibição enzimática, remoção do produto tóxico, estímulo da atividade enzimática residual, reposição do produto deficiente). O material elaborado sobre terapia para doenças lisossômicas e peroxissômicas inclui tabelas informativas sobre os tratamentos disponíveis. CONCLUSÕES: O tratamento dos erros inatos do metabolismo é uma situação complexa e que deve ser abordada por uma equipe multidisciplinar, na qual o pediatra é peça-chave. Este capítulo contém informações práticas relativas ao manejo de alguns erros inatos do metabolismo e proporciona ao pediatra uma visão geral dos desenvolvimentos recentes ocorrido nessa área da medicina.
OBJECTIVE: To describe the current state of treatment for disorders of intermediate metabolism (primarily of amino acids, urea cycle and organic acids) and for diseases related to two subcellular organelles (lysosomes and peroxisomes). SOURCES: In covering the treatment of disorders of intermediate metabolism, priority was given to the most important methods for managing intoxication, in view of the importance for pediatricians to treat acute and life-threatening cases. The article also provides a general overview of the treatment for lysosomal and peroxisomal diseases, with emphasis on enzyme replacement therapy, which is a treatment modality that is growing in use and with which pediatricians should make themselves familiar. SUMMARY OF THE FINDINGS: The most important measures used to manage the intoxication present in many inborn errors of intermediate metabolism were presented (restriction of substrate build-up by means of diet or enzymatic inhibition, removal of toxic products, stimulation of residual enzyme activity, replacement of the deficient product). The section on treatment for lysosomal and peroxisomal diseases includes tables providing information on the treatments available. CONCLUSIONS: Treating inborn errors of metabolism is a complex task that should be performed by a multidisciplinary team of which the pediatrician is the key member. This article provides practical information relating to the management of some inborn errors of metabolism and provides pediatricians with a general overview of recent developments in this area of medicine.
Humans , Metabolism, Inborn Errors/therapy , Amino Acid Metabolism, Inborn Errors/diet therapy , Amino Acid Metabolism, Inborn Errors/drug therapy , Enzymes/therapeutic use , Lysosomal Storage Diseases/therapy , Peroxisomal Disorders/therapy
Heredodegenerative Disorders, Nervous System/diagnosis , Heredodegenerative Disorders, Nervous System/therapy , Arginine/administration & dosage , Child , Coenzymes , Glucosylceramidase/administration & dosage , Heredodegenerative Disorders, Nervous System/genetics , Humans , Isoenzymes/administration & dosage , Lysosomal Storage Diseases/diagnosis , Lysosomal Storage Diseases/genetics , Lysosomal Storage Diseases/therapy , Mitochondrial Diseases/diagnosis , Mitochondrial Diseases/genetics , Mitochondrial Diseases/therapy , Molecular Diagnostic Techniques , Myotonic Dystrophy/diagnosis , Myotonic Dystrophy/genetics , Myotonic Dystrophy/therapy , Peripheral Nervous System Diseases/diagnosis , Peripheral Nervous System Diseases/genetics , Peripheral Nervous System Diseases/therapy , Peroxisomal Disorders/diagnosis , Peroxisomal Disorders/genetics , Peroxisomal Disorders/therapy , Trinucleotide Repeats , Ubiquinone/administration & dosage , Ubiquinone/analogs & derivatives , Vitamin E/administration & dosage , alpha-Galactosidase/administration & dosage
