Mecanismo de acción de la terapia celular en enfermedades hereditarias / Mechanism of action of cell therapy in hereditary diseases

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.

Visual loss as first clinical manifestation of X-linked adrenoleukodystrophy / Perda visual como primeira manifestação clínica de adrenoleucodistrofia ligada ao X

Abstract X-linked adrenoleukodystrophy (X-ALD) represents a group of diseases characterized by the accumulation of very long chain fattyacids (VLCFAs) in the tissues. Its clinical manifestations are usually manifold. Visual changes may be present, but they often appear later in the disease. We describe here the case of a 9-year-old boy with X-ALD, whose first symptom was visual loss, which began at 8 years of age. His ophthalmologic evaluation revealed no alterations. Shortly thereafter, he suffered a head injury. The magnetic resonance imaging of brain revealed findings that led to the suspicion of X-ALD. The plasma VLCFA dosage confirmed this diagnosis. This report aims toshow that in cases of visual loss with a normal ophthalmic examination, a high index of suspicion should be given for conditions suchas X-ALD, since it affects the cortical routes related to vision. Fundoscopy findings appear late in X-ALD.

Resumo A adrenoleucodistrofia ligada ao X (X-ALD) representa um grupo de doenças caracterizadas pelo acúmulo de ácidos graxos de cadeia muito longa (VLCFAs) nos tecidos. Suas manifestações clínicas costumam ser múltiplas. Alterações visuais podem estar presentes, contudo costumam surgir mais tardiamente na doença. Descrevemos aqui o caso de um menino de 9 anos com X-ALD, cujo primeiro sintoma foi perda visual, iniciada aos 8 anos de idade. A sua avaliação oftalmológica não revelou alterações. Pouco tempo depois, ele sofreu um traumatismo craniano. A imagem de ressonância magnética de encéfalo revelou achados que levaram a suspeita de X-ALD. A dosagem dos VLCFAs no plasma confirmou este diagnóstico. Este relato tem como objetivo mostrar que em casos de perda visual com um exame oftalmológico normal, deve-se ter um alto índice de suspeita para condições como a X-ALD, pois a mesma afeta as vias corticais relacionadas à visão. Nessa doença, os achados da fundoscopia aparecem mais tardiamente.

A review of the results of the very long chain fatty acid analyses for X-linked Adrenoleukodystrophy at the Biochemical Genetics Laboratory of the Institute of Human Genetics-National Institutes of Health, Manila

@#Background. X-linked adrenoleukodystrophy (X-ALD) is a progressive genetic disorder affecting the metabolism of very long chain fatty acids in the adrenal glands, spinal cord and white matter of the nervous system. It is an inherited metabolic storage disease whereby a defect in a specific enzyme results in the accumulation of very long-chain fatty acids (VLCFA) that are harmful to some cells and organs. VLCFA analysis for confirmation of X-linked adrenoleukodystrophy is one of the most requested tests among the send-out laboratory services of the Biochemical Genetics Laboratory at the Institute of Human Genetics. This paper aims to review the clinical characteristics and the results of the VLCFA analysis of the patients whose samples we received for testing.Methods. Overseas tests samples received by the Biochemical Genetics Laboratory for VLCFA from 2002-2016 were included. The details of the patients were collated in an overseas tests database and was the main source of the data for this study. The results of the VLCFA tests sent to the Kennedy Krieger Institute and The Children’s Hospital at Westmead were inputted into the said database. Descriptive statistics was utilized in order to examine the clinical and biochemical data of the patients.Results. The results showed that out of the 54 samples submitted to our laboratory, 19 (35%) of the samples received from male patients suspected to have X-ALD yielded positive results and another 10 (19%) females were found to be carriers. Visual defect followed by deteriorating mental status were the most frequent indications for VLCFA testing. Conclusion. Having a significant diagnostic yield of 54%, early diagnosis of X-linked adrenoleukodystrophy in our population is important so that proper management that could prevent the progression of the disease could be timely instituted.

Acidemia metilmalónica: presentación de un caso y revisión de literatura científica / Methylmalonic acidemia: report of a case and review of scientific literature / Acidemia orgânica metilmalônica: apresentação de caso e revisão de literatura cientifica

La acidemia metilmalónica es un desorden causado por anormalidad en la enzima metil malonil CoA mutasa o su cofactor Adenosilcobalamina. Esta holoenzima se encuentra implicada en el catabolismo de varios aminoácidos entre los que se incluyen dos de cadena ramificada (isoleucina y valina). Puede presentarse como una forma severa de inicio neonatal hasta formas con síntomas lentamente progresivos como hipotonía y retardo en el desarrollo. El diagnóstico y tratamiento oportuno, pueden modificar el curso y desenlace de la enfermedad, mejorando la calidad de vida del paciente. Reportamos el caso de un lactante de 3 meses, con pancitopenia, hipotonía, retardo en desarrollo y convulsiones. Se diagnosticó acidemia metilmalónica mediante cromatografía de ácidos orgánicos en orina. El paciente fue tratado con Cianocobalamina, restricción dietaria y levetiracetam con respuesta clínica favorable. Actualmente permanece libre de crisis, los índices de desarrollo son normales y la pancitopenia resolvió. Este caso muestra como el diagnóstico y tratamiento temprano en un paciente con acidemia metilmalónica, aun cuando se origine por déficit de cofactor, puede favorecer el pronóstico neurológico y funcional.

Methylmalonic Acidemia is a disorder caused by an abnormality of methylmalonyl-CoA mutase or a deficiency of adenosylcobalamin as cofactor. This holoenzyme is involved in the catabolism of branched chain amino acids. It can present clinically either as a severe neonatal-onset form, or some progressive symptoms as hypotonia and developmental delay. Early diagnosis and treatment can alter the course and outcome. We report the case of a 3- month- old boy, with pancytopenia, hypotonia, developmental delay and seizures. Methylmalonic Acidemia was diagnosed by urinary organic acid chromatography. Patient was treated with Cyanocobalamin, dietary restriction and levetiracetam with favorable response. He is currently seizure free, development indexes are normal and pancytopenia has resolved. This case shows how early diagnosis and treatment in a patient with Methylmalonic Acidemia caused by cofactor deficiency may favor functional and neurologic outcomes.

A acidémia metilmalónica é uma desordem causada pela anormalidade na enzima l-metil malonil- coa mutase o no seu cofator adenosilcobalamina. Esta holoenzima está envolvida no catabolismo de vários aminoácidos, entre os quais encontrasse os de cadeia ramificada (isoleucina e valina). Sua apresentação clínica pode ser uma forma grave em neonatos com sintomas lentamente progressivos, como hipotonia e atraso no desenvolvimento. O diagnóstico e tratamento precoce podem alterar a história natural da doença, melhorando a qualidade de vida dos pacientes. Relata-se o caso de uma criança de colo de três meses, com pancitopenia, hipotonia, atraso no desenvolvimento e convulsões. O diagnóstico de acidémia metilmalónica foi feito com cromatografia. O paciente foi tratado com Cianocobalamina, regime de dieta e levetiracetam, com resposta clínica favorável. Atualmente o paciente está sem crises, o desenvolvimento é normal para idade e a pancitopenia foi resolvida. Na acidémica metilmalónica, a despeito, da sua origem por déficit de cofator com diagnóstico e tratamento precoce, pode ter uma evolução neurológica e funcional.

A Korean boy with atypical X-linked adrenoleukodystrophy confirmed by an unpublished mutation of ABCD1 / 소아과

X-linked adrenoleukodystrophy (X-ALD) is a rare peroxisomal disorder, that is rapidly progressive, neurodegenerative, and recessive, and characteristically primary affects the central nervous system white matter and the adrenal cortex. X-ALD is diagnosed basaed on clinical, radiological, and serological parameters, including elevated plasma levels of very long chain fatty acids (VLCFA), such as C24:0 and C26:0, and high C24:0/C22:0 and C26:0/C22:0 ratios. These tests are complemented with genetic analyses. A 7.5-year-old boy was admitted to Department of Pediatrics, Chungnam National University Hospital with progressive weakness of the bilateral lower extremities. Brain magnetic resonance imaging confirmed clinically suspected ALD. A low dose adrenocorticotropic hormone stimulation test revealed parital adrenal insufficiency. His fasting plasma levels of VLCFA showed that his C24:0/C22:0 and C26:0/C22:0 ratios were significantly elevated to 1.609 (normal, 0-1.390) and 0.075 (normal, 0-0.023), respectively. Genomic DNA was extracted from peripheral whole blood samples collected from the patient and his family. All exons of ABCD1 gene were amplified by polymerase chain reaction (PCR) using specific primers. Amplified PCR products were sequenced using the same primer pairs according to the manufacturer's instructions. We identified a missense mutation (p.Arg163Leu) in the ABCD1 gene of the proband caused by the nucleotide change 488G>T in exon 1. His asymptomatic mother carried the same mutation. We have reported an unpublished mutation in the ABCD1 gene in a patient with X-ALD, who showed increased ratio of C24:0/C22:0 and C26:0/C22:0, despite a normal VLCFA concentrations.

Adrenomyeloneuropathy Presenting With Adrenal Insufficiency

Adrenomyeloneuropathy (AMN), one of the variants of X-linked adrenoleukodystrophy (ALD), is inherited peroxisomal disorder associated with the accumulation of very long chain fatty acids (VLCFA). AMN is characterized primarily by involvements of long ascending and descending tracts of the spinal cord and peripheral neuropathy, which leads to spastic paraparesis and urinary and erectile dysfunction. We experienced the AMN case of a 33-year-old man presenting bilateral progressive spastic paraparesis, impotence and urge incontinence with primary adrenal failures, as confirmed by increased serum of VLCFA concentrations. Considering that somatosensory evoked potentials in posterior tibial nerve was the only abnormal finding in electrophysiologic findings when compared with the severe spastic gait pattern shown, it is necessary to follow up with electrophysiologic studies.

Evidence of oxidative stress in peroxisomal disorders

<p><b>INTRODUCTION</b>Peroxisomal disorders are subdivided into peroxisome biogenesis disorders (PBDs) and single peroxisomal enzyme deficiency. Many peroxisomal diseases exhibit excessive oxidative stress, leading to neurological alterations and dysfunction. Peroxisomes use oxygen in oxidative reactions that generate hydrogen peroxide. This study aimed to investigate various oxidative stress parameters in patients suffering from peroxisomal disorders.</p><p><b>METHODS</b>A total of 20 patients with peroxisomal disorders, aged six months to 13 years (mean age 5.9 ± 3.2 years), were compared to 14 healthy controls. All individuals were subjected to full history-taking, including a three-generation pedigree analysis concerning parental consanguinity and similarly affected members in the family, with meticulous clinical examination to detect any malformation or anomaly. Estimation of very-long-chain fatty acids and phytanic acid was done to verify the diagnosis. Brain magnetic resonance imaging, electroencephalogram, visual evoked potential, auditory potential and plain radiography were conducted to assess the pathological condition of the patients. Oxidative stress parameters, including nitric oxide (NO), malondialdehyde (MDA) and superoxide dismutase (SOD), were estimated in both the patients and controls.</p><p><b>RESULTS</b>Significant increases in both MDA and NO were found in patients with PBDs. It was also demonstrated that SOD was significantly lower in patients with PDB than the controls.</p><p><b>CONCLUSION</b>This study sheds more light on the link between oxidative stress and peroxisomal disorders, as oxidative stress may be a hallmark of peroxisomal disorders. Consequently, one of the useful neuronal rescue strategies could be treatment with antioxidant agents in addition to other lines of treatments.</p>

Adrenoleucodistrofia ligada al cromosoma X: enfermedad peroxisomal / X-linked adrenoleukodystrophy: peroxisomal disease

Paciente varón de siete años, hijo único sin antecedentes personales de importancia y sin historia de consanguineidad ni de enfermedad neurológica en la familia, que presenta un curso progresivo de alteraciones de insuficiencia adrenal y del sistema nervioso tanto central como periférico. Se hizo el diagnóstico de adrenoleucodistrofia ligada al cromosoma X basado en los estudios de neuroimágenes, valores incrementados en plasma de ácidos graso de cadena muy larga y en el estudio genético.

A 7 year-old male patient, an unique son without an important past record nor history of neurological disease or consanguinity within the family, shows a progressive clinical course of changes related to adrenal insufficiency and central and peripheral nervous system. The diagnosis of X-linked adrenoleukodystrophy was done based on neuroimagings studies, increased plasma values of very long chain and genetic study.

Tratamento de erros inatos do metabolismo: [revisão] / Treatment of inborn errors of metabolism: [review]

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.

Acidemia orgánica (propiónica) en un neonato detectada por espectrometría de masas en tándem / Neonatal onset of organic acidemia (propionic) diagnosed by tandem mass spectrometry

Institución donde se llevó a cabo el trabajo: Instituto Materno-Infantil, Universidad Nacional de Colombia, Bogotá, D.C., Colombia. La acidemia propiónica es un error innato del metabolismo de herencia autosómica recesiva, causada por la deficiencia de la enzima propionil CoA carboxilasa, que cataliza la conversión de propionil CoA a malonil CoA. Es la principal causa de hiperglicinemia cetósica. En el período neonatal se manifiesta comúnmente con vómito, dificultad en la alimentación, hipotonía, letargia, acidosis metabólica, cetosis e hiperamonemia. Se presenta el caso de una recién nacida con cuadro clínico de encefalopatía asociada a hipoglucemia, cetonuria, hiperamonemia, acidosis metabólica con anión gap aumentado, anemia, leucopenia y trombocitopenia en quien se diagnosticó una acidemia orgánica mediante espectrometría de masas en tándem. Existían antecedentes de consanguinidad entre los padres, de un aborto, un mortinato y tres muertes neonatales, sugestivo de enfermedad genética.

Peroxisomal disorders / 한양의대학술지

Peroxisomes are subcellular organells catalyzing a number of important functions in cellular metabolism. Their functions are mostly related to lipid metabolism. Genetic disorders of peroxisomes are divided into 2 categories: peroxisomal biogenesis disorders and single peroxisomal enzyme deficiencies. This paper describes an overview of the peroxisomal disorders, including metabolic basis, and clinical and laboratory findings.

A Case of Neonatal Adrenoleukodystrophy Presented with Neonatal Seizure

Neonatal adrenoleukodystrophy(NALD) is an inherited autosomal recessive disease characterized by very early onset of neurologic deterioration, extreme hypotonia, poor sucking reflex, failure to thrive, poor or absent grasp and Moro reflexes, diminished deep tendon reflexes, neonatal seizure refractory to antiepileptic drugs, progressive hepatomegaly, and mild or absent craniofacial dysmorphism. In the peroxisomal biogenesis disorders, whose basic defect are the incapabilities to import one or more proteins into the organelle, include Zellweger syndrome(ZS), NALD, and infantile Refsum disease(IRD). These are now thought to represent a continuous spectrum of disease severity, ZS the most severe, IRD the least severe, and NALD intermediate. Furthermore, their biochemistry and microscopic pathology are nearly identical. The biochemical abnormalities of NALD are the elevated levels of very long chain fatty acid(VLCFA), phytanic acid, pristanic acid, pipecolic acid in plasma, cultured skin fibroblasts, and reduced plasmalogen contents in erythrocytes. There are no effective treatments until now. We experienced an one day old neonate with hypotonia and seizure, who was diagnosed as NALD by elevated plasma VLCFA. So we report the case with a brief review of literature.

Inborn Errors of Metabolism in Korea

Diseases of inborn errors of metabolism (IEMs) are very rare but the overall prevalence of IEMs is not low, and in the United States, about 5~10% of admitted patients have some genetic predispositions. Clinical manifestations of IEMs are very diverse, but most frequent manifestations are neurological symptoms and signs. IEMs in Korea have been underestimated because of prejudice, underdevelopment of diagnostic tools and ignorance. The Korean Pediatric Society has done a retrospective study in order to know the relative incidence of IEMs in 2001. All hospitals with over 100 beds participated in the study. The most frequent disease was Wilson disease (201 cases for 10 years) followed by phenylketonuria (98 cases for 10 years) and Hunters disease (69 cases for 10 years). Disorders of mineral metabolism were the most frequently diagnosed disease groups (252 cases for 10 years) followed by organic acidopathies (220 cases), aminoacidopathies (139 cases), mucopolysaccharidosis (131 cases), disorders of carbohydrate metabolism (84 cases), sphingolipidosis (69 cases), urea cycle disorders (39 cases), peroxisomal disorders (27 cases), porphyrias (16 cases), disorders of purine and pyrimidine metabolism (14 cases), disorders of membrane transport (13 cases), fatty acid oxidation disorders (9 cases), oligosaccharidosis (2 cases), and mucolipidosis (1 case). Clearly, Koreans are not protected from IEMs and a systematic approach is needed to make diagnosis more easy and accurate.

Zellweger Syndrome : First Confirmed Neonatal Case in Korea

We describe below a case of Zellweger syndrome case with facial dysmorphism, profound hypotonia, and hepatomegaly. He died at the age of 2 months. Zellweger syndrome is a disease marked by the absence of hepatic and renal peroxisomes. Because peroxisomes have many vital anabolic and catabolic functions within the cell, their absence results in profound cellular dysfunction. A biochemical study of plasma revealed elevation of very long chains of fatty acids and pipecolic acid, consistent with peroxisomal disorder. The cultured skin fibroblasts showed a marked decrease in plasmalogen synthesis enzyme : dihydroxyacetonephosphate acyl transferase(DHAP-AT) The clinical characteristics and biochemical findings led to the diagnosis of Zellweger syndrome. The pattern of inheritance is autosomal recessive, hence genetic counseling can help the families. In infantile hypotonia patients with unknown cause, peroxisomal disorder should be included in the differential diagnosis. We report the first confirmed case of Zellweger syndrome by enzyme assay in Korea.

Zellweger syndrome: a case report

Zellweger syndrome, an autosomal recessive disorder, is generally considered as the prototype of the group of the rare peroxisomal disorders. Infants with Zellweger syndrome have a striking constellation of clinical features, which usually suggest the diagnosis. The condition has been reported in all races and from all parts of the world. Considerable progress has been made recently in the biochemical and molecular aspects of the disease as well as identifying the genetic defects involved. Here we present a case of Zellweger syndrome and discuss the pathophysiology of the disease. To our knowledge, this is the first case of Zellweger syndrome reported from United Arab Emirates

Condrodisplasia punctata (Happle) / Chondrodysplasia punctata (Happle)

Se presentan 2 pacientes con condrodisplasia punctata atendidos en el Hospital de Pediatría Prof. Dr. Juan P. Garrahan entre los años 1990 y 1997. Ambas pacientes eran de sexo femenino con edades de 3 y de 30 días, respectivamente, en el momento de la consulta. Los dos casos presentaron lesiones cutáneas y óseas características del síndrome, con asimetría de miembros inferiores desde el nacimiento, confirmándose posteriormente mediante el estudio radiológico de huesos largos la presencia de displasia punteada de los mismos. Asimismo una de las dos pacientes presentaba polidactilia de mano izquierda, sindactilia de 2º, 3º y 4º dedos de pie derecho, microoftalmos con catarata de ojo izquierdo y alopecia. La condrodisplasia punctata tipo II es heredada en forma ligada al X, letal para los varones. Los cambios cutáneos ictiosiformes siguiendo las líneas de Blaschko son la característica más importante y permite diferenciar el tipo II de la CD de los demás grupos. Es importante remarcar que en ambos casos las manifestaciones cutáneas fueron fundamentales para el diagnóstico de esta enfermedad