ABSTRACT
El síndrome de deficiencia del transportador de glucosa tipo 1 es una enfermedad de causa genética, que involucra el gen SLC2A1. En general, se presenta durante los primeros años de vida con retraso en la adquisición de pautas madurativas, epilepsia farmacorresistente y desórdenes del movimiento. La clínica y la disminución de glucosa en líquido cefalorraquídeo permiten sospechar el diagnóstico, el cual debe ser confirmado mediante el estudio molecular del gen SLC2A1. Debido a que se trata de una enfermedad poco frecuente y de expresión clínica variable, el diagnóstico precoz suele representar un desafío para los equipos de salud. Este es importante, ya que la implementación de la terapia cetogénica logra controlar las manifestaciones clínicas y mejora el pronóstico a largo plazo. Presentamos una revisión sobre el déficit del transportador de glucosa tipo 1, que abarca sus características clínicas, bioquímicas, moleculares y terapéuticas.
Glucose transporter type 1 deficiency with a typical onset is a genetic disorder associated with the SLC2A1 gene. Usually appears during the first years of life with severe developmental delay, drugresistant epilepsy, and movement disorders. Diagnosis is suspected based on clinical manifestations and a low glucose level in cerebrospinal fluid, and should be confirmed by the molecular genetic study of the SLC2A1 gene. As it is a rare disease with variable clinical expression, early diagnosis is often challenging for the healthcare team. Nevertheless, this is important because early implementation of ketogenic therapy will lead to control of the clinical manifestations and a better long-term prognosis. Here we review the glucose transporter type 1 deficiency syndrome focusing on its clinical, biochemical, molecular, and therapeutic characteristics.
Subject(s)
Humans , Carbohydrate Metabolism, Inborn Errors/diagnosis , Carbohydrate Metabolism, Inborn Errors/genetics , Carbohydrate Metabolism, Inborn Errors/therapy , Monosaccharide Transport Proteins/genetics , Epilepsy/diagnosis , Epilepsy/genetics , MutationABSTRACT
Glucose transporter type 1 deficiency with a typical onset is a genetic disorder associated with the SLC2A1 gene. Usually appears during the first years of life with severe developmental delay, drugresistant epilepsy, and movement disorders. Diagnosis is suspected based on clinical manifestations and a low glucose level in cerebrospinal fluid,and should be confirmed by the molecular genetic study of the SLC2A1 gene. As it is a rare disease with variable clinical expression, early diagnosis is often challenging for the healthcare team. Nevertheless, this is important because early implementation of ketogenic therapy will lead to control of the clinical manifestations and a better long-term prognosis. Here we review the glucose transporter type 1 deficiency syndrome focusing on its clinical, biochemical, molecular, and therapeutic characteristics.
El síndrome de deficiencia del transportador de glucosa tipo 1 es una enfermedad de causa genética, que involucra el gen SLC2A1. En general, se presenta durante los primeros años de vida con retraso en la adquisición de pautas madurativas, epilepsia farmacorresistente y desórdenes del movimiento. La clínica y la disminución de glucosa en líquido cefalorraquídeo permiten sospechar el diagnóstico, el cual debe ser confirmado mediante el estudio molecular del gen SLC2A1. Debido a que se trata de una enfermedad poco frecuente y de expresión clínica variable, el diagnóstico precoz suele representar un desafío para los equipos de salud. Este es importante, ya que la implementación de la terapia cetogénica logra controlar las manifestaciones clínicas y mejora el pronóstico a largo plazo. Presentamos una revisión sobre el déficit del transportador de glucosa tipo 1, que abarca sus características clínicas, bioquímicas, moleculares y terapéuticas.
Subject(s)
Carbohydrate Metabolism, Inborn Errors , Humans , Carbohydrate Metabolism, Inborn Errors/diagnosis , Carbohydrate Metabolism, Inborn Errors/genetics , Carbohydrate Metabolism, Inborn Errors/therapy , Epilepsy/diagnosis , Epilepsy/genetics , Monosaccharide Transport Proteins/genetics , MutationABSTRACT
Glucose transporter type 1 deficiency syndrome is a rare pediatric neurometabolic disorder. There are two phenotypes: the classical phenotype (85%) and the non-classic (15%). Both phenotypes are associated with hypoglycorrhachia. Multiple mutations are described in the SCL2A1 gene. The treatment is the ketogenic diet. We report a case of a four-year-old male patient who started with hemichorea and hemidystonia and was medicated with drugs for seizures without clinical response, that's why his parents made another pediatric consultation at his six-year-old. With the suggestive clinical findings of glucose transporter type 1 deficiency syndrome the lumbar puncture was made confirming the diagnosis. Immediately after starting the ketogenic diet the patient stopped making abnormal movements up to the moment when he is fourteen years old, eight years after.
El síndrome de deficiencia del transportador de glucosa cerebral de tipo 1 es una enfermedad neurometabólica rara en pediatría. Existe un fenotípico clásico (85 %) y otro no clásico (15 %). Ambos fenotipos se asocian con hipoglucorraquia. Se identifican múltiples mutaciones en el gen SLC2A1. El tratamiento es la terapia cetogénica. Se presenta un varón que comenzó a los cuatro años con hemicorea y hemidistonía medicado con anticonvulsivantes sin respuesta clínica, por lo que consultó nuevamente a los seis años. Con sospecha diagnóstica de síndrome de déficit de glut-1 atípico se realizó punción lumbar; el diagnóstico se confirmó por la presencia de hipoglucorraquia. Inmediatamente después de iniciar la dieta cetogénica, el paciente no presentó más movimientos anormales durante los siguientes 8 años hasta la actualidad, ya cumplidos los 14 años.
Subject(s)
Carbohydrate Metabolism, Inborn Errors , Diet, Ketogenic , Carbohydrate Metabolism, Inborn Errors/complications , Carbohydrate Metabolism, Inborn Errors/diagnosis , Carbohydrate Metabolism, Inborn Errors/genetics , Glucose Transporter Type 1 , Humans , Male , Monosaccharide Transport Proteins/deficiency , Monosaccharide Transport Proteins/geneticsABSTRACT
El síndrome de deficiencia del transportador de glucosa cerebral de tipo 1 es una enfermedad neurometabólica rara en pediatría. Existe un fenotípico clásico (85 %) y otro no clásico (15 %). Ambos fenotipos se asocian con hipoglucorraquia. Se identifican múltiples mutaciones en el gen SLC2A1. El tratamiento es la terapia cetogénica. Se presenta un varón que comenzó a los cuatro años con hemicorea y hemidistonía medicado con anticonvulsivantes sin respuesta clínica, por lo que consultó nuevamente a los seis años. Con sospecha diagnóstica de síndrome de déficit de glut-1 atípico se realizó punción lumbar; el diagnóstico se confirmó por la presencia de hipoglucorraquia. Inmediatamente después de iniciar la dieta cetogénica, el paciente no presentó más movimientos anormales durante los siguientes 8 años hasta la actualidad, ya cumplidos los 14 años.
Glucose transporter type 1 deficiency syndrome is a rare pediatric neurometabolic disorder. There are two phenotypes: the classical phenotype (85%) and the non-classic (15%). Both phenotypes are associated with hypoglycorrhachia. Multiple mutations are described in the SCL2A1 gene. The treatment is the ketogenic diet. We report a case of a four-year-old male patient who started with hemichorea and hemidystonia and was medicated with drugs for seizures without clinical response, that's why his parents made another pediatric consultation at his six-year-old. With the suggestive clinical findings of glucose transporter type 1 deficiency syndrome the lumbar puncture was made confirming the diagnosis. Immediately after starting the ketogenic diet the patient stopped making abnormal movements up to the moment when he is fourteen years old, eight years after.
Subject(s)
Humans , Male , Adolescent , Carbohydrate Metabolism, Inborn Errors/complications , Carbohydrate Metabolism, Inborn Errors/diagnosis , Carbohydrate Metabolism, Inborn Errors/genetics , Diet, Ketogenic , Monosaccharide Transport Proteins/deficiency , Monosaccharide Transport Proteins/genetics , Glucose Transporter Type 1ABSTRACT
INTRODUCTION: Glucose Transporter Type 1 Deficiency Syndrome (GLUT1-DS) is caused by the SLC2A1 gene muta tion, which encodes the glucose transporter proteins to the brain Neurological manifestations occur in three main domains: seizures, abnormal movements, and cognitive disorders. The diagnosis is presumed upon the finding of low CSF glucose and confirmed by the gene molecular analysis. Ac curate diagnosis is important because it has a specific treatment, which is ketogenic diet. OBJECTIVE: To analyze two SD-GLUT1 pediatric patients with unusual phenotype. CLINICAL CASE: We present the case of two siblings who presented absence seizures and a paroxysmal movement disorder. Both patients were studied, finding low CSF glucose. The diagnosis of GLUT1-DS was confirmed with molecular analysis. Specific treatment with ketogenic diet achieved good response in both cases. Con clusions: We present their peculiar clinical characteristics that allowed us to suspect this wide phe notypic spectrum. Correct and timely diagnosis and treatment can significantly improve the quality of life of those affected.
Subject(s)
Carbohydrate Metabolism, Inborn Errors/diagnosis , Monosaccharide Transport Proteins/deficiency , Movement Disorders/etiology , Phenotype , Seizures/etiology , Carbohydrate Metabolism, Inborn Errors/complications , Child, Preschool , Female , Humans , MaleABSTRACT
Resumen: Introducción: La deficiencia del transportador de glucosa tipo 1 constituye un síndrome (SD-GLUT1), provocado por la mutación del gen SLC2A1, que codifica la proteína transportadora de glucosa al encéfalo. Las manifestaciones neurológicas se dan en tres dominios principales: crisis epilépticas, movimientos anormales y alteraciones cognitivas. El diagnóstico se presume ante el hallazgo de hipoglucorraquia y se confirma mediante el análisis molecular del gen. La importancia de precisarlo radica en que tiene tratamiento específico, la dieta cetogénica. Objetivo: Analizar dos casos clínicos de SD-GLUT1 de presentación atípica, destacando la variabilidad del fenotipo. Caso Clínico: Presentamos el caso de dos hermanos cuyas manifestaciones fueron crisis epilépticas de tipo ausencias típicas, y un trastorno paroxístico del movimiento. Los pacientes fueron estudiados encontrándose hipoglucorraquia en ambos y se confirmó diagnóstico de SD-GLUT1 con estudio molecular. El tratamiento específico con dieta cetogénica logró buena respuesta. Conclusiones: Exponemos sus características clínicas peculiares que nos permitieron sospechar este cuadro, de espectro fenotípico amplio, cuyo diagnós tico y tratamiento, correcto y oportuno, puede mejorar significativamente la calidad de vida de los afectados.
Abstract: Introduction: Glucose Transporter Type 1 Deficiency Syndrome (GLUT1-DS) is caused by the SLC2A1 gene muta tion, which encodes the glucose transporter proteins to the brain Neurological manifestations occur in three main domains: seizures, abnormal movements, and cognitive disorders. The diagnosis is presumed upon the finding of low CSF glucose and confirmed by the gene molecular analysis. Ac curate diagnosis is important because it has a specific treatment, which is ketogenic diet. Objective: To analyze two SD-GLUT1 pediatric patients with unusual phenotype. Clinical Case: We present the case of two siblings who presented absence seizures and a paroxysmal movement disorder. Both patients were studied, finding low CSF glucose. The diagnosis of GLUT1-DS was confirmed with molecular analysis. Specific treatment with ketogenic diet achieved good response in both cases. Con clusions: We present their peculiar clinical characteristics that allowed us to suspect this wide phe notypic spectrum. Correct and timely diagnosis and treatment can significantly improve the quality of life of those affected.
Subject(s)
Humans , Male , Female , Child, Preschool , Phenotype , Seizures/etiology , Monosaccharide Transport Proteins/deficiency , Carbohydrate Metabolism, Inborn Errors/diagnosis , Movement Disorders/etiology , Carbohydrate Metabolism, Inborn Errors/complicationsABSTRACT
Syndromes with noncraniofacial abnormalities can be a real challenge in terms of airway management. The key to success is effective preparation, presence of personnel with expertise in difficult pediatric airway management, regular training and familiarity with difficult intubation equipment, and teamwork. Considering that there are a very large number of syndromes, with variable phenotypic expression, the management strategy of every case will be dictated by the anatomical and functional airway as assessed on physical examination and subsidiary examinations before induction of anesthesia.
Subject(s)
Abnormalities, Multiple/surgery , Airway Management/methods , Airway Obstruction/etiology , Carbohydrate Metabolism, Inborn Errors/complications , Lymphangioma, Cystic/complications , Musculoskeletal Diseases/complications , Airway Obstruction/surgery , Carbohydrate Metabolism, Inborn Errors/surgery , Child , Humans , Intubation, Intratracheal , Lymphangioma, Cystic/surgery , Musculoskeletal Diseases/surgery , SyndromeABSTRACT
TITLE: Sindrome de deficiencia de GLUT-1.
Subject(s)
Carbohydrate Metabolism, Inborn Errors/diagnosis , Monosaccharide Transport Proteins/deficiency , Ataxia/etiology , Carbohydrate Metabolism, Inborn Errors/complications , Carbohydrate Metabolism, Inborn Errors/diet therapy , Carbohydrate Metabolism, Inborn Errors/genetics , Child , Chronic Disease , Delayed Diagnosis , Developmental Disabilities/etiology , Diarrhea/etiology , Diet, Ketogenic , Drug Resistant Epilepsy/etiology , Electroencephalography , Genes, Dominant , Glucose Transporter Type 1/deficiency , Glucose Transporter Type 1/genetics , Heterozygote , Humans , Male , Monosaccharide Transport Proteins/geneticsABSTRACT
This paper focuses on geneticists Salvador Armendares's and Rubén Lisker's studies from the 1960s to the 1980s, to explore how their work fits into the post-1945 human biological studies, and also how the populations they studied, child and indigenous, can be considered laboratories of knowledge production. This paper describes how populations were considered for different purposes: scientific inquiry, standardization of medical practices, and production or application of medicines. Through the narrative of the different trajectories and collaborations between Armendares and Lisker, this paper also attempts to show the contact of their scientific practices, which brought cytogenetics and population genetics together at the local and global levels from a transnational perspective.
Subject(s)
Genetics, Population/history , Human Genetics/history , Indigenous Peoples/history , Carbohydrate Metabolism, Inborn Errors/history , Child , Cytogenetics/history , Glucosephosphate Dehydrogenase Deficiency/history , History, 20th Century , Humans , Indigenous Peoples/genetics , Karyotyping/history , Lactase/deficiency , Lactase/history , MexicoABSTRACT
Abstract This paper focuses on geneticists Salvador Armendares's and Rubén Lisker's studies from the 1960s to the 1980s, to explore how their work fits into the post-1945 human biological studies, and also how the populations they studied, child and indigenous, can be considered laboratories of knowledge production. This paper describes how populations were considered for different purposes: scientific inquiry, standardization of medical practices, and production or application of medicines. Through the narrative of the different trajectories and collaborations between Armendares and Lisker, this paper also attempts to show the contact of their scientific practices, which brought cytogenetics and population genetics together at the local and global levels from a transnational perspective.
Resumo Aborda o trabalho dos geneticistas Salvador Armendares e Rubén Lisker, entre 1960 e 1980, para analisar como se insere nos estudos biológicos humanos do pós-1945, e demonstra como as populações estudadas por eles, a infantil e a indígena, podem ser consideradas laboratórios de produção de conhecimento. O artigo revela como as populações foram consideradas para diversos propósitos: investigação científica, padronização das práticas médicas e produção ou aplicação de suas medicinas. Por meio da narrativa das diferentes trajetórias e colaborações entre Armendares e Lisker, também procura discutir o contato de suas práticas científicas, que colocaram a citogenética e a genética de populações lado a lado nos níveis local e global a partir de uma perspectiva transnacional.
Subject(s)
Humans , Child , History, 20th Century , Human Genetics/history , Indigenous Peoples/history , Genetics, Population/history , Carbohydrate Metabolism, Inborn Errors/history , Cytogenetics/history , Lactase/deficiency , Lactase/history , Indigenous Peoples/genetics , Glucosephosphate Dehydrogenase Deficiency/history , Karyotyping/history , MexicoABSTRACT
Triosephosphate isomerase is the fifth enzyme in glycolysis and its canonical function is the reversible isomerization of glyceraldehyde-3-phosphate and dihydroxyacetone phosphate. Within the last decade multiple other functions, that may not necessarily always involve catalysis, have been described. These include variations in the degree of its expression in many types of cancer and participation in the regulation of the cell cycle. Triosephosphate isomerase may function as an auto-antigen and in the evasion of the immune response, as a factor of virulence of some organisms, and also as an important allergen, mainly in a variety of seafoods. It is an important factor to consider in the cryopreservation of semen and seems to play a major role in some aspects of the development of Alzheimer's disease. It also seems to be responsible for neurodegenerative alterations in a few cases of human triosephosphate isomerase deficiency. Thus, triosephosphate isomerase is an excellent example of a moonlighting protein.
Subject(s)
Anemia, Hemolytic, Congenital Nonspherocytic/veterinary , Animal Diseases/enzymology , Carbohydrate Metabolism, Inborn Errors/veterinary , Triose-Phosphate Isomerase/deficiency , Triose-Phosphate Isomerase/metabolism , Anemia, Hemolytic, Congenital Nonspherocytic/drug therapy , Anemia, Hemolytic, Congenital Nonspherocytic/metabolism , Animal Diseases/drug therapy , Animals , Carbohydrate Metabolism, Inborn Errors/drug therapy , Carbohydrate Metabolism, Inborn Errors/metabolism , Dihydroxyacetone Phosphate/metabolism , Glyceraldehyde 3-Phosphate/metabolism , Glycolysis , HumansABSTRACT
OBJECTIVES: To evaluate the role of next generation sequencing in genetic diagnosis of pediatric patients with persistent hypoglycemia. STUDY DESIGN: Sixty-four patients investigated through an extensive workup were divided in 3 diagnostic classes based on the likelihood of a genetic diagnosis: (1) single candidate gene (9/64); (2) multiple candidate genes (43/64); and (3) no candidate gene (12/64). Subsequently, patients were tested through a custom gene panel of 65 targeted genes, which included 5 disease categories: (1) hyperinsulinemic hypoglycemia, (2) fatty acid-oxidation defects and ketogenesis defects, (3) ketolysis defects, (4) glycogen storage diseases and other disorders of carbohydrate metabolism, and (5) mitochondrial disorders. Molecular data were compared with clinical and biochemical data. RESULTS: A proven diagnosis was obtained in 78% of patients with suspicion for a single candidate gene, in 49% with multiple candidate genes, and in 33% with no candidate gene. The diagnostic yield was 48% for hyperinsulinemic hypoglycemia, 66% per fatty acid-oxidation and ketogenesis defects, 59% for glycogen storage diseases and other carbohydrate disorders, and 67% for mitochondrial disorders. CONCLUSIONS: This approach provided a diagnosis in ~50% of patients in whom clinical and laboratory evaluation did not allow identification of a single candidate gene and a diagnosis was established in 33% of patients belonging to the no candidate gene class. Next generation sequencing technique is cost-effective compared with Sanger sequencing of multiple genes and represents a powerful tool for the diagnosis of inborn errors of metabolism presenting with persistent hypoglycemia.
Subject(s)
Carbohydrate Metabolism, Inborn Errors/diagnosis , Carbohydrate Metabolism, Inborn Errors/genetics , Genomics/methods , Hypoglycemia/diagnosis , Hypoglycemia/genetics , Adolescent , Child , Child, Preschool , Chronic Disease , Cohort Studies , DNA Mutational Analysis/methods , Genetic Predisposition to Disease/epidemiology , Gluconeogenesis/physiology , Glycogen Storage Disease/diagnosis , Glycogen Storage Disease/genetics , High-Throughput Nucleotide Sequencing/methods , Humans , Infant , Infant, Newborn , Italy , Male , Mitochondrial Diseases/diagnosis , Mitochondrial Diseases/genetics , Retrospective Studies , Sensitivity and SpecificityABSTRACT
Human triosephosphate isomerase (TIM) deficiency is a very rare disease, but there are several mutations reported to be causing the illness. In this work, we produced nine recombinant human triosephosphate isomerases which have the mutations reported to produce TIM deficiency. These enzymes were characterized biophysically and biochemically to determine their kinetic and stability parameters, and also to substitute TIM activity in supporting the growth of an Escherichia coli strain lacking the tim gene. Our results allowed us to rate the deleteriousness of the human TIM mutants based on the type and severity of the alterations observed, to classify four "unknown severity mutants" with altered residues in positions 62, 72, 122 and 154 and to explain in structural terms the mutation V231M, the most affected mutant from the kinetic point of view and the only homozygous mutation reported besides E104D.
Subject(s)
Anemia, Hemolytic, Congenital Nonspherocytic/enzymology , Carbohydrate Metabolism, Inborn Errors/enzymology , Mutation , Triose-Phosphate Isomerase/chemistry , Triose-Phosphate Isomerase/deficiency , Triose-Phosphate Isomerase/metabolism , Anemia, Hemolytic, Congenital Nonspherocytic/genetics , Carbohydrate Metabolism, Inborn Errors/genetics , Enzyme Stability , Humans , Kinetics , Models, Molecular , Mutagenesis, Site-Directed , Protein Conformation , Triose-Phosphate Isomerase/geneticsABSTRACT
BACKGROUND: Bariatric surgery continues to be the best treatment for weight loss and control of obesity related comorbidities. Gastric bypass and sleeve gastrectomy have demonstrated to be the most effective surgeries, but this has not been established in a Mexican (non-American) population. OBJECTIVE: To analyse the improvement in type 2 diabetes mellitus and carbohydrate intolerance in obese patients after bariatric surgery. MATERIAL AND METHODS: A retrospective analysis was performed on the data collected prospectively between 2013 and 2015 on every obese patient with diabetes and carbohydrate intolerance submitted for bariatric surgery. Analysis was performed at baseline, and at 1, 3, 6, 9 and 12 months, and included metabolic, clinical, lipid, and anthropometrical parameters. A peri-operative and morbidity and mortality analysis was also performed. Remission rates for patients with diabetes were also established. RESULTS: The analysis included 73 patients, 46 with diabetes and 27 with carbohydrate intolerance. Sixty-two patients were female with a mean age of 42 years. Baseline glucose and glycosylated haemoglobin were 123±34mg/dl and 6.8±1.6%, and at 12 months they were 90.1±8mg/dl and 5.4±0.3%, respectively. Diabetes remission was observed in 68.7% of patients, including 9.3% with partial remission and 21.8% with an improvement. There was also a significant improvement in all metabolic and non-metabolic parameters. CONCLUSIONS: Bariatric surgery safely improves the metabolic status of patients with diabetes mellitus or carbohydrate intolerance during the first year, inducing high rates of complete remission. It has also shown a significant improvement on blood pressure, lipid, and anthropometric parameters during the first year of follow-up.
Subject(s)
Bariatric Surgery , Carbohydrate Metabolism, Inborn Errors/surgery , Diabetes Mellitus, Type 2/surgery , Malabsorption Syndromes/surgery , Obesity/surgery , Adult , Carbohydrate Metabolism, Inborn Errors/complications , Cohort Studies , Diabetes Mellitus, Type 2/complications , Female , Humans , Malabsorption Syndromes/complications , Male , Mexico , Middle Aged , Obesity/complications , Retrospective Studies , Young AdultABSTRACT
OBJECTIVE: To profile the initial clinical events of glucose transporter 1 deficiency syndrome (Glut1 DS) in order to facilitate the earliest possible diagnosis. STUDY DESIGN: We retrospectively reviewed 133 patients with Glut1 DS from a single institution. Family interviews and medical record reviews identified the first clinical event(s) reported by the caregivers. RESULTS: Average age of the first event was 8.15 ± 11.9 months (range: 0.01-81). Ninety-one patients experienced the first symptom before age 6 months (68%). Thirty-three additional patients (25%) presented before age 2 years. Only 9 patients (7%), reported the first event after age 2 years. Seizures were the most common first event (n = 81, 61%), followed by eye movement abnormalities (n = 51, 38%) and changes in muscle strength and tone (n = 30, 22%). Eye movement abnormalities, lower cerebrospinal fluid glucose values, and lower Columbia Neurological Scores correlated with earlier onset of the first event (r: -0.17, 0.22, and 0.25 respectively, P < .05). There was no correlation with age of first event and red blood cell glucose uptake or mutation type. CONCLUSIONS: Glut1 DS is a treatable cause of infantile onset encephalopathy. Health care providers should recognize the wide spectrum of paroxysmal events that herald the clinical onset of Glut1 DS in early infancy to facilitate prompt diagnosis, immediate treatment, and improved long-term outcome.
Subject(s)
Carbohydrate Metabolism, Inborn Errors/diagnosis , Glucose Transporter Type 1/deficiency , Age of Onset , Anticonvulsants/therapeutic use , Brain/growth & development , Carbohydrate Metabolism, Inborn Errors/therapy , Caregivers , Child , Child, Preschool , Diet, Ketogenic , Early Medical Intervention , Epilepsy/diagnosis , Eye Movements , Female , Humans , Infant , Infant, Newborn , Male , Medical Records , Pediatrics/methods , Retrospective Studies , Seizures/diagnosis , Seizures/drug therapyABSTRACT
In some cases Neu-Laxova syndrome (NLS) is linked to serine deficiency due to mutations in the phosphoglycerate dehydrogenase (PHGDH) gene. We describe the prenatal and postnatal findings in a fetus with one of the most severe NLS phenotypes described so far, caused by a homozygous nonsense mutation of PHGDH. Serial ultrasound (US) and pre- and postnatal magnetic resonance imaging (MRI) evaluations were performed. Prenatally, serial US evaluations suggested symmetric growth restriction, microcephaly, hypoplasia of the cerebellar vermis, micrognathia, hydrops, shortened limbs, arthrogryposis, and talipes equinovarus. The prenatal MRI confirmed these findings prompting a diagnosis of NLS. After birth, radiological imaging did not detect any gross bone abnormalities. DNA was extracted from fetal and parental peripheral blood, all coding exons of PHGDH were PCR-amplified and subjected to Sanger sequencing. Sequencing of PHGDH identified a homozygous premature stop codon mutation (c.1297C>T; p.Gln433*) in fetal DNA, both parents (first-cousins) being heterozygotes. Based on previous associations of mutations in this gene with a milder NLS phenotype, as well as cases of serine deficiency, these observations lend further support to a genotype-phenotype correlation between the degree of PHGDH inactivation and disease severity.
Subject(s)
Abnormalities, Multiple/genetics , Brain Diseases/genetics , Carbohydrate Metabolism, Inborn Errors/genetics , Codon, Nonsense , Fetal Growth Retardation/genetics , Ichthyosis/genetics , Limb Deformities, Congenital/genetics , Microcephaly/genetics , Phenotype , Phosphoglycerate Dehydrogenase/deficiency , Phosphoglycerate Dehydrogenase/genetics , Psychomotor Disorders/genetics , Seizures/genetics , Abnormalities, Multiple/diagnosis , Abnormalities, Multiple/pathology , Base Sequence , Brain Diseases/diagnosis , Brain Diseases/pathology , Carbohydrate Metabolism, Inborn Errors/diagnosis , Carbohydrate Metabolism, Inborn Errors/pathology , Consanguinity , Female , Fetal Growth Retardation/diagnosis , Fetal Growth Retardation/pathology , Fetus , Gene Expression , Genes, Lethal , Genetic Variation , Genotype , Homozygote , Humans , Ichthyosis/diagnosis , Ichthyosis/pathology , Infant, Newborn , Limb Deformities, Congenital/diagnosis , Limb Deformities, Congenital/pathology , Male , Microcephaly/diagnosis , Microcephaly/pathology , Molecular Sequence Data , Pedigree , Psychomotor Disorders/diagnosis , Psychomotor Disorders/pathology , Seizures/diagnosis , Seizures/pathology , Sequence Analysis, DNA , Severity of Illness Index , Ultrasonography, PrenatalABSTRACT
TITLE: Enfermedades mitocondriales.
Subject(s)
Carbohydrate Metabolism, Inborn Errors/genetics , Lipid Metabolism, Inborn Errors/genetics , Muscular Diseases/genetics , HumansABSTRACT
The glucose transporter type 1 deficiency syndrome (GLUT-1 SD) (OMIM 606777) is an inborn error of metabolism of brain glucose transport. The characteristic clinical manifestations are seizures, hypotonia, developmental delay, microcephaly and hypoglycorrhachia. We report a girl with normal weight and height at birth. At 6 weeks of age she started with convulsions reaching up to 20 myoclonic seizures a day. She was treated with valproate, phenobarbital and carbamazepine without response. Blood analysis including aminoacids and acylcarnitines were all normal. The brain MRI showed frontal atrophy with an increased subarachnoidal space and Electroencephalography was abnormal. Blood glucose was 84 mg/dl and spinal fluid glucose 26 mg/dl with a ratio of 0.31 (Normal Ratio >0.65+/-00.1). These results suggested the diagnosis of GLUT-1 SD, and was confirmed with erythrocyte glucose uptake of 44% (Normal range 80-100%). A molecular study found the mutation 969del, C971T in exon 6 of the gene Glut-1. Treatment with a ketogenic diet was started immediately and after 7 days with this diet seizures ceased. Anticonvulsants were progressively suspended. At present, the patient is 6 years old, she continues on a ketogenic diet and supplements with L-carnitine, lipoic acid, vitamins and minerals. Growth and development are normal with an intelligence quotient of 103. It is concluded that it is necessary to include GLUT-1 SD in the differential diagnosis of children with early seizures that are non responsive to pharmacological treatment.
Subject(s)
Carbohydrate Metabolism, Inborn Errors/diet therapy , Dietary Fats/administration & dosage , Glucose Transporter Type 1/deficiency , Ketones/metabolism , Anticonvulsants/therapeutic use , Blood Glucose/metabolism , Carbohydrate Metabolism, Inborn Errors/blood , Carbohydrate Metabolism, Inborn Errors/genetics , Carnitine/therapeutic use , Dietary Fats/metabolism , Erythrocytes/metabolism , Female , Humans , Infant, Newborn , Seizures/diet therapy , Seizures/drug therapy , SyndromeABSTRACT
The glucose transporter type 1 deficiency syndrome (GLUT-1 SD) (OMIM 606777) is an inborn error of metabolism of brain glucose transport. The characteristic clinical manifestations are seizures, hypotonia, developmental delay, microcephaly and hypoglycorrhachia. We report a girl with normal weight and height at birth. At 6 weeks of age she started with convulsions reaching up to 20 myoclonic seizures a day. She was treated with valproate, phenobarbital and carbamazepine without response. Blood analysis including aminoacids and acylcarnitines were all normal. The brain MRI showed frontal atrophy with an increased subarachnoidal space and Electroencephalography was abnormal. Blood glucose was 84 mg/dl and spinal fluid glucose 26 mg/dl with a ratio of 0.31 (Normal Ratio >0.65+00.1). These results suggested the diagnosis of GLUT-1 SD, and was confirmed with erythrocyte glucose uptake of 44 percent (Normal range 80-100 percent). A molecular study found the mutation 969del, C971T in exon 6 of the gene Glut-1. Treatment with a ketogenic diet was started immediately and after 7 days with this diet seizures ceased. Anticonvulsants were progressively suspended. At present, the patient is 6 years old, she continues on a ketogenic diet and supplements with L-carnitine, lipoic acid, vitamins and minerals. Growth and development are normal with an intelligence quotient of 103. It is concluded that it is necessary to include GLUT-1 SD in the differential diagnosis of children with early seizures that are non responsive to pharmacological treatment.
Subject(s)
Female , Humans , Infant, Newborn , Carbohydrate Metabolism, Inborn Errors/diet therapy , Dietary Fats/administration & dosage , Glucose Transporter Type 1/deficiency , Ketones/metabolism , Anticonvulsants/therapeutic use , Blood Glucose/metabolism , Carbohydrate Metabolism, Inborn Errors/blood , Carbohydrate Metabolism, Inborn Errors/genetics , Carnitine/therapeutic use , Dietary Fats/metabolism , Erythrocytes/metabolism , Seizures/diet therapy , Seizures/drug therapy , SyndromeABSTRACT
La incorporación de los inhibidores de proteasas (IPs) al tratamiento antirre t roviral de gran actividad (TA R G A )ha mejorado rápidamente tanto el curso de la enfermedad como la morbi-mortalidad y la expectativa de vida de los pacientes con infección por HIV/ SIDA. Sin embargo, algunas evidencias indican que la exposición a los IP podríaimplicar el riesgo de desarrollar trastornos metabólicos tales como atero sclerosis, lipodistrofias, dislipemias y diabetes insulin o - resistente. En este trabajo se revisan los aspectos epidemiológicos, las implicancias, los mecanismos celulares y los aspectos de relevancia clínica para el manejo y control de las alteraciones metabólicas de los hidratos de carbono relacionadas con los antirretrovirales.