Mutación DGAT1 en dos hermanas con falla de medro: reporte de caso / DGAT1 mutation in two sisters with failure to thrive: a case report

Las diarreas y enteropatías congénitas (CODE por su sigla en inglés) son un grupo de trastornos monogénicos que se han descrito en los últimos años. Dentro de las CODE, la mutación del gen de la diacilglicerol o-aciltransferasa 1 (DGAT1) es un trastorno enzimático poco común asociado con diarrea crónica grave de aparición temprana. El objetivo es presentar a dos hermanas que consultaron por diarrea crónica, retraso en el crecimiento, vómitos e hipoalbuminemia en la primera infancia. En ambas pacientes se encontró un compuesto heterocigota de la mutación del DGAT1. Esta mutación se describió previamente en la población asiática; sin embargo, estas son las dos primeras pacientes en tener esta mutación en la población latinoamericana. Estos dos casos pueden ampliar nuestro conocimiento sobre las diarreas congénitas en general y las características clínicas de los pacientes con mutaciones en DGAT1 en particular.

Congenital diarrhea and enteropathies (CODEs) are a group of monogenic disorders that have been described in recent years. Within the CODEs, the mutation in the diacylglycerol O-acyltransferase 1 (DGAT1) gene is a rare enzyme disorder associated with severe, early-onset chronic diarrhea. Our objective is to describe the case of 2 sisters who consulted for chronic diarrhea, growth retardation, vomiting, and hypoalbuminemia in early childhood. A compound heterozygous DGAT1 mutation was found in both patients. This mutation was previously described in the Asian population; however, these are the first 2 patients to show this mutation in the Latin American population. These 2 cases may expand our knowledge about congenital diarrhea in general and the clinical characteristics of patients with DGAT1 mutations in particular.

DGAT1 mutation in two sisters with failure to thrive: a case report. / Mutación DGAT1 en dos hermanas con falla de medro: reporte de caso.

Congenital diarrhea and enteropathies (CODEs) are a group of monogenic disorders that have been described in recent years. Within the CODEs, the mutation in the diacylglycerol O-acyltransferase 1 (DGAT1) gene is a rare enzyme disorder associated with severe, early-onset chronic diarrhea. Our objective is to describe the case of 2 sisters who consulted for chronic diarrhea, growth retardation, vomiting, and hypoalbuminemia in early childhood. A compound heterozygous DGAT1 mutation was found in both patients. This mutation was previously described in the Asian population; however, these are the first 2 patients to show this mutation in the Latin American population. These 2 cases may expand our knowledge about congenital diarrhea in general and the clinical characteristics of patients with DGAT1 mutations in particular.

Las diarreas y enteropatías congénitas (CODE por su sigla en inglés) son un grupo de trastornos monogénicos que se han descrito en los últimos años. Dentro de las CODE, la mutación del gen de la diacilglicerol o-aciltransferasa 1 (DGAT1) es un trastorno enzimático poco común asociado con diarrea crónica grave de aparición temprana. El objetivo es presentar a dos hermanas que consultaron por diarrea crónica, retraso en el crecimiento, vómitos e hipoalbuminemia en la primera infancia. En ambas pacientes se encontró un compuesto heterocigota de la mutación del DGAT1. Esta mutación se describió previamente en la población asiática; sin embargo, estas son las dos primeras pacientes en tener esta mutación en la población latinoamericana. Estos dos casos pueden ampliar nuestro conocimiento sobre las diarreas congénitas en general y las características clínicas de los pacientes con mutaciones en DGAT1 en particular.

Association between insulin resistance and risk of complications in children and adolescents with type 1 diabetes.

BACKGROUND: It has been hypothesized that insulin resistance may be involved in the development of type 1 diabetes complications and early diagnosis would be important for their prevention. Our aim was to study insulin resistance in our population of children with type 1 diabetes and to identify associated early risk factors for micro- and macrovascular complications. METHODS: A descriptive, cross-sectional study was conducted including 150 children with type 1 diabetes. Anthropometric, bioelectric impedance, carotid Doppler ultrasonography, electromyography, and conduction velocity studies were performed. Baseline plasma glucose, lipid profile, uric acid, plasma thyrotropin, glycosylated hemoglobin A1C, and microalbuminuria were assessed. More insulin-resistant patients were defined as those having an estimated glucose disposal rate (eGDR) value below the first quartile. RESULTS: Clinically manifest microvascular complications were not found in any of the patients. More insulin-resistant patients had a greater sub scapular fold thickness, a higher incidence of obesity (12% vs. 1.7% p 0.007), higher fructosamine levels (496 vs. 403 p<0.00019, and a higher incidence of altered lipid metabolism (70% vs. 39% p 0.0007). CONCLUSION: In the subgroup of patients with lower eGDR there were more children with lipid disorders, obesity, and worse diabetic control, which, if not corrected, may lead to development of micro- and macrovascular complications.

Characterization of insulin antibodies by Surface Plasmon Resonance in two clinical cases: brittle diabetes and insulin autoimmune syndrome.

In this study, the characterization of insulin (auto)antibodies has been described, mainly in terms of concentration (q), affinity (Ka) and Ig (sub)isotypes by Surface Plasmon Resonance (SPR) in two particular clinical cases of individuals with severe episodes of impaired glycemia. Subject 1 suffers from brittle diabetes associated with circulating insulin antibodies (IA) due to insulin treatment. Subject 2 has insulin autoantibodies (IAA) associated with hypoglycemia in spite of not being diabetic and not having ever received exogenous insulin therapy. After conventional screening for IA/IAA by radioligand binding assay (RBA), we further characterized IA/IAA in sera of both patients in terms of concentration (q), affinity (Ka) and Ig (sub)isotypes by means of SPR technology. In both cases, q values were higher and Ka values were lower than those obtained in type 1 diabetic patients, suggesting that IA/IAA:insulin immunocomplexes could be responsible for the uncontrolled glycemia. Moreover, subject 1 had a predominat IgG1 response and subject 2 had an IgG3 response. In conclusion, SPR technology is useful for the complete characterization of IA/IAA which can be used in special cases where the simple positive/negative determination is not enough to achieve a detailed description of the disease fisiopathology.

[Obesity and risk factors for metabolic syndrome in young people with type 1 diabetes]. / Obesidad y factores de riesgo del síndrome metabólico en jóvenes con diabetes tipo 1.

Changes in the clinical presentation of diabetes mellitus in childhood and adolescence associated with obesity have resulted in an overlap of the two most common types of diabetes with a greater clinical heterogeneity. In order to characterize the type of diabetes at onset and assess the effect of obesity, 50 children with diabetes were studied. The patients were divided into two groups according to their nutritional status at diagnosis (over-weight/obese vs. normal weight). Insulin reserve was evaluated by measuring basal C-peptide and stimulated C-peptide in response to a mixed meal (MMTT) as well as HLA-DQB1 genotype, antibodies, and family history of risk factors for metabolic disease. Of all 50 patients, 38% was overweight/obese, 84% had a positive family history of metabolic syndrome, 82% had positive antibodies, and 100% were positive for the high-risk HLA-DQB1 genotype. No significant differences were found in fasting C-peptide or glycemic index/C-peptide levels between the two groups. In the overweight/obese group C-peptide response to MMTT showed higher levels at 60 and 120 minutes (p = 0.02 and 0.03) and the area under the curve for C-peptide was also higher (1.77 ng / ml vs. 5.5 ng/ ml, p = 0.0007) than in the normal-weight group. In conclusion, overweight/obese patients with type 1A diabetes had a greater pancreatic reserve, suggesting that nutritional status may accelerate disease onset.

[Presence of early risk markers of metabolic syndrome in prepubertal children with a history of intrauterine growth restriction]. / Marcadores tempranos de riesgo de síndrome metabólico en niños prepúberes con y sin antecedente de restricción de crecimiento intrauterino.

INTRODUCTION: Studies on people with low birth weight found metabolic syndrome associated with intrauterine growth restriction (IUGR). OBJECTIVE: To study the presence of early risk markers of metabolic syndrome in a prepubertal population with IUGR. DESIGN: We studied 45 prepubertal children with a history of IUGR, without apparent disease, and 47 children in a control group. BMI, weight, height, and BMI Z score, and body fat mass were calculated. Basal glycemia, insulin, proinsulin, cortisol, serum lipids and uric acid levels were analyzed. Insulin sensitivity was calculated by QUICKI and insulin resistance by HOMA-IR. RESULTS: Basal insulin levels were higher in the IUGR group compared with the controls (6.6 microU/ml vs. 4.4 microU/ml; p= 0.008). Similar results were found for the basal cortisol levels (18.8 ug/dl vs. 13.1 ug/dl; p= 0.006) and uric acid (4.2 mg/dl vs. 2.7 mg/dl; p= 0.0008). QUICKI index was lower in the IUGR group (2.06 vs. 2.86, p= 0.001). The IUGR children who developed obesity presented higher levels of proinsulin (26.04 ug/dl vs. 13.3 ug/dl; p= 0.05), insulin (11 microU/ml vs. 5.5 microU/ml, p= 0.005), and HOMA-IR (2.06 vs. 0.9, p= 0.004), and lower QUICKI (1.71 vs. 2.16, p= 0.01) than in the case of the IUGR children with appropriate weight; these differences weren't observed among the control group. CONCLUSIONS: Children with IUGR, without apparent disease, showed metabolic changes that were expressed through risk markers of metabolic syndrome in childhood.

Marcadores tempranos de riesgo de síndrome metabólico en niños prepúberes con y sin antecedente de restricción de crecimiento intrauterino / Presence of early risk markers of metabolic syndrome in prepubertal children with a history of intrauterine growth restriction

Introducción. Varios estudios comunican la asociación entre el síndrome metabólico y la restricción de crecimiento intrauterino (RCIU). Objetivo. Estudiar la presencia de marcadores de riesgo tempranos de síndrome metabólico en una población de niños prepuberales con antecedentede RCIU y sin él. Material y métodos. Fueron estudiados 45 niños con antecedente de RCIU sin enfermedad aparente y 47 niños como grupo control. Se evaluaron peso, talla, índice de masa corporal, puntaje Z de índice de masa corporal y masa grasa. Se midieron glucemia basal, insulina, proinsulina, cortisol, lípidos y ácido úrico. La sensibilidad insulínica fue calculada por QUICKI y la resistenciapor HOMA-IR. Resultados. Los niveles de insulina basal fueron mayores en los niños con RCIU que en los controles(6,6 μU/ml contra 4,4 μU/ml; p= 0,008). Se encontraron resultados similares en los niveles de cortisol (18,8 ug/dl contra 13,1 ug/dl; p= 0,006) y ácido úrico (4,2 mg/dl contra 2,7 mg/dl;p= 0,0008). El índice QUICKI fue menor en los niños con RCIU (2,06 contra 2,86; p= 0,001). El grupo de RCIU con obesidad presentó niveles mayores de proinsulina (26,04 ug/dl contra 13,3ug/dl; p= 0,05), insulina (11 μU/ml contra 5,5 μU/ml; p= 0,005), y HOMA-IR (2,06 contra 0,9; p= 0,004), y menor QUICKI (1,71 contra 2,16; p= 0,01) que los niños con RCIU y peso adecuado; estas diferencias no se observaron entre los niños del grupo control. Conclusiones. Los niños con antecedente de RCIU presentaron cambios metabólicos expresados en las variables de riesgo de síndrome metabólico.

Marcadores tempranos de riesgo de síndrome metabólico en niños prepúberes con y sin antecedente de restricción de crecimiento intrauterino / Presence of early risk markers of metabolic syndrome in prepubertal children with a history of intrauterine growth restriction

Introducción. Varios estudios comunican la asociación entre el síndrome metabólico y la restricción de crecimiento intrauterino (RCIU). Objetivo. Estudiar la presencia de marcadores de riesgo tempranos de síndrome metabólico en una población de niños prepuberales con antecedentede RCIU y sin él. Material y métodos. Fueron estudiados 45 niños con antecedente de RCIU sin enfermedad aparente y 47 niños como grupo control. Se evaluaron peso, talla, índice de masa corporal, puntaje Z de índice de masa corporal y masa grasa. Se midieron glucemia basal, insulina, proinsulina, cortisol, lípidos y ácido úrico. La sensibilidad insulínica fue calculada por QUICKI y la resistenciapor HOMA-IR. Resultados. Los niveles de insulina basal fueron mayores en los niños con RCIU que en los controles(6,6 μU/ml contra 4,4 μU/ml; p= 0,008). Se encontraron resultados similares en los niveles de cortisol (18,8 ug/dl contra 13,1 ug/dl; p= 0,006) y ácido úrico (4,2 mg/dl contra 2,7 mg/dl;p= 0,0008). El índice QUICKI fue menor en los niños con RCIU (2,06 contra 2,86; p= 0,001). El grupo de RCIU con obesidad presentó niveles mayores de proinsulina (26,04 ug/dl contra 13,3ug/dl; p= 0,05), insulina (11 μU/ml contra 5,5 μU/ml; p= 0,005), y HOMA-IR (2,06 contra 0,9; p= 0,004), y menor QUICKI (1,71 contra 2,16; p= 0,01) que los niños con RCIU y peso adecuado; estas diferencias no se observaron entre los niños del grupo control. Conclusiones. Los niños con antecedente de RCIU presentaron cambios metabólicos expresados en las variables de riesgo de síndrome metabólico.(AU)

[Evaluation of an intensive treatment education program for type 1 diabetes in a group of adolescents. A two year follow up]. / Evaluación de un programa de educación de tratamiento intensivo en adolescentes con diabetes tipo 1. Seguimiento por dos años.

During the past decade several reports were published showing that intensive treatment of type 1 diabetes can prevent and delay disease-related microvascular complications. However, several problems were reported in children and adolescents such as frequent hypoglycemic episodes and weight gain. The aim of this study was to describe the results of intensified treatment for type 1 diabetes in a group of Argentinean adolescents after a follow-up of two years. Twenty five adolescents with type 1 diabetes older than 10 years with at least one year from diagnosis were selected. All patients received a one-week teaching program during admission to our center. All patients were followed-up monthly during two years. Treatment schedule included 4-5 controls in fasting conditions, two doses of NPH insulin and four doses of regular insulin according to glycemia and the amount of calculated carbohydrate intake. Median age was 13.5 years (range 10 to 19 years). Mean time from diagnosis to inclusion in the study was 3.8 years (range 1.25 to 9 years). Mean total dose of NPH insulin decreased significantly when measured at the inclusion in the study (0.9 IU/kg) and after a year of follow-up 0.8 IU/kg (p 0.04). However, there were no changes in NPH insulin dose after two years follow-up (0.85 IU/kg). On the contrary, the dose of regular insulin administered on fasting conditions with normal glycemia increased from 0 to 0.21/kg after a year (p 0.0001) and to 0.69 after two years (non significant). Median HbA1C showed a significant reduction from 10 +/- 1.62% to 8.53 +/- 1.04% after a year (p 0.03) and to 8.72 +/- 0.81% after two years. BMI Z score increased from significantly from 0.7 +/- 0.9 to 1.06 +/- 1.15 after a year (p 0.03) with a further reduction without a significant difference from the basal value after two years. We found no significant differences in the frequency of hypoglycemia or other metabolic features. Our results show that intensive treatment of type 1 diabetes in children and adolescents can achieve significant and sustained reductions of HbA1C without increasing the risk of hypoglycemia or other adverse effects.

Evaluación de un programa de educación de tratamiento intensivo en adolescentes con diabetes tipo 1. Seguimiento por dos años. / [Evaluation of an intensive treatment education program for type 1 diabetes in a group of adolescents. A two year follow up]

During the past decade several reports were published showing that intensive treatment of type 1 diabetes can prevent and delay disease-related microvascular complications. However, several problems were reported in children and adolescents such as frequent hypoglycemic episodes and weight gain. The aim of this study was to describe the results of intensified treatment for type 1 diabetes in a group of Argentinean adolescents after a follow-up of two years. Twenty five adolescents with type 1 diabetes older than 10 years with at least one year from diagnosis were selected. All patients received a one-week teaching program during admission to our center. All patients were followed-up monthly during two years. Treatment schedule included 4-5 controls in fasting conditions, two doses of NPH insulin and four doses of regular insulin according to glycemia and the amount of calculated carbohydrate intake. Median age was 13.5 years (range 10 to 19 years). Mean time from diagnosis to inclusion in the study was 3.8 years (range 1.25 to 9 years). Mean total dose of NPH insulin decreased significantly when measured at the inclusion in the study (0.9 IU/kg) and after a year of follow-up 0.8 IU/kg (p 0.04). However, there were no changes in NPH insulin dose after two years follow-up (0.85 IU/kg). On the contrary, the dose of regular insulin administered on fasting conditions with normal glycemia increased from 0 to 0.21/kg after a year (p 0.0001) and to 0.69 after two years (non significant). Median HbA1C showed a significant reduction from 10 +/- 1.62

to 8.53 +/- 1.04

after a year (p 0.03) and to 8.72 +/- 0.81

after two years. BMI Z score increased from significantly from 0.7 +/- 0.9 to 1.06 +/- 1.15 after a year (p 0.03) with a further reduction without a significant difference from the basal value after two years. We found no significant differences in the frequency of hypoglycemia or other metabolic features. Our results show that intensive treatment of type 1 diabetes in children and adolescents can achieve significant and sustained reductions of HbA1C without increasing the risk of hypoglycemia or other adverse effects.

Marcadores inmunológicos y genéticos en diabetes mellitus tipo 1 en Argentina / Immunologic and genetic markers in type 1 diabetes mellitus in Argentina

El objetivo del trabajo fue evaluar la prevalencia y asociación de los marcadores inmunológicos (anticuerpo anti-islote pancreático: ICA, autoanticuerpo anti-insulina: IAA, anticuerpo antidecarboxilasa del ácido glutámico: GADA y anticuerpo anti ICA512) y con el genotipo HLA DQBl en pacientes con diabetes tipo 1 de reciente debut, hermanos de diabéticos y personas sin historia de enfermedad autoinmune en población argentina. Se estudiaron 79 niños con diabetes tipo 1 de reciente debut, 79 niños controles y 68 hermanos sanos de niños con diabetes 1. En todos ellos se determinó IAA, GADA, ICA, ICA512 y alelos HLA DQB1. La sensibilidad para ICA fue de 67.1 por ciento; para IAA de 36,7 por ciento; para GADA de 74,6 por ciento, y para ICA512 de 63,4 por ciento. Ninguno de los niños control presentó marcadores inmunológicos positivos. La sensibilidad combinada de ICA-IAA-GADA fue de 89,8 por ciento, similar a la de ICA512-GADA (87.3 por ciento) o la combinación de ICA512-GADA-IAA (91.1 por ciento). El valor de GADA presentó correlación positiva con el de ICA, no encontrándose correlación alguna entre los valores de IAA, ICA512 e ICA. El valor de IAA presentó correlación negativa y el de GADA positiva con la edad de los pacientes. La presencia de IAA se asoció con DQB1 *0201, mientras que la de ICA e ICA512 con DQB1 *0302. Entre los hermanos, 3/68 (4,4 por ciento) fueron positivos para IAA, uno (1,5 por ciento) lo fue para GADA y otro (1.5 por ciento) para ICA512. Nuestros resultados muestran que la combinación de múltiples marcadores incrementa la sensibilidad predictiva, siendo la asociación ICA512-GADA altamente sensible y equivalente a otras combinaciones propuestas como ICA-IAA-GADA

Marcadores inmunológicos y genéticos en diabetes mellitus tipo 1 en Argentina / Immunologic and genetic markers in type 1 diabetes mellitus in Argentina

El objetivo del trabajo fue evaluar la prevalencia y asociación de los marcadores inmunológicos (anticuerpo anti-islote pancreático: ICA, autoanticuerpo anti-insulina: IAA, anticuerpo antidecarboxilasa del ácido glutámico: GADA y anticuerpo anti ICA512) y con el genotipo HLA DQBl en pacientes con diabetes tipo 1 de reciente debut, hermanos de diabéticos y personas sin historia de enfermedad autoinmune en población argentina. Se estudiaron 79 niños con diabetes tipo 1 de reciente debut, 79 niños controles y 68 hermanos sanos de niños con diabetes 1. En todos ellos se determinó IAA, GADA, ICA, ICA512 y alelos HLA DQB1. La sensibilidad para ICA fue de 67.1 por ciento; para IAA de 36,7 por ciento; para GADA de 74,6 por ciento, y para ICA512 de 63,4 por ciento. Ninguno de los niños control presentó marcadores inmunológicos positivos. La sensibilidad combinada de ICA-IAA-GADA fue de 89,8 por ciento, similar a la de ICA512-GADA (87.3 por ciento) o la combinación de ICA512-GADA-IAA (91.1 por ciento). El valor de GADA presentó correlación positiva con el de ICA, no encontrándose correlación alguna entre los valores de IAA, ICA512 e ICA. El valor de IAA presentó correlación negativa y el de GADA positiva con la edad de los pacientes. La presencia de IAA se asoció con DQB1 *0201, mientras que la de ICA e ICA512 con DQB1 *0302. Entre los hermanos, 3/68 (4,4 por ciento) fueron positivos para IAA, uno (1,5 por ciento) lo fue para GADA y otro (1.5 por ciento) para ICA512. Nuestros resultados muestran que la combinación de múltiples marcadores incrementa la sensibilidad predictiva, siendo la asociación ICA512-GADA altamente sensible y equivalente a otras combinaciones propuestas como ICA-IAA-GADA (AU)

Immunologic and genetic markers in insulin-dependent diabetes mellitus (Type 1) in a argentine population

The objective was to evaluate the prevalence and association of several markers (islet cell antibodies: ICA, ainsulin autoantibodies: IAA, glutamic acid decarboxylase antibodies: GADA and ICA512 antibodies: ICA512A) along with HLA DQB1 genotype in type 1 diabetes mellitus of recent onset, including siblings and individuals without any history of this disease, in an Argentine population. A total of 79 children with type 1 diabetes mellitus of recent onset were studied, as well as 79 control children, and 68 healthy siblings of type 1 diabetic cases. IAA, ICA, GADA, ICA512A and HLA DQB1 alleles were determined. Sensitivity was 67.1 por ciento for ICA, 36.7 percent for IAA, 74.6 por ciento for GADA and 63.4 por ciento ICA512A. None of the control subjects was positive for the immunological markers. Combined sensitivity of ICA-IAA-GADA was 89.8 por ciento, similar to the ICA512A- GADA (87.3 percent) or ICA512A-GADA-IAA combination (91.1 por ciento ). GADA correlated positively with ICA, but no such correlation was found between IAA, ICA512A and ICA. IAA correlated negatively and GADA positively with age. IAA was associated to DQB1*0201, whereas ICA and ICA512A associated to DQB1*0302. Among siblings, 3/68 (4.4 percent) were positive for IAA and a single case (1.5 percent) was positive for GADA and one for ICA512A. Our findings show that the combination of multiple tests increases the sensitivity for prediction, with the ICA512A-GADA combination proving highly sensitive and equivalent to other proposed combinations, such as ICA-IAA-GADA.

Immunologic and genetic markers in insulin-dependent diabetes mellitus (Type 1) in a argentine population

The objective was to evaluate the prevalence and association of several markers (islet cell antibodies: ICA, ainsulin autoantibodies: IAA, glutamic acid decarboxylase antibodies: GADA and ICA512 antibodies: ICA512A) along with HLA DQB1 genotype in type 1 diabetes mellitus of recent onset, including siblings and individuals without any history of this disease, in an Argentine population. A total of 79 children with type 1 diabetes mellitus of recent onset were studied, as well as 79 control children, and 68 healthy siblings of type 1 diabetic cases. IAA, ICA, GADA, ICA512A and HLA DQB1 alleles were determined. Sensitivity was 67.1 por ciento for ICA, 36.7 percent for IAA, 74.6 por ciento for GADA and 63.4 por ciento ICA512A. None of the control subjects was positive for the immunological markers. Combined sensitivity of ICA-IAA-GADA was 89.8 por ciento, similar to the ICA512A- GADA (87.3 percent) or ICA512A-GADA-IAA combination (91.1 por ciento ). GADA correlated positively with ICA, but no such correlation was found between IAA, ICA512A and ICA. IAA correlated negatively and GADA positively with age. IAA was associated to DQB1*0201, whereas ICA and ICA512A associated to DQB1*0302. Among siblings, 3/68 (4.4 percent) were positive for IAA and a single case (1.5 percent) was positive for GADA and one for ICA512A. Our findings show that the combination of multiple tests increases the sensitivity for prediction, with the ICA512A-GADA combination proving highly sensitive and equivalent to other proposed combinations, such as ICA-IAA-GADA. (Au)