Estimating the prevalence of congenital disaccharidase deficiencies using allele frequencies from gnomAD.

BACKGROUND: There are currently three known congenital disaccharidase deficiencies: congenital lactase deficiency (CLD), congenital sucrase-isomaltase deficiency (CSD), and congenital trehalase deficiency (CTD). No congenital deficiency has been described for maltase-glucoamylase (MGAM). METHODS: A literature search was performed in PubMed for the pathogenic variants CLD, CSD, and CTD and the articles retrieved were analyzed to estimate the prevalence of congenital disaccharidase deficiencies. RESULTS: Based on reported variants, the estimated prevalence was 1.3 per 106 births (95% CI: 1.1-1.7) for CLD, and 31.4 per 106 births (95% CI: 28.3-34.8) for CSD. Using data on previously reported variants and variants predicted to be loss-of-function in gnomAD, the overall estimated prevalence was 2.3 per 106 births (95% CI: 1.9-2.9) for CLD, 57.6 per 106 births (95% CI:52.5-63.2) for CSD, and 9.2 per 106 births (95% CI: 2.5-3.7) for CTD. CONCLUSION: The prevalence of CSD was found to be relatively high, while for other congenital disaccharidase deficiencies, the estimated prevalence was very low.

[Genetically determined trehalase deficiency in various population groups of Russia and neighboring countries].

Due to the low specificity and sensitivity of non-invasive clinical tests trehalose malabsorption remained out of sight of gastroenterologists. Therefore, the specialists regard this disorder as rare. Trehalose became widely used in the food industry as a harmless sucrose substitute, sweetener and stabilizer. After the discovery of the trehalase gene (rs2276064 TREH), it was found that the A*TREH allele is the determinant of the disaccharide absorption disorders, and the allele's carriership may be high in some groups. There is not enough information on the A*TREH frequency in the population of Russia. The aim of the study was to analyze the allele and genotype frequencies of the trehalase gene (rs2276064 TREH) in the main population groups of the Russian Federation and neighboring countries. Methods. DNA samples from 1146 unrelated subjects belonging to 21 population groups of Russia, Azerbaijan, Tajikistan and Mongolia were genotyped by the two following methods: 1) using the Infinium iSelect HD Custom Genotyping BeadChip (Illumina, USA) on the iScan platform; 2) by the real time polymer-chain reaction (PCR) method on the Bio-Rad CFX96 Touch amplifier. Results. It has been found that on the territory of the Russian Federation the frequency of the A*TREH allele increases from the west to the east. The frequencies are lowest in the groups of Russians and Finns of the Northwest (0.01-0.03), up to 0.07 in the populations of Central Russia and the Volga region, and even higher toward the Southern Urals (Bashkirs 0.15), in the Transurals and Southern Siberia (0.19 in the Altai people, 0.30 in the Tuvinians and Mongols). Up to 1% of the population of the European part of the Russian Federation have the AA*TREH genotype (i.e. trehalose intolerance in phenotype), and up to 15% (GA*TREH genotype) have a reduced ability to absorb the disaccharide. In the Asian part of the country (Siberia, Altai, Baikal) the genotypes carriers constitute up to 12 and 46% respectively. Conclusion. Trehalose malabsorbtion is an underappreciated problem of particular practical importance for regions with high concentrations of indigenous population (Yakutia-Sakha, Buryatia, Tyva, etc.). It would be feasible to consider food labelling of trehalose.

Hypomorphic SI genetic variants are associated with childhood chronic loose stools.

OBJECTIVE: The SI gene encodes the sucrase-isomaltase enzyme, a disaccharidase expressed in the intestinal brush border. Hypomorphic SI variants cause recessive congenital sucrase-isomaltase deficiency (CSID) and related gastrointestinal (GI) symptoms. Among children presenting with chronic, idiopathic loose stools, we assessed the prevalence of CSID-associated SI variants relative to the general population and the relative GI symptom burden associated with SI genotype within the study population. METHODS: A prospective study conducted at 18 centers enrolled 308 non-Hispanic white children ≤18 years old who were experiencing chronic, idiopathic, loose stools at least once per week for >4 weeks. Data on demographics, GI symptoms, and genotyping for 37 SI hypomorphic variants were collected. Race/ethnicity-matched SI data from the Exome Aggregation Consortium (ExAC) database was used as the general population reference. RESULTS: Compared with the general population, the cumulative prevalence of hypomorphic SI variants was significantly higher in the study population (4.5% vs. 1.3%, P < .01; OR = 3.5 [95% CI: 6.1, 2.0]). Within the study population, children with a hypomorphic SI variant had a more severe GI symptom burden than those without, including: more frequent episodes of loose stools (P < .01), higher overall stool frequency (P < .01), looser stool form (P = .01) and increased flatulence (P = .02). CONCLUSION: Non-Hispanic white children with chronic idiopathic loose stools have a higher prevalence of CSID-associated hypomorphic SI variants than the general population. The GI symptom burden was greater among the study subjects with a hypomorphic SI variant than those without hypomorphic SI variants.

10 patients, 10 years - Long term follow-up of cardiovascular risk factors in Glut1 deficiency treated with ketogenic diet therapies: A prospective, multicenter case series.

BACKGROUND AND AIMS: Glut1 Deficiency (Glut1D) is caused by impaired glucose transport into brain. The resulting epileptic encephalopathy and movement disorders can be treated effectively by high-fat carbohydrate-restricted ketogenic diet therapies (KDT) mimicking fasting and providing ketones as an alternative cerebral fuel. Recently 6-24 months follow-ups of epileptic patients reported elevated blood lipids and intima thickening of the carotid artery raising concerns about potential cardiovascular risks by KDT. To clarify potential cardiovascular risks we performed a prospective 10 year follow up of 10 Glut1D patients. METHODS: Between August 2001 and January 2016 we enrolled Glut1D patients on KDT at two hospitals in Germany in this prospective, multicenter case series. The minimal follow up was 10 years. Standard deviation scores (SDS) of body mass index (BMI), total cholesterol (TC), HDL-/LDL cholesterol, and triglycerides (TG) before initiation of KDT were compared with respective values at 6 months, 2, 5 years, and 10 years after initiation. After 10 years on KDT cardiovascular risk, assessed by BMI, carotid intima-media thickness (CIMT) measurement, and blood pressure, was compared to a healthy reference population (n = 550). RESULTS: Baseline and 10 year follow-up investigations were available for 10 individuals with Glut1D on KDT. After two years on KDT BMI increased significantly, while total cholesterol, HDL-cholesterol, and LDL-cholesterol decreased. Within 3-5 years on KDT these differences disappeared, and after 10 years blood lipid parameters reflected the situation at initiation of KDT. Prior to KDT one child had dyslipidaemia, but no child after 10 years on KDT. No significant differences were observed with respect to BMI SDS (p = 0.26), CIMT (p = 0.63) or systolic and diastolic blood pressure (SDS p = 0.11 and p = 0.37, respectively) in Glut1D children treated with KDT for at least 10 years compared to healthy controls. CONCLUSIONS: In contrast to previous short-term reports on adverse effects of KDT, 10-year follow-up did not identify cardiovascular risks of dietary treatment for Glut1D.

Prevalence of Genetic Disorders and GLUT1 Deficiency in a Ketogenic Diet Clinic.

Between July of 2012 and December of 2014, 39 patients were enrolled prospectively to investigate the prevalence of glucose transporter 1 (GLUT1) deficiency in a ketogenic diet clinic. None of them had GLUT1 deficiency. All patients seen in the same clinic within the same period were reviewed retrospectively. A total of 18 of these 85 patients had a genetic diagnosis, including GLUT1 deficiency, pathogenic copy number variants, congenital disorder of glycosylation, neuronal ceroid lipofuscinosis type II, mitochondrial disorders, tuberous sclerosis, lissencephaly, and SCN1A-, SCN8A-, and STXBP1-associated epileptic encephalopathies. The prevalence of genetic diagnoses was 21% and prevalence of GLUT1 deficiency was 2.4% in our retrospective cohort study.

Factores de riesgo de diabetes en una población adolescente de Cangas de Morrazo (Galicia) (RIVACANGAS) / Diabetes risk factors in adolescent population from Cangas de Morrazo (Galicia) (RIVACANGAS)

Objetivos: Identificar factores de riesgo de desarrollar diabetes (DM) en una muestra de escolares. Material y método: Estudio epidemiológico, transversal, multicéntrico en alumnos de la ESO (12-17 años) de 4 centros escolares de Cangas do Morrazo (Pontevedra). Variables: edad, sexo, antecedentes personales y familiares de DM, peso, estatura, perímetro de cintura (PC), índice cintura/talla (ICT), índice de masa corporal (IMC), presión arterial. Cuestionario de riesgo de DM para niños y adolescentes (Findrisc-A) (modificado), características de la dieta (Kidmed) y de la actividad física (PAQ-A). Resultados: 630 escolares, 628 sin diabetes: 294 niñas (46,8%) y 334 niños (53,2%), media de edad 13,8±1,4 años. El 7,1% hipercolesterolemia; 1,7% ECV, 0,8% HTA y 0,3% DM. El 5,6% antecedentes familiares de 1er grado de DM. Antecedentes de 2º grado de DM el 18,6%. Sobrepeso el 23,3%. El 7,5% con obesidad central (PC >P90). El 21,0 % ICT >0,5. El 63,9% PAS >P90 y 23,7% PAD >P90. La puntuación media del Kidmed fue de 5,0±2,2. 21,7% con adherencia baja (<3 puntos) y 11,8% con adherencia alta (>8 puntos). Puntuación media PAQ-A de 2,6±0,7, mayor en niños (2,8±0,7 vs 2,5±0,7; p<0,001), con actividad física baja 1,6% y con actividad física alta el 19,4%. Puntuación media Findrisc-A 6,0±3,4. Relación directa entre Findrisc-A y PAS, PAD, PC, IMC e ICT. Inversa con Kidmed y PAQ-A. Conclusiones: El riesgo medio de diabetes resultó bajo, aunque más del 10% presentaba riesgo alto o muy alto. Uno de cada cuatro tiene exceso de peso y uno de cada diez, obesidad (AU)

Objectives: To identify risk factors of developing diabetes (DM) in a sample of students. Materials and methods: It was carried out an epidemiological, cross-sectional and multicenter study with students from 12 to 17 years of four schools from Cangas do Morrazo (Pontevedra). Variables: age, sex, personal and family history of DM, weight, height, waist circumference (WC), waist/height index (WHI), body mass index (BMI), blood pressure, cholesterol levels, presence of central obesity (PC>P 90). It was applied the Risk of DM questionnaire for children and adolescents (Findrisc-A) (modified). The characteristics of the diet were evaluated with the Kidmed Index (low adherence if result < 3 points and high if > 8 points) and the physical activity too (PAQ-A). Results: 628 students were included in the study: 294 girls (46.8%) with an average age of 13,8±1,4 years. The proportion of risk factors was: 7.1% hypercholesterolemia; 1.7% CVD, hypertension 0.8%. 5.6% had 1 rst degree family history of DM. 2 nd degree family history of DM, 18.6%. 23.3% were overweight. 7.5% had central obesity. 21.0% WHI>0.5. 63.9% SBP>P90 and 23.7% DBO>P90. The average of the Kidmed score was 5.0±2.2. 21.7% with low adherence and 11.8% with high adherence. PAQ-A average score was 2.6±0.7, higher in boys (2.8±0.7 vs 2.5±0.7; p<0.001), with low physical activity 1.6% and 19.4% with high physical activity. Findrisc average score 6.0±3.4. There was found a direct relationship between Findrisc-A and SBP, DBP, WC, BMI and WHI. On the other hand, an inverse correlation between Findrisc results and the Kidmed and PAQ-A values was shown. Conclusions: The average diabetes risk was low, but more than 10% had high or very high risk. One of every four students was overweight and one of every ten had obesity (AU)

Outcome of ketogenic diets in GLUT1 deficiency syndrome in Japan: A nationwide survey.

OBJECTIVES: To evaluate the outcome of ketogenic diets (KDs) in patients with glucose transport type 1 deficiency syndrome (GLUT1DS) in Japan. METHODS: A nationwide survey for GLUT1DS was conducted by sending questionnaires to board-certified pediatric neurologists nationwide to obtain clinical and laboratory data. RESULTS: Among 39 patients whose diagnosis was confirmed molecularly or by the 3-O-methylglucose uptake assay, 31 were treated with KDs for longer than 1month. Seventeen patients (55%) were on the modified Atkins diet, 11 (35%) were on the classic KD, and 3 were on the medium-chain triglyceride (MCT) diet. The median values and ranges of serum ß-hydroxybutyrate levels in patients on the modified Atkins diet, classic KD and MCT diet were 2.5mM (0.75-4.1), 1.7mM (0.23-3.5) and 2.6mM (1.5-3.0), respectively. The KDs were effective on seizures (80%), aggravation after fasting (80%) and ataxia (79%). Thus, ataxia was as responsive as seizures. Two patients on the classic KD with a ketogenic ratio as low as 1:1 showed improvement in neurological symptoms. The development or intelligence quotient measured using the same psychological scales before and after the KDs in 9 patients did not show a significant improvement; the median quotients before and after the diets were 40 (12-91) and 46 (12-67). CONCLUSION: The KDs were most effective on seizures, transient aggravation after fasting and ataxia. The efficacy on intellectual development was equivocal. The modified Atkins diet was more commonly used for GLUT1DS in this study, and its ketogenicity was equivalent to the classic KD.

Diagnosing and Treating Intolerance to Carbohydrates in Children.

Intolerance to carbohydrates is relatively common in childhood, but still poorly recognized and managed. Over recent years it has come to the forefront because of progresses in our knowledge on the mechanisms and treatment of these conditions. Children with intolerance to carbohydrates often present with unexplained signs and symptoms. Here, we examine the most up-to-date research on these intolerances, discuss controversies relating to the diagnostic approach, including the role of molecular analysis, and provide new insights into modern management in the pediatric age, including the most recent evidence for correct dietary treatment.

The role of SLC2A1 mutations in myoclonic astatic epilepsy and absence epilepsy, and the estimated frequency of GLUT1 deficiency syndrome.

The first mutations identified in SLC2A1, encoding the glucose transporter type 1 (GLUT1) protein of the blood-brain barrier, were associated with severe epileptic encephalopathy. Recently, dominant SLC2A1 mutations were found in rare autosomal dominant families with various forms of epilepsy including early onset absence epilepsy (EOAE), myoclonic astatic epilepsy (MAE), and genetic generalized epilepsy (GGE). Our study aimed to investigate the possible role of SLC2A1 in various forms of epilepsy including MAE and absence epilepsy with early onset. We also aimed to estimate the frequency of GLUT1 deficiency syndrome in the Danish population. One hundred twenty patients with MAE, 50 patients with absence epilepsy, and 37 patients with unselected epilepsies, intellectual disability (ID), and/or various movement disorders were screened for mutations in SLC2A1. Mutations in SLC2A1 were detected in 5 (10%) of 50 patients with absence epilepsy, and in one (2.7%) of 37 patient with unselected epilepsies, ID, and/or various movement disorders. None of the 120 MAE patients harbored SLC2A1 mutations. We estimated the frequency of SLC2A1 mutations in the Danish population to be approximately 1:83,000. Our study confirmed the role of SLC2A1 mutations in absence epilepsy with early onset. However, our study failed to support the notion that SLC2A1 aberrations are a cause of MAE without associated features such as movement disorders.

Nationwide survey of glucose transporter-1 deficiency syndrome (GLUT-1DS) in Japan.

OBJECTIVES: We conducted a nationwide survey of glucose transporter type-1 deficiency syndrome (GLUT-1DS) in Japan in order to clarify its incidence as well as clinical and laboratory information. SUBJECTS AND METHODS: A questionnaire to survey the number of genetically and clinically confirmed cases of GLUT-1DS was sent to 1018 board-certified pediatric neurologists, which resulted in 57 patients being reported. We obtained the clinical and laboratory data of 33 patients through a secondary questionnaire. RESULTS: The age of the 33 patients (male: 15, female: 18) at the time of the study ranged between 3 and 35 years (mean: 13.5 years). The age of these patients at the onset of initial neurological symptoms ranged between the neonatal period and 48 months (mean: 9.4 months). GLUT-1DS was diagnosed at a mean age of 8.4 years (range: 1 year to 33 years). The initial symptom was convulsive seizures, which occurred in 15 cases, and was followed by abnormal eye movements in 7 cases and apneic or cyanotic attacks in 4 cases. The latter two symptoms most frequently occurred early in infancy. Thirty-two patients (97%) exhibited some type of epileptic seizure. Neurological findings revealed that most patients had muscle hypotonia, cerebellar ataxia, dystonia, and spastic paralysis. Mild to severe mental retardation was detected in all 33 cases. Furthermore, paroxysmal episodes of ataxia, dystonia/dyskinesia, and motor paralysis were described in approximately 1/3 of all patients. The factors that frequently aggravated these events were hunger, exercise, fever, and fatigue, in that order. The mean CSF/blood glucose ratio was 0.36 (0.28-0.48). Pathological mutations in the SLC2A1 gene were identified in 28 out of 32 cases (87.5%). CONCLUSION: The results described herein provided an insight into the early diagnosis of GLUT1-DS, including unexplained paroxysmal abnormal eye movements, apneic/cyanotic attacks, and convulsive seizures in infancy, as well as uncommon paroxysmal events (ataxia, atonia, and motor paralysis) in childhood.

Elevada prevalencia de déficit de vitamina D entre los niños y adolescentes obesos españoles / High prevalence of vitamin D deficiency among spanish obese children and adolescents

INTRODUCCIÓN: El déficit de vitamina D ha sido relacionado con manifestaciones extraesqueléticas, como insulinorresistencia, diabetes mellitus tipo 2 y enfermedad cardiovascular. El objetivo de este estudio es determinar la prevalencia del déficit de vitamina D en niños obesos españoles y analizar la relación entre niveles de vitamina D y alteraciones del metabolismo hidrocarbonado. PACIENTES Y MÉTODOS: Estudio descriptivo, transversal, donde se recogieron datos clínicos y analíticos de 120 niños obesos y 50 niños con normopeso atendidos en las consultas externas de Pediatría entre enero del 2011 y enero del 2013. RESULTADOS: Los niveles medios de vitamina D fueron de 19,5 ng/ml en obesos y de 31,6 ng/ml en controles. El 58,3% de los obesos presentaron déficit de vitamina D frente al 10% de los controles. Los niveles de vitamina D eran significativamente menores en invierno. Se encontraron cifras más elevadas de HOMA-SDS (3,8 versus 2,4) y triglicéridos (97 versus 81 mg/dl) en los obesos con déficit de vitamina D respecto a los obesos que no tenían déficit. Se halló una correlación negativa entre los niveles de vitamina D y el valor absoluto de HOMA (r = −0,2; p = 0,04), que no se mantiene al analizar HOMA-SDS. CONCLUSIONES: Existe una elevada prevalencia de déficit de vitamina D entre la población obesa infantil de etiología multifactorial. Los niveles deficitarios de vitamina D podrían influir en el desarrollo de insulinorresistencia y diabetes mellitus tipo 2 en la población obesa

INTRODUCTION: Vitamin D deficiency has been associated with extra-skeletal outcomes such as, insulin resistance, type 2 diabetes, and cardiovascular disease. The aim of this study is to determine the prevalence of vitamin D deficiency among obese children and adolescents in Spain and to analyze the relationship between 25-OH-vitamin D (25-OH-D) levels and markers of abnormal glucose metabolism. PATIENTS AND METHODS: A cross-sectional study was conducted in which the clinical and biochemical data were recorded for 120 obese and 50 non-overweight children in Pediatric Clinics from January 2011 to January 2013. RESULTS: The mean 25-OH-D levels among obese children was 19.5 ng/ml and among non-overweight children was 31.6 ng/ml. 58,3% of obese subjects, and 10% of non-overweight subjects had vitamin D deficiency. Serum 25-OH-D levels were lower in winter. Higher HOMASDS (3.8 versus 2.4), and triglycerides (97 versus 81 mg/dl) were found in vitamin D deficient obese children compared to obese children without vitamin D deficiency. A negative correlation was found between 25-OH-D levels and HOMA in absolute values (r=-0.2; P=0.04) that was not maintained when HOMA-SDS was analyzed. CONCLUSIONS: There is a high prevalence of vitamin D deficiency among obese children with a multifactorial etiology. A lower 25-OH-D level could be a risk factor for developing insulin resistance and type 2 diabetes in obese population

Alteraciones del metabolismo hidrocarbonado en la acromegalia / Abnormalities of carbohydrate metabolism in acromegaly

Fundamento y objetivo: Hasta un 50% de los pacientes con acromegalia presentan alteraciones en el metabolismo hidrocarbonado (AMHC). La evolución natural de la enfermedad y las distintas alternativas terapéuticas impactan de forma diferente en esta predisposición. El objetivo de este trabajo fue valorar la prevalencia, las características de los pacientes y el efecto de los distintos tratamientos en la AMHC en los pacientes acromegálicos de nuestro centro. Pacientes y método: Se realizó un estudio transversal que incluyó a 55 pacientes con acromegalia. Se analizaron: edad, sexo, índice de masa corporal (IMC), factor de crecimiento insulínico tipo 1 (IGF-1), tamaño tumoral, tratamientos, y presencia de diabetes mellitus (DM) y grado de control metabólico inicial y tras las distintas alternativas terapéuticas. Resultados: De los 55 pacientes estudiados, el 54% eran varones, con una edad media (DE) de 50 (17) años y un IMC de 27,9 (3,8) kg/m2. Las AMHC estaban presentes en el 50,9% (n = 28) (DM en el 24% y glucosa basal alterada en el 27%). Los pacientes con DM no presentaban diferencias en el IMC, la edad ni el IGF-1 inicial respecto a los que no tenían DM. Sin embargo, presentaban más macroadenomas. En los pacientes diabéticos, la hemoglobina glucosilada (HbA1c) descendió después de la cirugía de 7,6 a 6,7% y después de los análogos de la somatostatina de 7,1 a 6,6%, pero solo con pegvisomant hemos observado una reducción significativa de HbA1c: del 9,8 al 5,6% (p < 0,05). Es más, solo pegvisomant ha permitido disminuir la intensidad del tratamiento hipoglucemiante. Conclusiones. La prevalencia de AMHC supera al 50% de los casos y se correlaciona con el tamaño tumoral. No hemos observado diferencias en el control glucémico en los pacientes tratados con las diferentes alternativas terapéuticas, excepto en el grupo que recibió pegvisomant, que logró una mejoría del mismo, junto con una reducción del tratamiento hipoglucemiante (AU)

Background and objective: Carbohydrate metabolism (CHM) is impaired in over 50% of acromegalic patients. Natural history of acromegaly and treatment modalities may impact in a different way on CHM. We assessed CHM alterations in acromegaly and their relationship with clinical features and treatment options. Patients and method: Retrospective study with 55 patients with acromegaly. Age, sex, body mass index (BMI), tumor size, insulin growth factor type 1 (IGF-1) levels and the presence of impaired fasting glucose (IFG) or diabetes mellitus (DM) were analyzed before and after surgery or medical treatment. Results: There were 30 men and 25 women. Mean age was 50 17 years and mean BMI was 27.9 3.8 Kg/ m2. Impaired CHM was found in 50.9% (n = 28) (DM in 27% and IFG in 24%). In diabetic patients, we found no differences in age, sex, BMI and IGF-1 levels between IFG/DM and patients without CHM impairment. However, IFG/DM patients had macroadenomas more commonly. In diabetic patients, glycosylated hemoglobin (HbA1c) decreased after surgery from 7.6 to 6.7% and after somatostatin analogues from 7.1 to 6.6%; in patients on pegvisomant we observed a significant reduction of HbA1c: from 9.8 to 5.6% (P < .005). Furthermore, only in the pegvisomant group, insulin and/or oral agents had to be lowered. Conclusions: Up to 50% of patients with active acromegaly have CHM impairment which correlates with tumor size. Only pegvisomant is associated with significant improvement in glycemic control and a reduction in hypoglycemic treatment (AU)

[Carbohydrate metabolism disorders among obese children and adolescents. Diabetes mellitus type 2]. / Störungen des Kohlenhydratstoffwechsels bei Kindern und Jugendlichen mit Adipositas. Diabetes mellitus Typ 2.

As obesity has become more prevalent, the incidence of type 2 diabetes mellitus in children and adolescents has also increased. Obesity during adolescence leads to an increased risk for disease and premature death during adulthood, independent of obesity during adulthood. Obesity is the major risk factor impacting insulin sensitivity. Subjects with insulin resistance are at risk for progression to diabetes. Type 2 diabetes mellitus in obese children and adolescents is frequently asymptomatic. It is essential to identify children at high risk who need aggressive lifestyle modification focused on weight reduction and increased physical activity. Early detection and therapy of obese children and adolescents with type 2 diabetes may reduce the risk of cardiometabolic consequences and other long-term complications in adulthood.

Diseases of glycosylation beyond classical congenital disorders of glycosylation.

BACKGROUND: Diseases of glycosylation are rare inherited disorders, which are often referred to as congenital disorders of glycosylation (CDG). Several types of CDG have been described in the last decades, encompassing defects of nucleotide-sugar biosynthesis, nucleotide-sugar transporters, glycosyltransferases and vesicular transport. Although clinically heterogeneous, most types of CDG are associated with neurological impairments ranging from severe psychomotor retardation to moderate intellectual disabilities. CDG are mainly caused by defects of N-glycosylation, owing to the simple detection of under-glycosylated serum transferrin by isoelectric focusing. SCOPE OF REVIEW: In the last years, several disorders of O-glycosylation, glycolipid and glycosaminoglycan biosynthesis have been described, which are known by trivial names not directly associated with the family of CDG. The present review outlines 64 gene defects affecting glycan biosynthesis and modifications, thereby underlining the complexity of glycosylation pathways and pointing to unexpected phenotypes and functional redundancies in the control of glycoconjugate biosynthesis. MAJOR CONCLUSIONS: The increasing application of whole-genome sequencing techniques unravels new defects of glycosylation, which are associated to moderate forms of mental disabilities. GENERAL SIGNIFICANCE: The knowledge gathered through the investigation of CDG increases the understanding of the functions associated to protein glycosylation in humans. This article is part of a Special Issue entitled Glycoproteomics.

Refractory absence epilepsy associated with GLUT-1 deficiency syndrome.

GLUT-1 deficiency syndrome (GLUT-1 DS) is a disorder of cerebral glucose transport associated with early infantile epilepsy and microcephaly. We report two boys who presented with refractory absence epilepsy associated with hypoglycorrhachia, both of whom have genetically confirmed GLUT-1 DS. We propose that these children serve to expand the phenotype of GLUT-1 DS and suggest that this condition should be considered as a cause of refractory absence seizures in childhood.

Tratamiento de los factores de riesgo cardiovascular en el paciente trasplantado / No disponible

No disponible

Screening using serum percentage of carbohydrate-deficient transferrin for congenital disorders of glycosylation in children with suspected metabolic disease.

BACKGROUND: Diagnoses of congenital disorders of glycosylation (CDG) are based on clinical suspicion and analysis of transferrin (Tf) isoforms. Here we present our experience of CDG screening in children with a suspected metabolic disease by determination of serum percentage of carbohydrate-deficient transferrin (%CDT) in tandem with isoelectric focusing (IEF) analysis of Tf and alpha(1)-antitrypsin (alpha(1)-AT). METHODS: We performed approximately 8000 serum %CDT determinations using %CDT turbidimetric immunoassay (TIA). In selected samples, IEF analysis of Tf and alpha(1)-AT was carried out on an agarose gel (pH 4-8) using an electrophoresis unit. The isoforms were detected by Western blotting and visualized by color development. We performed neuraminidase digestion of serum to detect polymorphic variants of Tf. RESULTS: We established a cutoff value for serum %CDT of 2.5% in our pediatric population. Sixty-five patients showed consistently high values of serum %CDT. In accordance with Tf and alpha(1)-AT IEF profiles, enzyme assays, and mutation analysis, we made the following diagnoses: 23 CDG-Ia, 1 CDG-Ib, and 1 conserved oligomeric Golgi 1 (COG-1) deficiency. In addition, we identified 13 CDG-Ix non Ia, non-Ib; 3 CDG-Ix; and 9 CDG-IIx cases, albeit requiring further characterization; 9 patients with a secondary cause of hypoglycosylation and 6 with a polymorphic Tf variant were also detected. CONCLUSION: The combined use of CDT immunoassay with IEF of Tf and alpha(1)-AT is a useful 1st-line screening tool for identifying CDG patients with an N-glycosylation defect. Additional molecular investigations must of course be carried out to determine the specific genetic disease.