The aim of this study was to perform a molecular characterization of 17 Argentinean pediatric patients with diagnosis of having epileptic encephalopathies (EEs) of the first year of life without ...known etiology, applying next-generation sequencing (NGS).
We included 17 patients with EE with age of onset under 12 months without known etiology after ruling out structural abnormalities, metabolic disorders, and large chromosomal abnormalities. They presented with the following clinical phenotypes: Dravet syndrome (DS; n: 7), epilepsy of infancy with migrating focal seizures (EIMFS; n: 3), West syndrome (WS; n: 2), and undetermined epileptic encephalopathy (UEE; n: 5). Neurologic examinations, seizure semiology, brain magnetic resonance imaging, and standard electroencephalography (EEG) or video-EEG studies were performed in all cases. Using a custom amplicon strategy, we designed an NGS panel to study 47 genes associated with EEs.
Pathogenic variants were detected in 8 cases (47%), including seven novel pathogenic variants and one previously reported as being pathogenic. The pathogenic variants were identified in 6 patients with DS (SCN1A gene), one with EIMFS (SCN2A gene), and one with UEE (SLC2A1 gene). Nonrelevant variants were identified in the patients with WS.
We demonstrated the feasibility of an NGS-gene panel approach for the analysis of patients with EE in our setting. A genetic diagnosis was achieved in nearly 50% of patients, 87% of them presenting with nonpreviously reported variants. The early identification of the underlying causative genetic alteration will be a valuable tool for providing prognostic information and genetic counselling and also to improve therapeutic decisions in Argentinean patients.
•A targeted NGS panel was designed to analyse a group of 17 Argentinean patients with EEs of the first year of life•A genetic diagnosis was identified in ∼50% of the patients, 87% of them presenting with a non-previously reported variant.•Molecular diagnosis in EE Latin American patients is relevant to increase our knowledge about our own mutational spectrum.•NGS diagnosis will be available for the patients with epilepsy attending a public tertiary paediatric hospital.
Classical galactosemia is an autosomal recessive inherited metabolic disorder caused by mutations in the galactose-1-phosphate uridyltransferase (GALT) gene. GALT enzyme deficiency leads to the ...accumulation of galactose-1-phosphate in various organs, causing hepatic, renal and cerebral impairment. Over 300 mutations have been reported in the GALT gene. The aim of this study was to describe molecular characterization of GALT gene in Argentinian patients with decreased GALT activity, and to correlate molecular results with enzyme activity.
37 patients with enzyme activity below 6.3 μmol/h/g Hb (35% of normal value) were included. GALT activity was measured on red blood cells. DNA was extracted from peripheral blood. p.Gln188Arg mutation was studied by PCR-RFLP and, on samples negative or heterozygous, GALT gene was sequenced. In vivo splicing analysis of the GALT gene was performed on RNA extracted from leukocytes of one patient.
14 different sequence variations were identified among 72 unrelated alleles. The two most common disease-causing mutations were p.Gln188Arg (24/72) and p.Lys285Asn (9/72). Three novel mutations were detected. One of them, c.688G>A, caused partial skipping of exon 9 of the GALT gene. Enzyme activity correlated with GALT genotype in 36 of the 37 patients.
This is the first report of sequence variations in the GALT gene in the Argentinian population. This study highlights the contribution of the molecular analysis to the diagnosis of Galactosemia and reveals c.688G>A as a novel Duarte-like variant, with a high prevalence in our population.
Background: Glutathione S-transferases (GSTs) are drug-metabolising enzymes involved in biotransformation of carcinogens, drugs, xenobiotics and oxygen free radicals. Polymorphisms of GST genes ...contribute to inter-individual and population variability in the susceptibility to environmental risk factors, cancer predisposition and pharmacotherapy responses. However, data about GST variability in Argentina are lacking.
Aim: The purpose was to determine the prevalence of GSTM1, GSTT1 and GSTP1 polymorphisms in the general population from a central region of Argentina and to perform inter-population comparisons.
Subjects and methods: GSTM1 and GSTT1 gene deletions and GSTP1 c.313A > G were genotyped by PCR assays in 609 healthy and unrelated Argentinians.
Results: The frequencies of variant genotypes in Argentinians were GSTM1-null (45%), GSTT1-null (17%) and GSTP1-GG (11%). GSTM1-present genotype was significantly associated with GSTP1-AG or GSTP1-GG variants (p = 0.037; p = 0.034, respectively). Comparison with worldwide populations demonstrated that the GST distributions in Argentina are similar to those reported for Italy and Spain, whereas significant differences were observed regarding Asian and African populations (p < 0.001).
Conclusion: This study has determined, for the first time, the normative profile of three pharmacogenetically relevant polymorphisms (GSTM1, GSTT1 and GSTP1) in the largest Argentinian cohort described to date, providing the basis for further epidemiological and pharmacogenetic studies in this country.
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Dostopno za:
DOBA, FSPLJ, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background: Pediatric patients with steroid-resistant nephrotic syndrome (SRNS) and focal segmental glomerulosclerosis (FSGS) may relapse and current second line agents include mycophenolate mofetil. ...However, there is no current information about the use of the sodium salt of mycophenolic acid (SMPA) in this population. Objectives: We conducted a prospective study on the efficacy and pharmacokinetics of SMPA in children with FSGS. Patients and Methods: Patients without NPHS2 pathogenic variants received SMPA at dosages between 460 to 720 mg/m2/d for 12 months after previous treatments failure. Clinical and biochemical assessments were performed. Blood samples were obtained after the first dose and at steady state (3 months after the onset of treatment) and total and free mycophenolic acid (MPA) was quantitated using HPLC-UV. Results: Two patients showed partial remission after the 12-month period of SMPA treatment with a notable decrease in proteinuria and an increase in serum albumin levels. Maximum MPA concentrations after the first dose and at steady state were 11.6 µg/mL and 10.5 µg/mL, respectively, without drug accumulation. Maximum MPA free levels after the first dose and at steady state were 192.9 and 120.6 ng/mL, respectively. MPA levels became undetectable after 4 hours of the administration in all cases. Conclusions: SMPA is a promising agent for pediatric patients with SRNS and FSGS but SMPA schedule of treatment should be revised with shorter intervals of administration and higher doses than those used in the present study in order to attain higher systemic exposures and accumulation of the immunosuppressant drug. Further efficacy and pharmacokinetic studies should be performed to confirm these findings.
Summary
Introduction Prader‐Willi syndrome (PWS) is a genetic disorder caused by the loss of expression of paternally transcribed genes in a highly imprinted region of chromosome 15q11‐13. The ...clinical phenotype has been well characterized, mostly related to hypothalamic dysfunction. Even though central hypothyroidism has been documented in 20–30% of patients with PWS, thyroid function during the first 2 years of life has not been clearly defined.
Objective To evaluate hypothalamic‐pituitary‐thyroid function in infant PWS patients.
Study design Eighteen patients with PWS, aged 0·16–2 years, were included in a prospective study. PWS diagnosis was based on clinical features and molecular analysis. Serum total (T) T4, free (F) T4, T3 and thyroid‐stimulating hormone (TSH) were evaluated in the patients with PWS included in the study. Serum hormone values were compared to those of a large reference population of the same age.
Results In 13 of 18 patients with PWS (72·2%), serum TT4 and/or FT4 levels were below the 2·5th percentile of the reference population, while in only one PWS patient serum T3 was below this cut‐off.
Conclusion The results of this study suggest that transient or definitive thyrotropin‐releasing hormone (TRH)‐TSH thyroid axis dysfunction may frequently be present in infant PWS patients. Paediatricians should be aware of this dysfunction in this critical period of thyroid hormone action on neurological development.
Abstract
The aim of this study was to evaluate the influence of the most common genetic variants in methylenetetrahydrofolate reductase (MTHFR), thiopurine methyltransferase (TPMT) and ...glutathione-S-transferases (GSTs) on the outcome of acute lymphoblastic leukemia (ALL) treatment in Argentinean children. Two hundred and eighty-six patients with ALL treated with two Berlin-Frankfurt-Münster (BFM)-based protocols were analyzed. Ten genetic variants were studied. Toxicity was evaluated during the consolidation phase. Children who received 2 g/m2/day of methotrexate and carried at least one 677T allele in MTHFR showed an increased risk of developing severe leukopenia (p = 0.004) and neutropenia (p = 0.003). Intermediate-risk (IR) patients with a heterozygous TPMT genotype had a higher probability of event-free survival than those with a wild-type genotype. Genotyping of MTHFR polymorphisms might be useful to optimize consolidation therapy, reducing the associated severe hematologic toxicity. Further studies are necessary to establish the usefulness of MTHFR and TPMT variants as additional markers to predict outcome in the IR group.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
New evidence suggests that different β(2)-adrenergic receptor (β2AR) polymorphisms may influence asthma control in patients receiving long-acting β(2)agonists (LABAs) as regular therapy.
To determine ...the influence of β2AR polymorphisms on asthma exacerbations in children with severe asthma from Argentina receiving inhaled corticosteroid (ICS) and LABAs regularly.
Ninety-seven children with severe asthma were genotyped for polymorphisms of β2AR at codons 16 and 27. The number of severe exacerbations, the time of first asthma exacerbation, and the number of hospitalizations during 12 months were assessed. Changes on pulmonary function from the beginning to the end of the study were also evaluated.
The number of overall asthma exacerbations and the proportion of children with these events were similar among β2AR genotypes at position 16 (Arg/Arg, Arg/Gly, and Gly/Gly) and at position 27 (Gln/Gln, Gln/Glu, and Glu/Glu). The time to first asthma exacerbation was similar among individuals carrying different β2AR polymorphisms. No β2AR genotype association was found in relation to the number of hospitalizations. Longitudinal analysis of forced expiratory volume in 1 second from baseline to the end of the study also showed no differences among β2AR genotypes at position 16 or 27. No association was observed among the 3 most common haplotypes (Arg/Arg-Gln/Gln, Gly/Gly-Gln/Gln, and Gly/Gly-Glu/Glu) and the number of participants with asthmatic crisis or with the overall number of exacerbations.
β2AR polymorphisms were not associated with an increased risk of having asthma exacerbations or lung function decline in a population of Argentinian children with severe asthma receiving ICS and LABAs regularly.
Abstract Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder, considered one of the leading causes of infant mortality. It is caused by mutations in the SMN1 gene. A highly ...homologous copy of this gene named SMN2 and other neighbouring genes, SERF1A and NAIP , are considered phenotypic modifiers of the disease. In recent years, notable advances have been made in SMA research regarding evaluation, prognosis, and therapeutic options. Thus, genotype-phenotype studies in SMA are important to stratify patients for motor function tests and for envisaged clinical trials. We performed a detailed clinical and molecular characterization of 144 Argentinean children with SMA (56 children with type I, 58 with type II, and 30 with type III). We classified our patients into clinical subtypes and correlated these with the SMN2, SERF1A and NAIP copy number. To improve clinical characterization we considered the initial symptoms that prompted the consultation, age of acquisition of motor abilities to independent walking and age at loss of gait. We also evaluated clinical and molecular features of sibling pairs in seven families. We observed intra- and interfamily differences among the SMA types. This first genotype-phenotype correlation study in Argentinean SMA children provides data to improve patient stratification and define more adequate follow-up parameters.
Abstract Background There is a considerable variation in the phenotype and course of the disease in cystic fibrosis (CF) even in patients with the same CFTR genotype, suggesting that other factors ...are important for prognosis. Mannose-binding lectin (MBL) has been proposed as one of these factors. We therefore investigated the influence of MBL2 gene variants on disease severity, age at acquisition of Pseudomonas aeruginosa , and survival in CF patients. Methods MBL2 variants were studied in 106 Argentinean pediatric CF patients carrying two severe CFTR mutations. Clinical phenotype was defined according to the Shwachman score and lung function tests. Age at infection with P. aeruginosa and age at death were also recorded. Results MBL insufficiency was associated with a 3.5-fold risk of having a severe phenotype (CI 95%: 1.2–10.3, p = 0.03). It was also associated with an earlier onset of infection with P. aeruginosa ( p = 0.035). No statistically significant differences were found in FEV1 and survival. Conclusions MBL insufficiency was associated with detrimental progression of the disease. These results together with previous findings suggest that the effect of MBL2 expression may be a major determinant of the severity of the clinical phenotype in patients with CF.
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