OBJECTIVES:Transcobalamin II (TC) promotes the cellular uptake of cobalamin (Cbl) through receptor-mediated endocytosis of the TC-cbl complex in peripheral tissues. TC deficiency is a rare disorder that causes intracellular Cbl depletion. It presents in early infancy with a failure to thrive, diarrhea, anemia, agammaglobulinemia, and pancytopenia. Data from five TC-deficient patients including clinical, biochemical, and molecular findings, as well as long-term outcomes, were collected.CASE PRESENTATION:Mutation analysis revealed one unreported pathogenic variant in the TCN2 gene. One patient had exocrine pancreatic insufficiency. We conducted a retrospective analysis of C3 and C3/C2 from dried blood samples, as this is implemented for newborn screening (NBS). We detected a marked increase in the C3/C2 ratio in two samples. Treatment was based on parenteral Cbl. Three patients treated before six months of age had an initial favorable outcome, whereas the two treated later or inadequately had neurological impairment.CONCLUSIONS:This is the first report of Argentinean patients with TC deficiency that detected a new variant in TCN2. NBS may be a tool for the early detection of TC deficiency. This data emphasizes that TC deficiency is a severe disorder that requires early detection and long-term, aggressive therapy. Accurate diagnosis is imperative, because early detection and treatment can be life-saving.

Participation in external quality assessment programmes focused on rare genetic diseases makes it possible to assess the laboratory technical and analytical performance and it is a prerequisite for accreditation according to ISO 15189. The objective of this study was to perform a retrospective evaluation of our performance in the EMQN (European Molecular Genetics Quality Network) and the CF Network (Cystic Fibrosis European Network) programmes in the 2014-2022 period. The laboratory performance on genotyping, interpretation and clerical accuracy and patient identifiers in a total of 88 schemes were assessed. The information of our scores and the mean scores of all participating laboratories in the three categories were collected. A total of 90.9% of the schemes were fully completed. The performance in genotyping showed scores above the mean scores in 89.3% of the schemes; 0.8% of the reports correspond to false negative results. Regarding interpretation category, 66.7% of the schemes presented scores above the mean scores and 33.3% below the mean scores. The clerical accuracy and patient identifiers were above the mean scores in 97.6% of the schemes. A statistically significant difference in the percentage of schemes with a score above the mean for the interpretation category in the year 2022 (10/12 schemes) was observed compared to the year 2014 (1/6 schemes) (p=0.0128). In conclusion, regular participation in external quality assessment programmes had a positive impact on the quality of the studies and allows for continuous improvements based on the recommendations suggested by these programmes.

Abstract Glycogen storage disease type I is an autosomal recessive disorder of carbohydrate metabolism that manifests mainly by hepatomegaly and hypoglycemia with short fasts. Despite strict therapy, patients present long-term renal and liver complications. Data of 36 patients,29 GSD Ia and 7 Ib from a high complexity Hospital in Argentina was collected retrospectively. Collected data included diagnosis, anthropometric, biochemical parameters, therapy and follow-up. Treatment increased Height SDS (p=0.012). Patients with good adherence to therapy presented better growth parameters (p=0.049). Instead, admissions were detrimental (p =0.031) and were more common in Ib patients (p=0.002). The early appearance of complications (liver adenomas and nephropathy) was related to sustained triglyceride values > 500mg / dl (p=0.009 and 0.046 respectively). With intensive dietary treatment, clinical and biochemical status improves but cannot be completely corrected in most patients. Growth improves with treatment and this is optimized with adequate adherence. We must take into account that with ageing, more complications will develop.

Abstract The clinical and biochemical findings in a cohort of 51 patients with urea cycle disorders followed at the Hospital Garrahan, Buenos Aires, Argentina were analyzed at the time of diagnosis (3 female patients were excluded). Of this cohort, 13/48 patients had early-onset (EO), 23/48 had late-onset (LO), and 12/48 had a different presentation because they had a family risk background (FRB) and had been diagnosed since they were born. The most frequent deficiency disorder was OTCD (65%). The initial ammonium value was evaluated, being higher in the EO group, with a statistically significant difference when compared with LO and FRB. 15/48 patients fell into a coma at the time of diagnosis, mean ammonia was 829.54 μmol / L, and 33/48 did not fell into a coma, the mean ammonium was of 159.3 μmol / L (p = 0.001). 15 patients died: 62% EO, 22% LO (p=0.0216), 17% FRB. A molecular study was performed on 35 patients. Patients with EO presentation suffer the most severe forms and still have high morbimortality. On the other hand, LO forms are forms of less severity that are finally diagnosed as a result of one or more acute episodes.

Female patient carrier of medium-chain acyl-CoA dehydrogenase deficiency (MCADD) with recurrent clinical episodes of hypoglycemia and altered level of consciousness, presented changes in blood acylcarnitine profile by tandem mass spectrometry and in the urinary organic acid analysis by gas chromatography/mass spectrometry (GC/MS). This case demonstrates the importance of fasting prior biological sample collection (when possible) when MCADD is suspected, and emphasizes that the time/momentum of biological sample collection is crucial to diagnosis, considering the possibility that MCADD is underdiagnosed in Brazil.

BACKGROUND: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. METHODS: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. RESULTS: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. CONCLUSION: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.

BackgroundThere 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.MethodsMBL2 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.ResultsMBL 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.ConclusionsMBL 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.