Molecular basis of various forms of maple syrup urine disease in Chilean patients.

BACKGROUND: Maple syrup urine disease (MSUD) is an autosomal recessive inherited metabolic disorder caused by the deficient activity of the branched-chain α-keto acid dehydrogenase (BCKD) enzymatic complex. BCKD is a mitochondrial complex encoded by four genes: BCKDHA, BCKDHB, DBT, and DLD. MSUD is predominantly caused by mutations in the BCKDHA, BCKDHB, and DBT genes which encode the E1α, E1ß, and E2 subunits of the BCKD complex, respectively. The aim of this study was to characterize the genetic basis of MSUD in a cohort of Chilean MSUD patients by identifying point mutations in the BCKDHA, BCKDHB, and DBT genes and to describe their impact on the phenotypic heterogeneity of these patients. METHODS: This manuscript describes a cross-sectional study of 18 MSUD patients carried out using PCR and DNA sequencing. RESULTS: Four novel pathogenic mutations were identified: one in BCKDHA (p.Thr338Ile), two in BCKDHB (p.Gly336Ser e p.Pro240Thr), and one in DBT (p.Gly406Asp). Four additional pathogenic mutations found in this study have been described previously. There were no correlations between the genotype and phenotype of the patients. CONCLUSION: If MSUD is diagnosed earlier, with a newborn screening approach, it might be possible to establish genotype-phenotype relationships more efficiently.

Maple syrup urine disease in Brazilian patients: variants and clinical phenotype heterogeneity.

BACKGROUND: Maple syrup urine disease (MSUD) is an autosomal recessive inherited metabolic disease caused by deficient activity of the branched-chain α-keto acid dehydrogenase (BCKD) enzymatic complex. BCKD is a mitochondrial complex encoded by BCKDHA, BCKDHB, DBT, and DLD genes. MSUD is predominantly caused by Variants in BCKDHA, BCKDHB, and DBT genes encoding the E1α, E1ß, and E2 subunits of BCKD complex, respectively. The aim of this study was to characterize the genetic basis of MSUD by identifying the point variants in BCKDHA, BCKDHB, and DBT genes in a cohort of Brazilian MSUD patients and to describe their phenotypic heterogeneity. It is a descriptive cross-sectional study with 21 MSUD patients involving molecular genotyping by Sanger sequencing. RESULTS: Eight new variants predicted as pathogenic were found between 30 variants (damaging and non-damaging) identified in the 21 patients analyzed: one in the BCKDHA gene (p.Tyr120Ter); five in the BCKDHB gene (p.Gly131Val, p.Glu146Glnfs * 13, p.Phe149Cysfs * 9, p.Cys207Phe, and p.Lys211Asn); and two in the DBT gene (p.Glu148Ter and p.Glu417Val). Seventeen pathogenic variants were previously described and five variants showed no pathogenicity according to in silico analysis. CONCLUSION: Given that most of the patients received late diagnoses, the study results do not allow us to state that the molecular features of MSUD variant phenotypes are predictive of clinical severity.

Evaluation of plasma biomarkers of inflammation in patients with maple syrup urine disease.

Maple syrup urine disease (MSUD) is an autosomal recessive inherited disorder that affects branched-chain amino acid (BCAA) catabolism and is associated with acute and chronic brain dysfunction. Recent studies have shown that inflammation may be involved in the neuropathology of MSUD. However, these studies have mainly focused on single or small subsets of proteins or molecules. Here we performed a case-control study, including 12 treated-MSUD patients, in order to investigate the plasmatic biomarkers of inflammation, to help to establish a possible relationship between these biomarkers and the disease. Our results showed that MSUD patients in treatment with restricted protein diets have high levels of pro-inflammatory cytokines [IFN-γ, TNF-α, IL-1ß and IL-6] and cell adhesion molecules [sICAM-1 and sVCAM-1] compared to the control group. However, no significant alterations were found in the levels of IL-2, IL-4, IL-5, IL-7, IL-8, and IL-10 between healthy controls and MSUD patients. Moreover, we found a positive correlation between number of metabolic crisis and IL-1ß levels and sICAM-1 in MSUD patients. In conclusion, our findings in plasma of patients with MSUD suggest that inflammation may play an important role in the pathogenesis of MSUD, although this process is not directly associated with BCAA blood levels. Overall, data reported here are consistent with the working hypothesis that inflammation may be involved in the pathophysiological mechanism underlying the brain damage observed in MSUD patients.

Bioelectrical Impedance Vector Analysis in Healthy Term Infants in the First Three Months of Life in Brazil.

OBJECTIVE: Bioelectrical impedance vectorial analysis (BIVA) can be considered a favorable method for evaluation and monitoring of nutritional and hydration status without assumptions regarding body composition or requirement of prediction formulas. The present study aimed to determine bivariate tolerance intervals of the whole-body impedance vector for healthy term infants aged 1 to 3 months. METHODS: This is a descriptive cross-sectional study. Anthropometric and bioelectrical impedance data (800 mA-50 kHz) were obtained. Bivariate vector analysis was conducted with the resistance-reactance (RXc) graph method. BIVA software was used to construct the graphs. RESULTS: A total of 150 appropriate for gestational age infants (48.7% boys) who were exclusively breastfed and were 56.4 (SD = 23.1) days of age were studied. RXc tolerance ellipses (50, 75, and 95%) were constructed for boys and girls, but a general reference graph was defined for all infants considering the overlapping of ellipses between the genders. All graphs differed from those in national and foreign studies. CONCLUSION: New reference tolerance ellipses (95, 75, and 50%) for 1- to 3-month-old infants were constructed, pointing out the need for specific reference values of total body impedance vectors in different regions of Brazil. The RXc tolerance ellipses can be used for clinical practice and provide an easy method to evaluate and monitor body composition and hydration status.

Living related versus deceased donor liver transplantation for maple syrup urine disease.

Maple syrup urine disease (MSUD) is an inherited disorder of branched chain ketoacid (BCKA) oxidation associated with episodic and chronic brain disease. Transplantation of liver from an unrelated deceased donor restores 9-13% whole-body BCKA oxidation capacity and stabilizes MSUD. Recent reports document encouraging short-term outcomes for MSUD patients who received a liver segment from mutation heterozygous living related donors (LRDT). To investigate effects of living related versus deceased unrelated grafts, we studied four Brazilian MSUD patients treated with LRDT who were followed for a mean 19 ± 12 postoperative months, and compared metabolic and clinical outcomes to 37 classical MSUD patients treated with deceased donor transplant. Patient and graft survival for LRDT were 100%. Three of 4 MSUD livers were successfully domino transplanted into non-MSUD subjects. Following LRDT, all subjects resumed a protein-unrestricted diet as mean plasma leucine decreased from 224 ± 306 µM to 143 ± 44 µM and allo-isoleucine decreased 91%. We observed no episodes of hyperleucinemia during 80 aggregate postoperative patient-months. Mean plasma leucine:isoleucine:valine concentration ratios were ~2:1:4 after deceased donor transplant compared to ~1:1:1.5 following LRDT, resulting in differences of predicted cerebral amino acid uptake. Mutant heterozygous liver segments effectively maintain steady-state BCAA and BCKA homeostasis on an unrestricted diet and during most catabolic states, but might have different metabolic effects than grafts from unrelated deceased donors. Neither living related nor deceased donor transplant affords complete protection from metabolic intoxication, but both strategies represent viable alternatives to nutritional management.

Bioelectrical impedance vector analysis (BIVA) in stable preterm newborns.

OBJECTIVE: To observe the behavior of the plotted vectors on the RXc (R - resistance - and Xc - reactance corrected for body height/length) graph through bioelectrical impedance analysis (BIVA) and phase angle (PA) values in stable premature infants, considering the hypothesis that preterm infants present vector behavior on BIVA suggestive of less total body water and soft tissues, compared to reference data for term infants. METHODS: Cross-sectional study, including preterm neonates of both genders, in-patients admitted to an intermediate care unit at a tertiary care hospital. Data on delivery, diet and bioelectrical impedance (800 mA, 50 kHz) were collected. The graphs and vector analysis were performed with the BIVA software. RESULTS: A total of 108 preterm infants were studied, separated according to age (< 7 days and ≥ 7 days). Most of the premature babies were without the normal range (above the 95% tolerance intervals) existing in literature for term newborn infants and there was a tendency to dispersion of the points in the upper right quadrant, RXc plan. The PA was 4.92° (±2.18) for newborns < 7 days and 4.34° (±2.37) for newborns ≥ 7 days. CONCLUSION: Premature infants behave similarly in terms of BIVA and most of them have less absolute body water, presenting less fat free mass and fat mass in absolute values, compared to term newborn infants.

Análise vetorial de impedância bioelétrica (BIVA) em recém-nascidos pré-termo estáveis / Bioelectrical impedance vector analysis (BIVA) in stable preterm newborns

OBJETIVO: Observar o comportamento dos vetores ponteados no gráfico de resistência e de reactância corrigidos pelo comprimento corporal (RXc) através da análise vetorial de impedância bioelétrica (BIVA) e os valores de ângulo de fase (AF) em recém-nascidos (RNs) pré-termo estáveis, considerando a hipótese que o RN pré-termo apresenta o seu comportamento vetorial na BIVA sugestivo de menor quantidade de água e de tecidos moles corporais, comparativamente à referência do RN a termo. MÉTODOS: Foi realizado estudo de corte transversal em RNs pré-termo, de ambos os sexos, que se encontravam em uma unidade de cuidados intermediários de um hospital terciário. Coletaram-se dados relacionados ao nascimento e à alimentação, bem como dados de bioimpedância elétrica (800 mA, 50 kHz). Os gráficos e as análises vetoriais foram realizados através do BIVA software. RESULTADOS: Um total de 108 RNs pré-termo foram estudados, separados por faixa etária (< 7 dias e > 7 dias). A maioria dos RNs pré-termo encontrou-se fora da normalidade (acima dos intervalos de tolerância de 95%) existentes na literatura para RNs a termo, e observou-se uma tendência para a dispersão dos pontos no quadrante superior direito no gráfico RXc. O AF dos RNs < 7 dias foi de 4,92° (±2,18), e a dos RNs > 7 dias, de 4,34° (±2,37). CONCLUSÃO: Os RNs pré-termo se comportam de maneira semelhante entre si. A maioria deles possui menor quantidade absoluta de água corporal e apresenta menor quantidade tanto de massa livre de gordura quanto de massa gorda, em valores absolutos, quando comparados com os RNs a termo.

OBJECTIVE: To observe the behavior of the plotted vectors on the RXc (R - resistance - and Xc - reactance corrected for body height/length) graph through bioelectrical impedance analysis (BIVA) and phase angle (PA) values in stable premature infants, considering the hypothesis that preterm infants present vector behavior on BIVA suggestive of less total body water and soft tissues, compared to reference data for term infants. METHODS: Cross-sectional study, including preterm neonates of both genders, in-patients admitted to an intermediate care unit at a tertiary care hospital. Data on delivery, diet and bioelectrical impedance (800 mA, 50 kHz) were collected. The graphs and vector analysis were performed with the BIVA software. RESULTS: A total of 108 preterm infants were studied, separated according to age (< 7 days and > 7 days). Most of the premature babies were without the normal range (above the 95% tolerance intervals) existing in literature for term newborn infants and there was a tendency to dispersion of the points in the upper right quadrant, RXc plan. The PA was 4.92° (±2.18) for newborns < 7 days and 4.34° (±2.37) for newborns > 7 days. CONCLUSION: Premature infants behave similarly in terms of BIVA and most of them have less absolute body water, presenting less fat free mass and fat mass in absolute values, compared to term newborn infants.