Characterising the urinary acylcarnitine and amino acid profiles of HIV/TB co-infection, using LC-MS metabolomics.

INTRODUCTION: The human immunodeficiency virus (HIV) and tuberculosis (TB) co-infection presents significant challenges due to the complex interplay between these diseases, leading to exacerbated metabolic disturbances. Understanding these metabolic profiles is crucial for improving diagnostic and therapeutic approaches. OBJECTIVE: This study aimed to characterise the urinary acylcarnitine and amino acid profiles, including 5-hydroxyindoleacetic acid (5-HIAA), in patients co-infected with HIV and TB using targeted liquid chromatography mass spectrometry (LC-MS) metabolomics. METHODS: Urine samples, categorised into HIV, TB, HIV/TB co-infected, and healthy controls, were analysed using HPLC-MS/MS. Statistical analyses included one-way ANOVA and a Kruskal-Wallis test to determine significant differences in the acylcarnitine and amino acid profiles between groups. RESULTS: The study revealed significant metabolic alterations, especially in TB and co-infected groups. Elevated levels of medium-chain acylcarnitines indicated increased fatty acid oxidation, commonly associated with cachexia in TB. Altered amino acid profiles suggested disruptions in protein and glucose metabolism, indicating a shift towards diabetes-like metabolic states. Notably, TB was identified as a primary driver of these changes, affecting protein turnover, and impacting energy metabolism in co-infected patients. CONCLUSION: The metabolic profiling of HIV/TB co-infection highlights the profound impact of TB on metabolic pathways, which may exacerbate the clinical complexities of co-infection. Understanding these metabolic disruptions can guide the development of targeted treatments and improve management strategies, ultimately enhancing the clinical outcomes for these patients. Further research is required to validate these findings and explore their implications in larger, diverse populations.

[Clinical analysis and genetic diagnosis of three children with Isoleucine metabolic disorders due to variants of HSD17B10 and ACAT1 genes].

OBJECTIVE: To explore the clinical, biochemical and genetic characteristics of three children with Isoleucine metabolic disorders due to variants of HSD17B10 and ACAT1 genes. METHODS: Two children with 17ß hydroxysteroid dehydrogenase 10 (HSD17B10) deficiency and a child with ß-ketothiolase deficiency (BKD) diagnosed at Shanghai Children's Hospital between 2014 and 2021 were selected as the study subjects. Clinical data of the children were collected. The children were subjected to blood acylcarnitine, urinary organic acid and genetic testing, and candidate variants were analyzed with bioinformatic tools. RESULTS: The main symptoms of the three children had included epilepsy, developmental delay, hypotonia and acidosis. Their blood acylcarnitine methylcrotonyl carnitine (C5:1), 3-hydroxyisovalerylcarnitine (C5-OH) and 3-hydroxybutylcarnitine (C4OH) were increased to various extents, and urine organic acids including methyl crotonylglycine and 2-methyl-3-hydroxybutyric acid were significantly increased. Child 1 and child 2 were respectively found to harbor a c.347G>A (p.R116Q) variant and a c.274G>A (p.A92T) variant of the HSD17B10 gene, and child 3 was found to harbor compound heterozygous variants of the ACAT1 gene, namely c.547G>A (p.G183R) and a c.331G>C (p.A111P). Among these, the c.274G>A (p.A92T) and c.331G>C (p.A111P) variants were unreported previously. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), they were respectively classified as variant of unknown significance (PP3_Strong+PM2_supporting) and likely pathogenic (PM3+PM2_Supporting+PP3_Moderate+PP4). CONCLUSION: Both the HSD17B10 deficiency and BKD can lead to Isoleucine metabolism disorders, which may be difficult to distinguish clinically. Genetic testing can further confirm the diagnosis. Discoveries of the HSD17B10: c.274G>A (p.A92T) variant and the ACAT1: c.331G>C (p.A111P) variant have enriched the mutational spectrum of the two diseases.

Elevated C5-hydroxy acylcarnitine in an infant girl as a result of holocarboxylase synthetase deficiency.

CONTEXT: Elevated 3-hydroxyisovaleryl-/2-methyl-3-hydroxybutyryl (C5-OH) acylcarnitine in blood can result from several genetic enzyme deficiencies: 3-methylcrotonyl CoA carboxylase deficiency, 3-hydroxy 3-methylglutaryl-CoA lyase deficiency, beta-ketothiolase deficiency, 2-methyl 3-hydroxybutyryl-CoA dehydrogenase deficiency, primary 3-methylglutaconic aciduria, multiple biotin-dependent carboxylase deficiencies and biotin metabolism disorders. Biochemical tests help differentiate these causes while molecular tests are usually required for definitive diagnosis. CASE DESCRIPTION: We reported an infant girl with newborn screen findings of elevated C5-OH acylcarnitine. She had further confirmational biochemical testing including plasma acylcarnitines, urine organic acids and urine acylglycines. Patient's urine organic acid profile showed markedly increased 3-hydroxyisovaleric acid and 3-methylcrotonylglycine. Urine acylglycine test reported a large increase of 3-methylcrotonylglycine and plasma acylcarnitine test repeated the finding of elevated C5-OH acylcarnitine together with propionyl acylcarnitine elevation. These results point to multiple biotin-dependent carboxylase deficiency. Molecular tests revealed a homozygous mutation in the holocarboxylase synthetase gene that is consistent with her biochemical test findings. This case demonstrated the critical role of newborn screen in identifying inborn errors of metabolism that may otherwise be missed and lead to severe morbidity later in life. It also showcased that both biochemical and molecular tests are essential tools in the diagnosis.

Comparación entre los niveles de carnitina libre y el estado nutricional en pacientes con cistinosis nefropática infantil / Comparison of free carnitine levels with nutritional status in infantile nephropathyc cistinosis patients

Introducción: la cistinosis nefropática infantil (CNI) es una enfermedad genética debida a un defecto del transporte de la cistina, con la subsecuente acumulación de este aminoácido predominantemente en el riñón. Existen pocos estudios sobre la evaluación del estado nutricional en pacientes con esta patología, pero se sabe que tienen una excreción de carnitina urinaria aumentada, lo que puede dar como resultado una deficiencia plasmática y muscular de este compuesto; sin embargo, la suplementación de carnitina en CNI es controversial. Objetivo: comparar la concentración sanguínea de carnitina libre (C0) con el estado nutricional de una cohorte de pacientes con CNI. Material y métodos: evaluación antropométrica mediante la medición de peso, talla, perímetro braquial (PB) y pliegue cutáneo tricipital (PCT). La C0 se cuantificó mediante espectrometría de masas en tándem en muestras de sangre en ayuno. Resultados: se analizaron 10 pacientes con CNI, 5 con y 5 sin trasplante renal. De acuerdo con el IMC, 3/10 presentaron desnutrición. La reserva de masa magra se encontró baja en 8/10 pacientes (3 no trasplantados y todos los trasplantados). El PB mostró correlación con las concentraciones sanguíneas de C0 (r2=0,353); Los pacientes no trasplantados tuvieron niveles de C0 significativamente más bajos que los trasplantados (Chi2=0,0027). Conclusión: en esta población de pacientes con CNI se encontró un 70% de sujetos con C0 baja, que se correlaciona con la masa magra disminuida. Es recomendable hacer una evaluación nutricional de rutina que incluya los tres parámetros antropométricos como parte del seguimiento médico-nutricional integral de estos pacientes (AU)

Introduction: infantile nephropathic cystinosis (INC) is an autosomal recessive disorder that causes defects in cystine transport with subsequent accumulation in almost all body tissues, especially kidneys. There are few studies regarding the nutritional status assessment of patients with INC. It has been reported that patients with INC showed increased urinary losses of carnitine, resulting in plasma and muscle carnitine deficiency also increased metabolic requirements of carnitine in this patients have also been proposed, but to date carnitine supplementation is controversial. Objective: the aim of this study was to compare carnitine blood concentrations with nutritional status assessed by three anthropometric parameters: body mass index, mid-upper arm circumference and tricipital skin fold in patients with INC. Material and methods: anthropometric assessment of 10 patients with INC which included measurement of weight, height, mid-upper arm circumference and tricipital skin fold thickness. Free carnitine (C0) was measured by tandem mass spectrometry in fasting blood samples. Results: a total of 10 patients with INC were analyzed, 5 with and 5 without renal graft. According to the body mass index, 3/10 presented malnutrition. Muscular mass was found low in 8/10 patients (3 without renal graft and all the transplanted) the mid-upper arm circumference showed correlation with C0 blood concentrations (r2=0.353); non transplanted patients had C0 levels significantly lower than the transplanted ones (Chi2=0.0027). Conclusion: in this study we found that 70% of patients had low C0 blood levels that had a correlation with depleted lean body mass. It is recommendable to evaluate the nutritional status of these patients as part of their routine medical evaluation (AU)