Neonatal Meningoencephalitis Caused by Streptococcus gallolyticus

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Heterogenous Clinical Landscape in a Consanguineous Malonic Aciduria Family

Malonic aciduria is an extremely rare inborn error of metabolism due to malonyl-CoA decarboxylase deficiency. This enzyme is encoded by the MLYCD (Malonyl-CoA Decarboxylase) gene, and the disease has an autosomal recessive inheritance. Malonic aciduria is characterized by systemic clinical involvement, including neurologic and digestive symptoms, metabolic acidosis, hypoglycemia, failure to thrive, seizures, developmental delay, and cardiomyopathy. We describe here two index cases belonging to the same family that, despite an identical genotype, present very different clinical pictures. The first case is a boy with neonatal metabolic symptoms, abnormal brain MRI, and dilated cardiomyopathy. The second case, the cousin of the first patient in a consanguineous family, showed later symptoms, mainly with developmental delay. Both patients showed high levels of malonylcarnitine on acylcarnitine profiles and malonic acid on urinary organic acid chromatographies. The same homozygous pathogenic variant was identified, c.346C > T; p. (Gln116*). We also provide a comprehensive literature review of reported cases. A review of the literature yielded 52 cases described since 1984. The most common signs were developmental delay and cardiomyopathy. Increased levels of malonic acid and malonylcarnitine were constant. Presentations ranged from neonatal death to patients surviving past adolescence. These two cases and reported patients in the literature highlight the inter- and intrafamilial variability of malonic aciduria

Analysis of Mucopolysaccharidosis Type VI through Integrative Functional Metabolomics

Metabolic phenotyping is poised as a powerful and promising tool for biomarker discovery in inherited metabolic diseases. However, few studies applied this approach to mcopolysaccharidoses (MPS). Thus, this innovative functional approach may unveil comprehensive impairments in MPS biology. This study explores mcopolysaccharidosis VI (MPS VI) or Maroteaux⁻Lamy syndrome (OMIM #253200) which is an autosomal recessive lysosomal storage disease caused by the deficiency of arylsulfatase B enzyme. Urine samples were collected from 16 MPS VI patients and 66 healthy control individuals. Untargeted metabolomics analysis was applied using ultra-high-performance liquid chromatography combined with ion mobility and high-resolution mass spectrometry. Furthermore, dermatan sulfate, amino acids, carnitine, and acylcarnitine profiles were quantified using liquid chromatography coupled to tandem mass spectrometry. Univariate analysis and multivariate data modeling were used for integrative analysis and discriminant metabolites selection. Pathway analysis was done to unveil impaired metabolism. The study revealed significant differential biochemical patterns using multivariate data modeling. Pathway analysis revealed that several major amino acid pathways were dysregulated in MPS VI. Integrative analysis of targeted and untargeted metabolomics data with in silico results yielded arginine-proline, histidine, and glutathione metabolism being the most affected. This study is one of the first metabolic phenotyping studies of MPS VI. The findings might shed light on molecular understanding of MPS pathophysiology to develop further MPS studies to enhance diagnosis and treatments of this rare condition

Clinical Metabolomics: The New Metabolic Window for Inborn Errors of Metabolism Investigations in the Post-Genomic Era

Inborn errors of metabolism (IEM) represent a group of about 500 rare genetic diseases with an overall estimated incidence of 1/2500. The diversity of metabolic pathways involved explains the difficulties in establishing their diagnosis. However, early diagnosis is usually mandatory for successful treatment. Given the considerable clinical overlap between some inborn errors, biochemical and molecular tests are crucial in making a diagnosis. Conventional biological diagnosis procedures are based on a time-consuming series of sequential and segmented biochemical tests. The rise of “omic” technologies offers holistic views of the basic molecules that build a biological system at different levels. Metabolomics is the most recent “omic” technology based on biochemical characterization of metabolites and their changes related to genetic and environmental factors. This review addresses the principles underlying metabolomics technologies that allow them to comprehensively assess an individual biochemical profile and their reported applications for IEM investigations in the precision medicine era

Clinical and Molecular Characterization of Patients with Mucopolysaccharidosis Type I in an Algerian Series

Mucopolysaccharidoses (MPS’s) represent a subgroup of lysosomal storage diseases related to a deficiency of enzymes that catalyze glycosaminoglycans degradation. Mucopolysaccharidosis type I (MPS I) is a rare autosomal recessive disorder caused by a deficiency of α-l-iduronidase encoded by the IDUA gene. Partially degraded heparan sulfate and dermatan sulfate accumulate progressively and lead to multiorgan dysfunction and damage. The aim of this study is to describe the clinical, biochemical, and molecular characteristics of 13 Algerian patients from 11 distinct families. MPS I diagnosis was confirmed by molecular study of the patients’ IDUA gene. Clinical features at the diagnosis and during the follow-up are reported. Eighty-four percent of the studied patients presented with a mild clinical phenotype. Molecular study of the IDUA gene allowed the characterization of four pathological variations at the homozygous or compound heterozygote status: IDUA NM_00203.4:c.1598C>G-p.(Pro533Arg) in 21/26 alleles, IDUA NM_00203.4:c.532G>A-p.(Glu178Lys) in 2/26 alleles, IDUA NM_00203.4:c.501C>G-p.(Tyr167*) in 2/26 alleles, and IDUA NM_00203. 4: c.1743C>G-p.(Tyr581*) in 1/26 alleles. This molecular study unveils the predominance of p.(Pro533Arg) variation in our MPS I patients. In this series, the occurrence of some clinical features linked to the Scheie syndrome is consistent with the literature, such as systematic valvulopathies, corneal opacity, and umbilical hernia; however, storage signs, facial dysmorphic features, and hepatomegaly were more frequent in our series. Screening measures for these debilitating diseases in highly consanguineous at-risk populations must be considered a priority health problem

Methylmalonyl-CoA Epimerase Deficiency Mimicking Propionic Aciduria

Methylmalonyl-CoA epimerase (MCE) converts d-methylmalonyl-CoA epimer to l-methylmalonyl-CoA epimer in the propionyl-CoA to succinyl-CoA pathway. Only seven cases of MCE deficiency have been described. In two cases, MCE deficiency was combined with sepiapterin reductase deficiency. The reported clinical pictures of isolated MCE are variable, with two asymptomatic patients and two other patients presenting with metabolic acidosis attacks. For combined MCE and sepiapterin reductase deficiency, the clinical picture is dominated by neurologic alterations. We report isolated MCE deficiency in a boy who presented at five years of age with acute metabolic acidosis. Metabolic investigations were consistent with propionic aciduria (PA). Unexpectedly, propionyl-CoA carboxylase activity was within the reference range. Afterward, apparently intermittent and mild excretion of methylmalonic acid (MMA) was discovered. Methylmalonic pathway gene set analysis using the next-generation sequencing approach allowed identification of the common homozygous nonsense pathogenic variant (c.139C > T-p.Arg47*) in the methylmalonyl-CoA epimerase gene (MCEE). Additional cases of MCE deficiency may help provide better insight regarding the clinical impact of this rare condition. MCE deficiency could be considered a cause of mild and intermittent increases in methylmalonic acid

Next-Generation Molecular Investigations in Lysosomal Diseases: Clinical Integration of a Comprehensive Targeted Panel

Diagnosis of lysosomal disorders (LDs) may be hampered by their clinical heterogeneity, phenotypic overlap, and variable age at onset. Conventional biological diagnostic procedures are based on a series of sequential investigations and require multiple sampling. Early diagnosis may allow for timely treatment and prevent clinical complications. In order to improve LDs diagnosis, we developed a capture-based next generation sequencing (NGS) panel allowing the detection of single nucleotide variants (SNVs), small insertions and deletions, and copy number variants (CNVs) in 51 genes related to LDs. The design of the LD panel covered at least coding regions, promoter region, and flanking intronic sequences for 51 genes. The validation of this panel consisted in testing 21 well-characterized samples and evaluating analytical and diagnostic performance metrics. Bioinformatics pipelines have been validated for SNVs, indels and CNVs. The clinical output of this panel was tested in five novel cases. This capture-based NGS panel provides an average coverage depth of 474× which allows the detection of SNVs and CNVs in one comprehensive assay. All the targeted regions were covered above the minimum required depth of 30×. To illustrate the clinical utility, five novel cases have been sequenced using this panel and the identified variants have been confirmed using Sanger sequencing or quantitative multiplex PCR of short fluorescent fragments (QMPSF). The application of NGS as first-line approach to analyze suspected LD cases may speed up the identification of alterations in LD-associated genes. NGS approaches combined with bioinformatics analyses, are a useful and cost-effective tool for identifying the causative variations in LDs

Sphingosine-1-Phosphate Levels Are Higher in Male Patients with Non-Classic Fabry Disease

International audienceFabry disease is an X-linked lysosomal disease in which defects in the alpha-galactosidase A enzyme activity lead to the ubiquitous accumulation of glycosphingolipids. Whereas the classic disease is characterized by neuropathic pain, progressive renal failure, white matter lesions, cerebral stroke, and hypertrophic cardiomyopathy (HCM), the non-classic phenotype, also known as cardiac variant, is almost exclusively characterized by HCM. Circulating sphingosine-1-phosphate (S1P) has controversially been associated with the Fabry cardiomyopathy. We measured serum S1P levels in 41 patients of the FFABRY cohort. S1P levels were higher in patients with a non-classic phenotype compared to those with a classic phenotype (200.3 [189.6–227.9] vs. 169.4 ng/mL [121.1–203.3], p = 0.02). In a multivariate logistic regression model, elevated S1P concentration remained statistically associated with the non-classic phenotype (OR = 1.03; p < 0.02), and elevated lysoGb3 concentration with the classic phenotype (OR = 0.95; p < 0.03). S1P levels were correlated with interventricular septum thickness (r = 0.46; p = 0.02). In a logistic regression model including S1P serum levels, phenotype, and age, age remained the only variable significantly associated with the risk of HCM (OR = 1.25; p = 0.001). S1P alone was not associated with cardiac hypertrophy but with the cardiac variant. The significantly higher S1P levels in patients with the cardiac variant compared to those with classic Fabry suggest the involvement of distinct pathophysiological pathways in the two phenotypes. S1P dosage could allow the personalization of patient management