Acute Respiratory Infection Unveiling CPT II Deficiency

Carnitine Palmitoyl transferase 2 (CPT II) is involved in long-chain fatty-acid mitochondrial transport. Three clinical phenotypes of CPT II deficiency have been described: Lethal neonatal onset, infantile severe form, and the late onset more common muscular form. The muscular form of CPT II deficiency is characterized by pain crises and rhabdomyolysis triggered by energy-dependent factors. This form has been described as a benign condition; however, the acute crises are insidious and thus, pose a risk of death. We report a 3-year-old female child with an acute pulmonary infection and a concomitant rhabdomyolysis. The acylcarnitine profile was consistent with CPT II deficiency and a molecular study allowed the identification of the common missense variant (NM_000098.2: c.338C>T – p. Ser113Leu) at the homozygous state. The striking difference between the initial cause and the decompensation severity prompted us to consider other diagnoses. Deciphering the symptoms linked to CPT II deficiency among those of the initial decompensation results in initiating a timely a targeted therapy

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

An Atypical Case of Head Tremor and Extensive White Matter in an Adult Female Caused by 3-Hydroxy-3-methylglutaryl-CoA Lyase Deficiency

3-Hydroxy-3-methylglutaryl-CoA (HMG-CoA) Lyase deficiency (HMGLD) (OMIM 246450) is an autosomal recessive genetic disorder caused by homozygous or compound heterozygous variants in the HMGCL gene located on 1p36.11. Clinically, this disorder is characterized by a life-threatening metabolic intoxication with a presentation including severe hypoglycemia without ketosis, metabolic acidosis, hyper-ammoniemia, hepatomegaly and a coma. HMGLD clinical onset is within the first few months of life after a symptomatic free period. In nonacute periods, the treatment is based on a protein- and fat-restricted diet. L-carnitine supplementation is recommended. A late onset presentation has been described in very few cases, and only two adult cases have been reported. The present work aims to describe an incidental discovery of an HMGLD case in a 54-year-old patient and reports a comprehensive review of clinical and biological features in adult patients to raise awareness about the late-onset presentation of this disease

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

Methylmalonyl-CoA Epimerase Deficiency Mimicking Propionic Aciduria

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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

NGLY1 Deficiency: A Rare Newly Described Condition with a Typical Presentation

NGLY1 deficiency is the first recognized autosomal recessive disorder of N-linked deglycosylation (NGLY1-CDDG). This severe multisystemic disease is still poorly known and, to date, most cases have been diagnosed through whole exome or genome sequencing. The aim of this study is to provide the clinical, biochemical and molecular description of the first NGLY1-CDDG patient from France along with a literature review. The index case presented with developmental delay, acquired microcephaly, hypotonia, alacrimia, feeding difficulty, and dysmorphic features. Given the complex clinical picture and the multisystemic involvement, a trio-based exome sequencing was conducted and urine oligosaccharides were assessed using mass spectrometry. The exome sequencing revealed a novel variant in the NGLY1 gene in a homozygous state. NGLY1 deficiency was confirmed by the identification of the Neu5Ac1Hex1GlcNAc1-Asn oligosaccharide in the urine of the patient. Literature review revealed the association of some key clinical and biological features such as global developmental delay—hypertransaminasemia, movement disorders, feeding difficulties and alacrima/hypolacrima

NGLY1 Deficiency: A Rare Newly Described Condition with a Typical Presentation

NGLY1 deficiency is the first recognized autosomal recessive disorder of N-linked deglycosylation (NGLY1-CDDG). This severe multisystemic disease is still poorly known and, to date, most cases have been diagnosed through whole exome or genome sequencing. The aim of this study is to provide the clinical, biochemical and molecular description of the first NGLY1-CDDG patient from France along with a literature review. The index case presented with developmental delay, acquired microcephaly, hypotonia, alacrimia, feeding difficulty, and dysmorphic features. Given the complex clinical picture and the multisystemic involvement, a trio-based exome sequencing was conducted and urine oligosaccharides were assessed using mass spectrometry. The exome sequencing revealed a novel variant in the NGLY1 gene in a homozygous state. NGLY1 deficiency was confirmed by the identification of the Neu5Ac1Hex1GlcNAc1-Asn oligosaccharide in the urine of the patient. Literature review revealed the association of some key clinical and biological features such as global developmental delay—hypertransaminasemia, movement disorders, feeding difficulties and alacrima/hypolacrima

Metabolic causes of nonimmune hydrops fetalis: A next-generation sequencing panel as a first-line investigation.

International audienceHydrops fetalis is a life-threatening fetal condition, and 85% of all cases are classified as nonimmune hydrops fetalis (NIHF). Up to 15% of NIHF cases may be due to inborn errors of metabolism (IEM), but a large proportion of cases linked to metabolic disorders remains undiagnosed. This lack of diagnosis may be related to the limitations of conventional biological procedures, which involve sequential investigations and require multiple samples and steps. In addition, this approach is time consuming. We have developed a next-generation sequencing (NGS) panel to investigate metabolic causes of NIHF, ascites, and polyhydramnios associated to another fetal abnormality

Large-scale screening of lipase acid deficiency in at risk population

International audienceBACKGROUND: Lysosomal acid lipase deficiency (LALD, OMIM#278000) is a rare lysosomal disorder with an autosomal recessive inheritance. The main clinical manifestations are related to a progressive accumulation of cholesteryl esters, triglycerides or both within the lysosome in different organs such as the liver, spleen, and cardiovascular system. A wide range of clinical severity is associated with LALD including a severe very rare antenatal/neonatal/infantile phenotype named Wolman disease and a late-onset form named cholesteryl ester storage disease (CESD). METHODS: This study aimed to investigate a cohort of at-risk patients (4174) presenting with clinical or biological signs consistent with LALD using the assessment of LAL activity on dried blood spots. RESULTS: LAL activity was lower than 0.05 nmol/punch/L (cut-off: 0.12) in 19 patients including 13 CESD and 6 Wolman. Molecular study has been conducted in 17 patients and succeeded in identifying 34 mutated alleles. Fourteen unique variants have been characterized, 7 of which are novel. CONCLUSION: This study allowed to identify a series of patients and expanded the molecular spectrum knowledge of LALD. Besides, a new screening criteria grid based on the clinical/biological data from our study and the literature has been proposed in order to enhance the diagnosis rate in at risk populations