Persistent Hypoglycemia in Children: Targeted Gene Panel Improves the Diagnosis of Hypoglycemia Due to Inborn Errors of Metabolism

Ponzi, Emanuela; Maiorana, Arianna; Lepri, Francesca Romana; Mucciolo, Mafalda; Semeraro, Michela; Taurisano, Roberta; Olivieri, Giorgia; Novelli, Antonio; Dionisi‐Vici, Carlo

doi:10.1016/j.jpeds.2018.06.050

Cited by 13 publications

(22 citation statements)

References 39 publications

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“…This difference is likely due to the number of participants, the nature of their clinical problems, and the selection bias of diagnostic tools between our study and others (Al‐Shamsi et al, ; Okazaki et al, ). Moreover, significantly higher detection rates with TRS analysis have been shown in this study (OR: 0.24; 95% CI (0.08–0.70); p : 0.01), as well as in previous studies (Coene et al, ; Ponzi et al, ). All the 31 diagnosed infants with the 11 most common disorders in our cohort were observed through TRS analysis.…”

Section: Discussionsupporting

confidence: 87%

Clinical utility in infants with suspected monogenic conditions through next‐generation sequencing

Hong

Wang

Zhao

et al. 2019

Molec Gen & Gen Med

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Background Rare diseases are complex disorders with huge variability in clinical manifestations. Decreasing cost of next‐generation sequencing (NGS) tests in recent years made it affordable. We witnessed the diagnostic yield and clinical use of different NGS strategies on a myriad of monogenic disorders in a pediatric setting. Methods Next‐generation sequencing tests are performed for 98 unrelated Chinese patients within their first year of life, who were admitted to Xin Hua Hospital, affiliated with Shanghai Jiao Tong University School of Medicine, during a 2‐year period. Results Clinical indications for NGS tests included a range of medical concerns. The mean age was 4.4 ± 4.2 months of age for infants undergoing targeting specific (known) disease‐causing genes (TRS) analysis, and 4.4 ± 4.3 months of age for whole‐exome sequencing (WES) (p > 0.05). A molecular diagnosis is done in 72 infants (73.47%), which finds a relatively high yield with phenotypes of metabolism/homeostasis abnormality (HP: 0001939) (odds ratio, 1.83; 95% CI, 0.56–6.04; p = 0.32) and a significantly low yield with atypical symptoms (without a definite HPO term) (odds ratio, 0.08; 95% CI, 0.01–0.73; p = 0.03). TRS analysis provides molecular yields higher than WES (p = 0.01). Ninety‐eight different mutations are discovered in 72 patients. Twenty‐seven of them have not been reported previously. Nearly half (43.06%, 31/72) of the patients are found to carry 11 common disorders, mostly being inborn errors of metabolism (IEM) and neurogenetic disorders and all of them are observed through TRS analysis. Eight positive cases are identified through WES, and all of them are sporadic, of highly variable phenotypes and severity. There are 26 patients with negative findings in this study. Conclusion This study provides evidence that NGS can yield high success rates in a tertiary pediatric setting, but suggests that the scope of known Mendelian conditions may be considerably broader than currently recognized.

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Section: Discussionsupporting

confidence: 87%

Clinical utility in infants with suspected monogenic conditions through next‐generation sequencing

Hong

Wang

Zhao

et al. 2019

Molec Gen & Gen Med

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“…NGS technologies show great utility, improving the rate of diagnosis of IEMs while shedding light on the complex underlying genetic architecture [12,38,39]. In this study, we detected differences in the rate of positive diagnosis between gene panels: higher rates were observed in cases for which a previous confirmatory assay was available, as for the INT MET panel, while lower rates were observed in cases of semi-untargeted analysis (e.g., the HYPO/HYPER and MITO panels).…”

Section: Discussionmentioning

confidence: 99%

“…The HYPO/HYPER panel had a lower rate of positive diagnosis (19.64%). Although hypo/hyperglycemia are common in clinical practice, the etiology of these spontaneous events remains difficult to decipher, as frequently the underlying defects do not directly influence glucose metabolism but are associated with other metabolic or non-metabolic disorders [39,42]. In these cases, the HYPO/HYPER panel is more challenging and difficult to design, and it is therefore highly likely that the causative gene may not have been included.…”

Section: Discussionmentioning

confidence: 99%

Utility of Gene Panels for the Diagnosis of Inborn Errors of Metabolism in a Metabolic Reference Center

Gouveia

Vázquez-Mosquera

Álvarez

et al. 2021

Genes

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Next-generation sequencing (NGS) technologies have been proposed as a first-line test for the diagnosis of inborn errors of metabolism (IEM), a group of genetically heterogeneous disorders with overlapping or nonspecific phenotypes. Over a 3-year period, we prospectively analyzed 311 pediatric patients with a suspected IEM using four targeted gene panels. The rate of positive diagnosis was 61.86% for intermediary metabolism defects, 32.84% for complex molecular defects, 19% for hypoglycemic/hyperglycemic events, and 17% for mitochondrial diseases, and a conclusive molecular diagnosis was established in 2–4 weeks. Forty-one patients for whom negative results were obtained with the mitochondrial diseases panel underwent subsequent analyses using the NeuroSeq panel, which groups all genes from the individual panels together with genes associated with neurological disorders (1870 genes in total). This achieved a diagnostic rate of 32%. We next evaluated the utility of a tool, Phenomizer, for differential diagnosis, and established a correlation between phenotype and molecular findings in 39.3% of patients. Finally, we evaluated the mutational architecture of the genes analyzed by determining z-scores, loss-of-function observed/expected upper bound fraction (LOEUF), and haploinsufficiency (HI) scores. In summary, targeted gene panels for specific groups of IEMs enabled rapid and effective diagnosis, which is critical for the therapeutic management of IEM patients.

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“…Blood and urine samples for fatty acid metabolite estimation ought to be drawn before carnitine supplementation otherwise the results would be erroneous. Targeted gene panel analysis in children presenting with hypoglycemia can reliably diagnose inborn errors of metabolism including FAOD[ 10 ].…”

Section: Fatty Acid Oxidation Defectsmentioning

confidence: 99%

Mitochondrial hepatopathy: Anticipated difficulties in management of fatty acid oxidation defects and urea cycle defects

Ravindranath¹,

Sarma²

2022

WJH

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Fatty acid oxidation defects (FAOD) and urea cycle defects (UCD) are among the most common metabolic liver diseases. Management of these disorders is dotted with challenges as the strategies differ based on the type and severity of the defect. In those with FAOD the cornerstone of management is avoiding hypoglycemia which in turn prevents the triggering of fatty acid oxidation. In this review, we discuss the role of carnitine supplementation, dietary interventions, newer therapies like triheptanoin, long-term treatment and approach to positive newborn screening. In UCD the general goal is to avoid excessive protein intake and indigenous protein breakdown. However, one size does not fit all and striking the right balance between avoiding hyperammonemia and preventing deficiencies of essential nutrients is a formidable task. Practical issues during the acute presentation including differential diagnosis of hyperammonemia, dietary dilemmas, the role of liver transplantation, management of the asymptomatic individual and monitoring are described in detail. A multi-disciplinary team consisting of hepatologists, metabolic specialists and dieticians is required for optimum management and improvement in quality of life for these patients.

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Persistent Hypoglycemia in Children: Targeted Gene Panel Improves the Diagnosis of Hypoglycemia Due to Inborn Errors of Metabolism

Cited by 13 publications

References 39 publications

Clinical utility in infants with suspected monogenic conditions through next‐generation sequencing

Clinical utility in infants with suspected monogenic conditions through next‐generation sequencing

Utility of Gene Panels for the Diagnosis of Inborn Errors of Metabolism in a Metabolic Reference Center

Mitochondrial hepatopathy: Anticipated difficulties in management of fatty acid oxidation defects and urea cycle defects

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