Newborn Screening for G6PD Deficiency in Xiamen, China: Prevalence, Variant Spectrum, and Genotype-Phenotype Correlations

Background: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a common inherited enzymatic defect. The purpose of this study was to evaluate the profile of G6PD deficiency and investigate the factors associated with the accuracy of newborn screening (NBS) in Xiamen, China.Methods: A total of 99,546 newborns were screened by modified fluorescent spot test at the Women and Children’s Hospital, Xiamen University. High-risk neonates were recalled for diagnosis by either a measurement of G6PD activity or genetic testing for the presence of pathogenic G6PD variants using a quantitative G6PD enzymatic assay or the MeltPro® G6PD assay, respectively.Results: In the first-tier screening, 1,256 newborns were categorized as high risk. Of these, 1,051 were diagnosed with G6PD deficiency, indicating a prevalence of 1.39% in Xiamen, China. Among the 1,013 neonates who underwent genotyping, 851 carried hemizygous, heterozygous, homozygous, or compound heterozygous variants, for a positive predictive value (PPV) of 84.01%. In total, 12 variants and 32 genotypes were identified, and the six most common variants were c.1376G>T, c.1388G>A, c.95A>G, c.1024C>T, c.871G>A, and c.392G>T, which accounted for approximately 94% of the identified alleles. Different variants showed characteristic enzymatic activities, although high phenotypic heterogeneity was observed for each variant. The use of cold-chain transportation significantly improved the PPV of NBS.Conclusions: We determined the profile of G6PD deficiency in Xiamen, including the prevalence, variant spectrum, and genotype-phenotype correlations and confirmed that maintaining a low temperature during sample transport is essential to ensure the high screening accuracy of NBS. Our data provides epidemiological, genotypic, phenotypic, and clinical practice references to standardize future interventions for G6PD deficiency.

Long-Term Outcome of Patients with TPO Mutations

Introduction: Thyroid peroxidase (TPO) deficiency is the most common enzymatic defect causing congenital hypothyroidism (CH). We aimed to characterize the long-term outcome of patients with TPO deficiency. Methods: Clinical and genetic data were collected retrospectively. Results: Thirty-three patients with primary CH caused by TPO deficiency were enrolled. The follow-up period was up to 43 years. Over time, 20 patients (61%) developed MNG. Eight patients (24%) underwent thyroidectomy: one of them had minimal invasive follicular thyroid carcinoma. No association was found between elevated lifetime TSH levels and the development of goiter over the years. Conclusions: This cohort represents the largest long-term follow up of patients with TPO deficiency. Our results indicate that elevated TSH alone cannot explain the high rate of goiter occurrence in patients with TPO deficiency, suggesting additional factors in goiter development. The high rate of MNG development and the risk for thyroid carcinoma indicate a need for long-term follow up with annual ultrasound scans.

Anestesia y Déficit de glucosa-6-fosfato deshidrogenasa. Revisión a propósito de un caso.

El déficit de glucosa-6-fosfato deshidrogenasa es el defecto enzimático más frecuente de los glóbulos rojos en los seres humanos. Esta alteración está relacionada con un defecto enzimático en la vía de las pentosas-fosfato y cursa con hemólisis. Evitar posibles desencadenantes de las crisis hemolíticas es la mejor estrategia de prevención; para ello, el anestesiólogo tiene que conocer adecuadamente los fármacos empleados para el procedimiento anestésico y cuales son aptos para su empleo en estos pacientes. Se presenta en el artículo una revisión sobre este déficit a propósito de un caso de un paciente que acude a someterse a una intervención quirúrgica con anestesia general. ABSTRACT Anesthesia and glucose-6-phosphate-dehydrogenase deficit. A case review The glucose-6-phosphate-dehydrogenase (G6PD) deficiency is the most common enzymatic disorder of the red blood cells in humans. This disorder is related with an enzymatic defect in the pentose-phosphate pathway which is characterized by hemolysis. The best prevention strategy is avoiding possible triggers of hemolytic crisis, for this purpose the anesthesiologist must know properly the drugs used in anesthesia that are suitable for using in these patients. We present in the article a review of this deficit by using a clinical case of a patient who goes to the operating room with general anesthesia.

Targeting an RNaseH2 Defect in Chronic Lymphocytic Leukaemia with PARP Inhibitors

The therapeutic exploitation of molecular defects within the DNA damage response (DDR) in tumour cells has become an important treatment paradigm. 'Synthetic lethality' relies on pharmacological inhibition of pathways upon which DDR-deficient tumour cells have become dependent for their survival. This induces an intolerable level of unrepaired DNA damage in the tumour cells resulting in cell death, whilst sparing DDR-proficient normal cells Deletion of 13q14 is a frequent, early event in the pathogenesis of CLL. Alongside well-described tumour suppressor genes this genomic region also encompasses the DDR gene, RNASEH2B, which encodes a subunit of the heterotrimeric enzymatic complex, RNaseH2. This complex is a principal component of ribonucleotide excision repair (RER), a DDR pathway that removes ribonucleotides incorporated into DNA by error prone DNA repair polymerases. If unremoved, these DNA-incorporated ribonucleotides lead to DNA damage, chromosome instability and mutagenesis (Reijns et al, Cell. 2012;149:1008). We recently reported a synthetically lethal interaction between the functional loss of RNaseH2 enzymatic complex and PARP inhibition (Zimmerman et al, Nature 2018, 559:285). We observed that inactivation of any of the three RNAseH2 subunits (A,B,C) leads to loss of enzymatic activity of this complex and also that primary CLL tumours with 13q14 deletion involving the RNASEH2B locus are sensitive to PARP inhibitors (PARPi) in vitro. In light of these preliminary observations, we addressed the following questions: a) Do monoalleic and biallelic RNASEH2B deletions have equal consequences for RNAseH2 enzymatic activity and sensitivity to PARP inhibition in CLL? d) Can loss of RNAseH2 activity be caused by an alternative mechanism, such as mutations in RNASEH2B? c) Can the PARPi sensitivity of RNaseH2-deficient CLLs be demonstrated in vivo, in patient-derived xenografts? d) Is PARP inhibition an option for RNAseH2 deficient tumours with limited response to other treatments? Analysis of 100 primary CLL tumours through a combination of multiplex ligation-dependent probe amplification (MLPA), CGH microarrays and Sanger sequencing identified 29 tumours with monoallelic and 14 with biallelic RNASEH2B deletions. None of the analysed tumours had mutations in RNASEH2B. Increased levels of genomic ribonucleotides were confirmed in all RNASEH2B deleted tumours by two complementary methods: alkaline gel electrophoresis and DNA nick translation. We found that the RNaseH2 enzymatic defect and sensitivity to PARP inhibition were evident in all RNASEH2B deleted tumours, but were more profound in those harbouring biallelic deletion compared to tumours that have lost only one RNASEH2B allele. Furthermore, sensitivity to PARP inhibitors was dependent on PARP-trapping capacity and therefore cytotoxicity was most prominent in response to PARP-inhibitors with a potent PARP trapping capacity such as talazoparib. In vivo experiments revealed similar trends, with CLL xenografts derived from tumours with biallelic RNASEH2B deletion being differentially sensitive to Talazoparib. Notably, the PARP inhibition sensitivity of RNAseH2-deficient primary CLLs was independent of patients' response to different treatments. In summary, we conclude that the RNASEH2B loss associated with 13q14 deletion represents a frequent cause of RNaseH2 enzymatic defect that renders primary CLL tumours sensitive to PARP-trapping inhibitors. Our findings expand the range of molecular defects in CLL that are amenable to treatment with clinically applicable PARP inhibitors and may have implications for the management of patients with limited response to other treatments. Disclosures No relevant conflicts of interest to declare.

Undiagnosed Partial Ornithine Transcarbamylase Deficiency Presenting Postoperatively as Agitated Delirium

Partial ornithine transcarbamylase deficiency (pOTCD), an enzymatic defect within the urea cycle, is an increasingly recognized etiology for hyperammonemia of unclear source following a stressor within female adults. Here we present a case of newly diagnosed pOTCD following a systemic stressor and prolonged hospitalization course. From a neurological perspective, prompt recognition provided the patient with a swift and near complete recovery. We briefly review the pertinent literature pertaining to this genetically based condition including historical context and current therapeutic approaches. Given the potential morbidity of prolonged hyperammonemia, neurohospitalists need to be aware of partial ornithine transcarbamylase as an entity.

Glusoce-6-phosphate dehydrogenase- History and diagnosis

Glucose-6-phosphate dehydrogenase deficiency is the most common enzymatic defect of red blood cells, which increases the vulnerability of erythrocytes to oxidative stress leading to hemolytic anemia. Since its identification more than 60 years ago, much has been done with respect to its clinical diagnosis, laboratory diagnosis and treatment. Association of G6PD is not just limited to anti malarial drugs, but a vast number of other diseases. In this article, we aimed to review the history of Glucose-6-phosphate dehydrogenase, the diagnostic methods available along with its association with other noncommunicable diseases.

17α-Hydroylase/17,20-lyase deficiency related to P.Y27*(c.81C>A) mutation in CYP17A1 gene

Abstract17α-Hydroxylase/17-20 lyase deficiency (17OHD) is a rare form of congenital adrenal hyperplasia. Genetic defects causing combined 17OHD lead to the impaired production of cortisol and sex steroids, accumulation of mineralocorticoids, and compensatory overproduction of pituitary adrenocorticotropic hormone. Consequently, individuals with this enzymatic defect present with both adrenal cortical hyperplasia and variable degrees of hypertension, hypokalemia, and sexual immaturity. The patient was aged 15 years and 3 months and she was diagnosed with 17OHD while she was being evaluated for complaints of delayed puberty. In the present case, p.Y27*(c.81C>A) mutation was revealed in the sequence analysis of the

The porphyrias

The porphyrias are metabolic diseases resulting from deficiency, or in one disease, an increase in the activity, of specific enzymes in the haem biosynthetic pathway (1, 2). Each of the eight main types of porphyria is defined by the association of characteristic clinical features with a specific pattern of excess production of pathway intermediates. Each pattern indicates the site of the underlying enzymatic abnormality (Fig. 12.3.3.1). The porphyrias can therefore be defined clinically as either an acute porphyria, characterized by acute neurovisceral attacks that are associated with the overproduction of the porphyrin precursor, 5-aminolaevulinic acid (ALA, OMIM 125270), usually accompanied by porphobilinogen, or a nonacute porphyria in which these attacks are absent and photocutaneous symptoms due to excess formation of porphyrins are the main clinical manifestation. Other classifications include division into erythropoietic or hepatic, depending on the principal site of expression of the specific enzymatic defect.

The Porphyrias

The porphyrias are uncommon disorders caused by deficiencies in the activities of the enzymes of the heme biosynthetic pathway. The enzymatic defects that cause porphyrias may be either inherited or acquired, and there is significant interplay between the genetic defect and acquired or environmental factors. Acute forms of the porphyrias may be life threatening and may be misdiagnosed because of the nonspecific nature of the clinical presentation (e.g., acute abdominal pain, psychiatric disturbances, and polyneuropathies). The course of the acute forms of disease is characterized by long latent periods interrupted by acute attacks, which are associated with substantial morbidity and mortality. Porphyrias may be classified as neurovisceral or photosensitive, depending on their prominent clinical characteristic, but in some cases of porphyria, both symptoms are present. Alternatively, the porphyrias can be classified as hepatic or erythropoietic, depending on the principal site of expression of the specific enzymatic defect involved, but the expressions overlap in some porphyrias. The neurovisceral porphyrias correspond with the hepatic porphyrias (ie, acute intermittent porphyria [AIP], variegate porphyria [VP], hereditary coproporphyria [HCP], and ALA deficiency porphyria [ADP]); and the photosensitive porphyrias correspond with the erythropoietic porphyrias (i.e., porphyria cutanea tarda [PCT], hepatoerythropoietic porphyria [HEP], erythropoietic protoporphyria [EPP], and congenital erythropoietic porphyria [CEP]). This chapter covers the classification and pathophysiology of porphyrias and the epidemiology, molecular defects and pathophysiology, diagnosis, and treatment of each of the clinical presentations of porphyria. A table lists the drugs that are safe and unsafe for patients with AIP, VP, HCP, and ADP. Figures illustrate the classification and major symptoms of the porphyrias and the corresponding defect in the biosynthesis of heme that causes the disease; the steps in the biosynthesis of heme; and the mechanisms that precipitate symptoms in AIP. This chapter contains 99 references.