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Biomolecules Mar 2020ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) are a family of multidomain extracellular protease enzymes with 19 members. A growing number of...
ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) are a family of multidomain extracellular protease enzymes with 19 members. A growing number of ADAMTS family gene variants have been identified in patients with various hereditary diseases. To understand the genomic landscape and mutational spectrum of ADAMTS family genes, we evaluated all reported variants in the ClinVar database and Human Gene Mutation Database (HGMD), as well as recent literature on Mendelian hereditary disorders associated with ADAMTS family genes. Among 1089 variants in 14 genes reported in public databases, 307 variants previously suggested for pathogenicity in Mendelian diseases were comprehensively re-evaluated using the American College of Medical Genetics and Genomics (ACMG) 2015 guideline. A total of eight autosomal recessive genes were annotated as being strongly associated with specific Mendelian diseases, including two recently discovered genes ( and ) for their causality in congenital diseases (nephronophthisis-related ciliopathy and nonsyndromic heart valve disease, respectively). Clinical symptoms and affected organs were extremely heterogeneous among hereditary diseases caused by ADAMTS family genes, indicating phenotypic heterogeneity despite their structural and functional similarity. was suggested as presenting undiscovered pathogenic mutations responsible for novel Mendelian disorders. Our study is the first to highlight the genomic landscape of ADAMTS family genes, providing an appropriate genetic approach for clinical use.
Topics: ADAMTS Proteins; ADAMTS9 Protein; Ciliopathies; Databases, Nucleic Acid; Heart Defects, Congenital; Humans; Mutation
PubMed: 32183147
DOI: 10.3390/biom10030449 -
Obstetrics and Gynecology Jan 2020To evaluate disease presentation, diagnosis, treatment, and clinical outcomes in pregnancy-associated atypical hemolytic uremic syndrome (aHUS).
OBJECTIVE
To evaluate disease presentation, diagnosis, treatment, and clinical outcomes in pregnancy-associated atypical hemolytic uremic syndrome (aHUS).
DATA SOURCES
We searched PubMed, MEDLINE, Cochrane Library, ClinicalTrials.gov, Web of Science, EMBASE and Google Scholar, from inception until March 2018.
METHODS OF STUDY SELECTION
We included English-language articles describing aHUS in pregnancy or postpartum. The diagnosis of aHUS was characterized by hemolysis, thrombocytopenia, and renal failure and was distinguished from typical diarrhea-associated hemolytic uremic syndrome. Patients were excluded if individual data could not be obtained, the diagnosis was unclear, or an alternative etiology was more likely, such as thrombotic thrombocytopenic purpura or Shiga toxin-producing Escherichia coli. Reports were appraised by two reviewers, with disagreements adjudicated by a third reviewer.
TABULATION, INTEGRATION, AND RESULTS
The search identified 796 articles. After review of titles, abstracts, and full text, we identified 48 reports describing 60 unique cases of pregnancy-associated aHUS, with 66 pregnancies. Twelve cases involved pregnancy in women with known aHUS, and 54 cases involved first-episode pregnancy-associated aHUS. Women with known aHUS, particularly those with baseline creatinine at or above 1.5 mg/dL, had a high rate of adverse pregnancy outcomes. For first-episode pregnancy-associated aHUS, diagnosis most often occurred postpartum (94%), after a cesarean delivery (70%), in nulliparous women (58%). Preceding obstetric complications were common and included fetal death, preeclampsia, and hemorrhage. Diagnosis was usually made clinically, based on the triad of microangiopathic hemolysis, thrombocytopenia, and renal failure. Additional testing included renal biopsy, complement genetic testing, and ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) testing. Treatment modalities included corticosteroids, plasma exchange, dialysis, and eculizumab. More women with first-episode pregnancy-associated aHUS achieved disease remission when treated with eculizumab, compared with those not treated with eculizumab (88% vs 57%, P=.02).
CONCLUSION
Pregnancy-associated aHUS usually presents in the postpartum period, often after a pregnancy complication, and eculizumab is effective for achieving disease remission.
SYSTEMATIC REVIEW REGISTRATION
PROSPERO, CRD42019129266.
Topics: Antibodies, Monoclonal, Humanized; Atypical Hemolytic Uremic Syndrome; Complement Inactivating Agents; Female; Humans; Plasma Exchange; Postpartum Period; Pregnancy; Pregnancy Complications, Hematologic; Renal Dialysis
PubMed: 31809447
DOI: 10.1097/AOG.0000000000003554