Author
M L Manco-Johnson
Other affiliations: University of California, San Diego, University of Colorado Boulder, Rose Medical Center
Bio: M L Manco-Johnson is an academic researcher from University of Colorado Denver. The author has contributed to research in topics: Autosomal dominant polycystic kidney disease & Polyhydramnios. The author has an hindex of 23, co-authored 37 publications receiving 3004 citations. Previous affiliations of M L Manco-Johnson include University of California, San Diego & University of Colorado Boulder.
Papers
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University of Colorado Denver1, Boston Children's Hospital2, Emory University3, Harvard University4, University of Texas at Austin5, University of Texas Southwestern Medical Center6, Cornell University7, Tulane University8, Primary Children's Hospital9, University of Pennsylvania10, University of New Mexico11, Children's Hospital Oakland Research Institute12, University of Hawaii at Manoa13, Children's Hospital of Orange County14, Oregon Health & Science University15, Children's Memorial Hospital16, Palmetto Health Richland17, Centers for Disease Control and Prevention18
TL;DR: Prophylaxis with recombinant factor VIII can prevent joint damage and decrease the frequency of joint and other hemorrhages in young boys with severe hemophilia A.
Abstract: Sixty-five boys younger than 30 months of age were randomly assigned to prophylaxis (32 boys) or enhanced episodic therapy (33 boys). When the boys reached 6 years of age, 93% of those in the prophylaxis group and 55% of those in the episodic-therapy group were considered to have normal index-joint structure on MRI (P = 0.006). The relative risk of MRI-detected joint damage with episodic therapy as compared with prophylaxis was 6.1 (95% confidence interval, 1.5 to 24.4). The mean annual numbers of joint and total hemorrhages were higher at study exit in the episodic-therapy group than in the prophylaxis group (P<0.001 for both comparisons). High titers of inhibitors of factor VIII developed in two boys who received prophylaxis; three boys in the episodic-therapy group had a life-threatening hemorrhage. Hospitalizations and infections associated with central-catheter placement did not differ significantly between the two groups. Conclusions Prophylaxis with recombinant factor VIII can prevent joint damage and decrease the frequency of joint and other hemorrhages in young boys with severe hemophilia A. (ClinicalTrials.gov number, NCT00207597.)
1,613 citations
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TL;DR: The results indicate that the early high incidence of hypertension in ADPKD correlates with the renal structural abnormalities in this disorder.
217 citations
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University of North Carolina at Chapel Hill1, Mahidol University2, University of Colorado Denver3, Gulf Coast Regional Blood Center4, Emory University5, Harvard University6, Rush University Medical Center7, University of Texas at Austin8, University of Texas Southwestern Medical Center9, Cornell University10, Boston Children's Hospital11, Tulane University12, Primary Children's Hospital13, University of Pennsylvania14, University of New Mexico15, Children's Hospital Oakland Research Institute16, University of Hawaii at Manoa17, Children's Hospital of Orange County18, Oregon Health & Science University19, Northwestern University20, Palmetto Health Richland21, Centers for Disease Control and Prevention22
TL;DR: The results may guide rational design of clinical trials using alternative AAV serotypes and suggest that younger patients who are given AAV gene therapy will benefit from the lower prevalence of NAbs.
Abstract: Recombinant adeno-associated virus (rAAV) is a promising gene delivery vector and has recently been used in patients with hemophilia. One limitation of AAV application is that most humans have experienced wild-type AAV serotype 2 exposure, which frequently generates neutralizing antibodies (NAbs) that may inhibit rAAV2 vector transduction. Employing alternative serotypes of rAAV vectors may circumvent this problem. We investigated the development of NAbs in early childhood by examining sera gathered prospectively from 62 children with hemophilia A, participating in a multi-institutional hemophilia clinical trial (the Joint Outcome Study). Clinical applications in hemophilia therapy have been suggested for serotypes AAV2, AAV5 and AAV8, therefore NAbs against these serotypes were serially assayed over a median follow-up of 4 years. NAbs prevalence increased during early childhood for all serotypes. NAbs against AAV2 (43.5%) were observed more frequently and at higher titers compared with both AAV5 (25.8%) and AAV8 (22.6%). NAbs against AAV5 or AAV8 were rarely observed in the absence of co-prevalent and higher titer AAV2 NAbs, suggesting that NAbs to AAV5 and AAV8 were detected following AAV2 exposure due to partial cross-reactivity of AAV2-directed NAbs. The results may guide rational design of clinical trials using alternative AAV serotypes and suggest that younger patients who are given AAV gene therapy will benefit from the lower prevalence of NAbs.
187 citations
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TL;DR: An algorithm for diagnostic screening for ADPKD utilizing blood pressure, serum creatinine and UOsm designed to maximize sensitivity is developed and would have spared 20% of unaffected subjects from the cost of ultrasound while failing to detect less than 2% of affected subjects.
123 citations
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TL;DR: Significant relationship between the severity of the renal structural involvement and the frequency of flank and back pain, hypertension, and impaired renal concentrating capacity was found, but GFR were not reduced in children with ADPKD and did not relate to structural severity.
Abstract: The natural history of autosomal dominant polycystic kidney disease (ADPKD) has not been well described in children, and it is not known whether a relationship exists between renal structural abnormalities and function in children as has been seen in adults. Therefore, 140 children from 67 ADPKD families were studied in a prospective study. Only 22 children came with a previous diagnosis of ADPKD. In 44% of all children, at least one cyst was found on ultrasound at a mean age of 8.7 yr. Of these, 60% were classified as having moderate disease on the basis of a total cyst number of 1 to 10 cysts, whereas 40% were considered to have severe disease with a total of more than 10 cysts. There was a significant relationship between the severity of the renal structural involvement and the frequency of flank and back pain, hypertension, and impaired renal concentrating capacity. However, GFR were not reduced in children with ADPKD and did not relate to structural severity. Thirty-nine children were seen for a follow-up visit 2 to 5 yr after the initial visit. No child had progressed from nonaffected to affected with ADPKD, but three of four children with only one cyst at the time of the initial study had progressed to bilateral cysts. Among the 22 ADPKD children who had a follow-up study, there was progression of the disease, reflected by an increase in cyst number and an increase in the frequency of pain and hypertension. However, GFR remained stable in all children.(ABSTRACT TRUNCATED AT 250 WORDS)
121 citations
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TL;DR: These evidence‐based guidelines offer practical recommendations on the diagnosis and general management of hemophilia, as well as the management of complications including musculoskeletal issues, inhibitors, and transfusion‐transmitted infections.
Abstract: Hemophilia is a rare disorder that is complex to diagnose and to manage. These evidence-based guidelines offer practical recommendations on the diagnosis and general management of hemophilia, as well as the management of complications including musculoskeletal issues, inhibitors, and transfusion-transmitted infections. By compiling these guidelines, the World Federation of Hemophilia aims to assist healthcare providers seeking to initiate and/or maintain hemophilia care programs, encourage practice harmonization around the world and, where recommendations lack adequate evidence, stimulate appropriate studies.
1,733 citations
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TL;DR: A second gene for autosomal dominant polycystic kidney disease was identified by positional cloning and it has amino acid similarity with PKD1, the Caenorhabditis elegans homolog of PKD 1, and the family of voltage-activated calcium channels.
Abstract: A second gene for autosomal dominant polycystic kidney disease was identified by positional cloning. Nonsense mutations in this gene (PKD2) segregated with the disease in three PKD2 families. The predicted 968-amino acid sequence of the PKD2 gene product has six transmembrane spans with intracellular amino- and carboxyl-termini. The PKD2 protein has amino acid similarity with PKD1, the Caenorhabditis elegans homolog of PKD1, and the family of voltage-activated calcium (and sodium) channels, and it contains a potential calcium-binding domain.
1,336 citations
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TL;DR: An increased understanding of the disorder's underlying genetic, molecular, and cellular mechanisms and a better appreciation of its progression and systemic manifestations have laid out the foundation for the development of clinical trials and potentially effective treatments.
1,319 citations
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TL;DR: The prospects and challenges for AAV gene therapy are to a large extent dependent on the target tissue and the specific disease.
Abstract: In vivo gene replacement for the treatment of inherited disease is one of the most compelling concepts in modern medicine. Adeno-associated virus (AAV) vectors have been extensively used for this purpose and have shown therapeutic efficacy in a range of animal models. Successful translation to the clinic was initially slow, but long-term expression of donated genes at therapeutic levels has now been achieved in patients with inherited retinal disorders and haemophilia B. Recent exciting results have raised hopes for the treatment of many other diseases. As we discuss here, the prospects and challenges for AAV gene therapy are to a large extent dependent on the target tissue and the specific disease.
792 citations
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TL;DR: Both kidneys were enlarged and had innumerable cysts with minimal intervening parenchyma and features were suggestive of autosomal dominant polycystic kidney disease.
Abstract: Autosomal dominant polycystic kidney disease (ADPKD) is a hereditary disease occurring in 1 in 200 to 1 in 1,000 individuals. ADPKD is characterized by cystic lesions in the kidneys and often by structural abnormalities in the gastrointestinal tract and cardiovascular system. The pathogenesis of the disorder appears to involve both cellular proliferation and altered extracellular matrix synthesis. Diagnosis can be established most readily by the sonographic demonstration of renal cysts or by gene linkage analysis. Renal manifestations of ADPKD include hypertension, infection, nephrolithiasis and malignancy. The prominent extrarenal manifestations include hepatic cysts, mitral valve prolapse and intracranial aneurysms. Although only 2% of nephrons appear to be involved in cyst formation, the renal function often slowly deteriorates. Presently, there is a 52% probability of an ADPKD subject’s being alive without renal replacement therapy at age 73. ADPKD patients with endstage renal disease respond to renal replacement therapy as well as other patient groups.
777 citations