A Pathologist’s Approach to Nonimmune Hydrops

Parks, W. Tony

doi:10.1007/s40556-015-0055-x

Cited by 9 publications

(10 citation statements)

References 36 publications

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“…One-phase decay curves were fitted to the data sets for Flag-NMNAT2 WT and Flag-NMNAT2 R232Q using non-linear regression. The R 2 value and half-life (t½) are reported. No intensity values could be obtained for Flag-NMNAT2 Q135Pfs*44 at any timepoint assessed after emetine addition precluding curve fitting and statistical analysis.…”

Section: Methodsmentioning

confidence: 99%

“…Fetal Akinesia Deformation Sequence (FADS) defines a broad range of disorders unified by absent fetal movement resulting in secondary defects often leading to stillbirth or limited postnatal survival 1; 2 . These secondary features include edema, hydrops fetalis, craniofacial anomalies including micrognathia, lung hypoplasia, rocker bottom feet, intrauterine growth restriction, and decreased muscle mass 3 .…”

Section: Introductionmentioning

confidence: 99%

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Severe Biallelic Loss-of-function Mutations inNicotinamide Mononucleotide Adenylyltransferase 2 (NMNAT2)in Two Fetuses with Fetal Akinesia Deformation Sequence

Lukacs

Gilley

Orsomando

et al. 2019

Preprint

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27The three nicotinamide mononucleotide adenylyltransferase (NMNAT) family members 28 synthesize the electron carrier nicotinamide adenine dinucleotide (NAD + ) and are essential for 29 cellular metabolism. In mammalian axons, NMNAT activity appears to be required for axon 30 survival and is predominantly provided by NMNAT2. NMNAT2 has recently been shown to also 31 function as a chaperone to aid in the refolding of misfolded proteins. Nmnat2 deficiency in 32 mice, or in its ortholog dNmnat in Drosophila, results in axon outgrowth and survival defects. 33Peripheral nerve axons in NMNAT2-deficient mice fail to extend and innervate targets, and 34 skeletal muscle is severely underdeveloped. In addition, removing NMNAT2 from established 35 axons initiates axon death by Wallerian degeneration. We report here on two stillborn siblings 36 with fetal akinesia deformation sequence (FADS), severely reduced skeletal muscle mass and 37 hydrops fetalis. Clinical exome sequencing identified compound heterozygous NMNAT2 38 variant alleles in both cases. Both protein variants are incapable of supporting axon survival in 39 mouse primary neuron cultures when overexpressed. In vitro assays demonstrate altered 40 protein stability and/or defects in NAD + synthesis and chaperone functions. Thus, both patient 41 NMNAT2 alleles are null or severely hypo-morphic. These data indicate a previously unknown 42 role for NMNAT2 in human neurological development and provide the first direct molecular 43 evidence to support the involvement of Wallerian degeneration in a human axonal disorder. 44 45 46 47 Fetal Akinesia Deformation Sequence (FADS) defines a broad range of disorders unified by 51 absent fetal movement resulting in secondary defects often leading to stillbirth or limited 52 postnatal survival 1; 2 . These secondary features include edema, hydrops fetalis, craniofacial 53 anomalies including micrognathia, lung hypoplasia, rocker bottom feet, intrauterine growth 54 restriction, and decreased muscle mass 3 . Through previous experimental models of fetal 55 paralysis, the secondary findings have been shown to be primarily caused by a lack of fetal 56 movement 1; 4 . FADS has both genetic and environmental causes that can affect any aspect of 57 the motor system including the central nervous system (CNS), peripheral nervous system 58 (PNS), neuromuscular junction (NMJ), and/or skeletal muscle. Although most cases of FADS 59 do not have a genetic diagnosis, multiple monogenic causes of FADS affecting PNS 60 innervation development have been identified to date including RAPSN, DOK7, MUSK 5-7 . 61 62Through whole exome sequencing and subsequent Sanger sequencing of a family with two 63 fetuses with FADS, we identified compound heterozygous mutations in a gene previously 64 unlinked to FADS, nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2). NMNAT 65 family members were first shown to play a role in axon degeneration with the discovery of the 66 slow Wallerian Degeneration (Wld S ) mutant mouse that showed delayed axon degenera...

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Severe Biallelic Loss-of-function Mutations inNicotinamide Mononucleotide Adenylyltransferase 2 (NMNAT2)in Two Fetuses with Fetal Akinesia Deformation Sequence

Lukacs

Gilley

Orsomando

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…19 Similar results have been reported by various other authors. 3,8,20,21 In this study, which evaluated the role and significance of a fetal autopsy in NIHF cases, we found that the most common etiological factor associated with this condition was cardiovascular disorders (11.3%) followed by chromosomal abnormalities (9.3%). Prior to 20 weeks of gestation, genetic anomalies and cystic hygroma were found to be the most commonly associated etiological factors while after 30 weeks of gestation, cardiac causes were identified as the most commonly associated etiological factors.…”

Section: Discussionmentioning

confidence: 79%

Non-immune hydrops fetalis: A retrospective analysis of 151 autopsies performed at a single center

et al. 2018

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“…In Table 1, the author listed chylothorax among the ''thoracic'' causes of NIH, but neither the table nor the text touches upon lymphatic dysplasia as an important (and often underdiagnosed) cause of NIH. With regard to this issue, I would like to add a brief comment to the article [1]. The role of malformative development or impaired function of the lymphatic system in the fetus leading to hydrops formation has been discussed extensively [3] as also cited by the author.…”

mentioning

confidence: 99%

“…The usefulness of immunohistochemical staining techniques to discern between blood and lymphatic microcapillaries and vessels is now well established [4]. We previously recommended [5] the use of CD-31, CD-34, D2-40 (or podoplanin), smooth muscle actin (SMA), anti-LYVE-1 (antibodies against lymphatic endothelium), and VEGFR-3 in the pathological workup of NIH. I would like to underline and reaffirm the importance of immunohistochemical studies in the absence of a definite diagnosis of NIH or, as an alternative in case of a strong suspicion of lymphatic system involvement.…”

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confidence: 99%

Comment on: A Pathologist’s Approach to Nonimmune Hydrops

Bellini

2016

Journal of Fetal Medicine

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A Pathologist’s Approach to Nonimmune Hydrops

Cited by 9 publications

References 36 publications

Severe Biallelic Loss-of-function Mutations inNicotinamide Mononucleotide Adenylyltransferase 2 (NMNAT2)in Two Fetuses with Fetal Akinesia Deformation Sequence

Severe Biallelic Loss-of-function Mutations inNicotinamide Mononucleotide Adenylyltransferase 2 (NMNAT2)in Two Fetuses with Fetal Akinesia Deformation Sequence

Non-immune hydrops fetalis: A retrospective analysis of 151 autopsies performed at a single center

Comment on: A Pathologist’s Approach to Nonimmune Hydrops

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