1) A mother experienced recurrent third-trimester fetal loss and her surviving infant was diagnosed with long-QT syndrome (LQTS).
2) Genetic testing found the infant had a mutation in the SCN5A gene known to cause LQTS. Initial testing of the mother found no mutation.
3) A more sensitive test found the mother had low-level (8-10%) mosaicism for the same SCN5A mutation, indicating she transmitted it to her fetuses and infant.
4) This case suggests parental mosaicism can cause recurrent late-term fetal loss or sudden infant death through transmission of LQTS mutations and has implications for genetic counseling.
Identification of a Novel Mutation (p.G328W) in the NR5A1 Gene in a Boy with ...CrimsonPublishersGJEM
The gene NR5A1 (nuclear receptor subfamily 5 group A member 1, OMIM +184757) encodes for the Steroidogenic factor1 (SF1), a key regulator of the adrenal/gonadal development and function. Disorders/Differences of Sex Development (DSD) are defined as conditions where the chromosomal/anatomical, phenotypic sex is atypical. Heterozygous mutations of NR5A1 gene are associated, in 46, XY DSD patients, with a wide phenotypic spectrum of the external genitalia, with or without adrenal failure. Here we report a 46, XY newborn carrying a novel heterozygous NR5A1 mutation that presents with ambiguous genitalia without adrenal failure.
A lysosomal storage disease caused by acid sphingomyelinase deficiency (ASMD), which catalyzes the hydrolysis of sphingomyelin (SM) to ceramide and phosphocholine.
Intra Cranial Stem Cell Transplant For Npc.Ppt 2Duriya Lakdawala
Finding a treatment for Niemann Pick Type C will provide hope not only to Aaditya Ravi Dasgupta and Tasneem Tankiwala in India but to many others like Addi and Cassi Hempel, Gabrielle Laverde and Peyton and Kayla Hadley in US, Husein Taher in Tanzania, South Africa, Roy Green in UK and so many more kids, teens and adults all over the world and in India that have not been diagnosed yet due to the cost and complexity of the diagnostic process. You can leave a wish for Aaditya (http://addiandcassi.com/guestbook) or for more information go to: www.HopeforAaditya.org
Fiona McKay-Diagnóstico prenatal no invasivo y diagnóstico genético reproductivoFundación Ramón Areces
Los días 8 y 9 de junio de 2017 organizamos en la Fundación Ramón Areces con el Ciberer y la Fundación Jiménez Díaz un simposio internacional sobre 'Diagnóstico prenatal no invasivo y diagnóstico genético reproductivo'. Coordinado por la doctora Ana Bustamante, del servicio de Genética del Hospital Universitario Fundación Jiménez Díaz, tuvo como objetivo mostrar los últimos avances en el campo de la genética reproductiva a nivel preimplantacional, prenatal, e, incluso, preconcepcional.
Identification of a Novel Mutation (p.G328W) in the NR5A1 Gene in a Boy with ...CrimsonPublishersGJEM
The gene NR5A1 (nuclear receptor subfamily 5 group A member 1, OMIM +184757) encodes for the Steroidogenic factor1 (SF1), a key regulator of the adrenal/gonadal development and function. Disorders/Differences of Sex Development (DSD) are defined as conditions where the chromosomal/anatomical, phenotypic sex is atypical. Heterozygous mutations of NR5A1 gene are associated, in 46, XY DSD patients, with a wide phenotypic spectrum of the external genitalia, with or without adrenal failure. Here we report a 46, XY newborn carrying a novel heterozygous NR5A1 mutation that presents with ambiguous genitalia without adrenal failure.
A lysosomal storage disease caused by acid sphingomyelinase deficiency (ASMD), which catalyzes the hydrolysis of sphingomyelin (SM) to ceramide and phosphocholine.
Intra Cranial Stem Cell Transplant For Npc.Ppt 2Duriya Lakdawala
Finding a treatment for Niemann Pick Type C will provide hope not only to Aaditya Ravi Dasgupta and Tasneem Tankiwala in India but to many others like Addi and Cassi Hempel, Gabrielle Laverde and Peyton and Kayla Hadley in US, Husein Taher in Tanzania, South Africa, Roy Green in UK and so many more kids, teens and adults all over the world and in India that have not been diagnosed yet due to the cost and complexity of the diagnostic process. You can leave a wish for Aaditya (http://addiandcassi.com/guestbook) or for more information go to: www.HopeforAaditya.org
Fiona McKay-Diagnóstico prenatal no invasivo y diagnóstico genético reproductivoFundación Ramón Areces
Los días 8 y 9 de junio de 2017 organizamos en la Fundación Ramón Areces con el Ciberer y la Fundación Jiménez Díaz un simposio internacional sobre 'Diagnóstico prenatal no invasivo y diagnóstico genético reproductivo'. Coordinado por la doctora Ana Bustamante, del servicio de Genética del Hospital Universitario Fundación Jiménez Díaz, tuvo como objetivo mostrar los últimos avances en el campo de la genética reproductiva a nivel preimplantacional, prenatal, e, incluso, preconcepcional.
widespread epidemic of Zika virus (ZIKV) infection was reported in 2015 in South and Central America and the Caribbean. A major concern associated with this infection is the apparent increased incidence of microcephaly in fetuses born to mothers infected with ZIKV. In this report, we describe the case of an expectant mother who had a febrile illness with rash at the end of the first trimester of pregnancy while she was living in Brazil. Ultrasonography performed at 29 weeks of gestation revealed microcephaly with calcifications in the fetal brain and pla-centa. After the mother requested termination of the pregnancy, a fetal autopsy was performed. Micrencephaly (an abnormally small brain) was observed, with almost complete agyria, hydrocephalus, and multifocal dystrophic calcifications in the cortex and subcortical white matter, with associated cortical displacement and mild focal inf lammation. ZIKV was found in the fetal brain tissue on reverse-transcriptase–polymerase-chain-reaction (RT-PCR) assay, with consistent findings on electron microscopy. The complete genome of ZIKV was recovered from the fetal brain
Cerebral Venous Sinus Thrombosis
Dr Rajiv Jha, MS
Senior Resident M Ch Neurosurgery
National Neurosurgical Referral Center
National Academy Of Medical Sciences
Open Source Pharma /Genomics and clinical practice / Prof Hosur opensourcepharmafound
Access to Research
Date 11-08-2018
Venue Conference HAll NIAS IISc campus
Conference and workshops for clinical practitioners to introduce them to modern tools and an alternative approach to modern scientific research.
Purpose
1. Build a network of physicians across the country
2 Train physicians to analyse clinical data and restructure it to make it compatible with research standards
3. Introduce modern tools to understand the mechanism of actions of medicine
4. Introduce artificial intelligence and machine learning to clinical practitioners to support decision-making processes
Access to Science
Clinical experience and traditional knowledge are important sources of data that affect decision making processes in modern healthcare systems. This data should be made accessible for scientific evaluation and validation to improve healthcare worldwide. The Open Source Pharma Foundation believes that clinical practitioners from various disciplines should have the right to access research so that they can help identify problems, contribute their scientific knowledge, and support the discovery ecosystem.
Background
The majority of medical practitioners working on the ground level with patients do not take part in open clinical research worldwide. However, the data collected and owned by them plays an important role in establishing better discovery pathways. Through this workshop, we seek to open opportunities to enhance health care systems around the world and to overcome the following challenges faced by medical practitioners.
1. Regulatory limitations
2. Academic limitations
3. Time constraints
4. Lack of access to modern tools
5. Lack of access to research facilities
My son had Wiskott Aldrich Syndrome (WAS). He had a bone marrow transplant in August 2006. His WAS is healed. This presentation was designed by some grad students. Some of the content is from my blog and it pictures my son, David. http://www.davidmcnally.blogspot.com
Dindigul district cervical screening study, india acceptability, effectivenes...Asha Reddy
Dindigul district cervical screening study, india acceptability, effectiveness and safety of treatment of cervical precancerous lesions by nurses using cryotherapy
Discordant noninvasive prenatal testing & cytogenetic results: 109 consecutive cases.
In conclusion, use of conventional cytogenetics as the reference
standard unravels a rather significant discordance with
positive NIPT results. These data should compel us to take a
cautious look at NIPT data sets and their sources. As more
commercial providers advocate this test, or sponsor academic
centers to carry them out, a more diligent comparison of NIPT
results with cytogenetic tests should be undertaken.
Expressed breast milk on refrigerator storageAsha Reddy
In conclusion, we can store mother’s milk at refrigerator temperature of 4ºC for 96 hours without changing its overall integrity in the form of pH, serum albumin, total protein, lipid and lactose content and can use it for feeding neonates and infants.
Human Milk Banking Guidelines -INDIAN ACADEMY OF PEDIATRICSAsha Reddy
Human Milk Banking Guidelines INFANT AND YOUNG CHILD FEEDING CHAPTER, INDIAN ACADEMY OF PEDIATRICS
Absent or insufficient lactation: Mothers with
multiple births, who can not secrete adequate
breastmilk for their neonates initially.
• For babies of non-lactating mothers, who adopt
neonates and if induced lactation is not possible.
• Abandoned neonates and sick neonates.
• Temporary interruption of breastfeeding.
• Infant at health risk from breastmilk of the biological
mother.
• Babies whose mother died in the immediate
postpartum period
These lecture slides, by Dr Sidra Arshad, offer a quick overview of the physiological basis of a normal electrocardiogram.
Learning objectives:
1. Define an electrocardiogram (ECG) and electrocardiography
2. Describe how dipoles generated by the heart produce the waveforms of the ECG
3. Describe the components of a normal electrocardiogram of a typical bipolar lead (limb II)
4. Differentiate between intervals and segments
5. Enlist some common indications for obtaining an ECG
6. Describe the flow of current around the heart during the cardiac cycle
7. Discuss the placement and polarity of the leads of electrocardiograph
8. Describe the normal electrocardiograms recorded from the limb leads and explain the physiological basis of the different records that are obtained
9. Define mean electrical vector (axis) of the heart and give the normal range
10. Define the mean QRS vector
11. Describe the axes of leads (hexagonal reference system)
12. Comprehend the vectorial analysis of the normal ECG
13. Determine the mean electrical axis of the ventricular QRS and appreciate the mean axis deviation
14. Explain the concepts of current of injury, J point, and their significance
Study Resources:
1. Chapter 11, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 9, Human Physiology - From Cells to Systems, Lauralee Sherwood, 9th edition
3. Chapter 29, Ganong’s Review of Medical Physiology, 26th edition
4. Electrocardiogram, StatPearls - https://www.ncbi.nlm.nih.gov/books/NBK549803/
5. ECG in Medical Practice by ABM Abdullah, 4th edition
6. Chapter 3, Cardiology Explained, https://www.ncbi.nlm.nih.gov/books/NBK2214/
7. ECG Basics, http://www.nataliescasebook.com/tag/e-c-g-basics
micro teaching on communication m.sc nursing.pdfAnurag Sharma
Microteaching is a unique model of practice teaching. It is a viable instrument for the. desired change in the teaching behavior or the behavior potential which, in specified types of real. classroom situations, tends to facilitate the achievement of specified types of objectives.
263778731218 Abortion Clinic /Pills In Harare ,sisternakatoto
263778731218 Abortion Clinic /Pills In Harare ,ABORTION WOMEN’S CLINIC +27730423979 IN women clinic we believe that every woman should be able to make choices in her pregnancy. Our job is to provide compassionate care, safety,affordable and confidential services. That’s why we have won the trust from all generations of women all over the world. we use non surgical method(Abortion pills) to terminate…Dr.LISA +27730423979women Clinic is committed to providing the highest quality of obstetrical and gynecological care to women of all ages. Our dedicated staff aim to treat each patient and her health concerns with compassion and respect.Our dedicated group ABORTION WOMEN’S CLINIC +27730423979 IN women clinic we believe that every woman should be able to make choices in her pregnancy. Our job is to provide compassionate care, safety,affordable and confidential services. That’s why we have won the trust from all generations of women all over the world. we use non surgical method(Abortion pills) to terminate…Dr.LISA +27730423979women Clinic is committed to providing the highest quality of obstetrical and gynecological care to women of all ages. Our dedicated staff aim to treat each patient and her health concerns with compassion and respect.Our dedicated group of receptionists, nurses, and physicians have worked together as a teamof receptionists, nurses, and physicians have worked together as a team wwww.lisywomensclinic.co.za/
Ozempic: Preoperative Management of Patients on GLP-1 Receptor Agonists Saeid Safari
Preoperative Management of Patients on GLP-1 Receptor Agonists like Ozempic and Semiglutide
ASA GUIDELINE
NYSORA Guideline
2 Case Reports of Gastric Ultrasound
Knee anatomy and clinical tests 2024.pdfvimalpl1234
This includes all relevant anatomy and clinical tests compiled from standard textbooks, Campbell,netter etc..It is comprehensive and best suited for orthopaedicians and orthopaedic residents.
ABDOMINAL TRAUMA in pediatrics part one.drhasanrajab
Abdominal trauma in pediatrics refers to injuries or damage to the abdominal organs in children. It can occur due to various causes such as falls, motor vehicle accidents, sports-related injuries, and physical abuse. Children are more vulnerable to abdominal trauma due to their unique anatomical and physiological characteristics. Signs and symptoms include abdominal pain, tenderness, distension, vomiting, and signs of shock. Diagnosis involves physical examination, imaging studies, and laboratory tests. Management depends on the severity and may involve conservative treatment or surgical intervention. Prevention is crucial in reducing the incidence of abdominal trauma in children.
Local Advanced Lung Cancer: Artificial Intelligence, Synergetics, Complex Sys...Oleg Kshivets
Overall life span (LS) was 1671.7±1721.6 days and cumulative 5YS reached 62.4%, 10 years – 50.4%, 20 years – 44.6%. 94 LCP lived more than 5 years without cancer (LS=2958.6±1723.6 days), 22 – more than 10 years (LS=5571±1841.8 days). 67 LCP died because of LC (LS=471.9±344 days). AT significantly improved 5YS (68% vs. 53.7%) (P=0.028 by log-rank test). Cox modeling displayed that 5YS of LCP significantly depended on: N0-N12, T3-4, blood cell circuit, cell ratio factors (ratio between cancer cells-CC and blood cells subpopulations), LC cell dynamics, recalcification time, heparin tolerance, prothrombin index, protein, AT, procedure type (P=0.000-0.031). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and N0-12 (rank=1), thrombocytes/CC (rank=2), segmented neutrophils/CC (3), eosinophils/CC (4), erythrocytes/CC (5), healthy cells/CC (6), lymphocytes/CC (7), stick neutrophils/CC (8), leucocytes/CC (9), monocytes/CC (10). Correct prediction of 5YS was 100% by neural networks computing (error=0.000; area under ROC curve=1.0).
Rasamanikya is a excellent preparation in the field of Rasashastra, it is used in various Kushtha Roga, Shwasa, Vicharchika, Bhagandara, Vatarakta, and Phiranga Roga. In this article Preparation& Comparative analytical profile for both Formulationon i.e Rasamanikya prepared by Kushmanda swarasa & Churnodhaka Shodita Haratala. The study aims to provide insights into the comparative efficacy and analytical aspects of these formulations for enhanced therapeutic outcomes.
Tom Selleck Health: A Comprehensive Look at the Iconic Actor’s Wellness Journeygreendigital
Tom Selleck, an enduring figure in Hollywood. has captivated audiences for decades with his rugged charm, iconic moustache. and memorable roles in television and film. From his breakout role as Thomas Magnum in Magnum P.I. to his current portrayal of Frank Reagan in Blue Bloods. Selleck's career has spanned over 50 years. But beyond his professional achievements. fans have often been curious about Tom Selleck Health. especially as he has aged in the public eye.
Follow us on: Pinterest
Introduction
Many have been interested in Tom Selleck health. not only because of his enduring presence on screen but also because of the challenges. and lifestyle choices he has faced and made over the years. This article delves into the various aspects of Tom Selleck health. exploring his fitness regimen, diet, mental health. and the challenges he has encountered as he ages. We'll look at how he maintains his well-being. the health issues he has faced, and his approach to ageing .
Early Life and Career
Childhood and Athletic Beginnings
Tom Selleck was born on January 29, 1945, in Detroit, Michigan, and grew up in Sherman Oaks, California. From an early age, he was involved in sports, particularly basketball. which played a significant role in his physical development. His athletic pursuits continued into college. where he attended the University of Southern California (USC) on a basketball scholarship. This early involvement in sports laid a strong foundation for his physical health and disciplined lifestyle.
Transition to Acting
Selleck's transition from an athlete to an actor came with its physical demands. His first significant role in "Magnum P.I." required him to perform various stunts and maintain a fit appearance. This role, which he played from 1980 to 1988. necessitated a rigorous fitness routine to meet the show's demands. setting the stage for his long-term commitment to health and wellness.
Fitness Regimen
Workout Routine
Tom Selleck health and fitness regimen has evolved. adapting to his changing roles and age. During his "Magnum, P.I." days. Selleck's workouts were intense and focused on building and maintaining muscle mass. His routine included weightlifting, cardiovascular exercises. and specific training for the stunts he performed on the show.
Selleck adjusted his fitness routine as he aged to suit his body's needs. Today, his workouts focus on maintaining flexibility, strength, and cardiovascular health. He incorporates low-impact exercises such as swimming, walking, and light weightlifting. This balanced approach helps him stay fit without putting undue strain on his joints and muscles.
Importance of Flexibility and Mobility
In recent years, Selleck has emphasized the importance of flexibility and mobility in his fitness regimen. Understanding the natural decline in muscle mass and joint flexibility with age. he includes stretching and yoga in his routine. These practices help prevent injuries, improve posture, and maintain mobilit
2. revealed no gross abnormalities, but a subsequent fetal echocardio-
gram identified frequent bursts of atrial and ventricular tachycardia
and episodes of 2:1 AV block. -Blockers were ineffective, and a
trial of amiodarone resulted in marked worsening of arrhythmias,
with development of myocardial dysfunction and fetal hydrops
necessitating emergency caesarian section. An ECG demonstrated
AV conduction abnormalities and a QTc interval of 550 milliseconds
(Figure 1A). After delivery, the newborn continued to have drug-re-
sistant ventricular tachyarrhythmias, frequent episodes of ventricular
flutter, and torsade de pointes (Figure 1B). A chest x-ray was
consistent with hyaline membrane disease and mild cardiomegaly.
Tachyarrhythmias were partially responsive to lidocaine infusion but
resisted a variety of other antiarrhythmic interventions, including
epicardial pacing, esmolol infusion, bicarbonate, magnesium, cal-
cium, mexiletine, flecainide, and left sympathetic ganglionectomy.
Ultimately, the infant received orthotopic heart transplantation at 5.5
months of age. He is now almost 3 years of age and has had no
further arrhythmias.
The infant’s mother was a 20-year-old black woman with no
clinical evidence or family history of heart disease, cardiac arrhyth-
mias, prematurity, syncope, cardiac arrest or sudden cardiac death, or
autoimmune disorders. Her baseline ECG was normal (Figure 1C),
Figure 1. Recurrent fetal demise and
fetal arrhythmias. A–C, ECG findings in
index case and mother. Leads I, II, and
VI are shown for each tracing. A, Index
case, 2 weeks of age: 3-lead ECG show-
ing prolonged QTc (550 ms) and 2:1 AV
block (arrows indicate p waves). B, Infant
ECG, showing torsade de pointes arising
on a background of ventricular paced
rhythm at 150 bpm and preceded by
T-wave alternans, a typical feature of
LQTS. C, Normal maternal ECG. D, Pedi-
gree of proband. Filled symbols indicate
intrauterine heart failure; IUFD, intrauter-
ine fetal death.
3030 Circulation June 22, 2004
at VA MED CTR BOISE on February 10, 2016http://circ.ahajournals.org/Downloaded from
3. and her QTc interval did not lengthen abnormally during amiodarone
infusion given for treatment of fetal arrhythmias (not shown). Her 1
previous pregnancy had ended in stillbirth at 28 weeks (Figure 1D);
a report of the postmortem evaluation of the male fetus described
marked cardiomegaly and a supernumerary digit but no other gross
abnormalities. Prenatal care was started 10 weeks into her second
pregnancy, and all prenatal laboratory studies were normal. The
infant’s father was 19 years of age and in excellent health, but he
declined to undergo genetic evaluation. The mother’s father and
mother were 23 and 18, respectively, at the time of her birth.
During these investigations, the mother became pregnant for a
third time by a second male partner. Regular prenatal examinations
and monthly ultrasound studies revealed no abnormalities until the
seventh month. At 28 weeks’ gestation, echocardiography revealed
no fetal heartbeat, and a stillborn female infant was delivered by
induction. Autopsy of this fetus revealed a severely enlarged but
structurally normal heart and nonimmune hydrops fetalis, consistent
with low-output cardiac failure; other organ systems were unremark-
able. Cord blood was obtained for genetic analysis.
All subjects were recruited and evaluated in accordance with
regulations set forth by the University of Miami Committee for the
Protection of Human Subjects and under a human subjects research
protocol approved by the University of Miami Institutional Review
Board. Autopsy results on the stillborn fetuses and cord blood from
the third fetus were provided with written consent of the mother.
DNA Isolation
Genomic DNA was obtained from lymphocytes, cultured skin
fibroblasts, paraffin-embedded tissue, and buccal swab with a
Puregene DNA Isolation Kit (Gentra Systems). DNA yields were
determined spectrophotometrically.
Single-Stranded Conformational
Polymorphism Analysis
The first 300 base pairs of exon 28 of SCN5A were amplified with
polymerase chain reaction (PCR).3 PCR was also performed on most
of the exons from LQT1, LQT2, KCNE1, and KCNE2 with the use of
published primers and conditions.3,12 Single-stranded conformational
polymorphism (SSCP) analysis was performed on a Bio-Rad Protean
II xi Cell electrophoresis apparatus. Gels were made with or without
glycerol using MDE Gel Solution (Cambrex BioScience) according
to the manufacturer’s recommendations. Gels were developed with a
silver stain kit from Bio-Rad according to their instructions.
DNA Sequence Analysis
PCR products to be sequenced were purified with a QIAquick PCR
Purification Kit (Qiagen). Cycle sequencing reactions were per-
formed by use of reagents from Applied Biosystems according to
their recommendation. The products were resolved on an ABI Prism
3100 Genetic Analyzer and analyzed with ABI Sequence Analysis
software. HinfI (10 U/L, New England Biolabs) digestions were
done for 3 hours at 37°C in 20-L reactions with up to 400 ng of
PCR product and 10 U of enzyme. Digestion products were analyzed
by electrophoresis in 2% agarose gels and staining with ethidium
bromide. The intensity of bands was quantified with Sigmascan
software (SPSS Science).
Results
Mutation Analysis
To identify the molecular abnormality in the index case, we
conducted mutation screening of 5 cardiac ion channel genes,
including KCNQ1, HERG, SCN5A, minK, and MiRP-1, cov-
ering Ϸ85% of the mutations known to be associated with
LQTS.3 Analysis of the proband’s lymphocyte DNA revealed
an unusual banding pattern of the first half of exon 28 of
SCN5A on SSCP analysis. DNA sequencing of this fragment
revealed that the infant was heterozygous for a previously
reported mutation at nucleotide 48683,13,14 (Genbank
NM_198056), with both a normal guanine residue and a
mutant adenine residue (Figure 2A). This introduces a muta-
tion in the second position of codon 1623, which changes a
positively charged arginine to a neutral glutamine (R1623Q).
No mutations were found in any of the other genes
investigated.
Detection of Maternal Mosaicism
Initial SSCP analysis of the mother’s lymphocyte DNA gave
an ambiguous result (not shown), but DNA sequencing
suggested that she was homozygous for the wild-type allele
(Figure 2B and 2E). To resolve this discrepancy, we took
advantage of the fact that the R1623Q mutation destroys an
Figure 2. Mutation detection in proband, mother, and third
fetus. A, B, D, and E, DNA sequence of sense strand of indi-
cated source. Arrows show position of mutation at nucleotide
4865. C, PCR products of DNA spanning mutation, after diges-
tion with HinfI, amplified from maternal lymphocytes (ML), pro-
band lymphocytes (PL), cord blood from third fetus (CB), mater-
nal fibroblasts (MF), maternal buccal epithelium (MB), and
lymphocytes from 3 unrelated individuals (NC). A, Proband lym-
phocyte DNA; B, maternal lymphocyte DNA. D, Maternal DNA
resistant to HinfI digestion; E, DNA from unaffected, unrelated
individual. Note that intensity of mutant band in stillborn cord
blood is intermediate between that of heterozygous brother (PL)
and the mosaic mother (ML), possibly reflecting incursion of
maternal blood after fetal demise.
Miller et al Recurrent Fetal Loss and Maternal LQTS Mosaicism 3031
at VA MED CTR BOISE on February 10, 2016http://circ.ahajournals.org/Downloaded from
4. HinfI restriction enzyme site (GANTC3AANTC). As ex-
pected, the wild-type exon 28 PCR product was completely
digested by HinfI, but more than half of the DNA from the
index case remained undigested, corresponding to the pres-
ence of homoduplex mutant and heteroduplex strands lacking
the restriction site (Figure 2C, lanes NC and PL). Analysis of
the mother’s lymphocyte DNA also revealed a small amount
of material resistant to complete digestion (Figure 2C, lanes
ML, MF, and MB). When purified, amplified, and sequenced,
this DNA was found to consist almost exclusively of the
mutant allele (Figure 2D), consistent with maternal somatic
mosaicism for the R1623Q mutation.
We next used the HinfI assay to compare levels of
mosaicism in several different maternal tissues (Figure 2C).
Using a standard curve developed by serial dilution of
proband DNA into normal DNA, we determined that the
HinfI assay was sufficiently sensitive to permit detection of
mutant DNA corresponding to Ϸ4% heterozygous cells.
Comparison of DNA from 3 different tissues suggested that
mosaicism was greatest in circulating lymphocytes (Ϸ10%),
less in buccal epithelium (8%), and least in skin fibroblasts
(4%) (Figure 2C). These differences may reflect genuine but
small variations in the proportion of mutation-bearing cells or
alternatively variability in PCR amplification. A comparably
low level of mosaicism in the heart would be consistent with
the mother’s lack of symptoms or ECG findings, although
this could not be directly confirmed.
The mother’s third pregnancy ended in stillbirth at 28
weeks. Analysis of fetal cord blood by HinfI digestion and
sequencing revealed the presence of the mutant allele (Figure
2C, lane CB).
Discussion
In this case report, we describe the late-term loss or near loss
of 3 successive pregnancies in a woman with somatic
mosaicism for a lethal LQTS mutation. Although material for
genetic studies was available only for 2 of the 3 infants, we
provide strong evidence for germ-line transfer of the mutation
in at least 2 and probably 3 pregnancies. Clinical and
postmortem evidence suggests that all 3 pregnancies were
complicated by fetal cardiac decompensation, and in the
second infant, heart failure was observed to develop in
connection with incessant ventricular tachyarrhythmias.
Heart failure, bradycardia, cardiac hypertrophy, and
tachyarrhythmias are frequent features of the antenatal pre-
sentation of LQTS.15
This case provides evidence that late-term fetal loss, like
SIDS, can stem from unsuspected LQTS. Fetal demise after
the sixth month of gestation is rare, occurring in Ͻ4 per 1000
pregnancies (National Center for Health Statistics, http://
www.cdc.gov/nchs/about/major/fetaldth/abfetal.htm), and
known causes (Rh incompatibility, maternal autoimmune
disease, thrombophilia, infection with TORCH pathogens,
major congenital malformations) were excluded in each of
the 3 pregnancies reported here. As with SIDS, fetal LQTS
and neonatal LQTS are rarely familial, and death may occur
in the absence of a documented ventricular tachyarrhythmia
or suggestive family history.16,17 Since Schwartz18 originally
proposed that some SIDS cases may reflect congenital LQTS,
several lines of supportive evidence have emerged, including
an ECG screening study of newborns,19 a case of a near-miss
SIDS infant who carried an apparently de novo SCN5A
mutation,5 and a case of a SIDS infant in whom postmortem
molecular screening identified an apparently de novo muta-
tion on KCNQ1.7 More recently, 2 of 93 sequential cases of
SIDS were found to have missense mutations in SCN5A.6 The
latter study likely underestimates the true contribution of
LQTS to unexplained infant death because even in clinically
well-defined cases, mutations are not always identified.3,4
Our findings demonstrate that LQTS mutations, particularly
those affecting the sodium channel encoded by SCN5A,
confer a risk for late-term fetal loss and for infant sudden
death.
In this case, the mother was found to harbor a small
population of cells with the same SCN5A (R1623Q) mutation
found in her children, indicating that she is a somatic mosaic
for LQTS. Genetic mosaicism results when a mutation occurs
in a single cell of the developing embryo and is propagated
only to its descendant cells in the adult. Mosaicism can affect
either somatic or germ-line lineages or both, depending on the
location and embryological stage at which the mutation
occurs. It has been estimated that 10% to 20% of ostensibly
de novo cases of retinoblastoma,9 hemophilia B,10 Duchenne
muscular dystrophy,8 and hemophilia A20 are the result of
parental mosaicism for these genetic disorders. Examples of
germ-line mosaicism in asymptomatic parents have been
documented in several autosomal dominant genetic diseases,
including neurofibromatosis,21 osteogenesis imperfecta,22 and
hypertrophic cardiomyopathy.23
The R1623Q mutation was first reported in an Asian
female infant who, like our proband, presented perinatally
with 2:1 AV block, lengthened QT interval, cardiac failure,
and life-threatening ventricular arrhythmias. The child is now
at least 8 years old and is free of arrhythmias on 600 mg/d
mexiletine.24 Our patient is now almost 3 years old and is also
free of arrhythmias after receiving an orthotopic heart trans-
plant. A third, sporadic instance of this mutation has also
been reported in an infant.3,25 The severe phenotype mani-
fested by these infants is typical of a subset of LQTS patients
who present in fetal and early neonatal life.5,13,16,17,26 A
review of 22 case studies from the English language litera-
ture16 described a subset of LQTS patients with a severe
neonatal-onset phenotype characterized by very long QTc
intervals (mean, 665 milliseconds), 2:1 AV block, T-wave
alternans, functional bradycardia, and a poor prognosis, with
9 of 22 dead in the first year of life and 50% mortality by 4
years of age. In comparison, a study of LQTS in a large
pediatric collaborative study (mean age at diagnosis, 7
years)27 found a mean QTc of 520 milliseconds and a low rate
of AV block (4%). A further striking feature of the perinatal
LQTS phenotype was the infrequency of a family history of
the disease (1 of 22, or 4.5%, compared with 60% in the
collaborative study of pediatric LQTS16). The important role
of de novo mutations in perinatal LQTS is supported by the
fact that disease-causing mutations at the same SCN5A
residue (1623) have arisen independently at least 3
times,3,14,25 and a number of other spontaneous mutations in
LQTS-associated genes have been linked to lethal arrhyth-
3032 Circulation June 22, 2004
at VA MED CTR BOISE on February 10, 2016http://circ.ahajournals.org/Downloaded from
5. mias in the fetus and neonate.5,28,29 The poor prognosis of
infants with neonatal LQTS undoubtedly also contributes to
low heritability.
The evidence for SCN5A mutations as a cause of perinatal
LQTS seems to conflict with earlier studies showing that
patients with LQTS generally have clinical manifestations
later in life than patients with mutations at other loci and that
SCN5A mutation penetrance is strongly age dependent.30
However, the findings presented here demonstrate that certain
SCN5A mutations can have an early, aggressive phenotype
characterized by arrhythmias and death before birth or in
early infancy. These mutations do not appear to overlap with
those previously reported to cause disease later in life.30
Additional work is required to explain the mechanisms
underlying these distinct clinical presentations.
The mutation detected in our patient lies in the S4 region of
SCN5A domain IV, which participates in coupling of channel
activation and inactivation.31 DNA sequence alignment of the
human isoforms of this sodium channel shows that the 3
brain-type (1A, 2A, and 3A), the skeletal muscle (4A), and
the cardiac (5A) isoforms are Ͼ90% identical in this region,
suggesting that this part of the protein serves a general and
essential function of the channel. The severity of disease
associated with mutations in this portion of the channel
further underscores its functional importance. In addition to 3
apparently de novo R1623Q mutations being associated with
a severe, early-onset phenotype of LQTS (this report and
others14,25), the same residue, when mutated to leucine instead
of glutamine, also causes the Romano-Ward form of LQTS,3
and another mutation 3 residues away has been associated
with the Brugada syndrome.32 Furthermore, mutation of the
homologous residue (R1448) in the skeletal SCN4A isoform
has been reported to cause paramyotonia congenita,33 a
disease characterized by cold-induced myotonia.34 In vitro
functional studies on the R1623Q mutant protein have found
unique inactivation gating defects that lead to both prolonged
spontaneous opening and early reopening, resulting in pro-
longed decay of INa.35 These gating defects were sensitive to
lidocaine, which restored more normal rapid inactivation
kinetics; possibly consistent with this, lidocaine was the only
antiarrhythmic agent demonstrating partial clinical benefit in
the surviving infant reported here.
The role of genetics in fetal demise is likely to be
overlooked, particularly when parents have no evidence of
disease. Dominant mutations such as those leading to LQTS,
hypertrophic cardiomyopathy, and other disorders associated
with sudden death are often assumed to have arisen de novo
in the affected individual (see elsewhere36 for review). The
possibility of genetic mosaicism might not be explored, partly
because of technical difficulties in detection and partly
because of a low level of suspicion when both parents are
clinically normal. Nonetheless, the distinction between de
novo mutation and parental germ-line mosaicism is critical
because mosaicism confers a considerably higher risk of
disease recurrence in subsequent pregnancies. The frequency
of de novo or transmitted mosaic LQTS mutations in fetal
demise or SIDS remains to be established. Our observation of
repeated germ-line transmission of LQTS from a mother with
unsuspected mosaicism implies that perinatal cardiac moni-
toring, in addition to genetic counseling, should be consid-
ered after recurrent late-term fetal loss or infant death.
Genetic disorders linked to cardiac sudden death may be an
important focus for future genetic epidemiological studies of
unexplained third-trimester pregnancy loss.
Acknowledgments
This work was supported by a collaborative grant from the Miami
Heart Research Institute (N.H.B. and R.J.M.), a Grant-in-Aid from
the Florida-Puerto Rico Affiliate of the American Heart Association
(L.B.), and a generous contribution from the Dr John T. Macdonald
Foundation for Medical Genetics. We are grateful to Drs Mark
Keating and Igor Splawski for providing control DNA samples,
unpublished data, and technical suggestions throughout these exper-
iments. We thank Dr Louis Elsas for his review and comments on the
manuscript.
References
1. Keating MT, Sanguinetti MC. Molecular and cellular mechanisms of
cardiac arrhythmias. Cell. 2001;104:569–580.
2. Mohler PJ, Schott JJ, Gramolini AO, et al. Ankyrin-B mutation causes
type 4 long-QT cardiac arrhythmia and sudden cardiac death. Nature.
2003;421:634–639.
3. Splawski I, Shen J, Timothy KW, et al. Spectrum of mutations in long-QT
syndrome genes. KVLQT1, HERG, SCN5A, KCNE1, and KCNE2. Circu-
lation. 2000;102:1178–1185.
4. van Langen IM, Birnie E, Alders M, et al. The use of genotype-phenotype
correlations in mutation analysis for the long QT syndrome. J Med Genet.
2003;40:141–145.
5. Schwartz PJ, Priori SG, Dumaine R, et al. A molecular link between the
sudden infant death syndrome and the long-QT syndrome. N Engl J Med.
2000;343:262–267.
6. Ackerman MJ, Siu BL, Sturner WQ, et al. Postmortem molecular analysis
of SCN5A defects in sudden infant death syndrome. JAMA. 2001;286:
2264–2269.
7. Schwartz PJ, Priori SG, Bloise R, et al. Molecular diagnosis in a child
with sudden infant death syndrome. Lancet. 2001;358:1342–1343.
8. van Essen AJ, Abbs S, Baiget M, et al. Parental origin and germline
mosaicism of deletions and duplications of the dystrophin gene: a
European study. Hum Genet. 1992;88:249–257.
9. Sippel KC, Fraioli RE, Smith GD, et al. Frequency of somatic and
germ-line mosaicism in retinoblastoma: implications for genetic coun-
seling. Am J Hum Genet. 1998;62:610–619.
10. Ketterling RP, Vielhaber E, Li X, et al. Germline origins in the human F9
gene: frequent G:C3A:T mosaicism and increased mutations with
advanced maternal age. Hum Genet. 1999;105:629–640.
11. Moyhuddin A, Baser ME, Watson C, et al. Somatic mosaicism in neu-
rofibromatosis 2: prevalence and risk of disease transmission to offspring.
J Med Genet. 2003;40:459–463.
12. Abbott GW, Sesti F, Splawski I, et al. MiRP1 forms IKr potassium
channels with HERG and is associated with cardiac arrhythmia. Cell.
1999;97:175–187.
13. Makita N, Shirai N, Nagashima M, et al. A de novo missense mutation of
human cardiac Naϩ
channel exhibiting novel molecular mechanisms of
long QT syndrome. FEBS Lett. 1998;423:5–9.
14. Yamagishi H, Furutani M, Kamisago M, et al. A de novo missense
mutation (R1623Q) of the SCN5A gene in a Japanese girl with sporadic
long QT syndrome: mutations in brief no. 140: online. Hum Mutat.
1998;11:481.
15. Cuneo BF, Ovadia M, Strasburger JF, et al. Prenatal diagnosis and in
utero treatment of torsades de pointes associated with congenital long QT
syndrome. Am J Cardiol. 2003;91:1395–1398.
16. Trippel DL, Parsons MK, Gillette PC. Infants with long-QT syndrome
and 2:1 atrioventricular block. Am Heart J. 1995;130:1130–1134.
17. Gorgels AP, Al Fadley F, Zaman L, et al. The long QT syndrome with
impaired atrioventricular conduction: a malignant variant in infants.
J Cardiovasc Electrophysiol. 1998;9:1225–1232.
18. Schwartz PJ. Cardiac sympathetic innervation and the sudden infant death
syndrome: a possible pathogenetic link. Am J Med. 1976;60:167–172.
19. Schwartz PJ, Stramba-Badiale M, Segantini A, et al. Prolongation of the
QT interval and the sudden infant death syndrome. N Engl J Med.
1998;338:1709–1714.
Miller et al Recurrent Fetal Loss and Maternal LQTS Mosaicism 3033
at VA MED CTR BOISE on February 10, 2016http://circ.ahajournals.org/Downloaded from
6. 20. Leuer M, Oldenburg J, Lavergne JM, et al. Somatic mosaicism in hemo-
philia A: a fairly common event. Am J Hum Genet. 2001;69:75–87.
21. Lazaro C, Gaona A, Lynch M, et al. Molecular characterization of the
breakpoints of a 12-kb deletion in the NF1 gene in a family showing
germ-line mosaicism. Am J Hum Genet. 1995;57:1044–1049.
22. Lund AM, Schwartz M, Raghunath M, et al. Gly802Asp substitution
in the pro alpha 2(I) collagen chain in a family with recurrent osteo-
genesis imperfecta due to paternal mosaicism. Eur J Hum Genet.
1996;4:39–45.
23. Forissier JF, Richard P, Briault S, et al. First description of germline
mosaicism in familial hypertrophic cardiomyopathy. J Med Genet. 2000;
37:132–134.
24. Miura M, Yamagishi H, Morikawa Y, et al. Congenital long QT
syndrome and 2:1 atrioventricular block with a mutation of the SCN5A
gene. Pediatr Cardiol. 2003;24:70–2.
25. Westenskow P, Splawski I, Timothy KW, et al. Compound mutations: a
common cause of severe long-QT syndrome. Circulation. 2004;109:
1834–1841.
26. Chang IK, Shyu MK, Lee CN, et al. Prenatal diagnosis and treatment of
fetal long QT syndrome: a case report. Prenat Diagn. 2002;22:
1209–1212.
27. Garson A Jr, Dick M 2nd, Fournier A, et al. The long QT syndrome in
children: an international study of 287 patients. Circulation. 1993;87:
1866–1872.
28. Valdivia CR, Ackerman MJ, Tester DJ, et al. A novel SCN5A arrhythmia
mutation, M1766L, with expression defect rescued by mexiletine. Car-
diovasc Res. 2002;55:279–289.
29. Wedekind H, Smits JP, Schulze-Bahr E, et al. De novo mutation in the
SCN5A gene associated with early onset of sudden infant death. Circu-
lation. 2001;104:1158–1164.
30. Schwartz PJ, Priori SG, Spazzolini C, et al. Genotype-phenotype corre-
lation in the long-QT syndrome: gene-specific triggers for life-threatening
arrhythmias. Circulation. 2001;103:89–95.
31. Stuhmer W, Conti F, Suzuki H, et al. Structural parts involved in acti-
vation and inactivation of the sodium channel. Nature. 1989;339:
597–603.
32. Chen Q, Kirsch GE, Zhang D, et al. Genetic basis and molecular
mechanism for idiopathic ventricular fibrillation. Nature. 1998;392:
293–296.
33. Ptacek LJ, George AL Jr, Barchi RL, et al. Mutations in an S4 segment
of the adult skeletal muscle sodium channel cause paramyotonia con-
genita. Neuron. 1992;8:891–897.
34. McClatchey AI, Van den Bergh P, Pericak-Vance MA, et al.
Temperature-sensitive mutations in the III-IV cytoplasmic loop region of
the skeletal muscle sodium channel gene in paramyotonia congenita. Cell.
1992;68:769–774.
35. Kambouris NG, Nuss HB, Johns DC, et al. Phenotypic characterization of
a novel long-QT syndrome mutation (R1623Q) in the cardiac sodium
channel. Circulation. 1998;97:640–644.
36. Zlotogora J. Germ line mosaicism. Hum Genet. 1998;102:381–386.
3034 Circulation June 22, 2004
at VA MED CTR BOISE on February 10, 2016http://circ.ahajournals.org/Downloaded from