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Article ; Online: De novo mutations in SCN1A are associated with classic Rett syndrome: a case report.

Henriksen, Mari Wold / Ravn, Kirstine / Paus, Benedicte / von Tetzchner, Stephen / Skjeldal, Ola H

BMC medical genetics

2018 Volume 19, Issue 1, Page(s) 184

Abstract: Background: Rett syndrome (RTT) is a neurodevelopmental disorder. In more than 95% of females with classic RTT a pathogenic mutation in MECP2 has been identified. This leaves a small fraction of classic cases with other genetic causes. So far, there has ...

Abstract	Background: Rett syndrome (RTT) is a neurodevelopmental disorder. In more than 95% of females with classic RTT a pathogenic mutation in MECP2 has been identified. This leaves a small fraction of classic cases with other genetic causes. So far, there has not been reported any other gene that may account for the majority of these cases. Case presentation: We describe two females who fulfill the diagnostic criteria for classic RTT, with pathogenic de novo mutations in SCN1A, which usually leads to Dravet syndrome. The developmental history and clinical features of these two females fits well with RTT, but they do have an unusual epileptic profile with early onset of seizures. Investigation of mRNA from one of the females showed a significantly reduced level of MECP2 mRNA. Conclusions: To our knowledge, this is the first report suggesting that SCN1A mutations could account for a proportion of the females with classic RTT without MECP2 mutations. As a consequence of these findings SCN1A should be considered in the molecular routine screening in MECP2-negative individuals with RTT and early onset epilepsy.
MeSH term(s)	Adult ; DNA Mutational Analysis ; Epilepsy/complications ; Epilepsy/diagnosis ; Epilepsy/genetics ; Epilepsy/physiopathology ; Female ; Gene Expression ; Genetic Predisposition to Disease ; Humans ; Methyl-CpG-Binding Protein 2/genetics ; Mutation ; NAV1.1 Voltage-Gated Sodium Channel/genetics ; Phenotype ; Rett Syndrome/complications ; Rett Syndrome/diagnosis ; Rett Syndrome/genetics ; Rett Syndrome/physiopathology
Chemical Substances	MECP2 protein, human ; Methyl-CpG-Binding Protein 2 ; NAV1.1 Voltage-Gated Sodium Channel ; SCN1A protein, human
Language	English
Publishing date	2018-10-11
Publishing country	England
Document type	Case Reports ; Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1471-2350
ISSN (online)	1471-2350
DOI	10.1186/s12881-018-0700-z
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Article ; Online: De novo mutations in SCN1A are associated with classic Rett syndrome

Mari Wold Henriksen / Kirstine Ravn / Benedicte Paus / Stephen von Tetzchner / Ola H Skjeldal

BMC Medical Genetics, Vol 19, Iss 1, Pp 1-

a case report

2018 Volume 5

Abstract: Abstract Background Rett syndrome (RTT) is a neurodevelopmental disorder. In more than 95% of females with classic RTT a pathogenic mutation in MECP2 has been identified. This leaves a small fraction of classic cases with other genetic causes. So far, ... ...

Abstract	Abstract Background Rett syndrome (RTT) is a neurodevelopmental disorder. In more than 95% of females with classic RTT a pathogenic mutation in MECP2 has been identified. This leaves a small fraction of classic cases with other genetic causes. So far, there has not been reported any other gene that may account for the majority of these cases. Case presentation We describe two females who fulfill the diagnostic criteria for classic RTT, with pathogenic de novo mutations in SCN1A, which usually leads to Dravet syndrome. The developmental history and clinical features of these two females fits well with RTT, but they do have an unusual epileptic profile with early onset of seizures. Investigation of mRNA from one of the females showed a significantly reduced level of MECP2 mRNA. Conclusions To our knowledge, this is the first report suggesting that SCN1A mutations could account for a proportion of the females with classic RTT without MECP2 mutations. As a consequence of these findings SCN1A should be considered in the molecular routine screening in MECP2-negative individuals with RTT and early onset epilepsy.
Keywords	Rett syndrome ; Epilepsy ; Genetics ; SCN1A ; Dravet syndrome ; Internal medicine ; RC31-1245 ; QH426-470
Subject code	616
Language	English
Publishing date	2018-10-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
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Article ; Online: Is it possible to diagnose Rett syndrome before classical symptoms become obvious? Review of 24 Danish cases born between 2003 and 2012.

Bisgaard, Anne-Marie / Schönewolf-Greulich, Bitten / Ravn, Kirstine / Rønde, Gitte

European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society

2015 Volume 19, Issue 6, Page(s) 679–687

Abstract: Background/purpose: Rett syndrome (RTT) is a neurodevelopmental disorder that affects mainly females; it results in multiple disabilities and carries a risk of medical comorbidities. Early diagnosis is important to help establish the best treatment ... ...

Abstract	Background/purpose: Rett syndrome (RTT) is a neurodevelopmental disorder that affects mainly females; it results in multiple disabilities and carries a risk of medical comorbidities. Early diagnosis is important to help establish the best treatment opportunities and preventive care in order to slow down the progression of symptoms. We wanted to test our hypothesis that it is possible to diagnose RTT before the classical symptoms become obvious. Methods: We analysed development and symptoms before and at the time of the RTT diagnosis, as well as the symptoms that triggered MECP2 mutation analysis, in a cohort of girls with RTT born in Denmark between 2003 and 2012. Results: Twenty-four girls were included, and 87.5% of these girls were diagnosed when the classical RTT symptoms were recognized. However, parents were concerned about their daughters between 3 and 58 months prior to the RTT diagnosis, and they felt that the professionals did not share their concern in the beginning. When reviewing medical files and questionnaires, we noted that the majority of girls did have combinations of concerning symptoms such as developmental delay and a collection of subtle signs such as autistic traits, placidity, floppiness with suspicion of muscular or mitochondrial diseases, hair pulling, teeth grinding, development of incontinence and problems with initiating movements. Conclusion: We conclude that many individuals with MECP2 mutation exhibit characteristics that should raise suspicion for RTT, prior to evolution of the core clinical criteria. As RTT is a rare disease, it is of importance to constantly educate clinicians for heightened awareness of RTT.
MeSH term(s)	Adolescent ; Autistic Disorder/genetics ; Child ; Child, Preschool ; Denmark ; Developmental Disabilities/genetics ; Early Diagnosis ; Female ; Humans ; Methyl-CpG-Binding Protein 2/genetics ; Mutation ; Phenotype ; Rett Syndrome/complications ; Rett Syndrome/diagnosis ; Rett Syndrome/genetics
Chemical Substances	MECP2 protein, human ; Methyl-CpG-Binding Protein 2
Language	English
Publishing date	2015-11
Publishing country	England
Document type	Journal Article
ZDB-ID	1397146-3
ISSN	1532-2130 ; 1090-3798
ISSN (online)	1532-2130
ISSN	1090-3798
DOI	10.1016/j.ejpn.2015.07.004
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Article ; Online: Hearing impairment and renal failure associated with RMND1 mutations.

Ravn, Kirstine / Neland, Mette / Wibrand, Flemming / Duno, Morten / Ostergaard, Elsebet

American journal of medical genetics. Part A

2015 Volume 170A, Issue 1, Page(s) 142–147

Abstract: Recently, two research groups reported that mutations in RMND1 were associated with encephalopathy, elevated lactate, hypotonia, and in some patients seizures or myoclonia in individuals from two consanguineous families. A combined respiratory chain ... ...

Abstract	Recently, two research groups reported that mutations in RMND1 were associated with encephalopathy, elevated lactate, hypotonia, and in some patients seizures or myoclonia in individuals from two consanguineous families. A combined respiratory chain deficiency and a defect in mitochondrial protein translation was found. In this study, we report two siblings who are compound heterozygous for the mutations, c.713A>G and c.1003delG, in RMND1. Respiratory chain enzymatic analysis and BN-PAGE showed a combined OXPHOS deficiency. Western blot analysis indicated normal levels of RMND1, but the assembly of the RMND1 homopolymeric complex was highly impaired. The two siblings had a markedly milder phenotype and longer survival compared to previously reported patients. In addition, they had renal failure and hearing impairment. These two newly described patients contribute to delineation of the clinical spectrum associated with RMND1 aberrations.
MeSH term(s)	Adolescent ; Amino Acid Sequence ; Cell Cycle Proteins/genetics ; Child ; Child, Preschool ; Female ; Hearing Loss/genetics ; Hearing Loss/pathology ; Humans ; Infant ; Infant, Newborn ; Male ; Mitochondria/genetics ; Mitochondria/pathology ; Mitochondrial Diseases/genetics ; Mitochondrial Diseases/pathology ; Molecular Sequence Data ; Mutation/genetics ; Pedigree ; Protein Biosynthesis ; Renal Insufficiency/genetics ; Renal Insufficiency/pathology ; Sequence Homology, Amino Acid
Chemical Substances	Cell Cycle Proteins ; RMND1 protein, human
Language	English
Publishing date	2015-09-23
Publishing country	United States
Document type	Case Reports ; Journal Article
ZDB-ID	1493479-6
ISSN	1552-4833 ; 1552-4825
ISSN (online)	1552-4833
ISSN	1552-4825
DOI	10.1002/ajmg.a.37399
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Article ; Online: Klinisk og molekylærgenetisk diagnostik af Retts syndrom i Danmark.

Schönewolf-Greulich, Bitten / Dunø, Morten / Ravn, Kirstine / Brøndum-Nielsen, Karen / Bisgaard, Anne-Marie

Ugeskrift for laeger

2015 Volume 177, Issue 27

Abstract: The neurodevelopmental disorder Rett syndrome was first described in 1966 by Andreas Rett, who described girls with loss of speech and hand use displaying characteristic hand stereotypies. Since then, the disease has been linked to mutations in the gene ... ...

Title translation	Clinical molecular genetics diagnostics of Rett syndrome in Denmark.
Abstract	The neurodevelopmental disorder Rett syndrome was first described in 1966 by Andreas Rett, who described girls with loss of speech and hand use displaying characteristic hand stereotypies. Since then, the disease has been linked to mutations in the gene MECP2. However, the basis of the diagnosis is still clinical as defined by the latest clinical criteria as proposed by Neul and colleagues in 2010. This article presents a short clinical and molecular overview of the latest in Rett syndrome with emphasis on the Danish patients, headlines for making the diagnosis, differential diagnoses and molecular diagnostic possibilities.
MeSH term(s)	Denmark ; Diagnosis, Differential ; Disease Progression ; Female ; Humans ; Rett Syndrome/diagnosis ; Rett Syndrome/genetics ; Rett Syndrome/pathology
Language	Danish
Publishing date	2015--29
Publishing country	Denmark
Document type	Journal Article ; Review
ZDB-ID	124102-3
ISSN	1603-6824 ; 0041-5782
ISSN (online)	1603-6824
ISSN	0041-5782
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Article ; Online: Three new loci for determining x chromosome inactivation patterns.

Bertelsen, Birgitte / Tümer, Zeynep / Ravn, Kirstine

The Journal of molecular diagnostics : JMD

2011 Volume 13, Issue 5, Page(s) 537–540

Abstract: The analysis of X chromosome inactivation (XCI) patterns is a widely used diagnostic tool in clinical practice when investigating X-linked diseases. The most commonly used assay to determine XCI patterns takes advantage of a locus within the androgen ... ...

Abstract	The analysis of X chromosome inactivation (XCI) patterns is a widely used diagnostic tool in clinical practice when investigating X-linked diseases. The most commonly used assay to determine XCI patterns takes advantage of a locus within the androgen receptor (AR) gene. This PCR-based assay relies on two differentially methylated restriction enzyme sites (HpaII) and a polymorphic repeat located within this locus. Although highly informative, this locus is not always sufficient to evaluate the X-inactivation status in X-linked disorders. We have identified three new loci that can be used to determine XCI patterns in a methylation-sensitive PCR-based assay. All three loci contain polymorphic repeats and a methylation-sensitive restriction enzyme (HpaII) site, methylation of which was shown to correlate with XCI. DNA from 60 females was used to estimate the heterozygosity of these new loci. The reliability of the loci was validated by showing a high correlation between the results obtained by employing the new loci and the AR locus using DNA from 15 females who were informative for all four loci. Altogether, we show that these loci can be applied easily in molecular diagnostic laboratories, either as a supplement or as an alternative to the existing AR assay.
MeSH term(s)	DNA Methylation/genetics ; Female ; Genetic Loci/genetics ; Heterozygote ; Humans ; Male ; Polymorphism, Genetic ; Receptors, Androgen/genetics ; X Chromosome Inactivation/genetics
Chemical Substances	Receptors, Androgen
Language	English
Publishing date	2011-07-02
Publishing country	United States
Document type	Journal Article
ZDB-ID	2000060-1
ISSN	1943-7811 ; 1525-1578
ISSN (online)	1943-7811
ISSN	1525-1578
DOI	10.1016/j.jmoldx.2011.05.003
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Article ; Online: Semaglutide Effects on Cardiovascular Outcomes in People With Overweight or Obesity (SELECT) rationale and design.

Ryan, Donna H / Lingvay, Ildiko / Colhoun, Helen M / Deanfield, John / Emerson, Scott S / Kahn, Steven E / Kushner, Robert F / Marso, Steve / Plutzky, Jorge / Brown-Frandsen, Kirstine / Gronning, Marianne O L / Hovingh, G Kees / Holst, Anders Gaarsdal / Ravn, Henrik / Lincoff, A Michael

American heart journal

2020 Volume 229, Page(s) 61–69

Abstract: Cardiovascular disease (CVD) is a major cause of morbidity and mortality. Although it has been widely appreciated that obesity is a major risk factor for CVD, treatments that produce effective, durable weight loss and the impact of weight reduction in ... ...

Abstract	Cardiovascular disease (CVD) is a major cause of morbidity and mortality. Although it has been widely appreciated that obesity is a major risk factor for CVD, treatments that produce effective, durable weight loss and the impact of weight reduction in reducing cardiovascular risk have been elusive. Instead, progress in CVD risk reduction has been achieved through medications indicated for controlling lipids, hyperglycemia, blood pressure, heart failure, inflammation, and/or thrombosis. Obesity has been implicated as promoting all these issues, suggesting that sustained, effective weight loss may have independent cardiovascular benefit. GLP-1 receptor agonists (RAs) reduce weight, improve glycemia, decrease cardiovascular events in those with diabetes, and may have additional cardioprotective effects. The GLP-1 RA semaglutide is in phase 3 studies as a medication for obesity treatment at a dose of 2.4 mg subcutaneously (s.c.) once weekly. Semaglutide Effects on Heart Disease and Stroke in Patients with Overweight or Obesity (SELECT) is a randomized, double-blind, parallel-group trial testing if semaglutide 2.4 mg subcutaneously once weekly is superior to placebo when added to standard of care for preventing major adverse cardiovascular events in patients with established CVD and overweight or obesity but without diabetes. SELECT is the first cardiovascular outcomes trial to evaluate superiority in major adverse cardiovascular events reduction for an antiobesity medication in such a population. As such, SELECT has the potential for advancing new approaches to CVD risk reduction while targeting obesity.
MeSH term(s)	Cardiotonic Agents/administration & dosage ; Cardiotonic Agents/adverse effects ; Cardiovascular Diseases/epidemiology ; Cardiovascular Diseases/prevention & control ; Clinical Trials, Phase III as Topic ; Double-Blind Method ; Female ; Glucagon-Like Peptide 1/agonists ; Glucagon-Like Peptides/administration & dosage ; Glucagon-Like Peptides/adverse effects ; Heart Disease Risk Factors ; Humans ; Hypoglycemic Agents/administration & dosage ; Hypoglycemic Agents/adverse effects ; Male ; Middle Aged ; Obesity/diagnosis ; Obesity/drug therapy ; Obesity/metabolism ; Outcome Assessment, Health Care ; Overweight/diagnosis ; Overweight/drug therapy ; Overweight/metabolism ; Randomized Controlled Trials as Topic ; Weight Loss/drug effects
Chemical Substances	Cardiotonic Agents ; Hypoglycemic Agents ; semaglutide (53AXN4NNHX) ; Glucagon-Like Peptides (62340-29-8) ; Glucagon-Like Peptide 1 (89750-14-1)
Language	English
Publishing date	2020-07-17
Publishing country	United States
Document type	Clinical Trial Protocol ; Journal Article
ZDB-ID	80026-0
ISSN	1097-6744 ; 0002-8703
ISSN (online)	1097-6744
ISSN	0002-8703
DOI	10.1016/j.ahj.2020.07.008
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Article ; Online: Segregation of a 4p16.3 duplication with a characteristic appearance, macrocephaly, speech delay and mild intellectual disability in a 3-generation family.

Schönewolf-Greulich, Bitten / Ravn, Kirstine / Hamborg-Petersen, Bente / Brøndum-Nielsen, Karen / Tümer, Zeynep

American journal of medical genetics. Part A

2013 Volume 161A, Issue 9, Page(s) 2358–2362

Abstract: Microscopically visible rearrangements of chromosome 4p includes the two well known abnormalities: partial trisomy 4p, and deletions of the Wolf-Hirschhorn critical regions 1 and 2 (WHSCR 1 and WHSCR2, respectively), which cause well-defined phenotypes ... ...

Abstract	Microscopically visible rearrangements of chromosome 4p includes the two well known abnormalities: partial trisomy 4p, and deletions of the Wolf-Hirschhorn critical regions 1 and 2 (WHSCR 1 and WHSCR2, respectively), which cause well-defined phenotypes including minor anomalies, and developmental delay/intellectual disability. In contrast small duplications of 4p are rare but with the advent of microarray techniques a few cases have been reported in recent years. Here we describe a 3 Mb duplication at 4p16.3 segregating with a characteristic phenotype, macrocephaly, speech delay and mild intellectual disability in a three generation family.
MeSH term(s)	Child ; Chromosome Duplication ; Chromosome Mapping ; Chromosomes, Human, Pair 4 ; Comparative Genomic Hybridization ; Female ; Humans ; In Situ Hybridization, Fluorescence ; Intellectual Disability/diagnosis ; Intellectual Disability/genetics ; Language Development Disorders/diagnosis ; Language Development Disorders/genetics ; Megalencephaly/diagnosis ; Megalencephaly/genetics ; Nondisjunction, Genetic ; Pedigree ; Phenotype
Language	English
Publishing date	2013-07-25
Publishing country	United States
Document type	Case Reports ; Journal Article
ZDB-ID	1493479-6
ISSN	1552-4833 ; 1552-4825
ISSN (online)	1552-4833
ISSN	1552-4825
DOI	10.1002/ajmg.a.36099
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Article: Neonatal mitochondrial hepatoencephalopathy caused by novel GFM1 mutations.

Ravn, Kirstine / Schönewolf-Greulich, Bitten / Hansen, Rikke M / Bohr, Anna-Helene / Duno, Morten / Wibrand, Flemming / Ostergaard, Elsebet

Molecular genetics and metabolism reports

2015 Volume 3, Page(s) 5–10

Abstract: Disorders caused by defects in the mitochondrial translation system are clinically and genetically heterogeneous. The elongation phase of mitochondrial protein synthesis requires, among many other components, three nuclear-encoded elongation factors: ... ...

Abstract	Disorders caused by defects in the mitochondrial translation system are clinically and genetically heterogeneous. The elongation phase of mitochondrial protein synthesis requires, among many other components, three nuclear-encoded elongation factors: EFTu (TUFM; 602389), EFTs (TSFM; 604723), and EFG1 (GFM1; 606639). Mutations have been identified in the genes encoding all three elongation factors, and they result in combined respiratory chain deficiencies and severe phenotypes with an early fatal outcome. So far, only eleven patients have been reported with mutations in GFM1. Here we describe an additional three patients with novel GFM1 mutations. Our results confirm the tissue-specific effect of GFM1 mutations, since we found only slightly decreased respiratory chain enzyme activities in muscle and fibroblasts, but a severe deficiency in the liver. Hence, a thorough biochemical evaluation is important to guide genetic investigation in patients suspected for a mitochondrial disorder.
Language	English
Publishing date	2015-02-20
Publishing country	United States
Document type	Journal Article
ZDB-ID	2821908-9
ISSN	2214-4269
ISSN	2214-4269
DOI	10.1016/j.ymgmr.2015.01.004
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Article ; Online: Diploid/triploid mosaicism: a rare event or an under-diagnosed syndrome?

Boonen, Susanne E / Hoffmann, Anne Lisbeth / Donnai, Dian / Tümer, Zeynep / Ravn, Kirstine

European journal of medical genetics

2011 Volume 54, Issue 3, Page(s) 374–375

MeSH term(s)	Abnormalities, Multiple/genetics ; Abnormalities, Multiple/pathology ; Adolescent ; Child ; Child, Preschool ; Chromosome Disorders/genetics ; Chromosome Disorders/pathology ; Diploidy ; Female ; Follow-Up Studies ; Humans ; Mosaicism ; Syndrome ; Triploidy
Language	English
Publishing date	2011-05
Publishing country	Netherlands
Document type	Case Reports ; Letter
ZDB-ID	2184135-4
ISSN	1878-0849 ; 1769-7212
ISSN (online)	1878-0849
ISSN	1769-7212
DOI	10.1016/j.ejmg.2011.01.002
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