Prenatal Testing Requisition
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Leading Article the Molecular and Genetic Base of Congenital Transport
Gut 2000;46:585–587 585 Gut: first published as 10.1136/gut.46.5.585 on 1 May 2000. Downloaded from Leading article The molecular and genetic base of congenital transport defects In the past 10 years, several monogenetic abnormalities Given the size of SGLT1 mRNA (2.3 kb), the gene is large, have been identified in families with congenital intestinal with 15 exons, and the introns range between 3 and 2.2 kb. transport defects. Wright and colleagues12 described the A single base change was identified in the entire coding first, which concerns congenital glucose and galactose region of one child, a finding that was confirmed in the malabsorption. Subsequently, altered genes were identified other aZicted sister. This was a homozygous guanine to in partial or total loss of nutrient absorption, including adenine base change at position 92. The patient’s parents cystinuria, lysinuric protein intolerance, Menkes’ disease were heterozygotes for this mutation. In addition, it was (copper malabsorption), bile salt malabsorption, certain found that the 92 mutation was associated with inhibition forms of lipid malabsorption, and congenital chloride diar- of sugar transport by the protein. Since the first familial rhoea. Altered genes may also result in decreased secretion study, genomic DNA has been screened in 31 symptomatic (for chloride in cystic fibrosis) or increased absorption (for GGM patients in 27 kindred from diVerent parts of the sodium in Liddle’s syndrome or copper in Wilson’s world. In all 33 cases the mutation produced truncated or disease)—for general review see Scriver and colleagues,3 mutant proteins. -
The Inherited Metabolic Disorders News
The Inherited Metabolic Disorders News Summer 2011 Volume 8 Issue 2 From the Editor I hope everyone is enjoying their summer thus far! Our 8th annual Metabolic Family Day and 7th annual Low In this Issue Protein Cooking Demonstration were once again a huge success. See the section ”What’s New” on page 9 for a full report of the events, as well as pictures. ♦ From the Editor…1 As always, your suggestions and stories are welcome. Please contact me by email: [email protected] or telephone 519-685-8453 if you wish to contribute to the ♦ From Dr. Chitra Prasad…1 newsletter. I hope everyone has a safe and happy summer! ♦ Personal Stories… 2 Janice Little ♦ Featured This Issue … 4 From Dr Chitra Prasad ♦ Suzanne’s Corner… 6 Dear Friends, ♦ What’s New… 8 Hope you all are having a wonderful summer. We had a great metabolic family workshop with around 198 registrants this year. This was truly phenomenal. Thanks to all the team members and ♦ Research & Presentations … 13 the families in the planning committee for doing such a fantastic job. I was really touched when one of our young metabolic patients told her parents that she would like to attend the ♦ How to Make a Donation… 14 metabolic family workshop! Please see some of the highlights of the metabolic workshop in the newsletter for those who could not make it. The speeches by our youth (Sadiq, Leanna and Laura) ♦ Contact Information … 15 were appreciated by everyone. Big thanks to Jill Tosswill (our previous social worker) who coordinated their talks. -
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CCR PEDIATRIC ONCOLOGY SERIES CCR Pediatric Oncology Series Recommendations for Childhood Cancer Screening and Surveillance in DNA Repair Disorders Michael F. Walsh1, Vivian Y. Chang2, Wendy K. Kohlmann3, Hamish S. Scott4, Christopher Cunniff5, Franck Bourdeaut6, Jan J. Molenaar7, Christopher C. Porter8, John T. Sandlund9, Sharon E. Plon10, Lisa L. Wang10, and Sharon A. Savage11 Abstract DNA repair syndromes are heterogeneous disorders caused by around the world to discuss and develop cancer surveillance pathogenic variants in genes encoding proteins key in DNA guidelines for children with cancer-prone disorders. Herein, replication and/or the cellular response to DNA damage. The we focus on the more common of the rare DNA repair dis- majority of these syndromes are inherited in an autosomal- orders: ataxia telangiectasia, Bloom syndrome, Fanconi ane- recessive manner, but autosomal-dominant and X-linked reces- mia, dyskeratosis congenita, Nijmegen breakage syndrome, sive disorders also exist. The clinical features of patients with DNA Rothmund–Thomson syndrome, and Xeroderma pigmento- repair syndromes are highly varied and dependent on the under- sum. Dedicated syndrome registries and a combination of lying genetic cause. Notably, all patients have elevated risks of basic science and clinical research have led to important in- syndrome-associated cancers, and many of these cancers present sights into the underlying biology of these disorders. Given the in childhood. Although it is clear that the risk of cancer is rarity of these disorders, it is recommended that centralized increased, there are limited data defining the true incidence of centers of excellence be involved directly or through consulta- cancer and almost no evidence-based approaches to cancer tion in caring for patients with heritable DNA repair syn- surveillance in patients with DNA repair disorders. -
EXTENDED CARRIER SCREENING Peace of Mind for Planned Pregnancies
Focusing on Personalised Medicine EXTENDED CARRIER SCREENING Peace of Mind for Planned Pregnancies Extended carrier screening is an important tool for prospective parents to help them determine their risk of having a child affected with a heritable disease. In many cases, parents aren’t aware they are carriers and have no family history due to the rarity of some diseases in the general population. What is covered by the screening? Genomics For Life offers a comprehensive Extended Carrier Screening test, providing prospective parents with the information they require when planning their pregnancy. Extended Carrier Screening has been shown to detect carriers who would not have been considered candidates for traditional risk- based screening. With a simple mouth swab collection, we are able to test for over 419 genes associated with inherited diseases, including Fragile X Syndrome, Cystic Fibrosis and Spinal Muscular Atrophy. The assay has been developed in conjunction with clinical molecular geneticists, and includes genes listed in the NIH Genetic Test Registry. For a list of genes and disorders covered, please see the reverse of this brochure. If your gene of interest is not covered on our Extended Carrier Screening panel, please contact our friendly team to assist you in finding a gene test panel that suits your needs. Why have Extended Carrier Screening? Extended Carrier Screening prior to pregnancy enables couples to learn about their reproductive risk and consider a complete range of reproductive options, including whether or not to become pregnant, whether to use advanced reproductive technologies, such as preimplantation genetic diagnosis, or to use donor gametes. -
CCR PEDIATRIC ONCOLOGY SERIES CCR Pediatric Oncology Series Recommendations for Surveillance for Children with Leukemia-Predisposing Conditions Christopher C
CCR PEDIATRIC ONCOLOGY SERIES CCR Pediatric Oncology Series Recommendations for Surveillance for Children with Leukemia-Predisposing Conditions Christopher C. Porter1, Todd E. Druley2, Ayelet Erez3, Roland P. Kuiper4, Kenan Onel5, Joshua D. Schiffman6, Kami Wolfe Schneider7, Sarah R. Scollon8, Hamish S. Scott9, Louise C. Strong10, Michael F. Walsh11, and Kim E. Nichols12 Abstract Leukemia, the most common childhood cancer, has long been patients. The panel recognized that for several conditions, recognized to occasionally run in families. The first clues about routine monitoring with complete blood counts and bone the genetic mechanisms underlying familial leukemia emerged marrow evaluations is essential to identify disease evolution in 1990 when Li-Fraumeni syndrome was linked to TP53 muta- and enable early intervention with allogeneic hematopoietic tions. Since this discovery, many other genes associated with stem cell transplantation. However, for others, less intensive hereditary predisposition to leukemia have been identified. surveillance may be considered. Because few reports describ- Although several of these disorders also predispose individuals ing the efficacy of surveillance exist, the recommendations to solid tumors, certain conditions exist in which individuals are derived by this panel are based on opinion, and local expe- specifically at increased risk to develop myelodysplastic syn- rience and will need to be revised over time. The development drome (MDS) and/or acute leukemia. The increasing identifica- of registries and clinical trials is urgently needed to enhance tion of affected individuals and families has raised questions understanding of the natural history of the leukemia-predis- around the efficacy, timing, and optimal methods of surveil- posing conditions, such that these surveillance recommenda- lance. -
Mutation of the Fumarase Gene in Two Siblings with Progressive Encephalopathy and Fumarase Deficiency T
Mutation of the Fumarase Gene in Two Siblings with Progressive Encephalopathy and Fumarase Deficiency T. Bourgeron,* D. Chretien,* J. Poggi-Bach, S. Doonan,' D. Rabier,* P. Letouze,I A. Munnich,* A. R6tig,* P. Landneu,* and P. Rustin* *Unite de Recherches sur les Handicaps Genetiques de l'Enfant, INSERM U393, Departement de Pediatrie et Departement de Biochimie, H6pital des Enfants-Malades, 149, rue de Sevres, 75743 Paris Cedex 15, France; tDepartement de Pediatrie, Service de Neurologie et Laboratoire de Biochimie, Hopital du Kremlin-Bicetre, France; IFaculty ofScience, University ofEast-London, UK; and IService de Pediatrie, Hopital de Dreux, France Abstract chondrial enzyme (7). Human tissue fumarase is almost We report an inborn error of the tricarboxylic acid cycle, fu- equally distributed between the mitochondria, where the en- marase deficiency, in two siblings born to first cousin parents. zyme catalyzes the reversible hydration of fumarate to malate They presented with progressive encephalopathy, dystonia, as a part ofthe tricarboxylic acid cycle, and the cytosol, where it leucopenia, and neutropenia. Elevation oflactate in the cerebro- is involved in the metabolism of the fumarate released by the spinal fluid and high fumarate excretion in the urine led us to urea cycle. The two isoenzymes have quite homologous struc- investigate the activities of the respiratory chain and of the tures. In rat liver, they differ only by the acetylation of the Krebs cycle, and to finally identify fumarase deficiency in these NH2-terminal amino acid of the cytosolic form (8). In all spe- two children. The deficiency was profound and present in all cies investigated so far, the two isoenzymes have been found to tissues investigated, affecting the cytosolic and the mitochon- be encoded by a single gene (9,10). -
The Counsyl Foresight™ Carrier Screen
The Counsyl Foresight™ Carrier Screen 180 Kimball Way | South San Francisco, CA 94080 www.counsyl.com | [email protected] | (888) COUNSYL The Counsyl Foresight Carrier Screen - Disease Reference Book 11-beta-hydroxylase-deficient Congenital Adrenal Hyperplasia .................................................................................................................................................................................... 8 21-hydroxylase-deficient Congenital Adrenal Hyperplasia ...........................................................................................................................................................................................10 6-pyruvoyl-tetrahydropterin Synthase Deficiency ..........................................................................................................................................................................................................12 ABCC8-related Hyperinsulinism........................................................................................................................................................................................................................................ 14 Adenosine Deaminase Deficiency .................................................................................................................................................................................................................................... 16 Alpha Thalassemia............................................................................................................................................................................................................................................................. -
Menkes Disease in 5 Siblings
Cu(e) the balancing act: Copper homeostasis explored in 5 siblings Poster with variable clinical course 595 Sonia A Varghese MD MPH MBA and Yael Shiloh-Malawsky MD Objective Methods Case Presentation Discussion v Present a unique variation of v Review literature describing v The graph below depicts the phenotypic spectrum seen in the 5 brothers v ATP7A mutations produce a clinical spectrum phenotype and course in siblings copper transport disorders v Mom is a known carrier of ATP7A mutation v Siblings 1, 2, and 5 follow a more classic with Menkes Disease (MD) v Apply findings to our case of five v There is limited information on the siblings who were not seen at UNC Menke’s course, while siblings 3 and 4 exhibit affected siblings v The 6th sibling is the youngest and is a healthy female infant (not included here) a phenotypic variation Sibling: v This variation is suggestive of a milder form of Background Treatment birth Presentation Exam Diagnostic testing Outcomes Copper Histidine Menkes such as occipital horn syndrome with v Mutations in ATP7A: copper deficiency order D: 16mos residual copper transport function (Menkes disease) O/AD: 1 Infancy/12mos N/A N/A No Brain v Siblings 3 and 4 had improvement with copper v Mutations in ATP7B: copper overload FTT, Seizures, DD hemorrhage supplementation, however declined when off (Wilson disease) O/AD: Infancy/NA D: 13mos supplementation -suggesting residual ATP7A v The amount of residual functioning 2 N/A N/A No FTT, FTT copper transport function copper transport influences disease Meningitis -
Harlequin Ichthyosis
orphananesthesia Anaesthesia recommendations for patients suffering from Harlequin ichthyosis Disease name: Harlequin ichthyosis ICD 10: Q80.4 Synonyms: Harlequin baby, ichthyosis congenita, Ichthyosis fetalis, keratosis diffusa fetalis, Harlequin fetus, Ichthyosis congenita gravior Disease summary: Harlequin ichthyosis (HI) is an autosomal recessive congenital ichthyosis. HI is an extremely rare and most severe form of ichthyosis. The condition is caused by mutation of the ABCA12 gene resulting in impaired lipid transport in the outermost layer of the skin, the epidermis. During the neontatal period, harlequin ichthyosis manifests phenotypically as dramatic large polygonal plate-like scaling of the skin that cracks and can slough, revealing the underlying diffusely bright red skin. These thick skin plates can pull and distort facial features. The tightness of the skin can also pull on the eyes and mouth resulting in difficulties with closing these structures. The tightness also causes the eyes and the mouth to turn inside out resulting in ectropion and eclabium. Other features include hypoplasia of the fingers, malformation of the ears and nose, and alopecia. Affected neonates often do not survive and mortality is commonly attributed to respiratory failure and/or sepsis. Clinical data obtained from 45 HI patients revealed 25 survivors and 20 deaths with an overall survival rate of only 56%. The ages of survivors ranged from 10 months to 25 years and death usually occurred in the first 3 months. HI infants need to be cared for in a neonatal intensive care unit immediately after birth. Several harlequin neonates have survived. They tend to have severe erythroderma and fine scaling, even with optimal management. -
Disease Reference Book
The Counsyl Foresight™ Carrier Screen 180 Kimball Way | South San Francisco, CA 94080 www.counsyl.com | [email protected] | (888) COUNSYL The Counsyl Foresight Carrier Screen - Disease Reference Book 11-beta-hydroxylase-deficient Congenital Adrenal Hyperplasia .................................................................................................................................................................................... 8 21-hydroxylase-deficient Congenital Adrenal Hyperplasia ...........................................................................................................................................................................................10 6-pyruvoyl-tetrahydropterin Synthase Deficiency ..........................................................................................................................................................................................................12 ABCC8-related Hyperinsulinism........................................................................................................................................................................................................................................ 14 Adenosine Deaminase Deficiency .................................................................................................................................................................................................................................... 16 Alpha Thalassemia............................................................................................................................................................................................................................................................. -
Saethre-Chotzen Syndrome
Saethre-Chotzen syndrome Authors: Professor L. Clauser1 and Doctor M. Galié Creation Date: June 2002 Update: July 2004 Scientific Editor: Professor Raoul CM. Hennekam 1Department of craniomaxillofacial surgery, St. Anna Hospital and University, Corso Giovecca, 203, 44100 Ferrara, Italy. [email protected] Abstract Keywords Disease name and synonyms Excluded diseases Definition Prevalence Management including treatment Etiology Diagnostic methods Genetic counseling Antenatal diagnosis Unresolved questions References Abstract Saethre-Chotzen Syndrome (SCS) is an inherited craniosynostotic condition, with both premature fusion of cranial sutures (craniostenosis) and limb abnormalities. The most common clinical features, present in more than a third of patients, consist of coronal synostosis, brachycephaly, low frontal hairline, facial asymmetry, hypertelorism, broad halluces, and clinodactyly. The estimated birth incidence is 1/25,000 to 1/50,000 but because the phenotype can be very mild, the entity is likely to be underdiagnosed. SCS is inherited as an autosomal dominant trait with a high penetrance and variable expression. The TWIST gene located at chromosome 7p21-p22, is responsible for SCS and encodes a transcription factor regulating head mesenchyme cell development during cranial tube formation. Some patients with an overlapping SCS phenotype have mutations in the FGFR3 (fibroblast growth factor receptor 3) gene; especially the Pro250Arg mutation in FGFR3 (Muenke syndrome) can resemble SCS to a great extent. Significant intrafamilial -
Alport Syndrome of the European Dialysis Population Suffers from AS [26], and Simi- Lar Figures Have Been Found in Other Series
DOCTOR OF MEDICAL SCIENCE Patients with AS constitute 2.3% (11/476) of the renal transplant population at the Mayo Clinic [24], and 1.3% of 1,000 consecutive kidney transplant patients from Sweden [25]. Approximately 0.56% Alport syndrome of the European dialysis population suffers from AS [26], and simi- lar figures have been found in other series. AS accounts for 18% of Molecular genetic aspects the patients undergoing dialysis or having received a kidney graft in 2003 in French Polynesia [27]. A common founder mutation was in Jens Michael Hertz this area. In Denmark, the percentage of patients with AS among all patients starting treatment for ESRD ranges from 0 to 1.21% (mean: 0.42%) in a twelve year period from 1990 to 2001 (Danish National This review has been accepted as a thesis together with nine previously pub- Registry. Report on Dialysis and Transplantation in Denmark 2001). lished papers by the University of Aarhus, February 5, 2009, and defended on This is probably an underestimate due to the difficulties of establish- May 15, 2009. ing the diagnosis. Department of Clinical Genetics, Aarhus University Hospital, and Faculty of Health Sciences, Aarhus University, Denmark. 1.3 CLINICAL FEATURES OF X-LINKED AS Correspondence: Klinisk Genetisk Afdeling, Århus Sygehus, Århus Univer- 1.3.1 Renal features sitetshospital, Nørrebrogade 44, 8000 Århus C, Denmark. AS in its classic form is a hereditary nephropathy associated with E-mail: [email protected] sensorineural hearing loss and ocular manifestations. The charac- Official opponents: Lisbeth Tranebjærg, Allan Meldgaard Lund, and Torben teristic renal features in AS are persistent microscopic hematuria ap- F.