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Newborn Screening for X-Linked Adrenoleukodystrophy: Information for Parents
Newborn Screening for X-linked Adrenoleukodystrophy: Information for Parents Baby girl with ABCD1 gene mutation What is newborn screening? the symptoms of ALD during childhood. Rarely, some women who are carriers of ALD develop mild symptoms as adults. It Newborn screening involves laboratory testing on a small is important for your family to meet with a genetic counselor sample of blood collected from newborns’ heels. Every state to talk about the genetics of ALD and implications for other has a newborn screening program to identify infants with rare family members. disorders, which would not usually be detected at birth. Early diagnosis and treatment of these disorders often prevents Why do only boys have ALD? serious complications. Only boys have ALD because it is caused by a mutation in What is adrenoleukodystrophy (ALD)? a gene (ABCD1) on the X chromosome, called “X-linked inheritance.” Males only have one X chromosome so they have ALD is one of over 40 disorders included in newborn screening one ABCD1 gene. Males with a nonfunctioning ABCD1 gene in New York State. It is a rare genetic disorder. People with have ALD. Females have 2 X chromosomes, so they have two ALD are unable to breakdown a component of food called ABCD1 genes. Females with one ABCD1 gene mutation will very long chain fatty acids (VLCFA). If VLCFA are not broken be carriers. When a mother is a carrier of ALD, each son has a down, they build up in the body and cause symptoms. 50% chance of inheriting the disorder and each daughter has a 50% chance of being a carrier. -
Tests Performed Through Our International Collaboration
Tests performed through our international collaboration Molecular Studies for Inborn Errors of Metabolism A Inborn Errors of Metabolism Defective Gene 1 Acyl - Co A oxidase deficiency ACOX 1 2 Argininosuccinate lyase deficiency ASL 3 Aromatic L – amino acid decarboxylase (AADC) DDC Deficiency 4 Carnitine – acylcarnitine translocase (CACT) CACT Deficiency 5 Primary (systemic) carnitine deficiency OCTN2 6 Carnitine palmitoyltransferase I (CPT1) CPT1A 7 Carnitine palmitoyltransferase 2 (CPT2) CPT2 8 CHILD Syndrome NSDHL 9 Conradi – Hunermann – Happle syndrome EBP (CDPX2) 10 D – Bifunctional protein (DBP) Deficiency DBP, MFE2 11 Desmosterolosis DHCR24 12 Dihydropyrimidinase (DHP) Deficiency DPYS 13 Dihydropyrimidine dehydrogenase (DPD) DPYD Deficiency 14 Ethylmalonaciduria ETHE1 (Ethylmalonic encephalopathy) 15 Fructose intolerance, hereditary ALDOB 16 Galactosemia, classic GALT 17 Galactokinase deficiency GALK1 18 Glutaric aciduria type I (Glutaryl – Co A GCDH dehydrogenase deficiency 19 Glycogen storage disease 0 GYS2 20 Greenberg skeletal dysplasia LBR (Sterol – delta 14 reductase deficiency) 21 GTP cyclohydrolase I deficiency GCH1 22 Hydroxyacyl – Co A dehydrogenase deficiency HADH2 (2 – Methyl – 3 – hydroxybutyryl – CoA dehydrogenase deficiency) 23 Hyper Ig D Syndrome MVK (Mevalonate Kinase deficiency) 24 Hyperoxaluria type I AGXT 25 Isovaleric acidemia IVD 26 Lathosterolosis SC5DL 27 3 – methylglutaconicaciduria type I (3 – AUH methylglutaconyl – CoA hydratase deficiency) 28 Medium – chain – acyl – Co A dehydrogenase ACADM (MCAD) Deficiency -
Inherited Peroxisomal Disorders Involving the Nervous System
Arch Dis Child: first published as 10.1136/adc.63.7.767 on 1 July 1988. Downloaded from Archives of Disease in Childhood, i988, 63, 767-770 Annotations Inherited peroxisomal disorders involving the nervous system For genetic reasons peroxisomes may be absent or defective. Because of the great importance of the lack one or more of their enzymes. The result may peroxisomal enzymes involved in the I oxidation of be subtle and long delayed, but is often catastrophic VLCFA and the use of measurements of VLCFA in and immediately recognisable as a serious disorder diagnosis, this group is itself subdivided. Group 3A at birth. The trouble for the clinician is that it is includes those conditions in which VLCFA oxidation often not possible to make a diagnosis unless the is impaired and thus VLCFA accumulates, and right tests are thought of: these tests are not part of group 3B those in which the single enzyme defect is routine 'metabolic screens.' It is first necessary to of another sort. frame the question 'could this be a peroxisomopathy?' The object of this annotation is to help with when GENERALISED PEROXISOMAL DISORDERS (GROUP 1) and how to answer this question. The now classical example is the cerebro-hepato- renal syndrome of Zellweger. l 2The typical neonate Peroxisomes is more dysmorphic than a baby with Down's syndrome with high forehead and huge fontanelle Peroxisomes are subcellular organelles with a single with metopic extension. Inactivity is even greater membrane which occur in every cell apart from the than in the Prader-Willi syndrome and hypotonia mature erythrocyte. -
Pseudo Infantile Refsum's Disease: Catalase- Deficient Peroxisomal Particles with Partial Deficiency of Plasmalogen Synthesis and Oxidation of Fatty Acids
003 I-3998/93/3403-0270$03.00/0 PEDIATRIC RESEARCH Vol. 34. No. 3. 1993 Copyright 8 1993 International Pediatric Research Foundation. Inc I'ritrrid in U S :I. Pseudo Infantile Refsum's Disease: Catalase- Deficient Peroxisomal Particles with Partial Deficiency of Plasmalogen Synthesis and Oxidation of Fatty Acids P. AUBOURG, K. KREMSER, M. 0. ROLAND. F. ROCCHICCIOLI. AND I. SlNGH ABSTRACT. Zellweger syndrome, neonatal adrenoleuko- RCDP, rhizomelic chondrodysplasia punctata dystrophy, and infantile Refsum's disease are genetic dis- IRD, infantile Refsum's disease orders characterized by the virtual absence of catalase- positive perosisomes and a general impairment of perosi- somal functions. Recent studies in these three disorders have provided morphologic evidence of perosisomal Peroxisomes are subcellular organelles that participate in the "ghosts" of density 1.10 g/cd that contain membrane @-oxidation of long-chain fatty acids and VLCFA (1-3), the proteins but lack a majority of the matrix enzyme activities. synthesis of plasmalogens (4), the oxidation of L-pipecolic acid We report here the biochemical studies in a female infant (5, 6). and bile acid synthesis (7). In addition, peroxisomes with clinical features of infantile Refsum's disease whose contain catalase that degrades the Hz02 produced by various liver and fibroblasts contained cytosolic catalase but no oxidases (8). Peroxisomes, like mitochondria. arise by growth catalase-positive peroxisomes. Oxidation of phytanic and and division of preexisting peroxisomes (9). All peroxisomal pipecolic acids was severely impaired, whereas osidation proteins studied so far are synthesized on free polyribosomes, of very-long-chain fatty acids and dihydrosyacetone phos- then translocated into preexisting peroxisomes. -
Diseases Catalogue
Diseases catalogue AA Disorders of amino acid metabolism OMIM Group of disorders affecting genes that codify proteins involved in the catabolism of amino acids or in the functional maintenance of the different coenzymes. AA Alkaptonuria: homogentisate dioxygenase deficiency 203500 AA Phenylketonuria: phenylalanine hydroxylase (PAH) 261600 AA Defects of tetrahydrobiopterine (BH 4) metabolism: AA 6-Piruvoyl-tetrahydropterin synthase deficiency (PTS) 261640 AA Dihydropteridine reductase deficiency (DHPR) 261630 AA Pterin-carbinolamine dehydratase 126090 AA GTP cyclohydrolase I deficiency (GCH1) (autosomal recessive) 233910 AA GTP cyclohydrolase I deficiency (GCH1) (autosomal dominant): Segawa syndrome 600225 AA Sepiapterin reductase deficiency (SPR) 182125 AA Defects of sulfur amino acid metabolism: AA N(5,10)-methylene-tetrahydrofolate reductase deficiency (MTHFR) 236250 AA Homocystinuria due to cystathionine beta-synthase deficiency (CBS) 236200 AA Methionine adenosyltransferase deficiency 250850 AA Methionine synthase deficiency (MTR, cblG) 250940 AA Methionine synthase reductase deficiency; (MTRR, CblE) 236270 AA Sulfite oxidase deficiency 272300 AA Molybdenum cofactor deficiency: combined deficiency of sulfite oxidase and xanthine oxidase 252150 AA S-adenosylhomocysteine hydrolase deficiency 180960 AA Cystathioninuria 219500 AA Hyperhomocysteinemia 603174 AA Defects of gamma-glutathione cycle: glutathione synthetase deficiency (5-oxo-prolinuria) 266130 AA Defects of histidine metabolism: Histidinemia 235800 AA Defects of lysine and -
1 a Clinical Approach to Inherited Metabolic Diseases
1 A Clinical Approach to Inherited Metabolic Diseases Jean-Marie Saudubray, Isabelle Desguerre, Frédéric Sedel, Christiane Charpentier Introduction – 5 1.1 Classification of Inborn Errors of Metabolism – 5 1.1.1 Pathophysiology – 5 1.1.2 Clinical Presentation – 6 1.2 Acute Symptoms in the Neonatal Period and Early Infancy (<1 Year) – 6 1.2.1 Clinical Presentation – 6 1.2.2 Metabolic Derangements and Diagnostic Tests – 10 1.3 Later Onset Acute and Recurrent Attacks (Late Infancy and Beyond) – 11 1.3.1 Clinical Presentation – 11 1.3.2 Metabolic Derangements and Diagnostic Tests – 19 1.4 Chronic and Progressive General Symptoms/Signs – 24 1.4.1 Gastrointestinal Symptoms – 24 1.4.2 Muscle Symptoms – 26 1.4.3 Neurological Symptoms – 26 1.4.4 Specific Associated Neurological Abnormalities – 33 1.5 Specific Organ Symptoms – 39 1.5.1 Cardiology – 39 1.5.2 Dermatology – 39 1.5.3 Dysmorphism – 41 1.5.4 Endocrinology – 41 1.5.5 Gastroenterology – 42 1.5.6 Hematology – 42 1.5.7 Hepatology – 43 1.5.8 Immune System – 44 1.5.9 Myology – 44 1.5.10 Nephrology – 45 1.5.11 Neurology – 45 1.5.12 Ophthalmology – 45 1.5.13 Osteology – 46 1.5.14 Pneumology – 46 1.5.15 Psychiatry – 47 1.5.16 Rheumatology – 47 1.5.17 Stomatology – 47 1.5.18 Vascular Symptoms – 47 References – 47 5 1 1.1 · Classification of Inborn Errors of Metabolism 1.1 Classification of Inborn Errors Introduction of Metabolism Inborn errors of metabolism (IEM) are individually rare, but collectively numerous. -
Peroxisomal Disorders in Neurology
Journal of the Neurological Sciences, 1988, 88:1-39 I Elsevier JNS 03095 Review article Peroxisomal disorders in neurology R. J. A. Wanders 1, H. S.A. Heymans 1'*, R. B. H. Schutgens l, P.G. Barth 2, H. van den Bosch 3 and J.M. Tager 4 Depts. of IPediatrics and 2Neurology, University Hospital Amsterdam, Amsterdam (The Netherlands), 3Laboratory of Biochemistry, State University Utrecht, Utrecht (The Netherlands), and 4Laboratory of Biochemistry, University of Amsterdam, Amsterdam (The Netherlands) (Received 18 August, 1988) (Accepted 29 August, 1988) SUMMARY Although peroxisomes were initially believed to play only a minor role in mam- malian metabolism, it is now clear that they catalyse essential reactions in a number of different metabolic pathways and thus play an indispensable role in intermediary metabolism. The metabolic pathways in which peroxisomes are involved include the biosynthesis of ether phospholipids and bile acids, the oxidation of very long chain fatty acids, prostaglandins and unsaturated long chain fatty acids and the catabolism of phytanate and (in man) pipecolate and glyoxylate. The importance of peroxisomes in cellular metabolism is stressed by the existence of a group of inherited diseases, the peroxisomal disorders, caused by an impairment in one or more peroxisomal functions. In the last decade our knowledge about per- oxisomes and peroxisomal disorders has progressed enormously and has been the subject of several reviews. New developments include the identification of several additional peroxisomal disorders, the discovery of the primary defect in several of these peroxisomal disorders, the recognition of novel peroxisomal functions and the applica- tion of complementation analysis to obtain information on the genetic relationship between the different peroxisomal disorders. -
D-Bifunctional Protein Deficiency – a Cause of Neonatal Onset Seizures and Hypotonia
Accepted Manuscript D-bifunctional protein deficiency – a cause of neonatal onset seizures and hypotonia João Nascimento, Céu Mota, Lúcia Lacerda, Sara Pacheco, Rui Chorão, Esmeralda Martins, Cristina Garrido PII: S0887-8994(15)00037-5 DOI: 10.1016/j.pediatrneurol.2015.01.007 Reference: PNU 8573 To appear in: Pediatric Neurology Received Date: 11 November 2014 Revised Date: 12 January 2015 Accepted Date: 17 January 2015 Please cite this article as: Nascimento J, Mota C, Lacerda L, Pacheco S, Chorão R, Martins E, Garrido C, D-bifunctional protein deficiency – a cause of neonatal onset seizures and hypotonia, Pediatric Neurology (2015), doi: 10.1016/j.pediatrneurol.2015.01.007. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. ACCEPTED MANUSCRIPT Abstract Background: Peroxisomal disorders are classified in two major groups: (1) Peroxisome Biogenesis Disorders and (2) single Peroxisomal Enzyme/Transporter Deficiencies. D-bifunctional protein deficiency (DBP; OMIM #261515) included in this last group of rare diseases leads to an impaired peroxisomal beta-oxidation. D-bifunctional protein deficiencies are classified in four types based on the degree of activity of the 2-enoyl-CoA hydratase and 3-hydroxyacyl-CoA dehydrogenase protein units. Case report/Result: The authors present the first portuguese reported type II DBP deficiency patient, whose neonatal clinical picture is indistinguishable from a Zellweger spectrum disease. -
Zellweger Spectrum Disorder
Zellweger spectrum disorder Description Zellweger spectrum disorder is a group of conditions that have overlapping signs and symptoms and affect many parts of the body. This group of conditions includes Zellweger syndrome, neonatal adrenoleukodystrophy (NALD), and infantile Refsum disease. These conditions were once thought to be distinct disorders but are now considered to be part of the same condition spectrum. Zellweger syndrome is the most severe form of the Zellweger spectrum disorder, NALD is intermediate in severity, and infantile Refsum disease is the least severe form. Because these three conditions are now considered one disorder, some researchers prefer not to use the separate condition names but to instead refer to cases as severe, intermediate, or mild. Individuals with Zellweger syndrome, at the severe end of the spectrum, develop signs and symptoms of the condition during the newborn period. These infants experience weak muscle tone (hypotonia), feeding problems, hearing and vision loss, and seizures. These problems are caused by the breakdown of myelin, which is the covering that protects nerves and promotes the efficient transmission of nerve impulses. The part of the brain and spinal cord that contains myelin is called white matter. Destruction of myelin (demyelination) leads to loss of white matter (leukodystrophy). Children with Zellweger syndrome also develop life-threatening problems in other organs and tissues, such as the liver, heart, and kidneys, and their liver or spleen may be enlarged. They may have skeletal abnormalities, including a large space between the bones of the skull (fontanelles) and characteristic bone spots known as chondrodysplasia punctata that can be seen on x-ray. -
Blueprint Genetics Peroxisomal Disorders Panel
Peroxisomal Disorders Panel Test code: ME0401 Is a 27 gene panel that includes assessment of non-coding variants. Is ideal for patients with a clinical suspicion of infantile Refsum disease, neonatal adrenoleukodystrophy, rhizomelic chondrodysplasia punctata or Zellweger syndrome. The genes on this panel are included in the Comprehensive Metabolism Panel. About Peroxisomal Disorders Peroxisome biogenesis disorders (PBDs) include a disease continuum of Zellweger syndrome spectrum. This spectrum includes three similar disorders. These are the most severe Zellweger syndrome (ZS), adrenoleukodystrophy with neonatal onset (N-ALD) and the mildest infantile Refsum disease (IRD). Disease onset is typically during childhood, when affected children are hypotonic, have seizures, hepatic dysfunction and distinctive craniofacial dysmorphism. Babies with ZS typically have no developmental progress and die during the first year of life. N-ALD and IRD have more variable manifestations from mild to severe. In addition to the Zellweger syndrome spectrum, PBDs include rhizomelic chondrodysplasia punctata (RCDP). PBDs are caused by mutations in the genes encoding proteins important for peroxisome function, assembly or biogenesis. Mutations in these genes results in the accumulation of very long chain fatty acids and branched chain fatty acids. The prevalence of Zellweger syndrome spectrum disorders is estimated at 1:50 000. In addition to peroxisomal biogenesis disorders, this panel has the ability to diagnose several related peroxisomal disorders such as -
Peroxisomes and Central Nervous System Dysgenesis and Dysfunction
Developmental Neurobiulogy, edited by Philippe Evrard and Alexandra Minkowski. Nestle Nutrition Workshop Series, Vol. 12. Nestec Ltd.. Vevey/Raven Press, Ltd., New York © 1989. Peroxisomes and Central Nervous System Dysgenesis and Dysfunction Sidney L. Goldfischer Department of Pathology, Albert Einstein College of Medicine, The Bronx, New York 10461 Peroxisomes play a key role in a number of genetic diseases. These include disor- ders in which the activity of a peroxisomal enzyme is deficient and an extraordinary group of diseases in which the formation of the organelle itself is defective (1-3) (Table 1). DISORDERS OF PEROXISOMAL BIOGENESIS Zellweger's cerebrohepatorenal syndrome (CHRS) is the first disease in which defective formation of peroxisomes was described (4,5). Infants affected with this rare autosomal recessive disorder usually die within one year. Clinical features of the syndrome include a typical facial appearance, with hypertelorism, a high fore- head, and pursed lips; minor skeletal abnormalities; renal cortical cysts; and severe hepatic fibrosis. Iron storage is frequently seen in the early stage of the disease. The most prominent findings are in the central nervous system and include profound hy- potonia. Cerebral abnormalities include polymicrogyria, pachygyria, olivary dys- plasia, and defective neuronal migration. Gliosis and accumulations of lipid in glia are associated with myelin breakdown, and the disease has been described as a suda- nophilic leukodystrophy (6-9). Hepatocellular peroxisomes have not been detected in children with this disease. This remarkable finding has been confirmed by many laboratories (10-13). It is par- ticularly surprising in view of the fact that there are approximately 1,000 peroxi- somes in a normal human hepatocyte (14). -
A New Defect of Peroxisomal Function Involving Pristanic Acid: a Case Report B N Mclean, J Allen, S Ferdinandusse,Rjawanders
J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.72.3.396 on 1 March 2002. Downloaded from 396 SHORT REPORT A new defect of peroxisomal function involving pristanic acid: a case report B N McLean, J Allen, S Ferdinandusse,RJAWanders ............................................................................................................................. J Neurol Neurosurg Psychiatry 2002;72:396–399 In general, peroxisomal disorders present either at birth AN adult onset novel disorder of peroxisomal function is with deficits resulting in severe hypotonia and craniofacial described, characterised by retinitis pigmentosa resulting dysmorphism or as later onset psychomotor retardation, in progressive visual failure, learning difficulties, a periph- seizures, and hepatomegaly. There is, however, a considerable eral neuropathy, and hypogonadism. The defect results in range of clinical problems within a disorder and overlap accumulation of pristanic acid, and the bile acid between disorders, so that some can only be differentiated on intermediates, dihydroxycholestanoic and trihydroxyc- biochemical grounds. holestanoic acid, and is due to a deficiency of We present a case of adult onset neurological disease the α -methylacyl-CoA racemase, making this the first fully features of which were reminiscent of a peroxisomal disorder, characterised description of this defect. Screening of but in a novel combination. patients with retinitis pigmentosa should be extended to The biochemical defect has been recently elucidated, and include pristanic acid and/or bile acid intermediate has been shown to be due to a deficiency of α-methylacyl-CoA concentrations, as dietary measures offer a potential treat- racemase (AMACR) making our patient one of the first adults ment for the disorder. to be described with this condition.16 CASE REPORT A 44 year old man presented with failing vision, having been eroxisomes are subcellular organelles found in all mammalian cell types, and are particularly abundant in suspected by his general practitioner of malingering.