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Krabbe Disease montekids.org The Changing Landscape of Newborn Screening Melissa Wasserstein, MD Chief, Division of Pediatric Genetic Medicine Associate Professor, Pediatrics and Genetics montekids.org Continuing Education Disclosures • Commercial Support This educational activity received no commercial support. • Disclosure of Conflict of Interest Dr. Wasserstein has a consulting relationship and has received reimbursement for travel as well as research support from Sanofi Genzyme Corporation. • Off Label Use The speaker has not disclosed the use of products for a purpose other than what they have had been approved for by the Food and Drug Administration. 2 montekids.org What is newborn screening? A public health program to identify children at increased risk for selected diseases in order to prevent • Death • Irreversible neurological and mental sequelae montekids.org PKU: Initial Discovery “These parents were intelligent and educated, and the children were attractive but severely retarded and irritable with destructive behavior. “ PEDIATRICS Vol. 105 No. 1 January 2000, pp. 89-103 montekids.org Jervis G. Phenylpyruvic oligophrenia: introductory study of 50 cases of mental deficiency associatedCOMMON with excretion of phenylpyruvic acid. Archives of Neurology and Psychiatry 1937;38:944. Bickle H, Gerrard J, Hickmans EM. TREATABLE Influence of phenylalanine intake on phenylketonuria. Lancet 1953;2:812. DETECTABLE Dr. Robert Guthrie, 1916-1995 montekids.org NYS Newborn Screening Panel: 2016 Inborn Errors of Metabolism: Fatty Oxidation Disorders 2,4-Dienoyl-CoA reductase (2,4-Di) deficiency Carnitine acylcarnitine translocase (CAT) deficiency Carnitine palmitoyltransferase 2 (CPT-II) deficiency Carnitine palmitoyltransferase I (CPT-I) deficiency Carnitine Uptake Defect (CUD) Long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency Medium-chain 3-ketoacyl-CoA thiolase (MCKAT) deficiency Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency Medium/short-chain 3-hydroxyacyl-CoA dehydrogenase (M/SCHAD) deficiency Multiple acyl-CoA dehydrogenase deficiency (MADD) Short-chain acyl-CoA dehydrogenase (SCAD) deficiency Trifunctional Protein (TFP) Deficiency Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency Inborn Errors of Metabolism: Organic Acid Disorders 2-methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency (MHBD) 2-Methylbutyryl-CoA dehydrogenase (2-MBCD) deficiency 3-hydroxy-3-methylglutaryl-CoA lyase (HMG-CoA lyase) deficiency 3-Methylcrotonyl-CoA carboxylase deficiency (3-MCC) 3-methylglutaconic acidemia, type 1 (3-MGA) Beta-ketothiolase (BKT) deficiency Cobalamin A,B cofactor deficiency (Cbl A,B) Cobalamin C,D cofactor deficiency (Cbl C,D) Galactosemia (GALT) Glutaric acidemia, type I (GA-I) Isobutyryl-CoA dehydrogenase (IBCD) deficiency Isovaleric Acidemia (IVA) Malonic Aciduria (MA) Methylmalonyl-CoA mutase deficiency (MUT) Multiple carboxylase deficiency (MCD) Propionic Acidemia (PA) montekids.org NYS Newborn Screening Panel 2016 (Cont’d) Inborn Errors of Metabolism: Urea Cycle Disorders Argininemia (ARG) Argininosuccinic aciduria (ASA) deficiency Citrullinemia (CIT) Infectious Diseases Human Immunodeficiency Virus (HIV) Inborn Errors of Metabolism: Amino Acid Disorders Homocystinuria (HCY) Hypermethionemia (HMET) Maple Syrup Urine Disease (MSUD) Phenylketonuria (PKU) Tyrosinemia type I Tyrosinemia type II Tyrosinemia type III Hemoglobinopathies Sickle Cell Disease (S/S and S/C) and Sickle Cell Trait (carrier) Endocrine disorders Congenital Adrenal Hyperplasia (CAH) Congenital Hypothyroidism (CH) Other Genetic Conditions Krabbe Disease Adrenoleukodystrophy (ALD) Biotinidase Deficiency (BIOT) Cystic Fibrosis (CF) Pompe Disease (GAA) Severe Combined Immunodeficiency (SCID) montekids.org Wilson and Jungner Criteria for inclusion on NBS panel • Accurate screening test • Regular review of scientific and medical rationale • Significant life-challenging risk of morbidity if the disorder is untreated • Total costs of the system from diagnosis to follow-up must be reasonably priced • Significant prevalence of the disorder • Natural history of the disease understood • Consumer involvement, physician and public health acceptance in the decision to mandate screening • Positive health benefits must outweigh risks and burdens • The disorder must be treatable and require early treatment • Resources for and access to confirmatory testing, treatment and counseling. montekids.org The ACHDNC and the RUSP • The Advisory Committee on Heritable Disorders in Newborns and Children (“the ACHDNC”) was established under the Public Health Service Act, Title XI, § 1109 (42 U.S.C. 300b-10), as amended by the Newborn Screening Saves Lives Reauthorization Act of 2014 (P.L. 113-240). • The Committee recommends that every newborn screening program include a Uniform Screening Panel that screens for 32 core disorders and 26 secondary disorders (aka “the RUSP”) • While the RUSP provides recommendations, states are free to choose their own NBS panels montekids.org NY State Newborn Screening for Krabbe Disease montekids.org Krabbe disease Progressive neurodegenerative leukodystrophy caused by inherited deficiency of galactocerebrosidase (GALC) Infantile form (85-90%) – Early infantile Krabbe disease presents before six months of age • Irritability, dysphagia, progressive spasticity, developmental regression, blindness, deafness, seizures, and death before 2 years of age – Late infantile Krabbe disease presents between six and twelve months of age • Progressive neurodegenerative course Late-Onset form (10-15%) – Variable age of onset from 6 months to 60 years of age – Weakness, vision loss, intellectual regression, ataxia montekids.org N Engl J Med. 2005 May 19;352(20):2069-81 montekids.org UCB Transplantation For Infantile Krabbe disease 25 patients with a form of infantile Krabbe disease . GALC activity and genotype not reported . Many diagnosed in utero because of + family history . 11 asymptomatic newborns (12-44 days of age) . 14 symptomatic infants (142-352 days of age) Underwent myeloablative chemotherapy and umbilical cord blood transplantation at Duke University . Newborn transplants: . No deaths, many had progressive myelination and most acquired developmental skills . Symptomatic transplants: . 57% died, no survivors showed improvement montekids.org Newborn Screening for Krabbe Disease Rationale: – Based on NEJM paper, bone marrow transplantation can favorably alter the outcome of infantile Krabbe disease if performed presymptomatically – As untreated infantile Krabbe disease is uniformly fatal, NBS for Krabbe disease was advocated by family support groups In 2006, NY was mandated to screen all newborns for Krabbe disease montekids.org But…. • The ACHDNC advised against including Krabbe disease on the RUSP, citing insufficient knowledge about: – Accuracy of screening • Screening can’t differentiate early vs later onset phenotype – Diagnostic strategy • How do you know which asymptomatic newborn needs treatment? – Benefits and harms of treatment • Bone marrow transplant has high morbidity and mortality – Long term prognosis of bone marrow transplantation • NEJM study had median follow up of 3 years • Reports of progressive gross motor delay in children with Krabbe disease after successful transplantation montekids.org The New York State Krabbe Consortium Established in 2006, prior to “live screening” Diverse group of experts in NBS, neurology, bone marrow transplantation, biochemical genetics, neuroradiologists, patient advocates, ethicists Initial Tasks – Develop risk category • To distinguish which asymptomatic newborns need further evaluation – Create neurodiagnostic algorithm and scoring system • To determine which “at risk” infants need emergent transplantation montekids.org Risk categorization Risk category based on GALC activity in leukocytes • Always performed at the Thomas Jefferson Lysosomal Diseases Testing Laboratory using a tritium-labeled galactosylceramide • Infants with the lowest enzyme activity were predicted to have the highest risk of developing Krabbe disease GALC Activity (nmol/hr/mg) Risk Category 2006-2011 After 2012 High 0-0.15 0-0.15 Moderate 0.16-0.29 0.16-0.29 or 0.30-0.50 + two mutations Low 0.30-0.50 Eliminated Not at risk >0.50 ≥0.30 montekids.org Neurodiagnostic evaluation for high risk infants Components - Brain MRI - Lumbar puncture to measure CSF protein - Nerve conduction velocity - Brainstem auditory evoked response montekids.org Assessment schedule 0-12 months 13-36 months 37-60 months Years 6-10 High Risk Neurological Every month Every 3 months Every 6 months Annual Examinations Neurodiagnostic 0, 4, 8, 12 months As needed As needed As needed Evaluations Moderate Risk Neurological Every 3 months Every 3 months Every 6 months Annual Examinations Neurodiagnostic At 12 months As needed As needed As needed Evaluations montekids.org Krabbe Scoring System • Based on neurodiagnostic scoring system Parameter Points Abnormal Neurologic Exam 2 Abnormal MRI 2 Elevated CSF Protein 2 Abnormal Nerve Conduction Velocity 2 Abnormal Brainstem Auditory Evoked Response 1 30KB Homozygous Deletion 4 Infants with a score ≥ 4 are candidates for bone marrow transplantation montekids.org Flow Diagram, 2006-2014 montekids.org Outcomes of Infants with Early Infantile Krabbe Disease Identified Through NYS Newborn Screening Patient 1 (del30kb /p.I546T+ p.*670Qext42) – Transplanted at 32 days of age – Z score weight -6.65, Z score height -4.23, HC 2.7th percentile at ~8 years of age – Lansky performance score 70, significant
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