This issue of eMedRef provides information to clinicians on the pathophysiology, diagnosis, and therapeutics of inborn errors of metabolism

Ritenuti, Michel

English

University of Missouri: MOspace

Inborn Errors of Metabolism Page 1 of 5    3.31.11 INBORN ERRORS OF METABOLISM (IEM) A GENERAL OVERVIEW   Background 1. General Information  o Classification   Traditionaly IEM have been classified according to the type of metabolism involved. (note Purine & Pyrimidine disorders, Porphyrias, and Metal metabolism disorders are classified as IEM by only some sources. They are included here in my attempts to be thorough.)    Amino Acid Dissorders   Organic Acidemias (acidurias)   Urea Cycle Defects   Dissorders of Carbohydrate Metabolism   Fatty Acid Oxidation Defects   Mitochondrial Disorders   Peroxisomal Dissorders   Lysosomal Storage Disseases   Purine and Pyrimidine Disorders   Porphyrias   Metal Metabolism Dissorders o Screening   Tandem Mass Spectrometry has been mandated in multiple states.   Information on current national & state-by-state screening can be found through the online resource: http://genes-r-us.uthscsa.edu/ (National Newborn Screening and Genetics Resource Center).  Pathophysiology 1. Pathology of Disease:  o IEM occur when an enzyme or its cofactor(s) are either absent or abnormal and as a result, leads to an accumulation of substrate or deficiency of metabolic products.  o The physiologic manifestations of an IEM are dependent on the specific metabolite(s) involved. 2. Incidence  o There is no consensus on the incidence of IEM  o Most estimates are regionally specific, and exhibit significant variation between different racial and ethnic groups.  o One estimate of the collective incidence of IEM was around 1:1500 persons  3. Risk Factors  o Positive Familial History (modes of inheritance of common IEM):   Autosomal dominant:   Marfan syndrome   Acute intermittent porphyria   Familial hypercholesterolemia  Autosomal recessive:   PKU (Phenylketonuria)  Inborn Errors of Metabolism Page 2 of 5    3.31.11  MSUD (Maple syrup urine disease)   Glycogen storage disease   Galactosemia   Organic acidurias   MCAD(medium chain acylCoA dehydrogenase deficiency)   Zellewerger syndrome  X-linked recessive:   Ornithine carbamylase deficiency   Fabry disease   Pyruvate dehydrogenase deficiency  Mitochondrial:   Kearns-Sayre syndrome   Leigh syndrome   Diagnostics 1. Presentation  o Onset & Severity may vary with:   individual disease processes/severity of disease   age of individual   changes in:   diet/fasting   hydration/dehydration   exercise/exertion/stress   concurrent illness/infection/trauma   medications/supplements o Symptomatic Infants:   The clinical picture varies between different metabolic disorders. However, there are general characteristics that are common.   Afflicted individuals are usually asymptomatic in the early stages of most inborn metabolic disorders.   Early signs of an IEM include (Acute presentation):  o Lethargy  o Decreased appetite / feeding  o Vomiting  o Tachypnea (associated with acidosis)  o Decreased perfusion  o seizures  As the metabolic derangement progresses, so does its manifestations o Increasing stupor or coma  o Progressive neuromuscular abnormalities   tone (increased or decreased)   spasticity   posturing (opisthotonus, fisting)   movements (lip smacking, tongue thrusting, myoclonic jerks) o Symptomatic Older Infants & Children (Chronic presentation)    Paroxysmal stupor / lethargy   Emesis  Inborn Errors of Metabolism Page 3 of 5    3.31.11  Failure to thrive   Organomegaly (classically hepatosplenomegally)   Neurometabolic findings   Macro/microcephaly   Hypotonia   Hypertonia +/- spasticity   seizures   Skeletal abnormalities   Coarse facial features   Macular or retinal changes   Corneal clouding   Skin changes  Regression of previously achieves developmental milestones.   Loss of cognitive milestones   Loss of expressive/receptive language abilities  Progressive decline/deficits in attention, focus, and/or concentration.   Maladaptive behavioral changes/decline 2. Diagnostic testing:  o Initial Laboratory Investigations   Blood   CBC (complete blood count)   CMP (complete metabolic panel/chem12)  o Hepatic & Renal Function  o Electrolytes  o Uric Acid  o Serum Ammonia  Obtain without tourniquet   Transport on ice for immediate analysis  ABG (arterial blood gas)  Urine   Urinalysis   pH   color   odor   specific gravity   ketones   Urine-reducing substances o Additional Laboratory Investigations   Blood/Plasma   quantitative amino acids   lactate o Obtain without tourniquet  o Transport on ice for immediate analysis  pyruvate  o Obtain without tourniquet  o Transport on ice for immediate analysis  o Collect in perchlorate to prevent degredation  aldolase, creatine kinase   acyl carnitine kinase  Inborn Errors of Metabolism Page 4 of 5    3.31.11  lipid Profile  Urine   quantitative amino acids   organic acids   myoglobin o Imaging   MRI brain   echocardiogram o Biopsy   muscle   skin o Genetic   as indicated o Laboratory findings & likely metabolism involved   Metabolic Acidosis with:   Anion gap  o Organic Acidemias  Respiratory Alkalosis   Urea Cycle Dissorders  Hyperammonemia   Urea Cycle Dissorders   Organic Acidemias  Lactic acidosis   Mitochondrial disorders   Glycogen storage diseases   Dissorders of Glyconeogenesis   Dissorders of Pyruvate metabolism   Organic acidemias   Dissorders of fatty acid oxidation   Aminoacidurias  High lactate/pyruvate ratio (normal: 10/1 to 20/1)   Mitochondrial dissorders   Pyruvate carboxylase deficiency  Acylcarnitine profile (abnormal)   Dissorders of fatty acid oxidation   Organic acidemias  Hypoglycemia   with ketosis  o Glycogen storage diseases  o Organic acidemias  without ketosis  o Glycogen storage diseases  o Maple syrup urine disease  o Dissorders of fatty acid oxidation  o Dissorders of ketogenesis  Quantitative amino acid profiles   Pattens are specific for individual dissorders  Urine organic acids   Pattens are specific for individual dissorders Inborn Errors of Metabolism Page 5 of 5    3.31.11   Management 1.  Specific to individual disorders and is outside the scope of this general overview.   References 1. Raghuveer TS, Garg U, Graf WD. Inborn Errors of Metabolism in Infancy and early Childhood: An Update. AFP 2006;73:1981-1990.  2. Weiner, DL. Metabolic Emergencies. In: Textbook of Pediatric Emergency Medicine, 5th ed, Fleisher, GR, Ludwig, S, Henretig, FM (Eds), Lippincott, Williams & Wilkins, Philadelphia 2006. p.1193.  3. Kamboj M. Clinical approach to the diagnoses of inborn errors of metabolism. Pediatric Clinics of North America. 55(5):1113-27, viii, 2008 Oct.   Author: Michel Ritenuti, MD, Penn State Hershey Medical Center, PA  Editor: Dongsheng Jiang, MD, Penn State Hershey Medical Center, PA  

Inborn errors of metabolism (IEM): a general overview

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Inborn errors of metabolism (IEM): a general overview

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