469 Review Article on Inborn Errors of Metabolism Page 1 of 8 Common metabolic disorder (inborn errors of metabolism) concerns in primary care practice Marisha Agana1, Julia Frueh1, Manmohan Kamboj2, Dilip R. Patel1, Shibani Kanungo1 1Department of Pediatric and Adolescent Medicine, Western Michigan University Homer Stryker MD School of Medicine, Kalamazoo, MI, USA; 2Department of Pediatrics, Nationwide Children’s Hospital, Columbus, Ohio, USA Contributions: (I) Conception and design: S Kanungo; (II) Administrative support: S Kanungo; (III) Provision of study materials or patients: S Kanungo; (IV) Collection and assembly of data: M Agana, J Frueh, S Kanungo; (V) Data analysis and interpretation: S Kanungo; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors. Correspondence to: Shibani Kanungo, MD, MPH. Department of Pediatric and Adolescent Medicine, Western Michigan University Homer Stryker MD School of Medicine, 1000 Oakland Drive, Kalamazoo, MI 49008, USA. Email: [email protected]. Abstract: Inborn errors of metabolism (IEMs) are rare genetic or inherited disorders resulting from an enzyme defect in biochemical and metabolic pathways affecting proteins, fats, carbohydrates metabolism or impaired organelle function presenting as complicated medical conditions involving several human organ systems. They involve great complexity of the underlying pathophysiology, biochemical workup, and molecular analysis, and have complicated therapeutic options for management. Age of presentation can vary from infancy to adolescence with the more severe forms appearing in early childhood accompanied by significant morbidity and mortality. The understanding of these complex disorders requires special in- depth training, American Board of Medical Genetics and Genomics (ABMGG) certification and experience. Most primary care physicians (PCPs) are reluctant to deal with IEM due to unfamiliarity and rarity of such conditions compounded by prompt progression to crisis situations along with paucity of time involved in dealing with such complex disorders. While there are biochemical geneticists aka metabolic specialists’ expertise available, mostly in larger academic medical centers, with expertise to deal with these rare complex issues, their initial clinical presentation in most newborns, children, adolescents or adults including asymptomatic positive newborn screen (NBS), occur in the out-patient PCP settings. Therefore, it is important that PCPs’ comfort to recognize early signs and symptoms is important to initiate appropriate diagnostic and therapeutic interventions, and be able to make appropriate referrals. The following article reviews common IEM clinical presentations for a robust diagnostic differential and discuss evaluation and management approaches of patients with known or suspected IEM. Keywords: Inborn errors of metabolism (IEMs); biochemical genetics; primary care physician (PCP); acute illness protocol; D10W Submitted Dec 17, 2018. Accepted for publication Dec 17, 2018. doi: 10.21037/atm.2018.12.34 View this article at: http://dx.doi.org/10.21037/atm.2018.12.34 Introduction maintaining daily life activities. Each pathway depends on certain substrates and specific enzymes to ensure smooth The term metabolism encompasses the net result of a functioning. Inborn errors of metabolism (IEMs) are a multitude of complex biochemical processes that occur group of disorders which results from deficiency activity in living organisms to maintain cellular activities vital of a single enzyme in a metabolic pathway (2). Majority to sustain life (1). These processes are organized into of the IEMs are inherited in an autosomal recessive specific metabolic pathways with the primary function of manner. While individually they are rare, collectively they © Annals of Translational Medicine. All rights reserved. atm.amegroups.com Ann Transl Med 2018;6(24):469 Page 2 of 8 Agana et al. IEM for PCP Table 1 PCP guidelines for considering IEM Common IEM presentations In differential diagnosis of sepsis, anoxic encephalopathy or Children and adolescents with IEMs have a wide spectrum toxic ingestion of clinical presentations from appearing physically normal If symptoms persist even after treatment for suspected common to having distinctive dysmorphic physical features. conditions While majority of them appear physically normal at If typical common laboratory tests fail to determine a definitive birth, many can present with significant non-specific diagnosis signs and symptoms common to other serious medical Can present either as acute illness or as chronic, recurrent or conditions (7). It is imperative to keep a high index progressive disease at any age of suspicion in differential diagnosis for prompt IEM Can occur even in the context of negative family history for identification as the institution of appropriate therapy, genetic or metabolic disorder. preventive measures and compliance helps avoid severe In cases of neonatal death from undetermined causes. morbidity or even mortality in some cases. PCP, primary care physician; IEM, inborn error of metabolism. In the antenatal period, true irreversible major malformations due to IEMs can be found in O-glycosylation disorder; in cholesterol synthesis defects, in amino acid are common with an overall incidence of greater than synthesis disorders (glutamine and asparagine) and in 1:1,000 (3). With onset of universal expanded newborn mitochondrial disorders (8,9). screening (NBS), as noted in another article in this issues on NBS, the current data on IEMs detected by NBS is 1 Newborn/infancy period (<12 months) in 3,234 (4). Examination of a newborn for subtle signs of IEMs starts from a cursory examination of the infant from head to Classification toe. It may be practical first to examine areas that require IEMs can be categorized based on their onset, predominant auscultation while the infant is quiet as he or she may be signs and symptoms, main organs or systems affected, somewhat irritable in early transition and undressing the or acuity or chronicity of presentation (5). Disorders infant or moving him or her around may be disruptive. in category 1 usually involve a single organ or uniform In a seemingly healthy newborn most of the information presenting symptom, identified by specific laboratory tests is structural involving the hair, skin, skeleton or all three and managed by specific organ system subspecialty practices that may anticipate future problems. Examination findings like endocrinology, hematology, allergy/immunology and usually relate to major organ dysfunction or failure, most will not be discussed in this review. commonly hepatic, neurologic or immunologic and less Disorders in category 2 affecting specific biochemical or commonly cardiac or pulmonary. While it is apparent that metabolic pathways in cytosol or organelle or intracellular some IEMs present with characteristic dysmorphic features, transport or cofactors can be common to a large number of majority of the newborns with IEM appear otherwise cells or organs presenting with more variable symptoms and normal but clinically sick presenting with overwhelming co-morbid conditions that include multiple organ systems. septicemia or failure to thrive (see Table 1). These disorders can be classified into three sub-groups including: (I) intoxication due to defects in the intermediary Dermatologic metabolic pathway resulting in the accumulation of toxic Absence of hair or alopecia can signal defects in mineral and compounds proximal to the metabolic block [example: urea vitamin metabolism such as acrodermatitis enteropathica (a cycle defect (UCD), amino acid disorders]; (II) deficiency disorder in zinc metabolism), biotin (vitamin B) responsive in energy production or utilization [example: mitochondrial multiple carboxylase deficiency (MCD), calciferol (vitamin disorders, glycogen metabolism disorders, fatty acid D) metabolism defects; nutritional deficit related fatty acid oxidation disorders (FAO)]; and (III) complex molecules deficiency as well as “classical” organic aciduria/acidemia. involving organelles (example: lysosomes, peroxisomes, Brittle hair can be seen in copper metabolism disorders, Golgi and endoplasmic reticulum) and cofactors (6). argininosuccinic aciduria or citrullinemia as well as © Annals of Translational Medicine. All rights reserved. atm.amegroups.com Ann Transl Med 2018;6(24):469 Annals of Translational Medicine, Vol 6, No 24 December 2018 Page 3 of 8 mucopolysaccharidosis. consider IEMs. Ichthyosis or dry, thickened scaly skin can be seen in lysosomal storage disorders (LSD), complex phospholipids Hepatic and fatty acid synthesis/remodeling defects, cholesterol In the examination of the abdomen, the presence of synthesis defects, peroxisomal disorders; dolichol synthesis organomegaly (liver, spleen and kidney) associated with and recycling defects and other lipid metabolism disorders. jaundice and findings of liver damage can be seen in The presence of vesicular or bullous lesions can suggest the form of: storage (glycogen, neutral lipids, complex acrodermatitis enteropathica, biotinidase deficiency, lipids); cholestasis, fibrosis/cirrhosis and inflammatory and holocarboxylase synthetase deficiency, lipin 2 deficiency, immune changes. A firm or rock-hard consistency of the zinc deficiency, classical organic acidurias/acidemias. liver indicates tyrosinemia type I, galactosemia, GSD type Cutis laxa syndrome is comprised of diseases IV, alpha 1 antitrypsin deficiency,