medizinische genetik 2021; 33(1): 21–27 Johannes Zschocke* Inherited disorders of intermediary metabolism – a group-based approach https://doi.org/10.1515/medgen-2021-2053 amino acids, peptides/amines, carbohydrates, and fatty Received February 5, 2021; accepted March 18, 2021 acids/carnitine/ketones. The disorders of intermediary en- Abstract: In the recently developed International Classi- ergy metabolism include a large number of diverse con- fcation of Inherited Metabolic Disorders (ICIMD), more ditions that interfere mostly with mitochondrial oxidative than one third of the 1450 listed conditions involve gene phosphorylation. Two categories are classifed as “other” products required for intermediary metabolism. 225 of disorders of intermediary metabolism; one of them covers these diseases represent defciencies of enzymes or trans- the small but growing number of disorders of metabolite port proteins in the breakdown of nutrients, many of repair. This category comprises defciencies of enzymes which cause acute “metabolic” presentations with typical that do not have a function in a particular biochemical biochemical features that are amenable to specifc treat- pathway but remove metabolites generated through non- ments. A group-based approach to these conditions not specifc side reactions of other enzymes. The ICIMD has only assists in understanding and remembering them but been endorsed by all international societies for inherited facilitates the best choice of diagnostic tests and acute metabolic disorders and is due to be used for the Or- treatment. This review describes the basic characteristics phanet classifcation and diferent electronic database re- of the 25 disease groups in the four categories of nutrient sources. Its hierarchical structure can also serve as a ba- breakdown in intermediary metabolism, outlines the often sis for didactic purposes and textbooks [2]. Here we review relatively straight-forward diagnostic approach, and sum- the prototypical clinical and biochemical presentations as marizes important therapeutic principles. It should also well as main diagnostic and therapeutic approaches to assist in the retrospective identifcation of likely metabolic the diferent disorders of nutrient breakdown in intermedi- disorders in the family history for genetic counselling. ary metabolism. This category contains many of the well- known inherited metabolic diseases that share elements Keywords: inherited metabolic diseases, intermediary of the clinical presentation and are recognized by stan- metabolism, classifcation, ICIMD dard “metabolic analyses.” The discussion of the clinical approach to other metabolic disease groups is beyond the scope of this manuscript. Introduction The recently developed International Classifcation of In- herited Metabolic Disorders (ICIMD) [1] contains a total Simplifed overview of intermediary number of 1450 individual disorders. They are defned metabolism as primary disturbances of a biochemical pathway with a known (or assumed) primary genetic cause, irrespec- Breakdown of the three major nutrient components – car- tive of the clinical consequences. Most conditions are bohydrates, proteins/peptides, and lipids – ultimately re- caused by reduced-function mutations in single genes al- sults in oxidative phosphorylation in the mitochondria for though some are due to activating mutations or other the generation of adenosine triphosphate (ATP). The main genetic or genomic alterations, e. g. in the mitochon- elements relevant for clinical needs and the relevant bio- drial genome. Within the ICIMD the disorders are hier- chemical tests are depicted – very simplifed – in Figure 1. archically structured into 24 categories comprising 124 – Cytosolic breakdown of glucose leads to pyruvate, disease groups (Table 1). The frst four categories refer which can be reversibly converted to lactate, the end to the disorders of nutrient breakdown in intermediary product of anaerobic glycolysis. After transport into metabolism and comprise disorders of the metabolism of the mitochondria, pyruvate is either fed into the Krebs cycle via the pyruvate dehydrogenase complex, or *Corresponding author: Johannes Zschocke, Institute of Human Genetics, Medical University Innsbruck, Peter-Mayr-Str. 1, 6020 serves as precursor of various metabolites via pyru- Innsbruck, Austria, e-mail: [email protected] vate carboxylase. Glycogen, the main storage form of Open Access. © 2021 Zschocke, published by De Gruyter. This work is licensed under the Creative Commons Attribution 4.0 International License. 22 | J. Zschocke, Inherited disorders of intermediary metabolism – a group-based approach Table 1: Disease categories in the International Classifcation of Inherited Metabolic Disorders. Disorders of amino acid metabolism Disorders of peptide and amine metabolism Disorders of intermediary metabolism: nutrients Disorders of carbohydrate metabolism Disorders of fatty acid and ketone body metabolism Disorders of energy substrate metabolism Mitochondrial DNA-related disorders Nuclear-encoded disorders of oxidative phosphorylation Disorder of intermediary metabolism: energy Disorders of mitochondrial cofactor biosynthesis Disorders of mitochondrial DNA maintenance and replication Disorders of mitochondrial gene expression Other disorders of mitochondrial function Disorders of metabolite repair/proofreading Disorders of intermediary metabolism: others Miscellaneous disorders of intermediary metabolism Disorders of lipid metabolism Disorders of lipid metabolism and transport Disorders of lipoprotein metabolism Disorders of nucleobase, nucleotide, and nucleic acid metabolism Disorders of heterocyclic compounds Disorders of tetrapyrrole metabolism Congenital disorders of glycosylation Disorders of complex molecule and organelle metabolism Disorders of organelle biogenesis, dynamics, and interactions Disorders of complex molecule degradation Disorders of vitamin and cofactor metabolism Disorders of cofactor and mineral metabolism Disorders of trace elements and metals Neurotransmitter disorders Disorders of metabolic cell signalling Endocrine metabolic disorders – Amino acids released from breakdown of proteins and peptides are often modifed in the cytosol before re- moval of the amino group. Deamination results in the generation of organic acids that are further catabo- lized and fnally enter the mitochondrial Krebs cy- + cle. Free ammonium ions (NH4 ) or amino groups are detoxifed mostly in the urea cycle. – Lipids in the form of triglycerides are the main long- term storage compounds for nutritive energy. Their re- lease is started after a few hours of fasting. Coenzyme A (CoA)-activated long-chain fatty acids are trans- Figure 1: Intermediary metabolism: overview and diagnostic tests. ported via the carnitine shuttle into the mitochon- dria, where they are broken down through successive Diferent biochemical categories and laboratory analyses are high- beta-oxidation cycles. This process generates large lighted in diferent colours. Yellow felds indicate basic laboratory tests that should be performed in every patient with an acute ill- amounts of acetyl-CoA, which enters the Krebs cycle ness potentially due to in inherited metabolic disease. Orange felds or – in the liver – is converted into ketone bodies that special metabolic investigations that may identify specifc metabolic function as energy source, e. g. for the brain. changes. In the subsequent Figures 2–7, felds that are shaded dark grey are not of primary relevance for the diagnosis of diseases in the The diferent nutrient breakdown pathways can be as- respective group. sessed with some basic laboratory tests which should be available for the investigation of patients with acute pre- glucose, is required for rapid provision of chemical en- sentations in every hospital: blood glucose, ketones (urine ergy, e. g. in the muscle or in the frst hours of fasting. stix test; quantifcation in blood is more reliable but avail- The other two main nutrient hexoses – galactose and able only in some centres), acid base status, lactate, and fructose – are fed into the glucose pathways through ammonium (in blood). Serum triglyceride levels may pro- specifc enzymes. vide information on lipolysis although the analysis of free J. Zschocke, Inherited disorders of intermediary metabolism – a group-based approach | 23 fatty acids is preferable for exact quantifcation. Selective metabolic screening tests that may show specifc abnor- malities diagnostic for particular disorders of intermediary metabolism include amino acid analysis in plasma/serum, urinary organic acid analysis, and the quantifcation of acylcarnitines (carnitine esters of mitochondrial CoA com- pounds) in dried blood spots. These laboratory tests in combination with the individual clinical presentation may allow a rapid diagnosis and start of specifc treatment in patients with an acute “metabolic” presentation. Figure 2: Urea cycle disorders. Disorders of amino acid metabolism later in life include acute/episodic or chronic neurologic Defciencies of enzymes involved in amino acid symptoms. Essential for diagnosis is the determination of metabolism frequently result in the accumulation of blood ammonium in the acute situation (Figure 2). Plasma toxic substances leading to acute or chronic organ dam- amino acid analysis usually shows elevated glutamine age. The brain, liver, and kidneys are most frequently concentrations and may reveal specifc alterations of other afected. Development of acute symptoms in many