Proposal for a simplified classification of IMD based on a pathophysiological approach: A practical guide for clinicians

• Published in: Journal of inherited metabolic disease Vol. 42; no. 4; pp. 706 - 727
• Main Authors: Saudubray, Jean‐Marie, Mochel, Fanny, Lamari, Foudil, Garcia‐Cazorla, Angeles
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01.07.2019; Blackwell Publishing Ltd
• Subjects: Biomarkers; complex lipids disorders; complex molecules; Defects; Energy metabolism; Food intake; Glycogen; Glycolipids; Glycosaminoglycans; inborn errors of metabolism classification; Intoxication; Lysosomal storage diseases; Metabolism; Mitochondria; Neurodegenerative diseases; neurodegenerative disorders; Neurodevelopmental disorders; Next-generation sequencing; Organelles; Phospholipids; Sphingolipids; Synaptic vesicles; trafficking disorders; tRNA; complex molecules; trafficking disorders; complex lipids disorders; neurodegenerative disorders; neurodevelopmental disorders; inborn errors of metabolism classification
• ISSN: 0141-8955; 1573-2665
• DOI: 10.1002/jimd.12086

In view of the rapidly expanding number of IMD discovered by next generation sequencing, we propose a simplified classification of IMD that mixes elements from a clinical diagnostic perspective and a pathophysiological approach based on three large categories. We highlight the increasing importance of complex molecule metabolism and its connection with cell biology processes. Small molecule disorders have biomarkers and are divided in two subcategories: accumulation and deficiency. Accumulation of small molecules leads to acute or progressive postnatal “intoxication”, present after a symptom‐free interval, aggravated by catabolism and food intake. These treatable disorders must not be missed! Deficiency of small molecules is due to impaired synthesis of compounds distal to a block or altered transport of essential molecules. This subgroup shares many clinical characteristics with complex molecule disorders. Complex molecules (like glycogen, sphingolipids, phospholipids, glycosaminoglycans, glycolipids) are poorly diffusible. Accumulation of complex molecules leads to postnatal progressive storage like in glycogen and lysosomal storage disorders. Many are treatable. Deficiency of complex molecules is related to the synthesis and recycling of these molecules, which take place in organelles. They may interfere with fœtal development. Most present as neurodevelopmental or neurodegenerative disorders unrelated to food intake. Peroxisomal disorders, CDG defects of intracellular trafficking and processing, recycling of synaptic vesicles, and tRNA synthetases also belong to this category. Only few have biomarkers and are treatable. Disorders involving primarily energy metabolism encompass defects of membrane carriers of energetic molecules as well as cytoplasmic and mitochondrial metabolic defects. This oversimplified classification is connected to the most recent available nosology of IMD.