Proposal For A Simplified Classification Of IMD Based On A .
Received: 6 January 2019Accepted: 13 March 2019DOI: 10.1002/jimd.12086ORIGINAL ARTICLEProposal for a simplified classification of IMD based on apathophysiological approach: A practical guide for cliniciansJean-Marie Saudubray1 Fanny Mochel1,2,3,4 Foudil Lamari1,2,5 Angeles Garcia-Cazorla61Groupe de Recherche CliniqueNeurométabolique, Université Pierre etMarie Curie, Paris, France2Centre de Référence NeurométaboliqueAdulte, Groupe Hospitalier Pitié-Salpêtrière,Paris, France3Sorbonne Universités, UPMC-Paris6, UMR S 1127 and Inserm U 1127, andCNRS UMR 7225, and ICM, F-75013,Paris, France4Département de Génétique, AssistancePublique-Hôpitaux de Paris, GroupeHospitalier Pitié-Salpêtrière, Paris, France5Département de Biochimie, AssistancePublique-Hôpitaux de Paris, GroupeHospitalier Pitié-Salpêtrière, Paris, France6Neurology Department, NeurometabolicUnit and Synaptic Metabolism Lab, InstitutPediàtric de Recerca, Hospital Sant Joan deDéu, metabERN and CIBERER-ISCIII,Barcelona, SpainAbstractIn view of the rapidly expanding number of IMD discovered by next generationsequencing, we propose a simplified classification of IMD that mixes elementsfrom a clinical diagnostic perspective and a pathophysiological approach based onthree large categories. We highlight the increasing importance of complex molecule metabolism and its connection with cell biology processes. Small moleculedisorders have biomarkers and are divided in two subcategories: accumulation anddeficiency. Accumulation of small molecules leads to acute or progressive postnatal“intoxication”, present after a symptom-free interval, aggravated by catabolism andfood 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 withcomplex molecule disorders. Complex molecules (like glycogen, sphingolipids,phospholipids, glycosaminoglycans, glycolipids) are poorly diffusible. Accumulation of complex molecules leads to postnatal progressive storage like in glycogenand lysosomal storage disorders. Many are treatable. Deficiency of complex molecules is related to the synthesis and recycling of these molecules, which take placeCorrespondenceJean-Marie Saudubray, Groupe deRecherche Clinique Neurométabolique,Université Pierre et Marie Curie, 22 rueJuliette Lamber Paris 75017, France.Email: jmsaudubray@orange.frin organelles. They may interfere with fœtal development. Most present as neu-Communicating Editor: JohannesZschockelism encompass defects of membrane carriers of energetic molecules as well asFunding informationFondo Europeo de desarrollo regional(FEDER), Grant/Award Number: FIS:PI15/01082; ISCIIIrodevelopmental or neurodegenerative disorders unrelated to food intake. Peroxisomal disorders, CDG defects of intracellular trafficking and processing, recyclingof synaptic vesicles, and tRNA synthetases also belong to this category. Only fewhave biomarkers and are treatable. Disorders involving primarily energy metabocytoplasmic and mitochondrial metabolic defects. This oversimplified classificationis connected to the most recent available nosology of IMD.KEYWORDScomplex lipids disorders, complex molecules, inborn errors of metabolism classification,neurodegenerative disorders, neurodevelopmental disorders, trafficking disorders1 INTRODUCTIONAbbreviations: CD, congenital disorders of glycosylation; GSD, glycogenstorage disorders; IMD, inborn metabolic disorder; LSD, lysosomal storagedisorders; NGS, next generation sequencing.J Inherit Metab Dis. 2019;1–22.Metabolism involves thousands of proteins, mostly enzymes,cofactors, receptors and transporters, the deficit of whichwileyonlinelibrary.com/journal/jimd 2019 SSIEM1
SAUDUBRAY ET AL.2causes an IMD. According to Morava, the “classification ofa disorder as an IMD requires only that impairment of specific enzymes or biochemical pathways is intrinsic to thepathomechanism”.1 Until recently, there was a tendency tomostly consider disorders affecting the catabolism of molecules while synthesis and transport defects were clearlyunderrepresented; in fact, they were almost ignored. In viewof the rapid recognition of these new categories of IMD bynext generation sequencing (NGS),2 it is now of utmostimportance to integrate them in the classification of IMDbased on these biochemical categories (synthesis, remodeling, transport, catabolic and trafficking defects) ratherthan on an organelle-centric approach that splits arbitrarilymetabolic pathways.2 TOWARD A NEW ANDSIMPLIFIEDPATHOPHYSIOLOGICALCLASSIFICATION OF I MDUsing this extended definition of IMD, the most recent tentative of IMD nosology encompasses more than 1100 disorders, provisionally classified into 130 groups.3 This is auseful and exhaustive list primarily based on biochemicalconsiderations. It fulfills the critical requirements for database programming, and the possibility of linking to nomenclatures via MIM gene numbers. In fact, this nosologyrepresents a framework in terms of nomenclature and“speaking a common language” within the metabolic community. Additionally, it is linked to an updated websitewww.iembase.org/nosology/index.asp. However, and inaddition to this detailed and helpful nosology, there are several reasons why a simplified classification, based on a pathophysiological approach, is needed:1. Guidelines to help clinicians to suspect, detect, understand and treat IMD are critical. The day-to-day clinicalreasoning is far from being a list of disorders grouped inbiochemical and organelle-based categories. In particular, such type of list has little in common with neurologists' clinical approach. By contrast, the number of newIMD affecting the brain is growing very quickly. Therefore a classification including both clinical phenotypesand mechanisms of disease, easy to understand andgrouped into few categories, is more likely to be learntand integrated in the clinical practice not only of metabolic physicians, but also general pediatricians, neurologists, internists, endocrinologists, etc.2. The proposal of a simplified classification focuses alsoon pathophysiology-based treatments. Therefore it stimulates the clinical exercise of linking symptoms,pathophysiology and therapeutic management, particularly in emergency situations.3. Exhaustive and accurate descriptions of each disease areessential to deepen the knowledge of metabolic diseases.However, a holistic, integrative approach is crucial inorder to decipher the complexity of mechanisms andphenotypes in IMD. Our simplified classification is inline with a system biology practice, and combines biochemistry with cellular biology processes.Accordingly, the following simplified classification isbased on a number of basic principles:- Whatever their size, metabolites involved in IMD maybehave as signaling molecules, structural components andfuels, and many metabolites can play different roles duringdevelopment.4- The proposal for a simplified classification of IMDmixes clinical diagnostic and pathophysiological approachesinto three large categories based on the size of molecules(“small” or “complex”) and their implication in energymetabolism (Figure 1).- This approach has been used for a long time in our clinical practice and has been partly exposed in classic pediatric5and metabolic textbooks6–8 as well as recent reviewpapers.9,10- This proposal is organized into categories in order tofacilitate the diagnosis and treatment of patients with IMD.However, patients have disorders in complex, overlapping,non-categorical biologic systems. Accordingly, the authors,and the readers, are faced with the classic dilemma ofbalancing the practicality of categorical thinking with thereality of biology complexity and individual clinical diversity. Compromises were made in seeking that balance andreflecting the core mechanism of each disease that correlatesthe most with clinical signs and biomarkers. This is the keyto this simplified classification that, most of all, aims attransforming the enormous complexity of IMD into a usefultool for clinicians.3 CLASSIFICATION3.1 Group 1: small moleculesAlmost all these IMD have plasma and/or urine metabolicmarker(s) (ie, small diffusible water-soluble molecules) thatcan be easily and rapidly measured in emergency, usually inone run (like amino acids, organic acids, acylcarnitines, porphyrins, fatty acid, purines, pyrimidines, etc.), or by usingspecific methods (like metals or galactose metabolites).These markers are also useful for therapy monitoring sincemost of these IMD are amenable to treatment. This groupcan be divided in 2 subcategories (Table 1).
SAUDUBRAY ET AL.3FIGURE 1Simplified classification « at a glance ». AA, amino acids; CDG, congenital disorders of glycosylation; FA, fatty acids; GAG,glycosaminoglycans; GSL, glycosphingolipids; ID, intellectual disability; IEM, inborn errors of metabolism; KB, ketone bodies; KC, Kreb's cycledefects; LSD, lysosomal storage diseases; Mit, mitochondrial; MPS, mucopolysaccharidosis; NRL, neurological; OLG, oligosaccharides, PC,pyruvate carboxylase deficiency; PDH, pyruvate dehydrogenase deficiency; PL, phospholipids; PPP, Pentose phosphate pathway; PT, pyruvatetransporter deficiency; Psych, psychiatric signs3.1.1 Accumulation of small moleculesThe accumulation of small molecules causes acute or progressive “intoxication” disorders. Signs and symptoms resultprimarily from the abnormal accumulation of thecompound(s) proximal to the block and can potentiallyreverse as soon as the compound(s) is (are) removed. Theydo not interfere with embryo and fetal neurodevelopmentand they present after a symptom-free interval (days toyears) with clinical signs of “intoxication” (acute, intermittent, chronic, and even progressive leading to neurodegeneration) provoked by fasting, catabolism, fever,intercurrent illness, and food intake. Most of these disordersare treatable and require the removal of the “toxin” by special diets, scavengers and cofactors (mostly vitamins).This group encompasses IMD of amino acid catabolism—like phenylketonuria, maple syrup urine disease, orhomocystinuria—, urea cycle defects, organic acidurias—like methylmalonic or glutaric aciduria type 1—, galactosemia, and metal accumulation—like Wilson disease, neuroferritinopathies and brain iron accumulation syndromes, orhypermanganesemia linked to SLC30A10 and SLC39A14mutations.15–17 Some small molecules accumulation maylead to visible crystals in diverse tissues like cystine incystinosis (a lysosomal defect), oxalate in oxalosis(a peroxysomal defect) or homogentisic acid (ochronosis) inalkaptonuria.Many purine and a few pyrimidine disorders may beclassified in this group. Indeed, most disorders involvingeither nucleotide synthesis, catabolism or salvage pathwaysmay be screened by plasma/urine purines and pyrimidinesprofiles. Clinical symptoms are very diverse and the pathophysiology is sometimes complex (linked to accumulation,deficiency or both) and still badly understood. Many enzymatic defects involve brain development by intricated mechanisms.18 Metabolite repair defects are a new growingcategory in which symptoms are linked to the accumulationof a toxic compound like in L-2-hydroxyglutaric aciduria,19or NAXE mutations—NAXE catalyzes the epimerization ofNAD(P)HX, thereby avoiding the accumulation of toxicmetabolites.20Vitamins (transport, and intracellular processing) interferewith many different metabolic pathways where they act asenzymatic cofactors, chaperones or signaling molecules. Inmost vitamin-responsive disorders, vitamin plasma levels arenormal and treatment relies on pharmacological doses of
6. Most IMD are easilytreatable but metaboliterepair, many nucleicacids and fatty aciddisorders5. Crisis induced by foodand catabolism4. Present after asymptom-free interval3. Do not interfere withfoetal development2. Signs result primarilyfrom accumulation ofthe compound and canreverse as soon as it isremoved.MMA, PA, IVACerebral OAB6,B12,FolateBiotin (causinghomocystinuria ororganic acidurias)B VitaminsPKU, MSUD, Tyr 1 andTyr 2, OATHomocystinurias.GlutathioneOrganic acidsAmino acids catabolismAAC, OAC, acylcarnitinesOAC, acylcarnitinesAAC, OACToxin removal Special dietsVitaminsScavengersDrugsSupplement of distalproductOrgan transplantationA-Disorders of nitrogen-containingcompounds:15-Disorders of lysine rs of vitamins, cofactors, metalsand minerals:A-Disorders of nitrogen-containingcompounds:9-Aminoacylase deficiencies14-Disorders of branched-chain amino acidmetab.15-Disorders of lysine metabolismB-Disorders of vitamins, cofactors, metalsand minerals:26-Disorders of cobalamine metabolismA-Disorders of nitrogen-containingcompounds:6-6-Disorders of glutathione metabolism11-Disorders of phenylalanine12-Disorders of tyrosine metabolism13-Disorders of sulfur amino acid and sulfidemetab.14-Disorders of branched-chain amino acidmetab.15-Disorders of lysine metabolism16-Disorders of proline and ornithinemetabolism18-Disorders of histidine metabolism24-Disorders of glycine metabolismB-Disorders of vitamins, cofactors, metalsand minerals:39-Disorders of molybdenum metabolism« Intoxication » disorders (potentially reversible)CATEGORIES /GROUPS UpdatedNosology3Accumulation 1. Causeacute or progressive“intoxication”TREATMENTAlmost all these IMD have plasma and urines metabolic marker(s) that can be easily and rapidly measured, making a metabolic signature easily accessibleDIAGNOSTIC TESTSI: Small molecules(water solublediffusible)MAIN DISORDERSGROUPS OFDISORDERSSimplified classification of inborn errors of metabolismCATEGORIESSimplified classificationTABLE 14SAUDUBRAY ET AL.
(Continued)I.2 Deficiency1. Symptoms resultprimarily from thedefective synthesis ortransportation of anessential moleculeFA accumulationobserved inperoxysome defectsshare many clinicalsimilarities withcomplex lipid synthesisdisorders suggestingthat many othermechanisms thanintoxication areinvolvedCATEGORIESSimplified classificationTABLE sPorphyriasL-2-OH glutaricD-2-OH glutaricNAXE deficitCatabolic disorders ofpurines and pyrimidinesand salvage pathwaydefectsPorphyrinsMetabolite repairNucleic acidsAA synthesisSerine, Glutamine,Asparagine, synthesisdefectsGlutathionPlasma/CSF aminoacidsMimic complex synthesis defects. Most but not all are irreversiblepurines/pyrimidines profile,uric and orotic acidAAC, OACGlycerolGlycerolGal-1P, GALTMolecular testSpecific metal testsT1-weighted brain MRICopper (Wilson)Iron (NBIA)Manganese (SLC39A14SLC30A10)MetalsDIAGNOSTIC TESTSAAC, OACOrotic acidMAIN DISORDERSUrea cycle defects andrelatedhyperammonaemiasGROUPS OFDISORDERSNot or poorly treatable(Serine?)Low purine dietAllopurinolERT, BMT and genetherapy in ADA, PNPand thymidinephosphorylaseNot or poorlytreatableTREATMENTA. Disorders of nitrogen-containingcompounds:6-Disorders of glutathion metabolism21-Disorders of glutamine metabolism22-Disorders of asparagine metabolism23-Disorders of serine metabolism24-Disorders of glycine metabolismA. Disorders of nitrogen-containingcompounds:1-Disorders of pyrimidine metabolism2-Disorders of purine metabolismD. Mitochondrial disorders of energymetabolism56-Disorders of metabolite repairF-Disorders of tetrapyrroles98-Disorders of heme metabolismE. Disorders of lipids87-Disorders of glycerol metabolismC-Disorders of carbohydrates47-Disorders of galactose metabolism48-Disorders of fructose metabolismB-Disorders of vitamins, cofactors, metalsand minerals:32-Disordes of pantothenate metabolism40-Disorders of copper metabolism41-Disorders of iron metabolism42-Disorders of manganese metabolismA-Disorders of nitrogen-containingcompounds:7-Disorders of ammonia detoxification26-Disorders of cobalamin. 27-folate. 28-biotin29-thiamine. 30-riboflavin. 32-pantothenate.33-pyridoxineCATEGORIES /GROUPS UpdatedNosology3SAUDUBRAY ET AL.5
Purine and PyrimidineSynthesis defectsNucleic acidsdisordersPlasma ManganesePlasma CopperCeruloplasminSLC39A8 (Mn)ATP7A (Cu)(Menkes disease)AP1S1 (Cu)SLC33A1 (Cu)(acetylCoA transporter:AT1)purine/pyrimidine profile,uric and orotic acidPlasma, urine,CSFMonoaminesAA, NeopterinsUrines OAFA profile in fibroblastsMolecular testsELOV 1,4,5, otherLeukotriene defectGABAMonoaminesGlycineSerineGlutamateplasma LPCVLCFA activation infibroblastsPlasma/CSF AAPlasma/CSF AAPlasma/urinesAADIAGNOSTIC TESTSMFSD2A deficiencyFA transport protein 4deficiencyBCAASLC7A5SLC7A7 (LPI)SLC6A19 (Hartnup disease)MAIN DISORDERS« Classical »NeurotransmittersSynthesisCatabolism TransportReceptors5. A few are or should be FA transporttreatable bysupplementing themissing product distalFA synthesis and recyclingto the block like Niacinin tryptophanmalabsorbtion (HartnupMetalsdisease) and catabolismdefects4. Metabolic markersare decreasedBCKDHAA brain orepithelial transport2. Defects may causeneurodevelopmentdisruption, withcongenital presentation3. Share manycharacteristics withdisorders in thecomplex moleculesgroupGROUPS OFDISORDERS(Continued)CATEGORIESSimplified classificationTABLE 1AdenineThiopurinesL-DOPA carbidopaBiopterinsOthersChelation therapyZinc acetateMetal supplementationNot treatableDHA? LPC?BCAA and high proteindietBCAA?Citrulline. Lysine;NiacinTREATMENTA. Disorders of nitrogen-containingcompounds:A. Disorders of nitrogen-containingcompounds:10-Disorders of monoamine metabolism11-Disorders of phenylalanine andtetrahydrobiopterin17-Disorders of beta and gamma amino acids20-Disorders of glutamate metabolism23-Disorders of serine metabolismB. Disorders of vitamins, cofactors, metalsand minerals:40-Disorders of copper metabolism42-Disorders of manganese metabolism43-Disorders of zinc metabolism44-Disorders of selenium metabolism45-Disorders of magnesium metabolismE. Disorders of lipids:85-Disorders of fatty acid synthesis andelongationE. Disorders of lipids:83-Disorders of fatty acid oxidation andtransportA. Disorders of nitrogen-containingcompounds:14-Disorders of branched-chain amino acidmetab.A. Disorders of nitrogen-containingcompounds:8-Disorders of amino acid transport14-Disorders of branched-chain amino acidmetab.19-Disorders of tryptophan metabolism(Hartnup)B. Disorders of vitamins cofactors, metalsand minerals31. Disorders of niacin and NAD metabolismCATEGORIES /GROUPS UpdatedNosology36SAUDUBRAY ET AL.
II.1 AccumulationCatabolism or transportdefects lead typically tostorage of a visiblecompound like inclassical LSD. or GSD.In general there is s displayprogressive disorderswith neurodegenerationwith or without obviousvisceral « storage »signs.Of note cystine andoxalate, although theyare small molecules arepresented in this sectionbecause they clinicallypresent withprogressive storagedisorders leading torenal failure and multisystemic signsMPSPZO biogenesis and FAOdefects:X-ALD, X-AMNother PZO FAO, RefsumdiseaseSjogren-LarssonNiemann-PickWolman diseaseSphingolipidosis (nervoussystem)Ceroid lidosisMucolipidosesNLSDMany othersGAGFatty mentsOligosaccharidesGlycoproteinsSialic acidGlucosaminesNeutral lipids(steatosis)(lysosomal)Glycogenosis(liver, muscle, heart, brain)Heart ,Muscle(Pompe)Glycogen (GSD)(cytoplasmic)SymptomaticNot or poorly treatableUrinary OligosaccharidesJordan's anomalyPlasma TriglyceridesMolecular testNot treatableERT,SRTBMTSRT: Miglustat,ERTBMT, Gene therapy in XALDDiet in RefsumZyleuton in SLSERT, SRTBMTSpecial dietOrgan transplantERT, BMTGene therapy in clinicaltrialsEnzyme assaysMolecular testsUrinary SulfatidesEnzyme assaysEnzymatic, molecular testsPlasma/fibroVLCFA profileEnzyme testing MoleculartestsUrinary GAGSEnzyme assaysFunction testsEnzyme assaysMolecular testsE. Disorders of lipids:88-Disorders of cytoplasmic triglyceridemetabolismG. Storage diseases:102-Oligosaccharidoses104-MucolipidosesE. Disorders of lipids:92-Disorders of palmitoylation (CLN1)G. Storage diseases:102-SphingolipidosesG. Storage diseases:106-Disorders of lysosomal cholesterolmetabolismE-Disorders of lipids:86-Disorders of the fatty alcohol cycleH. Disorders of peroxisomes and oxalate:110-Disorders of peroxisome beta-oxidation111-Disorders of peroxisome alpha-oxidation112-Disorders of peroxisomal biogenesisG. Storage diseases:105-MucopolysaccharidosesC. Disorders of carbohydrates:51-Glycogen storage diseases53-Disorders of glycolysis1-Disorders of pyrimidine metabolism2-Disorders of purine metabolismAllopurinolUridine (CAD, UMPS)Progressive storage disease leading to loss of function. Potentially partially reversible on treatmentCATEGORIES /GROUPS UpdatedNosology3TREATMENTAlthough considered as small molecules, fatty acids and cholesterol were added to this group because of similarities in clinical findings with complex lipids andmolecules.IMD that disturb the metabolism of complex molecules; Pathways involve cellular trafficking and organelles, require protein transporters or vesicles.Symptoms are permanent, progressive and independent of undercurrent events, unrelated to food intake. Most diseases do not present with metabolic crises.May present like neurodevelopment and neurodegenerative disordersDIAGNOSTIC TESTSII. Complex molecules(water insolublepoorly diffusible)MAIN DISORDERSGROUPS OFDISORDERS(Continued)CATEGORIESSimplified classificationTABLE 1SAUDUBRAY ET AL.7
Urinary OxalateMolecular testsLeukocytecystineDIAGNOSTIC TESTSKidney TransplantB6 in PH1CysteamineKidney TransplantTREATMENTH. Disorders of peroxisomes and oxalate:113. Peroxisomal disorders not involving lipidmetabolism114-Disorders of oxalate metabolismG. Storage diseases:107-Disorders of lysosomal transport orsortingCATEGORIES /GROUPS UpdatedNosology3Ether phospholipids(Plasmalogens)Molecular testsMolecular testsplasma LPCVLCFA activation infibroblastsFA profile in fibroblastsMolecular testsPlasma/fibroVLCFA profileEnzyme testing MoleculartestsPlasma RBC, PlasmalogensFibroblasts EnzymesMolecular testsGSD 00 A (liver)0 B (muscle)GlycogeninMany defects SLC10A7 isthe most recentMFSD2A deficiencyFA transport protein 4deficiencyELOV 1,4,5, otherLeukotriene defectCYP2U1Peroxysome biogenesis andFAO defectsRefsum diseaseSjogren-LarssonFA elongationPZO Biogenesisplasmalogen synthesisdefects (RCDP II-V)FARNoneBMT (X-ALD)Diet (Refsum)Zyleuton in SLSMany are not treatableNot treatableDHA? LPC?NoneH. Disorders of peroxisomes and oxalate:109-Disorders of plasmalogen synthesisH. Disorders of peroxisomes and oxalate:110-Disorders of peroxisome beta-oxidation111-Disorders of peroxisome alpha-oxidation112-Disorders of peroxisomal biogenesisE-Disorders of lipids:86-Disorders of the fatty alcohol cycle37. Disorder of vitamin E metabolismE. Disorders of lipids:85-Disorders of fatty acid synthesis andelongationE-Disorders of lipids:91-Disorders of eicosanoid metabolismE. Disorders of lipids:83-Disorders of fatty acid oxidation andtransportI. Congenital disorders of glycosylation117-Disorders of O-xylosylation andglycosaminoglycan synthesisC-Disorders of Carbohydrate51. Glycogen storage diseasesMuscle glycogenin 1, Muscle glycogensynthase deficiency, Hepatic glycogensynthase deficiencyDefects of synthesis, recycling. No storage material. May interfere with fetal development. Most are irreversible disordersMAIN DISORDERSGROUPS OFDISORDERSMost of them are notGlycogentreatableOnly few have metabolicmarkers butperoxisome andcholesterol disorders.GAGFor all othersthe diagnosis is mostlybased on NGS.FA transportUntargeted Metabolomicsand lipidomicsare promising methodsFA synthesis and recycling.Arachidonic acidLiposoluble vitamins A,derivativesand E defectsmay mimick someclinical findings ofcomplex lipid andNon mitochondrial FAperoxisome disorders.metabolismVitamin D and K defects (recycling, synthesis,display very specificcatabolism ,transport)presentations:Rickets and hemorrhagicsyndromes respectivelyII. 2 DeficiencyCATEGORIESSimplified classificationTABLE 18SAUDUBRAY ET AL.
(Continued)already 15 DisordersPL synthesis and recyclingdefects ( 15)SphingolipidsPhospholipids tidylethanolamineCholine, EthanolamineRetinol disordersCholesterolBile acidsGlucocorticoidsMineralocorticoisAndrogens OestrogensCholesterol and bile acidsBilirubin metabolismBiliary transportSteroid disordersand vitamin D disordersB. Disorders of vitamins ,metals andminerals38. Disorders of vitamin K metabolism96. Disorders of steroid metabolism36. Disorders of vitamin D metabolismE-Disorders of lipids:95-Disorders of cholesterol biosynthesis97-Disorders of bile acid synthesis99. Disorders of bilirubin metabolism andbiliary transportE-Disorders of lipids:93-Disorders of phosphoinositides metabolismE-Disorders of lipids:35-Disorders of vitamin A metabolism:89. Disorders of non-mitochondrialphospholipid metabolismA-Disorders of nitrogen-containingcompounds:5-Disorders of choline metabolismE-Disorders of lipids:90. Disorders of non-lysosomal sphingolipidmetabolismCATEGORIES /GROUPS UpdatedNosology3ProteinN glycosylationO-GlycosylationLipid glycosylationGPI anchorMultiple pathwayDolicholDeglycosylationSerum tranferrin andApolipoproteinC-IIIanalysisGlycomicsMolecular testsNot treatableI. Congenital disorders of glycosylationbut MPI, DPAGT1,From 115 to 1303GFPT1, and PGM1-CDGCDG syndromes( 100)Factors supplementationVitamin KHormonal substitutionBile acid replacementNoneNoneNoneTREATMENTMost these disordersshare findings withdisorders of II.21. Only few havemetabolic markers2. Many havemultisystemicpresentationInvestigations ofcoagulationHormonemeasurements in plasmaPlasma OxysterolsPlasma and urinary Bileacids profileMolecular testsMolecular testsMolecular testsMolecular testsDeoxy-sphingolipids(MSMS)DIAGNOSTIC TESTSNearly all the molecules reach their correct intracellular locations by virtue of sophisticated transport-and-delivery systems among which the intracellularmembrane-transport apparatus is crucial.11 A particular model of compartmentalized signaling and metabolism occurs at the synapse that uses anindependent organelle, the synaptic vesicle12Coagulation factorsVitamin KMany types (OCRL, FIG4,INPP5K ) includingmTor signaling l metabolismMAIN DISORDERSGROUPS OFDISORDERSII.3 Cellular processingand traffickingCATEGORIESSimplified classificationTABLE 1SAUDUBRAY ET AL.9
Many defects: Structure and Exome/genome sequencingcomposition of the SV,Exocytic and endocyticprocesses, Proteins/lipidinteractions .Mito t-RNACyto t-RNAMit/cyt t-RNA(KARS and GARS)RibosomopathiesDNA repair andmethylationSynaptic vesicle (SV)t-RNAsynthetasesDisorders of nucleotidemetabolismTREATMENTInterferon (AGS)Exome /genome sequencing Not treatableExome /genome sequencing Not treatableNot treatableExome /genome sequencing Not treatableMany disordersSNAP 29AP5Z1CHMP2BRabenosyn-5Senda, Vici syndromes TraffickingVesiculationProcessingQuality ControlAutophagy.DIAGNOSTIC TESTS3. Most involve nervoussystem4. Almost all present aschronic or progressivediseases independent offood and intercurrentevent5. They are not treatable6. Diagnosis is mostlybased on exome/genome sequencingMAIN DISORDERSGROUPS OFDISORDERS(Continued)CATEGORIESSimplified classificationTABLE 1A-Disorders of nitrogen-containingcompounds:3-Disorders of nucleotide metabolismD-Mitochondrial disorders of energymetabolism:73. Disorders of mitochondrial tRNAA-Disorders of nitrogen-containingcompounds:10-Disorders of monoamine metabolism(VMAT2, DNAJC12)D-Mitochondrial disorders of energymetabolism:79-Disorders of mitochondrial protein qualitycontrol(PINK1)E-Disorders of lipids:93-Disorders of phosphoinositide metabolism(ie, synaptojanin 1 deficiency)G. Storage diseases:100-Disorders of autophagy (ie, SNX14,SPG11)101-Neuronal ceroidlipofuscinosis: CLN4(DNAJC5), ATP13A2D-Mitochondrial disorders of energymetabolism:79-Disorders of mitochondrial proteinquality control80-Other disorders of mitochondrialhomeostasis (ie, trafficking kinesinbinding protein 1 [TRAK1] deficiency)G. Storage diseases:100-Disorders of autophagyI. Congenital disorders of glycosylation128-Glycosylation disorders of vesiculartrafficking129-Disorders of Golgi homeostasisCATEGORIES /GROUPS UpdatedNosology310SAUDUBRAY ET AL.
III.2Cytoplasmic energydefectsDisturbed glucosehomeostasis.TubulopathyGLUT2 (SLC2A2)(Hepatocyte, pancreaticβcellsenterocyte)Not included in Ferreira's nosologyT3 analoguesHigh T3,low T4 and TSH(Allan transporterGlycolysis and PentosePhosphate PathwaydefectsAll enzymesHemolytic anemiaC-Disorders of Carbohydrates49-Disorders of the pentose phosphate pathwayand polyol metabolismDiagnosis is generally easy to suspect on a clinical basis and function tests in Glycolysis, and Glycogen defects and on brain H-NMR spectroscopy for creatinedefectsA-Disorders of nitrogen-containingcompounds:4-Disorders of creatinemetabolism:Creatine transporter deficiencyCreatineE-Disorders of lipids:84. Disorders of ketone body metabolismMonocarboxylate transporter 1 deficiency andsuperactivityC-Disorders of Carbohydrates34-Disorder of vitamin C metabolism:46 Disorders of carbohydrate transport andabsorptionLow plasma creatinelow U creatinineLow brain creatine peak(NMR)DiazoxideSpecial dietSpecial dietSpecial dietMCT12 (SLC16A12)Creatine transportEI hyperinsulinism(Overactivity)KetoacidosisMuscle injury(deficiency)Low CSF GlucoseGLUT1 (SLC2A1)(Cerebral)Monocarboxylic transporter MCT1 (SLC16A1)Lactate, Pyruvate,Ketones ance testsSGLT1(SLC5A1)SGLT2 (SLC5A2)(sodium dependent glucosetransporterGlucosemonosaccharide transporterproteinsGlucose, lactate, pyruvateand ketone bodies arethe most important
A-Disorders of nitrogen-containing compounds: 6-6-Disorders of glutathione metabolism 11-Disorders of phenylalanine 12-Disorders of tyrosine metabolism 13-Disorders of sulfur amino acid and sulfide metab. 14-Disorders of branched-chain amino acid metab. 15-Disorders of lysine metabolism 16-Disorders of proline and ornithine metabolism 18 .
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Den kanadensiska språkvetaren Jim Cummins har visat i sin forskning från år 1979 att det kan ta 1 till 3 år för att lära sig ett vardagsspråk och mellan 5 till 7 år för att behärska ett akademiskt språk.4 Han införde två begrepp för att beskriva elevernas språkliga kompetens: BI
**Godkänd av MAN för upp till 120 000 km och Mercedes Benz, Volvo och Renault för upp till 100 000 km i enlighet med deras specifikationer. Faktiskt oljebyte beror på motortyp, körförhållanden, servicehistorik, OBD och bränslekvalitet. Se alltid tillverkarens instruktionsbok. Art.Nr. 159CAC Art.Nr. 159CAA Art.Nr. 159CAB Art.Nr. 217B1B
