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Inborn errors of metabolism

February 16, 2024

Inborn errors of metabolism form a large class of genetic diseases involving congenital disorders of enzyme activities.[1] The majority are due to defects of single genes that code for enzymes that facilitate conversion of various substances (substrates) into others (products). In most of the disorders, problems arise due to accumulation of substances which are toxic or interfere with normal function, or due to the effects of reduced ability to synthesize essential compounds. Inborn errors of metabolism are often referred to as congenital metabolic diseases or inherited metabolic disorders.[2] Another term used to describe these disorders is "enzymopathies". This term was created following the study of biodynamic enzymology, a science based on the study of the enzymes and their products. Finally, inborn errors of metabolism were studied for the first time by British physician Archibald Garrod (1857–1936), in 1908. He is known for work that prefigured the "one gene-one enzyme" hypothesis, based on his studies on the nature and inheritance of alkaptonuria. His seminal text, Inborn Errors of Metabolism, was published in 1923.[3]

Classification and symptoms of metabolic diseases edit

See also: Metabolic disorders

Traditionally the inherited metabolic diseases were classified as disorders of carbohydrate metabolism, amino acid metabolism, organic acid metabolism, or lysosomal storage diseases.[4] In recent decades, hundreds of new inherited disorders of metabolism have been discovered and the categories have proliferated. Following are some of the major classes of congenital metabolic diseases, with prominent examples of each class.[5]

Because of the enormous number of these diseases the wide range of systems affected badly, nearly every "presenting complaint" to a healthcare provider may have a congenital metabolic disease as a possible cause, especially in childhood and adolescence. The following are examples of potential manifestations affecting each of the major organ systems.

Diagnostic edit

Dozens of congenital metabolic diseases are now detectable by newborn screening tests, especially expanded testing using mass spectrometry.[6] Gas chromatography–mass spectrometry-based technology with an integrated analytics system has now made it possible to test a newborn for over 100 mm genetic metabolic disorders. Because of the multiplicity of conditions, many different diagnostic tests are used for screening. An abnormal result is often followed by a subsequent "definitive test" to confirm the suspected diagnosis.

 
Gas chromatography–mass spectrometry (GCMS) machine

Common screening tests used in the last sixty years:

Specific diagnostic tests (or focused screening for a small set of disorders):

A 2015 review reported that even with all these diagnostic tests, there are cases when "biochemical testing, gene sequencing, and enzymatic testing can neither confirm nor rule out an IEM, resulting in the need to rely on the patient's clinical course".[7] A 2021 review showed that several neurometabolic disorders converge on common neurochemical mechanisms that interfere with biological mechanisms also considered central in ADHD pathophysiology and treatment. This highlights the importance of close collaboration between health services to avoid clinical overshadowing.[8]

Treatment edit

In the middle of the 20th century the principal treatment for some of the amino acid disorders was restriction of dietary protein and all other care was simply management of complications. In the past twenty years, new medications, enzyme replacement, gene therapy, and organ transplantation have become available and beneficial for many previously untreatable disorders. Some of the more common or promising therapies are listed:

Epidemiology edit

In a study in British Columbia, the overall incidence of the inborn errors of metabolism were estimated to be 40 per 100,000 live births or 1 in 2,500 births,[9] overall representing more than approximately 15% of single gene disorders in the population.[9] While a Mexican study established an overall incidence of 3.4: 1000 live newborns and a carrier detection of 6.8:1000 NBS.[10]

Type of inborn error Incidence
Disease involving amino acids (e.g. PKU, Tyrosinemia), organic acids,
primary lactic acidosis, galactosemia, or a urea cycle disease 		24 per 100 000 births[9] 1 in 4,200[9]
Lysosomal storage disease 8 per 100 000 births[9] 1 in 12,500[9]
Peroxisomal disorder ~3 to 4 per 100 000 of births[9] ~1 in 30,000[9]
Respiratory chain-based mitochondrial disease ~3 per 100 000 births[9] 1 in 33,000[9]
Glycogen storage disease 2.3 per 100 000 births[9] 1 in 43,000[9]

References edit

  1. ^ MedlinePlus Encyclopedia: Inborn errors of metabolism
  2. ^ "Inherited metabolic disorders - Symptoms and causes". Mayo Clinic.
  3. ^ Garrod, Archibald E (1923). Inborn errors of metabolism. OCLC 1159473729.[page needed][non-primary source needed]
  4. ^ Bartolozzi, Giorgio (2008). "Errori congeniti del metabolismo" [Inborn errors of metabolism] (PDF). Pediatria: principi e Pratica clinica [Pediatrics: Principles and Clinical Practice] (in Italian). Elsevier srl. pp. 361–386. ISBN 978-88-214-3204-0. OCLC 884592549.
  5. ^ Sghirlanzoni, Angelo (2010). Terapia delle malattie neurologiche. doi:10.1007/978-88-470-1120-5. ISBN 978-88-470-1119-9.
  6. ^ Geerdink, R.B; Niessen, W.M.A; Brinkman, U.A.Th (March 2001). "Mass spectrometric confirmation criterion for product-ion spectra generated in flow-injection analysis". Journal of Chromatography A. 910 (2): 291–300. doi:10.1016/s0021-9673(00)01221-8. PMID 11261724.
  7. ^ Vernon, Hilary J. (1 August 2015). "Inborn Errors of Metabolism: Advances in Diagnosis and Therapy". JAMA Pediatrics. 169 (8): 778–782. doi:10.1001/jamapediatrics.2015.0754. PMID 26075348.
  8. ^ Cannon Homaei S, Barone H, Kleppe R, Betari N, Reif A, Haavik J (2021). "ADHD symptoms in neurometabolic diseases: Underlying mechanisms and clinical implications". Neuroscience and Biobehavioral Reviews. 132: 838–856. doi:10.1016/j.neubiorev.2021.11.012. PMID 34774900. S2CID 243983688.
  9. ^ a b c d e f g h i j k l Applegarth, Derek A.; Toone, Jennifer R.; Lowry, R. Brian (1 January 2000). "Incidence of Inborn Errors of Metabolism in British Columbia, 1969–1996". Pediatrics. 105 (1): e10. doi:10.1542/peds.105.1.e10. PMID 10617747. S2CID 30266513.
  10. ^ Navarrete-Martínez, Juana Inés; Limón-Rojas, Ana Elena; Gaytán-García, Maria de Jesús; Reyna-Figueroa, Jesús; Wakida-Kusunoki, Guillermo; Delgado-Calvillo, Ma. del Rocío; Cantú-Reyna, Consuelo; Cruz-Camino, Héctor; Cervantes-Barragán, David Eduardo (May 2017). "Newborn screening for six lysosomal storage disorders in a cohort of Mexican patients: Three-year findings from a screening program in a closed Mexican health system". Molecular Genetics and Metabolism. 121 (1): 16–21. doi:10.1016/j.ymgme.2017.03.001. PMID 28302345.

Further reading edit

  • Price, Nicholas C; Stevens, Lewis (1996). Principi di enzimologia [Principles of enzymology] (in Italian). A. Delfino. ISBN 978-88-7287-100-3. OCLC 879866185.
  • Mazzucato, Fernando; Giovagnoni, Andrea (2019). Manuale di tecnica, metodologia e anatomia radiografica tradizionali [Manual of traditional radiographic technique, methodology and anatomy] (in Italian). Piccin. ISBN 978-88-299-2959-7. OCLC 1141547603.
  • Torricelli, P; Antonelli, F; Ferorelli, P; Borromeo, I; Shevchenko, A; Lenzi, S; De Martino, A (March 2020). "Oral nutritional supplement prevents weight loss and reduces side effects in patients in advanced lung cancer chemotherapy". Amino Acids. 52 (3): 445–451. doi:10.1007/s00726-020-02822-7. PMID 32034492. S2CID 211053578.

External links edit

  • Portal of Chemistry (Italian)

February 16, 2024
inborn, errors, metabolism, form, large, class, genetic, diseases, involving, congenital, disorders, enzyme, activities, majority, defects, single, genes, that, code, enzymes, that, facilitate, conversion, various, substances, substrates, into, others, product. Inborn errors of metabolism form a large class of genetic diseases involving congenital disorders of enzyme activities 1 The majority are due to defects of single genes that code for enzymes that facilitate conversion of various substances substrates into others products In most of the disorders problems arise due to accumulation of substances which are toxic or interfere with normal function or due to the effects of reduced ability to synthesize essential compounds Inborn errors of metabolism are often referred to as congenital metabolic diseases or inherited metabolic disorders 2 Another term used to describe these disorders is enzymopathies This term was created following the study of biodynamic enzymology a science based on the study of the enzymes and their products Finally inborn errors of metabolism were studied for the first time by British physician Archibald Garrod 1857 1936 in 1908 He is known for work that prefigured the one gene one enzyme hypothesis based on his studies on the nature and inheritance of alkaptonuria His seminal text Inborn Errors of Metabolism was published in 1923 3 Contents 1 Classification and symptoms of metabolic diseases 2 Diagnostic 3 Treatment 4 Epidemiology 5 References 6 Further reading 7 External linksClassification and symptoms of metabolic diseases editSee also Metabolic disordersTraditionally the inherited metabolic diseases were classified as disorders of carbohydrate metabolism amino acid metabolism organic acid metabolism or lysosomal storage diseases 4 In recent decades hundreds of new inherited disorders of metabolism have been discovered and the categories have proliferated Following are some of the major classes of congenital metabolic diseases with prominent examples of each class 5 Disorders of carbohydrate metabolism glycogen storage disease G6PD deficiency Disorders of amino acid metabolism phenylketonuria maple syrup urine disease glutaric acidemia type 1 Urea Cycle Disorder or Urea Cycle Defects Carbamoyl phosphate synthetase I deficiency Citrullinemia type II citrin deficiency Disorders of organic acid metabolism organic acidurias alkaptonuria Combined malonic and methylmalonic aciduria CMAMMA 2 hydroxyglutaric acidurias Disorders of fatty acid oxidation and mitochondrial metabolism Medium chain acyl coenzyme A dehydrogenase deficiency MCADD Disorders of porphyrin metabolism acute intermittent porphyria Disorders of purine or pyrimidine metabolism Lesch Nyhan syndrome AMPD1 Deficiency MADD Disorders of steroid metabolism lipoid congenital adrenal hyperplasia congenital adrenal hyperplasia Disorders of mitochondrial function Kearns Sayre syndrome Disorders of peroxisomal function Zellweger syndrome Lysosomal storage disorders Gaucher s disease Niemann Pick disease Because of the enormous number of these diseases the wide range of systems affected badly nearly every presenting complaint to a healthcare provider may have a congenital metabolic disease as a possible cause especially in childhood and adolescence The following are examples of potential manifestations affecting each of the major organ systems Growth failure failure to grow loss of weight Ambiguous genitalia delayed puberty precocious puberty Developmental delay seizures dementia encephalopathy stroke Deafness blindness pain agnosia Skin rash abnormal pigmentation lacking of pigmentation excessive hair growth lumps and bumps Dental abnormalities Immunodeficiency low platelet count low red blood cell count enlarged spleen enlarged lymph nodes Many forms of cancer Recurrent vomiting diarrhea abdominal pain Excessive urination kidney failure dehydration edema Low blood pressure heart failure enlarged heart hypertension myocardial infarction Liver enlargement jaundice liver failure Unusual facial features congenital malformations Excessive breathing hyperventilation respiratory failure Abnormal behavior depression psychosis Joint pain muscle weakness cramps Hypothyroidism adrenal insufficiency hypogonadism diabetes mellitusDiagnostic editDozens of congenital metabolic diseases are now detectable by newborn screening tests especially expanded testing using mass spectrometry 6 Gas chromatography mass spectrometry based technology with an integrated analytics system has now made it possible to test a newborn for over 100 mm genetic metabolic disorders Because of the multiplicity of conditions many different diagnostic tests are used for screening An abnormal result is often followed by a subsequent definitive test to confirm the suspected diagnosis nbsp Gas chromatography mass spectrometry GCMS machineCommon screening tests used in the last sixty years Ferric chloride test detects abnormal metabolites in urine Ninhydrin paper chromatography detects abnormal amino acid patterns Guthrie test detects excessive amounts of specific amino acids in blood The dried blood spot can be used for multianalyte testing using Tandem Mass Spectrometry MS MS This given an indication for a disorder The same has to be further confirmed by enzyme assays IEX Ninhydrin GC MS or DNA Testing Quantitative measurement of amino acids in plasma and urine IEX Ninhydrin post column derivitization liquid ion chromatography detects abnormal amino acid patterns and quantitative analysis Urine organic acid analysis by gas chromatography mass spectrometry Plasma acylcarnitine analysis by mass spectrometry Urine purine and pyrimidine analysis by gas chromatography mass spectrometrySpecific diagnostic tests or focused screening for a small set of disorders Tissue biopsy liver muscle brain bone marrow Skin biopsy and fibroblast cultivation for specific enzyme testing Specific DNA testingA 2015 review reported that even with all these diagnostic tests there are cases when biochemical testing gene sequencing and enzymatic testing can neither confirm nor rule out an IEM resulting in the need to rely on the patient s clinical course 7 A 2021 review showed that several neurometabolic disorders converge on common neurochemical mechanisms that interfere with biological mechanisms also considered central in ADHD pathophysiology and treatment This highlights the importance of close collaboration between health services to avoid clinical overshadowing 8 Treatment editIn the middle of the 20th century the principal treatment for some of the amino acid disorders was restriction of dietary protein and all other care was simply management of complications In the past twenty years new medications enzyme replacement gene therapy and organ transplantation have become available and beneficial for many previously untreatable disorders Some of the more common or promising therapies are listed Dietary restriction E g reduction of dietary protein remains a mainstay of treatment for phenylketonuria and other amino acid disorders Dietary supplementation or replacement E g oral ingestion of cornstarch several times a day helps prevent people with glycogen storage diseases from becoming seriously hypoglycemic Medications E g Nitisisone prevents the formation of toxic metabolites for patients with Tyrosinemia Type I and enables normal growth and development in combination with a low protein diet Vitamins E g thiamine supplementation benefits several types of disorders that cause lactic acidosis Intermediary metabolites compounds or drugs that facilitate or retard specific metabolic pathways Dialysis Enzyme replacement E g Acid alpha glucosidase for Pompe disease Gene therapy Bone marrow or organ transplantation Treatment of symptoms and complications Prenatal diagnosisEpidemiology editIn a study in British Columbia the overall incidence of the inborn errors of metabolism were estimated to be 40 per 100 000 live births or 1 in 2 500 births 9 overall representing more than approximately 15 of single gene disorders in the population 9 While a Mexican study established an overall incidence of 3 4 1000 live newborns and a carrier detection of 6 8 1000 NBS 10 Type of inborn error IncidenceDisease involving amino acids e g PKU Tyrosinemia organic acids primary lactic acidosis galactosemia or a urea cycle disease 24 per 100 000 births 9 1 in 4 200 9 Lysosomal storage disease 8 per 100 000 births 9 1 in 12 500 9 Peroxisomal disorder 3 to 4 per 100 000 of births 9 1 in 30 000 9 Respiratory chain based mitochondrial disease 3 per 100 000 births 9 1 in 33 000 9 Glycogen storage disease 2 3 per 100 000 births 9 1 in 43 000 9 References edit MedlinePlus Encyclopedia Inborn errors of metabolism Inherited metabolic disorders Symptoms and causes Mayo Clinic Garrod Archibald E 1923 Inborn errors of metabolism OCLC 1159473729 page needed non primary source needed Bartolozzi Giorgio 2008 Errori congeniti del metabolismo Inborn errors of metabolism PDF Pediatria principi e Pratica clinica Pediatrics Principles and Clinical Practice in Italian Elsevier srl pp 361 386 ISBN 978 88 214 3204 0 OCLC 884592549 Sghirlanzoni Angelo 2010 Terapia delle malattie neurologiche doi 10 1007 978 88 470 1120 5 ISBN 978 88 470 1119 9 Geerdink R B Niessen W M A Brinkman U A Th March 2001 Mass spectrometric confirmation criterion for product ion spectra generated in flow injection analysis Journal of Chromatography A 910 2 291 300 doi 10 1016 s0021 9673 00 01221 8 PMID 11261724 Vernon Hilary J 1 August 2015 Inborn Errors of Metabolism Advances in Diagnosis and Therapy JAMA Pediatrics 169 8 778 782 doi 10 1001 jamapediatrics 2015 0754 PMID 26075348 Cannon Homaei S Barone H Kleppe R Betari N Reif A Haavik J 2021 ADHD symptoms in neurometabolic diseases Underlying mechanisms and clinical implications Neuroscience and Biobehavioral Reviews 132 838 856 doi 10 1016 j neubiorev 2021 11 012 PMID 34774900 S2CID 243983688 a b c d e f g h i j k l Applegarth Derek A Toone Jennifer R Lowry R Brian 1 January 2000 Incidence of Inborn Errors of Metabolism in British Columbia 1969 1996 Pediatrics 105 1 e10 doi 10 1542 peds 105 1 e10 PMID 10617747 S2CID 30266513 Navarrete Martinez Juana Ines Limon Rojas Ana Elena Gaytan Garcia Maria de Jesus Reyna Figueroa Jesus Wakida Kusunoki Guillermo Delgado Calvillo Ma del Rocio Cantu Reyna Consuelo Cruz Camino Hector Cervantes Barragan David Eduardo May 2017 Newborn screening for six lysosomal storage disorders in a cohort of Mexican patients Three year findings from a screening program in a closed Mexican health system Molecular Genetics and Metabolism 121 1 16 21 doi 10 1016 j ymgme 2017 03 001 PMID 28302345 Further reading editPrice Nicholas C Stevens Lewis 1996 Principi di enzimologia Principles of enzymology in Italian A Delfino ISBN 978 88 7287 100 3 OCLC 879866185 Mazzucato Fernando Giovagnoni Andrea 2019 Manuale di tecnica metodologia e anatomia radiografica tradizionali Manual of traditional radiographic technique methodology and anatomy in Italian Piccin ISBN 978 88 299 2959 7 OCLC 1141547603 Torricelli P Antonelli F Ferorelli P Borromeo I Shevchenko A Lenzi S De Martino A March 2020 Oral nutritional supplement prevents weight loss and reduces side effects in patients in advanced lung cancer chemotherapy Amino Acids 52 3 445 451 doi 10 1007 s00726 020 02822 7 PMID 32034492 S2CID 211053578 External links editPortal of Chemistry Italian Retrieved from https en wikipedia org w index php title Inborn errors of metabolism amp oldid 1193556305, wikipedia, wiki, book, books, library,

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