Inborn errors of metabolism
Inborn errors of metabolismform a large class ofgenetic diseasesinvolvingcongenitaldisorders of enzyme activities.[1]The majority are due to defects of singlegenesthat code forenzymesthat 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 ascongenital metabolic diseasesorinherited metabolic disorders.[2]Another term used to describe these disorders is "enzymopathies". This term was created following the study ofbiodynamic enzymology,a science based on the study of the enzymes and their products. Finally,inborn errors of metabolismwere studied for the first time by British physicianArchibald 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 of metabolic diseases[edit]
Traditionally the inherited metabolic diseases were classified as disorders ofcarbohydratemetabolism,amino acidmetabolism,organic acidmetabolism, orlysosomal 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
- Disorders ofamino acidmetabolism
- Urea Cycle Disorder or Urea Cycle Defects
- Disorders oforganic acidmetabolism (organic acidurias)
- Disorders offatty acid oxidationandmitochondrialmetabolism
- Disorders ofporphyrinmetabolism
- Disorders ofpurine or pyrimidinemetabolism
- Disorders ofsteroidmetabolism
- Disorders ofmitochondrialfunction
- Disorders ofperoxisomalfunction
- Lysosomal storage disorders
Signs and symptoms[edit]
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
- Skinrash,abnormalpigmentation,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 ofcancer
- Recurrentvomiting,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,muscleweakness, cramps
- Hypothyroidism,adrenal insufficiency,hypogonadism,diabetes mellitus
Diagnostic[edit]
Dozens of congenital metabolic diseases are now detectable bynewborn screeningtests, 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 differentdiagnostic testsare used for screening. An abnormal result is often followed by a subsequent "definitive test" to confirm the suspected diagnosis.
Common screening tests used in the last sixty years:
- Ferric chloride test(detects abnormal metabolites in urine)
- Ninhydrinpaper chromatography(detects abnormalamino acidpatterns)
- 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 ofamino acidsinplasmaandurine
- IEX-Ninhydrinpost-column derivitization liquidion chromatography(detects abnormalamino acidpatterns and quantitative analysis)
- Urineorganic acidanalysis bygas chromatography–mass spectrometry
- Plasmaacylcarnitineanalysis bymass spectrometry
- Urinepurineandpyrimidineanalysis by gas chromatography-mass spectrometry
Specific diagnostic tests (or focused screening for a small set of disorders):
- Tissuebiopsy:liver,muscle,brain,bone marrow
- Skin biopsy and fibroblast cultivation for specific enzyme testing
- SpecificDNA testing
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 inADHDpathophysiology and treatment. This highlights the importance of close collaboration between health services to avoidclinical overshadowing.[8]
Treatment[edit]
In the middle of the 20th century the principal treatment for some of theamino acid disorderswas 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 forphenylketonuriaand otheramino acid disorders
- Dietary supplementation or replacement
- E.g.,oral ingestionof cornstarch several times a day helps prevent people withglycogen storage diseasesfrom becoming seriouslyhypoglycemic.
- Medications
- E.g.,Nitisinoneprevents the formation of toxicmetabolitesfor patients withTyrosinemia Type Iand enables normal growth and development in combination with alow-protein diet
- Vitamins
- E.g.,thiaminesupplementation benefits several types of disorders that causelactic acidosis.
- Intermediary metabolites, compounds, or drugs that facilitate or retard specificmetabolic pathways
- Dialysis
- Enzyme replacementE.g.Acid- Alpha glucosidaseforPompe disease
- Gene therapy
- Bone marrowororgan transplantation
- Treatment of symptoms and complications
- Prenatal diagnosis
Epidemiology[edit]
In a study inBritish 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% ofsingle gene disordersin 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-basedmitochondrial 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.OCLC1159473729.[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.ISBN978-88-214-3204-0.OCLC884592549.
- ^Sghirlanzoni, Angelo (2010).Terapia delle malattie neurologiche.doi:10.1007/978-88-470-1120-5.ISBN978-88-470-1119-9.
- ^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.PMID11261724.
- ^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.PMID26075348.
- ^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.PMID34774900.S2CID243983688.
- ^abcdefghijklApplegarth, 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.PMID10617747.S2CID30266513.
- ^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.PMID28302345.
Further reading[edit]
- Price, Nicholas C; Stevens, Lewis (1996).Principi di enzimologia[Principles of enzymology] (in Italian). A. Delfino.ISBN978-88-7287-100-3.OCLC879866185.
- Mazzucato, Fernando; Giovagnoni, Andrea (2019).Manuale di tecnica, metodologia e anatomia radiografica tradizionali[Manual of traditional radiographic technique, methodology and anatomy] (in Italian). Piccin.ISBN978-88-299-2959-7.OCLC1141547603.
- 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.PMID32034492.S2CID211053578.