View source for Inborn errors of metabolism

{{short description|Class of genetic diseases}}
'''Inborn errors of metabolism''' form a large class of [[genetic disease]]s involving [[congenital]] disorders of enzyme activities.<ref>{{MedlinePlusEncyclopedia|002438|Inborn errors of metabolism}}</ref> The majority are due to defects of single [[gene]]s that code for [[enzyme]]s that facilitate conversion of various substances ([[substrate (biochemistry)|substrate]]s) into others ([[Product (chemistry)|product]]s). 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'''.<ref name="mayo">{{Cite web |title=Inherited metabolic disorders - Symptoms and causes |url=https://www.mayoclinic.org/diseases-conditions/inherited-metabolic-disorders/symptoms-causes/syc-20352590 |website=Mayo Clinic |language=en}}</ref> Another term used to describe these disorders is "enzymopathies". This term was created following the study of [[Biochemical Processes|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|"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.<ref>{{Cite book |last=Garrod |first=Archibald E |url=http://www.esp.org/books/garrod/inborn-errors/facsimile/ |title=Inborn errors of metabolism |date=1923 |oclc=1159473729}}{{page needed|date=September 2021}}{{primary source inline|date=September 2021}}</ref>

== Classification of metabolic diseases ==
{{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 disease]]s.<ref>{{Cite book |last=Bartolozzi |first=Giorgio |title=Pediatria: principi e Pratica clinica |date=2008 |publisher=Elsevier srl |isbn=978-88-214-3204-0 |pages=361–386 |language=Italian |trans-title=Pediatrics: Principles and Clinical Practice |chapter=Errori congeniti del metabolismo |trans-chapter=Inborn errors of metabolism |oclc=884592549 |chapter-url=http://www.doctor33.it/cont/download-center-files/18319/cap-errori-congeniti-metabolismo-x21770allp1.pdf}}</ref> 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.<ref>{{Cite book |last=Sghirlanzoni |first=Angelo |title=Terapia delle malattie neurologiche |year=2010 |isbn=978-88-470-1119-9 |doi=10.1007/978-88-470-1120-5}}</ref> {{columns-list|colwidth=30em|
* [[Inborn errors of carbohydrate metabolism|Disorders of carbohydrate metabolism]]
** [[glycogen storage disease]]
** [[Glucose-6-phosphate dehydrogenase deficiency|G6PD deficiency]]
* Disorders of [[List of amino acid metabolism disorders|amino acid]] metabolism
** [[phenylketonuria]]
** [[tyrosinemia]]
** [[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 aciduria]]s)
** [[alkaptonuria]]
** [[Combined malonic and methylmalonic aciduria]] (CMAMMA)
** [[2-Hydroxyglutaric aciduria|2-hydroxyglutaric acidurias]]
* Disorders of [[List of fatty acid metabolism disorders|fatty acid oxidation]] and [[mitochondrial]] metabolism
** [[Medium-chain acyl-coenzyme A dehydrogenase deficiency]] (MCADD)
* Disorders of [[porphyrin]] metabolism
** [[acute intermittent porphyria]]
* Disorders of [[Inborn errors of purine–pyrimidine metabolism|purine or pyrimidine]] metabolism
** [[Lesch–Nyhan syndrome]]
** [[Adenosine monophosphate deaminase deficiency type 1|AMPD1 Deficiency]] (MADD)
* Disorders of [[Inborn errors of steroid metabolism|steroid]] metabolism
** [[lipoid congenital adrenal hyperplasia]]
** [[congenital adrenal hyperplasia]]
* Disorders of [[mitochondrial]] function
** [[Kearns–Sayre syndrome]]
* Disorders of [[peroxisomal]] function
** [[Zellweger syndrome]]
* [[Lysosomal storage disorder]]s
** [[Gaucher's disease]]
** [[Niemann–Pick disease]]
}}
==Signs and symptoms==
Because of the enormous number of these diseases and the numerous systems negatively impacted, 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.{{cn|date=October 2024}}
{{columns-list|colwidth=30em|
* [[Growth failure]], failure to grow, loss of weight
* [[intersex|Ambiguous genitalia]], [[delayed puberty]], [[precocious puberty]]
* [[Developmental disability|Developmental delay]], [[seizure]]s, [[dementia]], [[encephalopathy]], [[stroke]]
* [[Deafness]], [[blindness]], [[pain agnosia]]
* Skin [[rash]], abnormal [[pigmentation]], lacking of pigmentation, [[hirsutism|excessive hair growth]], lumps and bumps
* Dental abnormalities
* [[Immunodeficiency]], [[thrombocytopenia|low platelet count]], [[anemia|low red blood cell count]], [[Splenomegaly|enlarged spleen]], [[Lymphadenopathy|enlarged lymph nodes]]
* Many forms of [[cancer]]
* Recurrent [[vomiting]], [[diarrhea]], [[abdominal pain]]
* [[Polyuria|Excessive urination]], [[kidney failure]], [[dehydration]], [[edema]]
* [[Hypotension|Low blood pressure]], [[heart failure]], [[Cardiomegaly|enlarged heart]], [[hypertension]], [[myocardial infarction]]
* [[Hepatomegaly|Liver enlargement]], [[jaundice]], [[liver failure]]
* Unusual facial features, [[congenital malformation]]s
* Excessive breathing ([[hyperventilation]]), [[respiratory failure]]
* Abnormal behavior, [[clinical depression|depression]], [[psychosis]]
* Joint pain, [[muscle]] weakness, cramps
* [[Hypothyroidism]], [[adrenal insufficiency]], [[hypogonadism]], [[diabetes mellitus]]
}}

==Diagnostic==
Dozens of congenital metabolic diseases are now detectable by [[newborn screening]] tests, especially expanded testing using mass spectrometry.<ref>{{Cite journal |last=Geerdink |first=R.B |last2=Niessen |first2=W.M.A |last3=Brinkman |first3=U.A.Th |date=March 2001 |title=Mass spectrometric confirmation criterion for product-ion spectra generated in flow-injection analysis |journal=Journal of Chromatography A |volume=910 |issue=2 |pages=291–300 |doi=10.1016/s0021-9673(00)01221-8 |pmid=11261724}}</ref> [[Gas chromatography–mass spectrometry]]-based technology with an integrated analytics system  has now made it possible to test a newborn for over 100&nbsp;mm genetic metabolic disorders. Because of the multiplicity of conditions, many different [[diagnostic test]]s are used for screening. An abnormal result is often followed by a subsequent "definitive test" to confirm the suspected diagnosis.{{cn|date=October 2024}}
[[File:GCMS closed.jpg|thumb|Gas chromatography–mass spectrometry (GCMS) machine]]
Common screening tests used in the last sixty years:{{cn|date=October 2024}}
* [[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 [[Blood plasma|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 spectrometry

Specific diagnostic tests (or focused screening for a small set of disorders):{{cn|date=October 2024}}
* Tissue [[biopsy]]: [[liver]], [[muscle]], [[brain]], [[bone marrow]]
* Skin biopsy and fibroblast cultivation for specific enzyme testing
* Specific [[DNA 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".<ref>{{Cite journal |last=Vernon |first=Hilary J. |date=1 August 2015 |title=Inborn Errors of Metabolism: Advances in Diagnosis and Therapy |journal=JAMA Pediatrics |volume=169 |issue=8 |pages=778–782 |doi=10.1001/jamapediatrics.2015.0754 |pmid=26075348}}</ref> 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 [[diagnostic overshadowing|clinical overshadowing]].<ref>{{Cite journal |vauthors=Cannon Homaei S, Barone H, Kleppe R, Betari N, Reif A, Haavik J |date=2021 |title=ADHD symptoms in neurometabolic diseases: Underlying mechanisms and clinical implications |journal=[[Neuroscience and Biobehavioral Reviews]] |volume=132 |pages=838–856 |doi=10.1016/j.neubiorev.2021.11.012 |pmid=34774900 |s2cid=243983688 |doi-access=free}}</ref>

==Treatment==
In the middle of the 20th century the principal treatment for some of the [[amino acid disorder]]s 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:{{cn|date=October 2024}}
{{columns-list|colwidth=30em|
* Dietary restriction
** E.g., reduction of dietary protein remains a mainstay of treatment for [[phenylketonuria]] and other [[amino acid disorder]]s
* Dietary supplementation or replacement
** E.g., [[oral ingestion]] of cornstarch several times a day helps prevent people with [[glycogen storage disease]]s from becoming seriously [[hypoglycemia|hypoglycemic]].
* Medications
** E.g., [[Nitisinone]] prevents the formation of toxic [[metabolites]] for patients with [[Tyrosinemia type I|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]]
* [[Kidney dialysis|Dialysis]]
* [[Enzyme replacement]] E.g. [[Alglucosidase alfa|Acid-alpha glucosidase]] for [[Pompe disease]]
* [[Gene therapy]]
* [[bone marrow transplant|Bone marrow]] or [[organ transplantation]]
* Treatment of symptoms and complications
* [[Prenatal diagnosis]]
}}

==Epidemiology==
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,<ref name="BC">{{Cite journal |last=Applegarth |first=Derek A. |last2=Toone |first2=Jennifer R. |last3=Lowry |first3=R. Brian |date=1 January 2000 |title=Incidence of Inborn Errors of Metabolism in British Columbia, 1969–1996 |journal=Pediatrics |volume=105 |issue=1 |pages=e10 |doi=10.1542/peds.105.1.e10 |pmid=10617747 |s2cid=30266513}}</ref> overall representing more than approximately 15% of [[single gene disorders]] in the population.<ref name=BC/> While a Mexican study established an overall incidence of 3.4:1,000 live newborns and a carrier detection of 6.8:1,000 NBS.<ref>{{Cite journal |last=Navarrete-Martínez |first=Juana Inés |last2=Limón-Rojas |first2=Ana Elena |last3=Gaytán-García |first3=Maria de Jesús |last4=Reyna-Figueroa |first4=Jesús |last5=Wakida-Kusunoki |first5=Guillermo |last6=Delgado-Calvillo |first6=Ma. del Rocío |last7=Cantú-Reyna |first7=Consuelo |last8=Cruz-Camino |first8=Héctor |last9=Cervantes-Barragán |first9=David Eduardo |date=May 2017 |title=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 |journal=Molecular Genetics and Metabolism |volume=121 |issue=1 |pages=16–21 |doi=10.1016/j.ymgme.2017.03.001 |pmid=28302345}}</ref>

{|class="wikitable"
|-
! Type of inborn error !!colspan=2| Incidence
|-
| Disease involving amino acids (e.g. [[phenylketonuria|PKU]], [[Tyrosinemia]]), organic acids,<br /> primary lactic acidosis, [[galactosemia]], or a urea cycle disease
| 24 per 100,000 births<ref name=BC/> || 1 in 4,200<ref name=BC/>
|-
| [[Lysosomal storage disease]]
| 8 per 100,000 births<ref name=BC/> || 1 in 12,500<ref name=BC/>
|-
| [[Peroxisomal disorder]]
| ~3 to 4 per 100,000 of births<ref name=BC/> || ~1 in 30,000<ref name=BC/>
|-
| Respiratory chain-based [[mitochondrial disease]]
| ~3 per 100,000 births<ref name=BC/> || 1 in 33,000<ref name=BC/>
|-
| [[Glycogen storage disease]]
| 2.3 per 100,000 births<ref name=BC/> || 1 in 43,000<ref name=BC/>
|}

==References==
{{reflist}}

==Further reading==
* {{Cite book |last=Price |first=Nicholas C |title=Principi di enzimologia |last2=Stevens |first2=Lewis |date=1996 |publisher=A. Delfino |isbn=978-88-7287-100-3 |language=it |trans-title=Principles of enzymology |oclc=879866185}}
* {{Cite book |last=Mazzucato |first=Fernando |title=Manuale di tecnica, metodologia e anatomia radiografica tradizionali |last2=Giovagnoni |first2=Andrea |date=2019 |publisher=Piccin |isbn=978-88-299-2959-7 |language=it |trans-title=Manual of traditional radiographic technique, methodology and anatomy |oclc=1141547603}}
* {{Cite journal |last=Torricelli |first=P |last2=Antonelli |first2=F |last3=Ferorelli |first3=P |last4=Borromeo |first4=I |last5=Shevchenko |first5=A |last6=Lenzi |first6=S |last7=De Martino |first7=A |date=March 2020 |title=Oral nutritional supplement prevents weight loss and reduces side effects in patients in advanced lung cancer chemotherapy. |journal=Amino Acids |volume=52 |issue=3 |pages=445–451 |doi=10.1007/s00726-020-02822-7 |pmid=32034492 |s2cid=211053578}}

== External links ==
{{Medical resources
|   DiseasesDB     =
|   ICD11          = {{ICD11|5C50}}-{{ICD11|5C59}}, {{ICD11|5C5A}}
|   ICD10          = {{ICD10|E|70||e|70}}-{{ICD10|E|90||e|70}}
|   ICD9           = {{ICD9|270}}-{{ICD9|279}}
|   ICDO           =
|   OMIM           =
|   MedlinePlus    = 002438
|   eMedicineSubj  = emerg
|   eMedicineTopic = 768
|   eMedicine_mult = {{eMedicine2|article|804757}}
|   MeshID         = D008661
}}
* [[:it:Portale:Chimica|Portal of Chemistry (Italian)]]

{{Carbohydrate metabolic pathology}}
{{Amino acid metabolic pathology}}
{{Fatty-acid metabolism disorders}}
{{Lipid metabolism disorders}}
{{Heme metabolism disorders}}
{{Inborn errors of purine-pyrimidine metabolism}}
{{Defects of steroid metabolism}}
{{Metabolic disorders of vitamins, coenzymes, and cofactors}}

[[Category:Inborn errors of metabolism| ]]
[[Category:Medical genetics]]
[[Category:Metabolism]]