inborn errors of metabolism

{{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.{{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}} 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.{{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}} {{columns-list|colwidth=30em|

• Disorders of carbohydrate metabolism
• glycogen storage disease
• G6PD deficiency
• Disorders of 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 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

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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}}

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• 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 mellitus

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Dozens of congenital metabolic diseases are now detectable by newborn screening tests, especially expanded testing using mass spectrometry.{{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}} 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.{{cn|date=October 2024}}

File:GCMS closed.jpg

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 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".{{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}} 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.{{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}}

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:{{cn|date=October 2024}}

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• 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., Nitisinone 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 diagnosis

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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,{{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}} overall representing more than approximately 15% of single gene disorders in the population. 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.{{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}}

{{reflist}}

• {{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}}

{{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

}}

• 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:Medical genetics

Category:Metabolism