Inborn errors of metabolism

Short description: Class of genetic diseases

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 of metabolic diseases
* 2 Signs and symptoms
* 3 Diagnostic
* 4 Treatment
* 5 Epidemiology
* 6 References
* 7 Further reading
* 8 External links

## Classification of metabolic diseases

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]

* 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

## 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.[citation needed]

* 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

## Diagnostic

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.[citation needed]

Gas chromatography–mass spectrometry (GCMS) machine

Common screening tests used in the last sixty years:[citation needed]

* 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):[citation needed]

* 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".[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

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:[citation needed]

* 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

## 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,[9] overall representing more than approximately 15% of single gene disorders in the population.[9] While a Mexican study established an overall incidence of 3.4:1,000 live newborns and a carrier detection of 6.8:1,000 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

1. ↑ MedlinePlus Encyclopedia Inborn errors of metabolism
2. ↑ "Inherited metabolic disorders - Symptoms and causes" (in en). https://www.mayoclinic.org/diseases-conditions/inherited-metabolic-disorders/symptoms-causes/syc-20352590.
3. ↑ Garrod, Archibald E (1923). Inborn errors of metabolism. OCLC 1159473729. http://www.esp.org/books/garrod/inborn-errors/facsimile/. [non-primary source needed]
4. ↑ Bartolozzi, Giorgio (2008). "Errori congeniti del metabolismo" (in Italian). Pediatria: principi e Pratica clinica. Elsevier srl. pp. 361–386. ISBN 978-88-214-3204-0. OCLC 884592549. http://www.doctor33.it/cont/download-center-files/18319/cap-errori-congeniti-metabolismo-x21770allp1.pdf.
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. ↑ "ADHD symptoms in neurometabolic diseases: Underlying mechanisms and clinical implications". Neuroscience and Biobehavioral Reviews 132: 838–856. 2021. doi:10.1016/j.neubiorev.2021.11.012. PMID 34774900.
9. ↑ 9.00 9.01 9.02 9.03 9.04 9.05 9.06 9.07 9.08 9.09 9.10 9.11 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.
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 et al. (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

* Price, Nicholas C; Stevens, Lewis (1996) (in it). Principi di enzimologia. A. Delfino. ISBN 978-88-7287-100-3. OCLC 879866185.
* Mazzucato, Fernando; Giovagnoni, Andrea (2019) (in it). Manuale di tecnica, metodologia e anatomia radiografica tradizionali. 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.

## External links

Classification|

* ICD-11: 5C50-5C59, 5C5A
* ICD-10: E70-E90
* ICD-9-CM: 270-279
* MeSH: D008661

|

External resources|

* MedlinePlus: 002438
* eMedicine: emerg/768 article/804757

* Portal of Chemistry (Italian)

* v
* t
* e

Inborn error of carbohydrate metabolism: monosaccharide metabolism disorders (E73–E74, 271)
Including glycogen storage diseases (GSD)

Sucrose, transport
(extracellular)|

| Disaccharide catabolism|

* Congenital alactasia
* Sucrose intolerance

|

Monosaccharide transport|

* Glucose-galactose malabsorption
* Inborn errors of renal tubular transport (Renal glycosuria)
* Fructose malabsorption

Hexose → glucose|

| Monosaccharide catabolism|

| Fructose:|

* Essential fructosuria
* Fructose intolerance

|

Galactose / galactosemia:|

* GALK deficiency
* GALT deficiency/GALE deficiency

Glucose ⇄ glycogen]]|

| Glycogenesis|

* GSD type 0 (glycogen synthase deficiency)
* GSD type IV (Andersen's disease, branching enzyme deficiency)
* Adult polyglucosan body disease (APBD)

|

Glycogenolysis|

| Extralysosomal:|

* GSD type III (Cori's disease, debranching enzyme deficiency)
* GSD type VI (Hers' disease, liver glycogen phosphorylase deficiency)
* GSD type V (McArdle's disease, myophosphorylase deficiency)
* GSD type IX (phosphorylase kinase deficiency)

|

Lysosomal (LSD):|

* GSD type II (Pompe's disease, glucosidase deficiency)

Glucose ⇄ CAC]]|

| Glycolysis|

* MODY 2/HHF3
* GSD type VII (Tarui's disease, phosphofructokinase deficiency)
* Triosephosphate isomerase deficiency
* Pyruvate kinase deficiency

|

Gluconeogenesis|

* PCD
* Fructose bisphosphatase deficiency
* GSD type I (von Gierke's disease, glucose 6-phosphatase deficiency)

Pentose phosphate pathway|

* Glucose-6-phosphate dehydrogenase deficiency
* Transaldolase deficiency
* 6-phosphogluconate dehydrogenase deficiency

Other|

* Hyperoxaluria
* Primary hyperoxaluria
* Pentosuria
* Aldolase A deficiency

* v
* t
* e

Inborn error of amino acid metabolism (E70–E72, 270)

[[Chemistry:Ketogenic amino K→acetyl-CoA]]|

| Lysine/straight chain|

* Glutaric acidemia type 1
* type 2
* Hyperlysinemia
* Pipecolic acidemia
* Saccharopinuria

|

Leucine|

* 3-hydroxy-3-methylglutaryl-CoA lyase deficiency
* 3-Methylcrotonyl-CoA carboxylase deficiency
* 3-Methylglutaconic aciduria 1
* Isovaleric acidemia
* Maple syrup urine disease

Tryptophan|

* Hypertryptophanemia

| G→pyruvate→citrate|

| Glycine|

* D-Glyceric acidemia
* Glutathione synthetase deficiency
* Sarcosinemia

* Glycine]]→Creatine: GAMT deficiency
* Glycine encephalopathy

|

G→glutamate→
α-ketoglutarate|

| Histidine|

* Carnosinemia
* Histidinemia
* Urocanic aciduria

|

Proline|

* Hyperprolinemia
* Prolidase deficiency

Glutamate/glutamine|

* SSADHD

G→propionyl-CoA→
succinyl-CoA|

| Valine|

* Hypervalinemia
* Isobutyryl-CoA dehydrogenase deficiency
* Maple syrup urine disease

|

Isoleucine|

* 2-Methylbutyryl-CoA dehydrogenase deficiency
* Beta-ketothiolase deficiency
* Maple syrup urine disease

Methionine|

* Cystathioninuria
* Homocystinuria
* Hypermethioninemia

General BC/OA|

* Methylmalonic acidemia
* Methylmalonyl-CoA mutase deficiency
* Propionic acidemia

G→fumarate|

| [[Chemistry:PhenylPhenylalanine]]/tyrosine|

| Phenylketonuria|

* 6-Pyruvoyltetrahydropterin synthase deficiency
* Tetrahydrobiopterin deficiency

|

Tyrosinemia|

* Alkaptonuria/Ochronosis
* Tyrosinemia type I
* Tyrosinemia type II
* Tyrosinemia type III/Hawkinsinuria

Tyrosine→Melanin|

* Albinism: Ocular albinism (1)
* Oculocutaneous albinism (Hermansky–Pudlak syndrome)
* Waardenburg syndrome

Tyrosine→Norepinephrine|

* Dopamine beta hydroxylase deficiency
* reverse: Brunner syndrome

G→oxaloacetate|

| Urea cycle/Hyperammonemia
(arginine

* aspartate)

* Argininemia
* Argininosuccinic aciduria
* Carbamoyl phosphate synthetase I deficiency
* Citrullinemia
* N-Acetylglutamate synthase deficiency
* Ornithine transcarbamylase deficiency/translocase deficiency

|

Transport/
IE of RTT|

* Solute carrier family: Cystinuria
* Hartnup disease
* Iminoglycinuria
* Lysinuric protein intolerance

* Fanconi syndrome: Oculocerebrorenal syndrome]]
* Cystinosis

Other|

* 2-Hydroxyglutaric aciduria
* Aminoacylase 1 deficiency
* Ethylmalonic encephalopathy
* Fumarase deficiency
* Trimethylaminuria

* v
* t
* e

Inborn error of lipid metabolism: fatty-acid metabolism disorders (E71.3, 277.81–277.85)

Synthesis|

* Biotinidase deficiency (BTD)

Degradation|

| Acyl
transport|

* Carnitine
* CPT1
* CPT2
* CDSP
* CACTD
* Adrenoleukodystrophy (ALD)

|

Beta
oxidation|

| General|

* Acyl CoA dehydrogenase
* Short-chain SCADD
* Medium-chain MCADD
* Long-chain 3-hydroxy LCHAD
* Very long-chain VLCADD

* Mitochondrial trifunctional protein deficiency (MTPD): Acute fatty liver of pregnancy]]

|

Unsaturated|

* 2,4 Dienoyl-CoA reductase deficiency (DECRD)

Odd chain|

* Propionic acidemia (PCC deficiency)

Other|

* 3-hydroxyacyl-coenzyme A dehydrogenase deficiency (HADHD)
* Glutaric acidemia type 2 (MADD)

acetyl-CoA|

* Malonic aciduria (MCD)

Aldehyde|

* Sjögren–Larsson syndrome (SLS)

Template:Lipid metabolism disorders Template:Heme metabolism disorders

* v
* t
* e

Inborn error of purine–pyrimidine metabolism (E79, 277.2)

Purine metabolism|

| Anabolism|

* Adenylosuccinate lyase deficiency
* Adenosine Monophosphate Deaminase Deficiency type 1

|

Nucleotide salvage|

* Lesch–Nyhan syndrome/Hyperuricemia
* Adenine phosphoribosyltransferase deficiency

Catabolism|

* Adenosine deaminase deficiency
* Purine nucleoside phosphorylase deficiency
* Xanthinuria
* Gout
* Mitochondrial neurogastrointestinal encephalopathy syndrome

Pyrimidine metabolism|

| Anabolism|

* Orotic aciduria
* Miller syndrome

|

Catabolism|

* Dihydropyrimidine dehydrogenase deficiency

Template:Defects of steroid metabolism Template:Metabolic disorders of vitamins, coenzymes, and cofactors

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