Inborn errors of metabolism form a large class of

genetic disease A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosomal abnormality. Although polygenic disorders ...

s involving congenital disorders of enzyme activities. The majority are due to defects of single

gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...

s that code for

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...

s that facilitate conversion of various substances ( substrates) into others (

product Product may refer to: Business * Product (business), an item that serves as a solution to a specific consumer problem. * Product (project management), a deliverable or set of deliverables that contribute to a business solution Mathematics * Produ ...

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 now often referred to as congenital metabolic diseases or inherited metabolic disorders. To this concept it's possible to include the new term of Enzymopathy. This term was created following the study of Biodynamic Enzymology, a science based on the study of the enzymes and their derivated products. Finally, ''inborn errors of metabolism'' were studied for the first time by British physician

Archibald Garrod Sir Archibald Edward Garrod (25 November 1857 – 28 March 1936) was an English physician who pioneered the field of inborn errors of metabolism. He also discovered alkaptonuria, understanding its inheritance. He served as Regius Professor of ...

(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.

Classification and symptoms of metabolic diseases

Traditionally the inherited metabolic diseases were classified as disorders of

carbohydrate In organic chemistry, a carbohydrate () is a biomolecule consisting of carbon (C), hydrogen (H) and oxygen (O) atoms, usually with a hydrogen–oxygen atom ratio of 2:1 (as in water) and thus with the empirical formula (where ''m'' may or m ...

metabolism,

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha a ...

metabolism, organic acid metabolism, or

lysosomal storage disease Lysosomal storage diseases (LSDs; ) are a group of over 70 rare inherited metabolic disorders that result from defects in lysosomal function. Lysosomes are sacs of enzymes within cells that digest large molecules and pass the fragments on to other ...

s. 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. 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

Dozens of congenital metabolic diseases are now detectable by

newborn screening Newborn screening (NBS) is a public health program of screening in infants shortly after birth for conditions that are treatable, but not clinically evident in the newborn period. The goal is to identify infants at risk for these conditions e ...

tests, especially expanded testing using mass spectrometry.

gas chromatography–mass spectrometry Gas chromatography–mass spectrometry (GC-MS) is an analytical method that combines the features of gas-chromatography and mass spectrometry to identify different substances within a test sample. Applications of GC-MS include drug detection, ...

-based technology with an integrated analytics system, which 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 test A medical test is a medical procedure performed to detect, diagnose, or monitor diseases, disease processes, susceptibility, or to determine a course of treatment. Medical tests such as, physical and visual exams, diagnostic imaging, genetic ...

s are used for screening. An abnormal result is often followed by a subsequent "definitive test" to confirm the suspected diagnosis. GCMS closed

Common screening tests used in the last sixty years: * Ferric chloride test (detects abnormal metabolites in urine) *

Ninhydrin Ninhydrin (2,2-dihydroxyindane-1,3-dione) is an organic compound with the formula C6H4(CO)2C(OH)2. It is used to detect ammonia and amines. Upon reaction with these amines, ninhydrin gets converted into deep blue or purple derivatives, which are ...

paper chromatography Paper chromatography is an analytical method used to separate coloured chemicals or substances. It is now primarily used as a teaching tool, having been replaced in the laboratory by other chromatography methods such as thin-layer chromatography ...

(detects abnormal

patterns) *

Guthrie test The neonatal heel prick is a blood collection procedure done on newborns. It consists of making a pinprick puncture in one heel of the newborn to collect their blood. This technique is used frequently as the main way to collect blood from neonat ...

(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 Urine is a liquid by-product of metabolism in humans and in many other animals. Urine flows from the kidneys through the ureters to the urinary bladder. Urination results in urine being excreted from the body through the urethra. Cellular ...

* IEX-

post-column derivitization liquid

ion chromatography Ion chromatography (or ion-exchange chromatography) separates ions and polar molecules based on their affinity to the ion exchanger. It works on almost any kind of charged molecule—including large proteins, small nucleotides, and amino acid ...

(detects abnormal

patterns and quantitative analysis) *Urine organic acid analysis by

*Plasma acylcarnitine analysis by mass spectrometry *Urine

purine Purine is a heterocyclic aromatic organic compound that consists of two rings ( pyrimidine and imidazole) fused together. It is water-soluble. Purine also gives its name to the wider class of molecules, purines, which include substituted purines ...

and pyrimidine analysis by gas chromatography-mass spectrometry Specific diagnostic tests (or focused screening for a small set of disorders): *Tissue

biopsy A biopsy is a medical test commonly performed by a surgeon, interventional radiologist, or an interventional cardiologist. The process involves extraction of sample cells or tissues for examination to determine the presence or extent of a dise ...

liver The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it ...

, muscle,

brain A brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as vision. It is the most complex organ in a ve ...

, bone marrow *Skin biopsy and fibroblast cultivation for specific enzyme testing *Specific

DNA testing Genetic testing, also known as DNA testing, is used to identify changes in DNA sequence or chromosome structure. Genetic testing can also include measuring the results of genetic changes, such as RNA analysis as an output of gene expression, o ...

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". 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.

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:

Epidemiology

In a study in

British Columbia British Columbia (commonly abbreviated as BC) is the westernmost province of Canada, situated between the Pacific Ocean and the Rocky Mountains. It has a diverse geography, with rugged landscapes that include rocky coastlines, sandy beaches, ...

, 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, overall representing more than approximately 15% of single gene disorders in the population. While a Mexican study established an overall incidence of 3.4: 1000 live newborns and a carrier detection of 6.8:1000 NBS.

References

External links