OMD

OMDs, Other Metabolic Disorders, are a significant number of different inherited metabolic diseases that involve metabolic disturbances.

Congenital errors of metabolism, metabolic errors or congenital metabolic diseases are a group of inherited diseases that involve alterations in metabolism with which the body is not able to transform food properly. They are included among rare diseases, since their incidence ranges from one affected per ten thousand (1: 10,000) or double (1: 20,000) for frequent, or (1: 300,000) for rare.

Methylmalonic Aciduria
Propionic aciduria
Urea cycle defects
Citrullinemia
OTC
HHH
Maple Syrup Urine Disease
Tyrosinemia type 1
LPI
Classic homocystinuria
Homocystinuria with Methylmalonic Aciduria CblC

Inborn Errors of Metabolism (IEM)

Methylmalonic aciduria

Methylmalonic aciduria is a protein breakdown disorder, which causes the accumulation in plasma, urine and tissues of a toxic product, methylmalonic acid.

In methylmalonic aciduria, the deficiency of an enzyme (methylmalonyl CoA mutase) or a derivative of vitamin B (adenosyl-12cobalamin), necessary for the proper functioning of the enzymatic reaction, causes the accumulation of toxic methylmalonic acid. Ammonium and lactate, also toxic, accumulate secondarily.

Propionic aciduria

Propionic aciduria is a protein breakdown disorder, which causes the accumulation in plasma, urine and tissues of toxic products, propionic acid and its derivatives.

In the case of propionic aciduria, the deficiency of an enzyme (propionyl CoA carboxylase (PCC)) causes the accumulation of propionic acid and other compounds derived from it, all of them toxic. Ammonium and lactate, also toxic, accumulate secondarily.

Urea Cycle Defects

A urea cycle defect is a congenital error of amino acid metabolism. When there is an error in the metabolism, some of these reactions do not occur with due efficiency and the compounds before the reaction accumulate, while the later ones are not synthesized correctly. In our case, any of the reactions of the urea cycle can fail, causing an accumulation of ammonia in the blood and in the brain, which is known as hyperammonemia. In addition to ammonium, other compounds accumulate before the defect that can also be toxic and the subsequent ones are not synthesized: arginine, which thus becomes an essential amino acid for protein synthesis.

Citrullinemia

Citrullinemia is a congenital disease – present from the moment of birth – and inherited according to an autosomal recessive pattern. It is caused by a deficiency of the enzyme argininosuccinate synthetase, which causes an accumulation in the body of the amino acid citrulline and ammonia. Ammonia is a toxic substance that causes brain damage. This disease occurs infrequently, about one case in every 60,000 children born, which is why it is considered a rare disease.

The most common form of presentation is type I citrullinemia, also known as classic citrullinemia. Mutations in the ASS gene reduce the activity of the enzyme argininosuccinate synthetase, which disrupts the urea cycle and prevents the body from efficiently processing nitrogen. Excess nitrogen, in the form of ammonia, and other by-products of the urea cycle, accumulate in the bloodstream, giving rise to the characteristic features of citrullinemia type I. Affected children are born normal, but from the first days, As ammonia builds up in the body, they begin to experience irritability, poor appetite, vomiting, muscle weakness, seizures, and brain swelling leading to coma. If no treatment is done, the child dies in the first weeks of life. Treatment consists of a diet that includes a reduced level of protein and foods prepared using special formulas.

Ornithine Transcarbamylase Deficiency (OTC)

OTC is the third enzyme in UC, whose activity is only expressed in the liver and, to a much lesser extent, in the duodenum. OTC activity deficiency interferes with urea cycle function, causing hyperammonemia. It is one of the most frequent and serious defects, especially in males. The boy has a single X chromosome, inherited from his mother, since his father has passed him a Y chromosome, which determines his male sex. If the OTC gene located on the X chromosome contains a mutation, as it only has one, the enzymatic activity of the resulting OTC protein will be more or less deficient depending on the severity of the mutation. In general, children have a severe neonatal form of the disease, although there may be some milder cases caused by less severe mutations. In women, mild chronic forms are more frequent, with some neurological symptoms (mental retardation, ataxia, irritability, aggressiveness, confusion, hallucinations), digestive (anorexia, protein intolerance) and hepatic or almost asymptomatic forms.

Hyperornithinemia, Homocitrullinuria and Hyperammonemia (HHH) Syndrome

It is a disorder of amino acid metabolism caused by a deficiency of the citrulline-ornithine transporter across the mitochondrial membrane. It results in a secondary defect of the urea cycle.

When there is an error in the metabolism, some of these reactions in the cycle do not occur with due efficiency and the compounds before the reaction accumulate, while the later ones are not synthesized correctly. In HHH syndrome, the defect of the ornithine-citrulline transporter across the mitochondrial membrane causes an accumulation of ornithine (hyperornithinemia) in the cell cytosol, so that this amino acid cannot enter the mitochondria and serve as a substrate for the enzyme ornithine transcarbamylase (OTC). As a result, the urea cycle is interrupted, causing a build-up of ammonia in the blood and brain, which is known as hyperammonemia. In addition, homocitrulline (homocitrullinuria), a derivative of lysine that is excreted in large quantities in the urine, also accumulates.

Maple Syrup Urine Disease or Leucinosis

It is a congenital error in the metabolism of the branched chain amino acids, leucine, isoleucine and valine, which causes the accumulation in plasma, urine and tissues of neurotoxic products, the branched amino acids and keto acids.

When there is an error in the metabolism, some of these reactions do not take place with due efficiency and the compounds before the reaction accumulate, while the later ones are not synthesized correctly. Maple syrup urine disease is a defect in the metabolism of branched amino acids, which causes the accumulation of these (leucine, isoleucine and valine) and also that of branched keto acids, which smell like maple syrup (giving name disease). These three amino acids are degraded by different routes, but they share the same reaction catalyzed by an enzyme complex, branched keto acid dehydrogenase (DCR), which is the one that is deficient, causing this disease. Leucine and its keto acid are the compounds that accumulate the most in this disease and are also the most toxic. For this reason, this disease is also called leucinosis.

Tyrosinemia type 1

Tyrosinemia type 1 is a congenital error of tyrosine metabolism, which causes the accumulation in plasma, urine and tissues of this amino acid and also of potentially toxic products, especially succinylacetone.

Tyrosinemia type 1 is caused by a deficiency of an enzyme, fumarylacetoacetate hydrolase (FAH). Due to this, amino acids accumulate, such as tyrosine and methionine, and toxic substances, such as succinylacetoacetate and succinylacetoacetate, which in turn inhibit porphyrin metabolism.

Lysinuric Protein Intolerance (LPI)

LIP is a congenital error in the transport of dibasic amino acids (AA +) due to a defect in the intestinal and renal transporter of the same. It causes poor intestinal absorption and increased renal elimination of these amino acids.

The AA + transporter is made up of two different proteins, one of which (y + LAT1) can be totally or partially inactivated if mutations (stable and inherited changes) occur in the gene that encodes it (SLC7A7). This causes a “transport error” that results in low intestinal absorption of AA + and high renal excretion of these amino acids.

Classic Homocystinuria

Homocystinuria is a disorder of the metabolism of homocysteine, which causes the accumulation in plasma, urine and tissues of this amino acid.

Homocystinuria is an error in the metabolism of homocysteine, which can be caused by the deficiency of different enzymes, the most common being cystathionine β-synthase (CBS) deficiency, also called classic homocystinuria. Due to this, some amino acids accumulate, such as homocysteine and methionine, while others are deficient, such as cysteine. This last amino acid, in turn, is a precursor of other substances of great metabolic importance, such as glutathione, which is an important antioxidant and may be deficient in homocystinuria.

Homocystinuria with Methylmalonic Aciduria (CblC)

It is a congenital error in the metabolism of vitamin B12 or cobalamin, which causes the accumulation in plasma, urine and tissues of homocysteine and methylmalonic acid.

Vitamin B12 or cobalamin is a substance that we cannot synthesize and must be ingested with our diet (meat and dairy products). Once ingested, it is absorbed in the intestine, it is transported to the cells of our body and transformed into two substances, adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl), which act by facilitating two reactions of protein metabolism.

When the synthesis of these two forms of cobalamin is interfered with, these reactions do not occur efficiently and potentially toxic products accumulate, homocysteine and methylmalonic acid, with undesirable consequences for our body.