Browsing Pathways

Methylcobalamin (MeCbl) is the cofactor of methionine synthase and involved in the conversion of homocysteine to methionine. Adenosylcobalamin (AdoCbl) is a cofactor for methylmalonyl CoA mutase converting methylmalonic acid into succinic acid. Methylmalonyl-CoA mutase is involved in key metabolic pathways, catalyzing the isomerization of methylmalonyl-CoA to succinyl-CoA. It requires its Vitamin B12 derived prosthetic group, adenosylcobalamin, to function.It catalyzes the isomerization of methylmalonyl-CoA to succinyl-CoA. It requires its Vitamin B12 derived prosthetic group, adenosylcobalamin, to function. Defects in these cofactors for methylmalonyl CoA mutase cause accumulation of ammonia in blood; methylmalonic acid in plasma; creatinine and uric acid in serum; 3-Aminoisobutyric acid, 3-Hydroxypropionic acid, 3-Hydroxyvaleric acid, glycine, methylcitric acid and methylmalonic acid in urine; and methylmalonic acid in spinal fluid. Symptoms include anemia, dehydration, growth retardation, nephrosis, respiratory distress and metabolic acidosis.

GABA-transaminase deficiency, also known as gamma-amino butyric acid transaminase (GABA-T) deficiency, is an extremely rare autosomal recessive inborn error of metabolism (IEM) that is caused by a defect in the ABAT gene, which codes for 4-aminobutyrate (GABA) aminotransferase. This enzyme is present in several tissues in addition to brain and is most active in liver, and it catalyzes the conversion of GABA and 2-oxoglutarate into succinic semialdehyde and L-glutamate, and when it is deficient, GABA levels in the body, specifically the cerebrospinal fluid, are elevated. GABA is a neurotransmitter found in the nervous system that inhibits neurons from firing, and also affects the development of the brain, as well as regulating muscle tone. GABA-T can also convert beta-alanine and oxoglutaric acid to L-glutamic acid and malonic semialdehyde as part of the beta-alanine metabolism pathway, and when it is mutated, leads to an accumulation of beta-alanine within the cell. GABA-T deficiency is characterized by an increase of GABA levels in the cerebrospinal fluid. Symptoms of this disorder include low muscle tone and psychomotor retardation, as well as potential epilepsy and excessive sleeping. Treatment with Flumanezil, sold as Anexate, Lanexat, Mazicon or Romazicon, a GABA-A antagonist, has been tested and may be beneficial in some cases, and potentially more effective if started at a young age. It is estimated that GABA-T deficiency affects less than 1 in 1,000,000 individuals, as only five cases have been reported in literature as of 2017.

Ocular non-nephropathic cystinosis, also known as adult-onset cystinosis, is a rare inborn error of metabolism (IEM) and autosomal recessive disorder of the cysteine metabolism pathway. It is caused by a defect in the CTNS gene, which encodes the protein cystinosin, which acts as a cystine/H+ symporter that transports L-cysteine out of the lysosome. Ocular non-nephropathic cystinosis is characterized by a buildup of cysteine in cells, in the case of this form in the cornea. Symptoms include photophobia and damage to the cornea due to crystals forming from the excess cysteine. However, unlike other forms of cystinosis, no or minimal kidney damage occurs. Treatment with cysteamine, a drug that can convert cysteine into a form that can be secreted by the lysosome, can be effective in all of the forms of cystinosis. It is estimated that ocular non-nephropathic cystinosis affects less than 1 in 100,000 to 200,000 individuals, which is the rate of the more severe nephropathic cystinosis.

DOPA-Responsive Dystonia is a condition in which the muscles contract, experience tremors and uncontrolled movements (dystonia). Some cases are mild, while others can be severe. The beginning signs of this condition are dystonia in the legs, and clubfeet. The cause of this condition is usually a mutation in the GCH1 gene, but can sometimes be attributed to mutations in the TH or SPR genes. Tetrahydrobiopterin is an important compound in the production of neurotransmitters, specifically dopamine and serotonin, and the processing of quite a few amino acids, The mutation on GCH1 causes GTP cyclohydrase production to be reduced or absent which causes the first three steps of tetrahydrobiopterin biosynthesis to be compromised. The mutation on the SPR gene affects tetrahydrobiopterin biosynthesis by interfering with the production of sepiapterin reductase, which is needed to complete the final step of tetrahydrobiopterin biosynthesis. The TH gene mutation also affects dopamine production through the decreased function of an enzyme called tyrosine hydroxylase, which is responsible for converting tyrosine to dopamine. Dopamine is imperative in maintaining smooth muscle movements, which is why patients with DOPA-responive dystonia experience tremors and movement problems.

2-Aminobenzoic acid, also known as anthranilic acid or O-aminobenzoate, belongs to the class of organic compounds known as aminobenzoic acids. These are benzoic acids containing an amine group attached to the benzene moiety. Within humans, 2-aminobenzoic acid participates in a number of enzymatic reactions. In particular, 2-aminobenzoic acid and formic acid can be biosynthesized from formylanthranilic acid through its interaction with the enzyme kynurenine formamidase. In addition, 2-aminobenzoic acid and L-alanine can be biosynthesized from L-kynurenine through its interaction with the enzyme kynureninase. It is a substrate of enzyme 2-Aminobenzoic acid hydroxylase in benzoate degradation via hydroxylation pathway (KEGG). In humans, 2-aminobenzoic acid is involved in tryptophan metabolism. Outside of the human body, 2-Aminobenzoic acid has been detected, but not quantified in several different foods, such as mamey sapotes, prairie turnips, rowals, natal plums, and hyacinth beans. This could make 2-aminobenzoic acid a potential biomarker for the consumption of these foods. 2-Aminobenzoic acid is a is a tryptophan-derived uremic toxin with multidirectional properties that can affect the hemostatic system. Uremic syndrome may affect any part of the body and can cause nausea, vomiting, loss of appetite, and weight loss. Chronic exposure of uremic toxins can lead to a number of conditions including renal damage, chronic kidney disease and cardiovascular disease. It can also cause changes in mental status, such as confusion, reduced awareness, agitation, psychosis, seizures, and coma. Kynureninase catalyzes the cleavage of L-kynurenine (L-Kyn) and L-3-hydroxykynurenine (L-3OHKyn) into anthranilic acid (AA) (which is also known as 2-Aminobenzoic acid) and 3-hydroxyanthranilic acid (3-OHAA), respectively. Has a preference for the L-3-hydroxy form. Also has cysteine-conjugate-beta-lyase activity.

11-beta-Hydroxylase Deficiency, also called congenital adrenal hyperplasia (CAH), is an autosomal recessive disorder and caused by a defective 11-beta-hydroxylase. 11-beta-hydroxylase catalyzes the conversion of cortexolone into cortisol which is useful for maintaining blood sugar levels and suppressing inflammation. This disorder is characterized by a large accumulation of cortexolone in the endoplasmic reticulum (ER). Symptoms of the disorder include abnormality of hair growth rate and menstrual cycle. It is estimated that 11-beta-hydroxylase deficiency affects 1 in 100,000 to 200,000 newborns.

Vitamin A deficiency can be caused by many causes. A defect in the BCMO1 gene which codes for beta,beta-carotene 15,15’-monooxygenase is one of them. Beta,beta-carotene 15,15’-monooxygenase catalyzes the chemical reaction where the two substrates are beta-carotene and O2, whereas its product is retinal. A defect in this enzyme results in decrease of levels of retinal and vitamin A in serum; Signs and symptoms include night blindness, poor adaptation to darkness, dry skin and hair.

Glycogenosis, Type IC, a sub-category of glycogen storage disease type I, is a rare inborn error of metabolism (IEM) and caused by a defective glucose-6-phosphatase translocase. Glucose-6-phosphate translocase transports glucose 6-phosphate from endoplasmic reticulum (ER) to cell, which glucose 6-phosphate is required for various pathways as the substrate. This disorder damages the ability of converting glycogen into glucose. Symptoms of the disorder include longer sleeping time through night, tiredness and seizures due to low blood sugar. Treatment with diet management is very effective. Currently, only few cases have been reported.

17-beta hydroxysteroid dehydrogenase III deficiency, also known as 17-KSR deficiency or male pseudohermaphroditism with gynecomastia (MPH), is as rare inborn error of metabolism (IEM) and autosomal recessive disorder of the androgen and estrogen metabolism pathway. It is caused by a mutation in the HSD17B3 gene, which encodes the enzyme testosterone 17-beta-dehydrogenase 3, which is responsible for catalyzing the reversible formation of androstenedione from testosterone. This leads to an accumulation of androstenedione and dehydroepiandrosterone in the body, as well as a lack of testosterone produced. 17-KSR deficiency is characterized by an absence of testosterone in the testis until puberty, where testosterone is produced outside of the gonads. Symptoms include infertility and external female genitalia until puberty, when secondary male sex characteristics occur, as well as gynecomastia. Due to this, many individuals with this disorder are raised as female despite being genetically male, until puberty. Treatment can include removal of testes before puberty, preventing any masculinization at puberty, as well as surgical treatment of genitalia. However, there is no known treatment for restoring the fertility of affected individuals. It is estimated that 17-KSR deficiency affects 1 in 150,000 individuals in The Netherlands, without much information for the rest of the world.

Disease Pathway Succinyl CoA: 3-Ketoacid CoA Transferase (SCOT) deficiency is a rare inherited metabolic disorder causing reduction of ketone body utilization. In normal functioning patients, ketone bodies such as Acetoacetate (AcAc) and 3‐hydroxybutyrate (3HB) are metabolized inside the liver from free fatty acids. Next, ketone bodies are transported to extrahepatic tissues via the blood stream. Once in extrahepatic tissues, SCOT converts AcAc to acetoacetyl‐CoA and T2 cleaves acetoacetyl‐CoA into acetyl‐CoA. This process is crucial for producing alternative energy sources to glucose in order to maintain blood glucose levels. Patients with SCOT deficiency have this process disturbed and ketoacidosis which is the acidification of the bloodstream due to excess ketone body accumulation, can occur. Current treatments include avoiding actions that could onset ketoacidosis such as fasting and early infusion of glucose. The severity of SCOT deficiency differs from patient to patient. Some exhibit severe genotypes where ketones are always in abundance in the body, while others could have mild genotypes with no preeminent ketosis however both could exhibit ketoacidotic episodes.