Browsing Pathways

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.

Hyperprolinemia Type II (HPII), also known as 1-pyrroline-5-carboxylate dehydrogenase deficiency, is an extremely rare inborn error of metabolism (IEM) and autosomal recessive disorder of the arginine and proline metabolism pathway. It is caused by a mutation in the ALDH4A1 gene (also called the P5CDH gene) that encodes the mitochondrial enzyme delta-1-pyrroline-5-carboxylate dehydrogenase. This enzyme is responsible for catalyzing the dehydrogenation of 1-pyrroline-5-carboxylic acid or L-glutamic gamma-semialdehyde into L-glutamic acid. If mutated, allows L-proline, 4-hydroxyproline and D-proline, compounds further upstream from these reactions, to accumulate. HPII is characterized by an accumulation of proline in the blood. Symptoms include hydroxyprolinuria and hyperglycinuria, and can include seizures and some amount of mental retardation. However, the disorder varies in severity and these symptoms may not be present in all individuals. There are no currently known treatments for HPII, and a reduced proline diet has not been shown to reduce symptoms. There are no current estimates for the frequency of this disorder.

Hypoacetylaspartia, also known as N-acetylaspartate (NAA) deficiency is an extremely rare autosomal recessive inborn error of metabolism (IEM) caused by a mutation in the NAT8L gene. This gene encodes the N-acetylaspartate synthase protein, which catalyzes the formation of N-acetyl-L-aspartate from L-aspartate and acetyl-CoA, with CoA and a hydrogen ion being byproducts. This reaction occurs as part of the aspartate metabolism pathway. This disorder is characterized by a deficiency of NAA in the brain, as shown by magnetic resonance spectroscopy (MRS). Symptoms of the disorder include microcephaly, developmental delays, ataxia and seizures, which have been shown to worsen the ataxia. So, only one patient has been diagnosed with Hypoacetylaspartia.

Isovaleric acidemia (IVA) is caused by mutation in the isovaleryl CoA dehydrogenase gene. Isovaleryl CoA dehydrogenase is part of the acyl-CoA dehydrogenase family and is involved in the catabolism of leucine. A defect in this enzyme causes accumulation of ammonia, ketone bodies, Isovaleryl/2-Methylbutyrylcarnitine (C5) in blood; carnitine in plasma; creatinine, and glucose in serum; 3-Hydroxybutyric acid, 3-Hydroxyisovaleric acid, 4-Hydroxyvaleric acid, acetyltryptophan, glycine, acylcarnitin, isovalerylasparagine, isovalerylglycine, isovaleryllysine, isovalerylhistidine and isovaleryltryptophan in urine. Symptoms include encephalopathy, ketosis, metabolic acidosis, pancreatitis, sweaty feet odor, and thrombocytopenia.

Increased lactic acid concentrations in urine or serum can be a result of many metabolic disorders but also of other origin (infections, etc.). Respiratory chain defects account for most of the metabolic causes of lactic acid accumulation. Often alanine is also high. A urine spectrum indicating an increased lactic acid and alanine concentration is shown.

Lactose intolerance is a condition in which the body does not support the ingestion of lactose through the consumption of milk, cheese, and other dairy products. This intolerance occurs due to the lack of the enzyme intestinal lactase, which is an enzyme found in newborns. The frequency of this enzyme declines rapidly after the child stops breastfeeding. Lactase deficiency is most prevalent in Asia, Africa and Indigenous populations in North and South America. The symptoms of lactose intolerance include diarrhea, bloating, abdominal pain and excessive flatus. The cause of these symptoms is the processing of the ingested lactose being fermented by intestinal bacteria instead of in the small intestine, where lactose is meant to be processed.

Leigh Syndrome, also called Leigh Disease or infantile subacute necrotizing encephalopathy, is a rare inborn error of metabolism (IEM) and autosomal recessive disorder that is caused by a mutation of any one of 75 different genes. Disruptions of the complexes I or IV are the most common reasons for Leigh syndrome. Complex IV is crucial in the electron transfer steps of oxidative phosphorylation, which is needed to provide energy to the mitochondria. This disorder is characterized by a large accumulation of lactate in the body. Symptoms of the disorder include diarrhea, dysphagia and vomiting. There is no cure for Leigh syndrome and the loss motor skills degenerate rapidly. It is estimated that Leigh syndrome affects 1 in 40,000 individuals.

Orotic aciduria, also known as UMP synthase deficiency, is an autosomal recessive disorder of pyrimidine metabolism caused by a defective uridine monophosphate synthetase (UMPS). UMPS is a multifunctional protein which carries out the functions of both orotate phosphoribosyltransferase (OPRT) and orotidine 5'-phosphate decarboxylase (ODC). UMPS catalyzes the conversion of orotic acid into uridine monophosphate (UMP) which is a nucleotide incorporated into ribonucleic acid (RNA). This disease is characterized by a very large accumulation of orotic acid in the urine, occasionally causing urinary obstruction. Symptoms of the disease include megaloblastic anemia as well as retarded growth and development.

Lesch-Nyhan Syndrome is a syndrome identified through its neurological, behavioural metabolic impact. It is characterized by a mental deficit and self-mutilation, accompanied with an overproduction of uric acid. A mutation of the HPRT1 gene are responsible for this condition, as they cause the enzyme hypoxanthine phosphoribosyltransferase 1 to be present in extremely low levels or absent altogether. This causes an overproduction of uric acid as the purines are not recycled, but only broken down. This gene is also connected to dopamine production, which a lack of causes smooth muscle function to suffer, resulting in dystonia, ballismus and chorea. Patients are usually unable to walk, and the connection between a lack of hypoxanthine phosphoribosyltransferase 1 and the behavioural abnormalities associated with this condition are unknown.

Tyrosinemia type I, also known as fumarylacetoacetase or FAH deficiency, is the most severe type of tyrosinemia, a buildup of tyrosine in the body. It is caused by an autosomal recessive mutation in the the FAH gene that encodes for fumarylacetoacetase, an enzyme that is responsible for the last of five steps that are involved in the metabolic breakdown of tyrosine in the liver and kidneys. The lack of this enzyme's function leads to a buildup of 4-fumarylacetoacetic acid as it couldn't be broken down to fumaric acid and acetoacetic acid. This also leads to an increased concentration of maleylacetoacetic acid. This eventually leads to the increased concentration of L-tyrosine in the body. Symptoms of tyrosinemia type I include jaundice and an enlarged liver, kidney dysfunction, as well as a failure to grow, as foods with high protein and amino acids lead to increased symptoms. Additionally, individuals are more at risk for future liver cancer.