Browsing Pathways

Guanidinoacetate methyltransferase deficiency, also called GAMT deficiency, is a rare inborn error of metabolism (IEM) and autosomal recessive disorder of creatine metabolism caused by a defective guanidinoacetate methyltransferase (GAMT). GAMT catalyzes the conversion of guanidinoacetate into creatine which is used by creatine kinase to resynthesize adenosine triphosphate (ATP) from adenosine diphosphate (ADP). This disease is characterized by a large accumulation of guanidinoacetate and a decrease in creatine in the blood and urine. Symptoms of the disease include developmental delay, hypotonia, and seizures. Treatment with creatine supplementation is very effective. It is estimated that GAMT deficiency affects 1 in 250 000 individuals.

Hyperprolinemia type I (HPI, proline oxidase deficiency) is caused by mutation in the proline dehydrogenase gene (PRODH), which codes for proline dehydrogenase (proline oxidase). This enzyme converts proline to delta-1-pyrroline-5-carboxylate. A defect in proline dehydrogenase causes accumulation of proline in plasma, and glycine, hydroxyproline, and proline in urine. Symptoms include mental retardation, renal cysts, and seizures.

Malonyl CoA decarboxylase deficiency, also claled MCD deficiency, is a rare inborn error of fatty acid metabolism and autosomal-recessive metabolic disorder, which is caused by a defective mitochondrial malonyl CoA decarboxylase due to reduced activity. Mitochondrial malonyl CoA decarboxylase catalyzes the conversion of intramitochondrial malonyl CoA to acetyl CoA, which is a key product that involve in many biochemical reactions. This disorder is characterized by a large accumulation of methylmalonic acid in the mitochondrial. Symptoms of the disorder include hypotonia (i.e. weak muscle tone), hypoglycemia (i.e. low blood sugar), diarrhea, seizures and vomiting. The Malonyl CoA decarboxylase deficiency is an extremely rare genetic disease happened in early childhood, which only less than 30 cases have been reported. There is currently no cure for Malonyl CoA decarboxylase deficiency, treatment involves managing the disorder's symptoms.

Malonyl-CoA decarboxylase deficiency, also called malonic aciduria, is a rare inborn error of metabolism (IEM) and autosomal recessive disorder caused by a defective MLYCD gene. The MLYCD gene codes for the protein malonyl-CoA decarboxylase which regulates the creation and degradation of fatty acids. This disorder is characterized by a large accumulation of fatty acid byproducts in the tissues. Symptoms of the disorder include delayed development, hypotonia, seizures, vomiting, diarrhea and cardiomyopathy. Treatment with L-carnitine is very effective, as it encourages beta-oxidation of fatty acids. Less than 30 cases globally have ever been reported, making this disorder extremely rare.

Purine nucleoside phosphorylase deficiency (Nucleoside phosphorylase; Immunodeficiency) is a rare disease causing severe immunodeficiency. The disease is caused by a mutation in the enzyme purine nucleoside phosphorylase. The enzyme is necessary for purine breakdown. The mutation causes deoxy-GTP (dGTP) to accumulate which causes T-cell toxicity. The disease results in accumulation of guanosine, inosine, and uric acid in serum; and orotic acid in some cases in the urine. Symptoms include anemia, ataxia, hypotonia, lymphopenia, mental retardation, and tremor or twitching.

Mitochondrial DNA depletion syndromes are a group of autosomal recessive disorders. They are characterized by decreased levels of mitochondrial DNA (mtDNA), resulting in decreased energy production. Mitochondrial DNA depletion syndrome-3 is caused by a mutation in the gene coding for deoxyguanosine kinase (DGUOK). DGUOK aids in maintaining the levels of available deoxyguanosine triphosphate (dGTP), thus the deficiency of DGUOK impairs the synthesis of dGTP. Symptoms of DGUOK deficiency can arise in the form of a multi-system disease in neonates or an isolated hepatic disease in infancy, with the former being more common. The most common cause of death in both forms is progressive hepative disease.

Molybdenium cofactor deficiency (Sulfite oxidase deficiency) is caused by mutations in the genes MOCS1 and MOCS2 in the formation of molybdenum cofactor. A molybdenum-containing cofactor is essential to the function of 3 enzymes: sulfite oxidase, xanthine dehydrogenase, and aldehyde oxidase. Xanthine dehydrogenase is a molybdenum-containing hydroxylase involved in the oxidative metabolism of purines. Defects in this enzyme cause accumulation of hypoxanthine,, s-s-sulfocysteine, taurine, and xanthine in the urine. Symptoms include hemorrhage, cerebral atrophy, encephalopathy, lactic acidosis, nystagmus, spastic diplegia/quadriplegia, and vomiting.

Histidinemia (Histidine Ammonia-Lyase Deficiency; HAL Deficiency; Histidase Deficiency; HIS Deficiency) is an autosomal recessive disease caused by a mutation in the HAL gene which codes for hisitidine ammonia-lyase. A deficiency in this enzyme results in accumulation of L-histidine in serum, spinal fluid, and urine; histamine in plasma and urine; and imidazoleacetic acid, imidazolactic acid, and 1-methylhistamine in urine. Symptoms include organic acids in urine, mental retardation, and delayed speech development. Treatment includes a low-histamine diet.

Hydroxyglutaric aciduria is a rare genetic disorder. Both isoforms are believed to have autosomal recessive inheritance. The compound 2-hydroxyglutarate is the product of gain-of-function mutations producing mutIDH1 and mutIDH2 in the cytosolic and mitochondrial isoforms of isocitrate dehydrogenase (IDH). This compound is derived from the TCA cycle. The compound 2-hydroxyglutarate shares enough structural similarity to 2-oxogluratate (2OG) to inhibit a range of 2OG-dependent dioxygenases, including histone lysine demethylases (KDMs) and the ten-eleven translocation (TET) family of 5-methylcytosine (5mC) hydroxylases. This results in modulations of HIF-mediated hypoxia responses and alterations in gene expression through global epigenetic remodelling that may contribute to malignant transformation. L-2-hydroxyglutarate dehydrogenase (L2HGDH) converts L-2-hydroxyglutarate to α-ketoglutaric acid. L-2-Hydroxyglutarate is an oncometabolite and is produced by gain-of-function IDH mutations. When IDH is mutated, L-2-Hydroxyglutaric acid production is increased. L-2-hydroxyglutarate is a competitive inhibitor of 2OG-dependent dioxygenases resulting in genetic changes and malignancies.

Familial Hypercholanemia can be caused by mutations in the TJP2, BAAT or EPHX1 genes which code for bile acid-CoA:amino acid N-acyltransferase, which plays a part in the metabolism of in bile acids. This enzyme plays a particularly important role in the hepatocytes of the liver. In this region the said enzyme is in part responsible for the catalysis of C24 bile acids (also known as choloneates) at a point preceding excretion into bile canaliculi. Bile is made up of many components, though two major ones are chenodeoxycholic acid and cholic acid. First, the bile acids undergo a process of conversion into acyl-CoA thioester. This occurs in two regions: in peroxisomes or endoplasmic reticulum (the latter are known as the secondary bile acids). Second, the bile acids undergo a process of conjugation which increases the detergent property, in particular in the intestine. In turn, the absorption of vitamins which are lipid soluble is faciliatated. In later steps, the deconjugation of bile acids is performed by bacteria and at this stage the bile acids are then returned to the liver to once again undergo the process of reconjugation. Familial hypercholanemia is characterized by increased bile acids in plasma. Symptoms include rickets and steatorrhea.