Browsing pathways

Porphyria variegata (PV) is caused by a defect in the PPOX gene which codes for protoporphyrinogen oxidase. A defect in this enzyme results in accumulation of the porphyrin precursors porphobilinogen and 5-aminolevulinic acid in plasma; increase of fecal and urinary levels of porphyrin and coproporphyrin. Symtpoms include abdominal pain, vomiting, diarrhea, constipation, muscle weakness, seizures, and mental changes such as anxiety and hallucinations. Some people with variegate porphyria have skin that is overly sensitive to sunlight. Areas of skin exposed to the sun develop severe blistering, scarring, changes in pigmentation, and increased hair growth.

Phenylketonuria (Hyperphenylalaninemia ; HPA ; PKU) is an autosomal recessive genetic disorder characterized by a deficiency in the enzyme hepatic phenylalanine hydroxylase (PAH). PAH is necessary to metabolize the amino acid phenylalanine to the amino acid tyrosine. When PAH is deficient, phenylalanine accumulates and is converted into phenylpyruvate, which is detected in the urine. Left untreated, this condition can cause problems with brain development, leading to progressive mental retardation and seizures.

Ornithine transcarbamylase (Ornithine carbamoyltransferase deficiency; OTC) deficiency is the most common urea cycle disorder. A mutant enzyme protein impairs the formation of citrulline from carbamoyl phosphate and ornithine. This impairment leads to reduced ammonia incorporation, which, in turn, causes symptomatic hyperammonemia. The gene for this enzyme is normally expressed in the liver and is intramitochondrial. The hepatic urea cycle is the major route for waste nitrogen disposal, which is chiefly generated by protein and amino acid metabolism. Low-level synthesis of certain cycle intermediates in extrahepatic tissues makes a small contribution to waste nitrogen disposal. A portion of the cycle is mitochondrial in nature; mitochondrial dysfunction may impair urea production and result in hyperammonemia. Overall, activity of the cycle is regulated by the rate of synthesis of N-acetylglutamate, the enzyme activator that initiates incorporation of ammonia into the cycle. Failure to form citrulline from carbamoyl phosphate and ornithine results in an excess of both substrates for the reaction. The consequent increase in hepatic ornithine is often reflected in an elevated serum level. By contrast, excessive mitochondrial carbamoyl phosphate travels to the cytosol, where it functions as substrate for CAD protein. CAD protein, an enzyme from the de novo pyrmidine biosynthesis pathway, is a fusion protein that catalyzes a series of three reactions resulting in orotic acid. Pyrimidine biosynthesis is regulated very tightly because it is a pathway involved in nucleic acid biosynthesis; thus, increases in urinary excretion of orotate are rarely observed in normal humans. Neither conversion of carbamoyl phosphate to orotate nor hepatic leakage of ornithine can prevent the rapid development of hyperammonemia.

Ornithine Aminotransferase Deficiency, (OAT Deficiency, Ornithine Keto Acid Aminotransferase Deficiency, OKT Deficiency, Ornithine-Delta-Aminotransferase Deficiency, Hyperornithinemia With Gyrate Atrophy Of Choroid And Retina; Hoga Gyrate Atrophy, Ornithine Aminotransferase) is caused by a defect in the gene that codes for ornithine-delta-aminotransferase, which catalyzes the major catalytic reaction for ornithine. A defect in this enzyme causes accumulation of ornithine. Symptoms include tunnel vision, night blindness, myopia, and progressive vision loss.

In Obesity/Metabolic Syndrome, high plasma fatty acids regulate genes responsible for increase insulin resistance, visceral fat deposits, fatty acid oxidation, and thermogenesis. Many of these responses have a role in metabolic syndrome, obesity and diabetes. Glucocorticoid receptor (GR) regulates several genes that have been implicated in insulin sensitivity. The glucocorticoid receptor is activated by binding to cortisol which is supplied by the conversion of cortisone by corticosteroid 11-beta-dehydrogenase. The mechanism for increased visceral fat levels is the over expression of lipoprotein lipase from glucocorticoid receptor activity. Lipoprotein lipase increases free fatty acids in tissues by cleaving fatty acids from triacylglycerols. PPAR-gamma is a fatty acid activated transcription factor involved in a complicated regulatory network of transcription factors that modulated fatty acid oxidation, thermogenesis and mitochondria biogenesis.

Non Ketotic Hyperglycinemeia (Glycine encephalopathy; Glycine cleavage system deficiency; NKH) is caused by mutations in several genes in the mitochondrial glycine cleavage system. These include the genes encoding P protein (GLDC), T protein (GCST), and, in one case, the H protein (GCSH). Most patients with GCE (Glycine Encephalopathy, or NKH) have a defect in the GLDC gene.The enzyme system for cleavage of glycine (glycine cleavage system), which is confined to the mitochondria, is composed of 4 protein components: P protein (a pyridoxal phosphate-dependent glycine decarboxylase), H protein (a lipoic acid-containing protein), T protein (a tetrahydrofolate-requiring enzyme), and L protein (a lipoamide dehydrogenase). NKH is characterized by accumulation of glycine in plasma, spinal fluid and urine. Symptoms include seizures, respiratory distress, mental retardation, chorea, visual impairment and hydrocephalus.

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.

Myoneurogastrointestinal encephalopathy, or mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE), is a multisystem disorder caused by mutations in the gene encoding thymidine phosphorylase, which normally uses thymidine and phosphate as substrates to catalyze the reaction between these two substrates to create thymine and 2-deoxy-alpha-D-ribose 1-phosphate. MNGIE causes accumulation of thymidine and deoxyuridine in the urine. Symptoms of MNGIE include ptosis, progressive external ophthalmoplegia, gastrointestinal dysmotility (often pseudoobstruction), diffuse leukoencephalopathy, peripheral neuropathy, and myopathy.

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.

Methylmalonic acidemia cause defects (Methylmalonaciduria due to methylmalonic CoA mutase; Acidemia, methylmalonic; MMA) in the metabolic pathway where methylmalonyl-coenzyme A (CoA) is converted into succinyl-CoA by the enzyme methylmalonyl-CoA mutase. Defects in the enzyme Methylmalonyl-CoA mutase causes 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.

Methylmalonate Semialdehyde Dehydrogenase Deficiency (MMSDH Deficiency; Aldehyde Dehydrogenase 6 Family, Member A1; ALDH6A1 Deficiency)is caused by a defect in methylmalonate semialdehyde dehydrogenase, which catalyzes the irreversible oxidative decarboxylation of malonate and methylmalonate semialdehydes to acetyl- and propionyl-CoA, respectively. A defect in methylmalonate semialdehyde dehydrogenase causes accumulation of 3-Aminoisobutyric acid, 3-Hydroxyisobutyric acid, 3-hydroxypropionic acid, beta-Alanine, lactate, and methylmalonic acid in urine. Symptoms inclue failure to thrive, large liver, mental and motor retardation and vomiting.

Methylenetetrahydrofolate reductase deficiency (MTHFRD; Homocystinuria due to defect of n(5,10)-methylene THF deficiency) is caused by a defect in the MTHFR gene which codes for methylenetetrahydrofolate reductase. Methylenetetrahydrofolate reductase catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a co-substrate for homocysteine remethylation to methionine. A defect in this enzyme results in accumulation of homocysteine and methionine in both plasma and urine. Some of the symptoms and signs include mental retardation, withdrawal, hallucinations, delusions, muscle weakness. Some patients remain asymptomatic until adulthood.

Methionine adenosyltransferase (MAT; Hypermethioninemia; MAT I/III deficiency) deficiency is caused by mutations in the MAT1A gene which causes isolated hypermethioninemia. MAT catalyzes the formation of adenosylmethionine from methionine and ATP. Adenosylmethionine is an important methyl donor in most transmethylation reactions. MAT dificiency is characterized by increased homocysteine and methionine levels in plasma; and accumulation of methionine in urine. Symptoms include dystonia, mental retardation and unusual odor.

Metachromatic leukodystrophy (MLD) is caused by a defect in the ARSA gene which does for arylsulfatase A. A defect in this enzyme results in accumulation of 3-O-sulfogalactosylceramide in urine, neural and non neural tisues like kidney and gallbladder. There are several forms of MLD. In the late infantile form, which is the most common form MLD, affected children begin having difficulty walking after the first year of life. Symptoms include muscle wasting and weakness, muscle rigidity, developmental delays, progressive loss of vision leading to blindness, convulsions, impaired swallowing, paralysis, and dementia. Children may become comatose. Untreated, most children with this form of MLD die by age 5, often much sooner. Children with the juvenile form of MLD (onset between 3–10 years of age) usually begin with impaired school performance, mental deterioration, and dementia and then develop symptoms similar to the late infantile form but with slower progression. Age of death is variable, but normally within 10 to 15 years of symptom onset. The adult form commonly begins after age 16 as a psychiatric disorder or progressive dementia. Adult-onset MLD progresses more slowly than the late infantile and juvenile forms, with a protracted course of a decade or more.

Maple Syrup Urine Disease (Branched-chain alpha-keto acid dehydrogenase deficiency, MSUD) is caused by a deficiency of the branched-chain alpha-keto acid dehydrogenase enzyme complex (BCKDH), which normally degrades the branched chain amino acids leucine, isoleucine, and valine. The disease is characterized in an infant by the presence of sweet-smelling urine, with an odor similar to that of maple syrup. Increased amounts of valine, leucine and isoleucine and their toxic byproducts accumulate in the blood, plasma, and urine. Symptoms include ataxia, encephalopathy, ketosis, mental retardation, seizures, and a maple syrup or caramel odor.

Malonic Aciduria, is an autosomal recessive metabolic disorder caused by a genetic mutation which disrupts the activity of Malonyl-Coa decarboxylase. This enzyme breaks down Malonyl-CoA (a fatty acid precursor and a fatty acid oxidation blocker) into Acetyl-CoA and carbon dioxide. A defect in Malonyl-CoA decarboxylase results in accumulation of ammonia in the blood; methylmalonic acid in the plasma; creatinine in the serum; 3-Aminoisobutyric acid, 3 Hydroxypropionic acid, 3 hydoxyvaleric acid, glycine, acylcrnitine and methylmalonic acid in the urine; and methylmalonic acid in the spinal fluid. Symptoms include cardiomyopathy, growth retardation, ketosis, nephrosis, pancreatitis, respiratory distress, and neutropenia.

Lysosomal Acid Lipase Deficiency (Wolman disease) is caused by a defect in lysosomal acid lipase (LIPA, or LAL), otherwise known as acid cholesteryl ester hydrolase, which is coded for by a gene (LIPA) on chromosome 10. Two major disorders, the severe infantile-onset Wolman disease and the milder late-onset cholesteryl ester storage disease (CESD), may be caused by mutations in separate parts of the LIPA gene. Wolman disease is characterized by increased transaminases in serum, and increased cholesteryl esters and triglycerides in various tissues. Symptoms include anemia, diarrhea, failure to thrive, enlarged liver, malabsorption, steatorrhea and abdominal pain.

Lysinuric protein intolerance (Hyperdibasic aminoaciduria II; Dibasic aminoaciduria II; Hyperdibasic aminoaciduria II; LPI), also called hyperdibasic aminoaciduria type 2 or familial protein intolerance, is an autosomal recessive metabolic disorder affecting amino acid transport. LPI is caused by a defect in SLC7A7, Solute carrier family 7, a cationic amino acid transporter. A defect in this enzyme results in accumulation of ammmonia and reticulocytes in blood; glutamine in plasma, carnitine and ferritin in serum, and arginine, lysine and ornithine in urine. Symptoms include bone marrow abnormality, growth retardation, hyperammoniemia, mental retardation, pancreatitis, and seizures.

Leukotriene C4 synthetase deficiency is caused by a defect in the enzyme leukotriene C4 synthetase (LTC4S). This enzyme catalyzes the synthesis of leukotriene C4 (LTC4) through conjugation of LTA4 with reduced glutathione (GSH), which is synthesized by glutathione synthetase. Leukotriene C4 and its receptor-binding metabolites LTD4 and LTE4 are cysteinyl leukotrienes that are potent lipid mediators of tissue inflammation. In general, leukotrienes are potent proinflammatory mediators synthesized from membrane-derived arachidonic acid after activation of certain granulocytes. A defect in LTC4 results in decreased concentrations of cysteinyl leukotrienes LTC4, LTD4 and LTE4 in plasma, spinal fluid and urine. Symptoms include early death, failure to thrive, motor retardation, microcephaly, and progressive neurological defect.

Lesch-Nyhan Syndrome (LNS; Hypoxanthin guanine phosphoribosyltransferase deficiency) is caused by a complete defect in the HPRT1 gene which codes for hypoxanthine-guanine phosphoribosyltransferase. Hypoxanthine-guanine phosphoribosyltransferase is an enzyme in purine metabolism. Its primarily functions to salvage purines from degraded DNA to renewed purine synthesis. In this role, it acts as a catalyst in the reaction between guanine and phosphoribosyl pyrophosphate (PRPP) to form GMP. A complete deficiency in this enzyme causes overproduction of uric acid, therefore it results in accumulation of uric acid in serum and increase urinary excretion of uric acid. Symptoms and signs include severe gout and kidney problems, poor muscle control, and moderate mental retardation. These complications usually appear in the first year of life. A striking feature of LNS is self-mutilating behaviors, characterized by lip and finger biting, that begin in the second year of life. Neurological symptoms include facial grimacing, involuntary writhing, and repetitive movements of the arms and legs similar to those seen in Huntington's disease. Treatment for LNS is symptomatic. Gout can be treated with allopurinol to control excessive amounts of uric acid. Kidney stones may be treated with lithotripsy, a technique for breaking up kidney stones using shock waves or laser beams. There is no standard treatment for the neurological symptoms of LNS. Some may be relieved with the drugs carbidopa/levodopa, diazepam, phenobarbital, or haloperidol.

Leigh's disease (Encephalopathy), a form of Leigh syndrome, also known as Subacute Necrotizing Encephalomyelopathy (SNEM), is a rare neurometabolic disorder that affects the central nervous system. It is an inherited disorder that usually affects infants between the age of three months and two years, but, in rare cases, teenagers and adults as well. In the case of the disease, mutations in mitochondrial DNA (mtDNA) or in nuclear DNA (gene SURF1[1] and some COX assembly factors) cause degradation of motor skills and eventually death. Leigh syndrome is caused by defects in many mitocondrial and nuclear encoded genes involved in energy metabolism, resulting in accumulation of L-Alanine and in plasma and urine. Symptoms include dystonia, ataxia, encephalopathy, muscle weakness, and tremor or twitching.

Lactose Intolerance (Hypolactasia, Adult type; Adult Lactase Deficiency; Disaccaride Intolerance III; Lactase Persistence, Included) is caused by a deceased expression of intestinal lactase, an enzyme expressed in newborns. Its activity declines following weaning. As a result, adult mammals are normally lactose-intolerant and more than 75% of the human adult population suffers from lactase deficiency. Lactase deficiency is present in up to 80 percent of blacks and Latinos, and up to 100 percent of American Indians and Asians. Persons with lactose intolerance are unable to digest significant amounts of lactose. Due to the reduced lactase level, lactose present in dairy products cannot be digested in the small intestine and instead are fermented by intestinal bacteria. Common symptoms include abdominal pain and bloating, excessive flatus, and watery stool following the ingestion of foods containing lactose. Excess lactose may be present in the urine.

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.

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.

Iminoglycinuria, sometimes called familial iminoglycinuria, is an autosomal recessive disorder of renal tubular transport affecting reabsorption of the amino acid glycine, and the imino acids proline and hydroxyproline, leading to accumulation of these three acids in the urine. Iminoglycinuria is a rare and complex disorder, associated with a number of genetic mutations which cause defects in both renal and intestinal transport systems of glycine and imino acids. Symptoms include urolithiasis, excessive imino acids in the urine, and mental retardation.