Browsing Pathways

Transaldolase deficiency, also known as Eyaid syndrome or TALDO deficiency, is a desease caused by homozygous or compound heterozygous mutations in the TALDO1 gene that encodes for transaldolase. The mutation found in one study was a base pair deletion leading to a premature truncation of the protein, preventing its activity in the cell. Other mutations reported in other studies include other deletions or homozygous base pair substitutions that cause a misfolded and non-functional protein. Transaldolase is an enzyme that reversibly converts D-erythrose 4-phosphate and fructose 6-phosphate to D-sedoheptulose 7-phosphate and D-glyceraldehyde 3-phosphate, as a part of the pentose phosphate pathway. Almost all affected patients show hepatosplenomegaly, liver dysfunction, low counts for all blood cell types, cardiac defects, and come from consanguinous families. They also show dysmorphic features, including a triangular face, low set ears, and a wide mouth with thin lips. Other signs include abnormal concentrations of polyols in urine and plasma, as well as ribose-, xylulose-, and ribulose-5-phosphate being elevated in urine.

Cystathionine Beta-Synthase Deficiency (CBS Deficiency; Homocystinuria) is an autosomal recessive disease caused by a mutation in the CBS gene which codes for cystathionine beta-synthase. A deficiency in this enzyme results in accumulation of L-cystathionine, homocysteine, and L-homocystine in plasma and urine; and L-methionine and ornithine in plasma. Symptoms include osteoporosis, myopia, fatty-liver, mental retardation, and early death. Treatment includes folic acid, vitamin B6, vitamin B12, and a methionine-restricted diet.

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.

Gaucher disease, also known as glucocerebrosidase deficiency, acid beta-glucosidase deficiency or GBA deficiency, refers to a group of autosomal recessively inherited rare inborn error of metabolism (IEM) that affect the sphingolipid metabolism pathway. All forms of Gaucher disease is caused by a mutation in the GBA gene that encodes lysosomal acid glucosylceramidase, an enzyme that is responsible for catalyzing the formation of ceramide and glucose from glucosylceramide via a hydrolysis reaction. Gaucher disease is characterized by the intracellular buildup of glucosylceramides, particularly in phagocytes, forming what are known as Gaucher cells. Symptoms include anemia, fatigue, hepatomegaly and splenomegaly, however these may vary based on the type of Gaucher disease. For example, type 1 (GD1) involves hepato- and splenomegaly, and types 2 and 3 (GD2 and GD3) also typically affect the brain and spinal cord, and as such tend to be more severe and more likely to become lethal. Treatment for Gaucher disease includes enzyme replacement therapy for type 1, which also helps treat types 2 and 3, but as the enzymes cannot cross the blood-brain barrier, cannot help with the brain damage associated with these types. A drug called miglustat, sold as Zavesca, can also be used to treat the symptoms of type 1 Gaucher disease in individuals who cannot have enzyme replacement therapy. It is estimated that Gaucher disease affects 1 in 100,000 individuals, with the rates being higher in certain populations such as Ashkenazi Jews. GD1 is the most common in most populations representing around 90% of cases of Gaucher disease, with GD2 and GD3 representing roughly 5% each.

Congenital Bile Acid Synthesis Defect Type III (CBASIII) is caused by a defect in 25-hydroxycholesterol 7-alpha-hydroxylase, which plays a role in synthesis of bile acids. The synthesis of primary bile acids from cholesterol occurs via two pathways: the classic neutral pathway involving cholesterol 7-alpha-hydroxylase (CYP7A1), and the acidic pathway involving a distinct microsomal oxysterol 7-alpha-hydroxylase (CYP7B1). CBASIII is characterized by accumulation of bile acids in the urine. Symptoms include severe cholestasis, cirrhosis, and liver failure.

The condition pyridoxine dependent-epilepsy is a condition that sees seizures beginning in infancy. In some cases, the seizures begin before birth. The seizures involve status epilepticus, which are seizures that last several minutes. The symptoms specific to pyridoxine dependent seizures can include hypothermia, dystonia and irritability right before an episode. They also include loss of consciousness, convulsions, and muscle rigidity. Rarely does this condition manifest between 1 to 3 years of age, although it has occured. Traditional anticonvulsant medication has proven ineffective in patients with this condition; patients are instead treated with pyridoxine daily in large doses. This compound is a b-vitamin found in food. Encephalopathy can occur if this condition is not treated, which can result in permanent brain damage. Although this condition is treated with pyridoxine, it can still cause neurological issues, such as learning disorders or developmental delay, regardless of treatment.

Saccharopinuria (also known as: saccharopinemia, saccharopine dehydrogenase deficiency, and alpha-aminoadipic semialdehyde synthase deficiency, hyperlysinemia type II) is an autosomal recessive disease characterized by high concentrations of saccharopine in the plasma and urine.It is caused by the deficiency of the enzyme alpha-aminoadipic semialdehyde synthase (AASS). AASS contains a lysine ketoglutarate reductase (LKR) domain which catalyzes the conversion of lysine to saccharopine, and a saccharapine dehydrogenase (SDH) domain which catalyzes the conversion of saccharopine to alpha-aminoadipic semialdehyde. Hyperlysinemia type II is categorized by the loss in SDH activity but the preservation of significant amounts of LKR activity. This leads to the accumulation of saccharopine. The loss of both enyzmatic functions is categorized as hyperlysinemia type I.

Saccharopinuria (also known as: saccharopinemia, saccharopine dehydrogenase deficiency, and alpha-aminoadipic semialdehyde synthase deficiency) is caused by a partial deficiency of aminoadipic semialdehyde synthase (AASS) enzyme and causes an increase in saccharopine in the urine. Saccharopinuria is another form of hyperlysinemia. AASS has lysine ketoglutarate reductase (LKR) and saccharopine dehydrogenase (SDH) activity. AASS acts in the first 2 steps in lysine degradation. A defect in this enzyme results in accumulation of citrulline, lysine and saccharopin in the plasma; lysine in the spinal fluid; and citrulline, lysine and saccharopine in the urine. Symptoms include growth and mental retardation.

Brompheniramine is a first-generation alkylamine H1-antihistamine. H1-antihistamines interfere with the agonist action of histamine at the H1 receptor and are administered to attenuate inflammatory process in order to treat conditions such as allergic rhinitis, allergic conjunctivitis, and urticaria. Reducing the activity of the NF-κB immune response transcription factor through the phospholipase C and the phosphatidylinositol (PIP2) signalling pathways also decreases antigen presentation and the expression of pro-inflammatory cytokines, cell adhesion molecules, and chemotactic factors. Furthermore, lowering calcium ion concentration leads to increased mast cell stability which reduces further histamine release. First-generation antihistamines readily cross the blood-brain barrier and cause sedation and other adverse central nervous system (CNS) effects (e.g. nervousness and insomnia). Second-generation antihistamines are more selective for H1-receptors of the peripheral nervous system (PNS) and do not cross the blood-brain barrier. Consequently, these newer drugs elicit fewer adverse drug reactions.

Dexchlorpheniramine is a first-generation alkylamine H1-antihistamine. H1-antihistamines interfere with the agonist action of histamine at the H1 receptor and are administered to attenuate inflammatory process in order to treat conditions such as allergic rhinitis, allergic conjunctivitis, and urticaria. Reducing the activity of the NF-κB immune response transcription factor through the phospholipase C and the phosphatidylinositol (PIP2) signalling pathways also decreases antigen presentation and the expression of pro-inflammatory cytokines, cell adhesion molecules, and chemotactic factors. Furthermore, lowering calcium ion concentration leads to increased mast cell stability which reduces further histamine release. First-generation antihistamines readily cross the blood-brain barrier and cause sedation and other adverse central nervous system (CNS) effects (e.g. nervousness and insomnia). Second-generation antihistamines are more selective for H1-receptors of the peripheral nervous system (PNS) and do not cross the blood-brain barrier. Consequently, these newer drugs elicit fewer adverse drug reactions.