Browsing Pathways

Fumarase deficiency, also called fumaric aciduria, is a rare inborn error of metabolism (IEM) and autosomal recessive metabolic disorder caused by a defective mitochondrial fumarate hydratase. Fumarate hydratase catalyzes the conversion of fumaric acid into L-Malic acid or other way around. This disorder is characterized by a large accumulation of fumaric acid in the mitochondrial. Symptoms of the disorder include microcephaly (i.e. small head), severe developmental delay, hypotonia (i.e. weak muscle), and etc. Treatment with oral malic acid is very effective since malic acid can keep the Krebs cycle to function. Fumarase deficiency has been reported in approximately 100 people.

Biotinidase deficiency (Multiple carboxylase deficiency) is an autosomal recessive disease caused by a mutation in the BTD gene which codes for biotinidase. A deficiency in this enzyme results in accumulation of ammonia and ketone bodies in blood; 3-hydroxyisovaleric acid in plasma, spinal fluid, and urine; hydroxypropionic acid, 2-hydroxybutyric acid, 3-Hydroxybutyric acid, and citric acid in spinal fluid; and 3-methylcrotonylglycine, hydroxypropionic acid, and L and D-lactic acid in urine. Symptoms, which can present from birth into adulthood include hypotonia, ketosis, hyperammonemia, motor retardation, coma, and seborrhoic skin rash. Treatment includes biotin.

Momoamine oxidase A (MAO-A) deficiency, or Brunner syndrome, is an X-linked recessive genetic disorder caused by a mutation in the MAOA gene that encodes for monoamine oxidase A. As such it is almost exclusively found in men. MAO-A is an enzyme that catalyzes the deamination of amines such as epinephrine, dopamine and tyramine, as part of the tyrosine metabolism pathway. In this disorder, some neurotransmitters such as serotonin and dopamine build up in the brain due to their inability to be properly metabolized. Since serotonin helps to regulate emotions and mood, with epinephrine and norepinephrine regulating stress, the unnecessary presence of the chemicals in the brain can lead to poor impulse control, aggression and other effects. The buildup of chemicals may also damage the brain, leading to a lower IQ in individuals with this disorder. In addition, foods containing the compounds that cannot be broken down, such as tyramine, can cause episodes of increased symptoms in the patients. In the subpathway that converts dopamine to homovanillic acid, there are two instances of MAO-A that are inactivated in this disorder, both in different branches. The first reaction converts dopamine to 3,4-dihydroxyphenylacetaldehyde, while the second converts 3-methoxytyramine to homovanillin. With the inactivation of MAO-A, 3-methoxytyramine builds up as there are no reactions that use it, and both of these paths lead to a decrease in the concentration of homovanillic acid, as there are no other reactions present that produce it. Another reaction, this time converting tyramine to homovanillin, is also prevented by the lack of MAO-A, which leads to an accumulation of tyramine in the body. In another branch of tyrosine metabolism, the absence of MAO-A prevents the oxidation of norepinephrine and epinephrine into 3,4-dihydroxymandelaldehyde. Its absence also prevents the oxidative deamination of metanephrine and normetanephrine into 3-methoxy-4-hydroxyphenylglycolaldehyde. As this is no longer produced, it leads to a decrease in the concentration of vanillylmandelic acid, which is produced from 3-methoxy-4-hydroxyphenylglycolaldehyde in a reaction catalyzed by aldehyde dehydrogenase.

Hawkinsinuria (4-Hydroxyphenylpyruvate Hydroxylase Deficiency) is an autosomal dominant disease caused by a mutation in the HPD gene which codes for 4-hydroxyphenylpyruvate dioxygenase. A deficiency in this enzyme results in accumulation of hawkinsin in urine and plasma; cis-4-hydroxycyclohexylacetic acid, trans-4-hydroxycyclohexylaceid, vanillactic acid, 4-hydroxyphenylpyruvic acid, pyroglutamic acid in urine; and L-tyrosine in plasma. Symptoms include ketosis, metabolic acidosis, swimming-pool odor, and mental retardation. Treatment includes a low-protein diet and vitamin C.

Hyperphenylalaninemia due to dihydropteridine reductase deficiency (DHPR) is the high presence of phenylalanine in the system/blood caused by a genetic mutation. More specificially, mutations in the QDPR gene are the root cause of the condition. One observes that such a mutation results in an error encoding a reductase enzyme, and from there a chain reaction of effects lead to the observed effects of the disease. The mutation is autosomal recessive. When tetrahydrobiopterin levels drop, the breakdown of many several amino acids, such as phenylalanine, is reduced and as a result their levels in the blood augment. Symptoms of hyperphenylalaninemia due to dihydropteridine reductase deficiency include: dysphagia, global development delay, microcephaly, and intellectual disability (among others). Treatment consists of BH4 supplements as well as other medical treatments.

3-Phosphoglycerate dehydrogenase deficiency is a disorder of L-serine biosynthesis that is characterized by congenital microcephaly, psychomotor retardation, and seizures.The disorder is caused by homozygous or compound heterozygous or homozygous mutation in the gene encoding phosphoglycerate dehydrogenase on chromosome 1p12. Defects in the gene lead to a decrease of Glycine and Serine.

Dihydropyrimidine Dehydrogenase Deficiency (DHPD; Thymine-uraciluria) is a rare autosomal recessive disorder caused by a mutation in the DPYD gene which codes for dihydropyrimidine dehydrogenase. A deficiency in this enzyme results in accumulation of 5-hydroxymethyluracil, thymine, and uracil in urine. Symptoms include nystagmus, large liver, hypotonia, growth and mental retardation, and seizures.

Dimethylglycine dehydrogenase deficiency, also called DMGDH deficiency and dimethylglycinuria, is a rare inborn error of metabolism (IEM) and autosomal recessive disorder of glycine metabolism caused by a defective DMGDH gene. DMGDH codes for the mitochondrial protein dimethylglycine dehydrogenase which catalyzes the conversion of dimethylglycine into sarcosine. This disorder is characterized by a large accumulation of N,N-dimethylglycine (DMG) and creatinine kinase in serum, and DMG in the urine. Symptoms of the disorder include an unusual fish-like odour and muscle weakness. It is estimated that DMGDH deficiency affects 1 in 1 000 000 individuals.

2-Hydroxyglutarate is a compound formed from isocitric acid, a component of the TCA cycle. Isocitric acid becomes dehydrogenated by isocitrate dehydrogenase using NADP as a cofactor, and forming oxoglutaric acid. Oxoglutaric acid then forms 2-hydroxyglutarate in a reaction catalyzed by a mutant isocitrate dehydrogenase 2 enzyme, which also uses NADP as a cofactor. Normally, the isocitrate dehydrogenase 2 enzyme, encoded by the IDH2 gene, is responsible for the formation of 2-oxoglutaric acid from isocitrate. However, some gain-of-functions mutations to the IDH2 gene allow the enzyme to produce 2-hydroxyglutarate instead. This functionality is associated with several types of cancer, including glioma and acute myeloid leukemia. This is due to the buildup of 2-hydroxyglutarate, which inhibits several enzymes which rely on 2-oxoglutaric acid, such as methylcytosine dioxygenase and lysine-specific demethylase 2A. Both of these enzymes use 2-oxoglutarate to demethylate DNA, and when repressed, allow DNA to become hypermethylated. This in turn changes which genes are normally expressed, as methylation is used to suppress genes, and can lead to the expression of oncogenes or the repression of tumor-suppressing genes. This is the effect responsible for 2-hydroxyglutarate in cancer and other diseases.

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.