Browsing Pathways

Congenital Erythropoietic Porphyria (CEP), also known as Gunther Disease, uroporphyrinogen III synthase defiency or UROS deficiency, is a rare autosomal recessive rare inborn error of metabolism (IEM). It is a disorder of the porphyrin metabolism pathway caused by a mutation in the UROS gene which encodes for uroporphyrinogen-III synthase. This enzyme catalyzes the dehydrogenation of hydroxymethylbilane into water and uroporphyrinogen III, which will undergo several more reactions to eventually form heme. This disorder is characterized by a large accumulation of porphyrins in the feces, urine and plasma, as well as in bones and teeth, potentially giving them a darkened or red appearance. Symptoms of this disorder include sensitivity to light, leading to potential skin damage as children, which can then lead to severe deformities. Red urine and teeth can also be seen in infancy. Treatment of CEP includes limiting or eliminating exposure to the sun, blood transfusions, and potentially bone marrow transplants or stem cell treatment. It is estimated that CEP affects less than 1 in 1,000,000 individuals.

Congenital Lipoid Adrenal Hyperplasia (CLA),also called steroid 20-22 desmolase deficiency and lipoid CAH, is an autosomal recessive disorder and caused by a defective cholesterol side-chain cleavage enzyme. Cholesterol side-chain cleavage enzyme catalyzes the conversion of cholesterol into 20α-Hydroxycholesterol which is also a substrate of cholesterol side-chain cleavage enzyme. This disorder is characterized by a large accumulation of cholesterol in the mitochondrial. Symptoms of the disorder is not clear. Extra glucocorticoid and mineral replacement could be the potential treatments.

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.

Desmosterolosis is caused by a mutation in the DHCR24 gene, which codes for the enzyme 24-dehydrocholesterol reductase, which catalyzes the reduction of the delta-24 double bond of sterol intermediates. A defect in 24-dehydrocholesterol reductase causes accumulation of desmosterol in plasma. Symptoms include cleft palate, clubfoot, dysmorphism, mental and motor retardation, and speech development.

Dihydropyrimidinase Deficiency (DHPA, Dihydropyrimidinuria Deficiency, DPH Deficiency) is an autosomal recessive disease caused by a mutation in the DPYS gene which codes for dihydropyrimidinase. A deficiency in this enzyme results in accumulation of dihydrothymine, dihydrouracil, thymine, and uracil in urine. Symptoms, which present at birth, include metabolic acidosis, difficulty feeding, and seizures.

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.

Ethylmalonic Encephalopathy (Epema Syndrome; EE) is a rare autosomal recessive disorder caused by a mutation in the ETHE1 gene which codes for protein ETHE1. A deficiency of this protein inhibits proper energy production in mitochondria and a deficiency in cytochrome c oxidase. This results in accumulation of 2-methylbutyrylglycine, N-butyrylglycine, isobutyrylglycine, isovalerylglycine, and methylsuccinic acid in urine. Concentrations of L-carnitine are reduced in plasma. Symptoms, which present at birth, include peripheral neuropathy, seizures, microcephaly, and hypotonia lead to premature death. Treatment includes riboflavin and L-carnitine.

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.

GABA-transaminase deficiency, also known as gamma-amino butyric acid transaminase (GABA-T) deficiency, is an extremely rare autosomal recessive inborn error of metabolism (IEM) that is caused by a defect in the ABAT gene, which codes for 4-aminobutyrate (GABA) aminotransferase. This enzyme is present in several tissues in addition to brain and is most active in liver, and it catalyzes the conversion of GABA and 2-oxoglutarate into succinic semialdehyde and L-glutamate, and when it is deficient, GABA levels in the body, specifically the cerebrospinal fluid, are elevated. GABA is a neurotransmitter found in the nervous system that inhibits neurons from firing, and also affects the development of the brain, as well as regulating muscle tone. GABA-T can also convert beta-alanine and oxoglutaric acid to L-glutamic acid and malonic semialdehyde as part of the beta-alanine metabolism pathway, and when it is mutated, leads to an accumulation of beta-alanine within the cell. GABA-T deficiency is characterized by an increase of GABA levels in the cerebrospinal fluid. Symptoms of this disorder include low muscle tone and psychomotor retardation, as well as potential epilepsy and excessive sleeping. Treatment with Flumanezil, sold as Anexate, Lanexat, Mazicon or Romazicon, a GABA-A antagonist, has been tested and may be beneficial in some cases, and potentially more effective if started at a young age. It is estimated that GABA-T deficiency affects less than 1 in 1,000,000 individuals, as only five cases have been reported in literature as of 2017.