Browsing Pathways

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.

Hereditary coproporphyria (HCP) is a rare inborn error of metabolism (IEM) which arises from a defective gene called CPOX. This gene is responsible for mitochondrial coproporphyrinogen-III oxidase. A defect in this enzyme results in accumulation of the porphyrin precursors porphobilinogen and 5-aminolevulinic acid; increase of fecal and urinary excreation of coproporphyrins. Symptoms for this condition vary substantially, with anything from reddish-purple urine, to bouts of acute abdominal and nerve pain, to episodes of photosensitive skin eruptions so extreme that the induced scratching often leads to permanent scarring. At the present time the condition has no cure. The following are some measures which are designed to help prevent and/or regulate the above and more symptoms: a diet which is high in carbohydrates and sugars, and a balanced lifestyle which abstains from alcohol and drug use.

Familial lipoprotein lipase deficiency (LPLD), also known as familial chylomicronemia syndrome, chylomicronemia, chylomicronemia syndrome, and hyperlipoproteinemia type Ia, is an extremely rare inherited inborn error of metabolism (IEM) of lipid metabolism. LPLD affects about 1 out of 1 000 000 people. It is an autosomal recessive disorder that is caused by a defect or deficiency in the enzyme lipoprotein lipase. Lipoprotein lipase is a water-soluble enzyme that hydrolyzes triglycerides in lipoproteins, such as those found in chylomicrons and very-low-density lipoproteins (VLDL), into two free fatty acids and one monoacylglycerol molecule. Defects in lipoprotein lipase will lead to accumulations of triglycerides and massive accumulation of fatty droplets called chylomicrons in the blood. As a result, LPLD is characterized by abnormally elevated levels of triglycerides and chylomicrons in serum and plasma (chylomicronemia). Affected individuals often experience episodes of abdominal pain, acute recurrent inflammation of the pancreas (pancreatitis), abnormal enlargement of the liver and/or spleen, and the development of skin lesions known as eruptive xanthomas. Most cases of LPLD are identified before the age of 10. In roughly one-quarter of patients, the disorder is identified during the first year of life. Some affected individuals may not be identified until adulthood. Treatment of LPLD is mainly based on medical nutrition therapy to maintain plasma triglyceride concentration below 11.3 mmol/L. Lipid-lowering agents such as fibrates and omega-3-fatty acids can be used to lower triglyceride levels in LPLD.

Hyperlysinemia type I is a rare inherited inborn error of metabolism (IEM) of lysine metabolism. It is an autosomal recessive disorder that is caused by a defect in the alpha-aminoadipic semialdehyde synthase gene (AASS). The AASS gene encodes a bifunctional enzyme that contains lysine alpha-ketoglutarate reductase and saccharopine dehydrogenase. In hyperlysinemia type I, both enzymatic functions of AASS are defective. AASS is involved in the first two steps of the lysine degradation pathway. Lysine-alpha-ketoglutarate reductase catalyzes the metabolism of lysine to saccharopine, which is then cleaved to alpha-aminoadipic semialdehyde and glutamic acid by saccharopine dehydrogenase. Hyperlysinemia type I is characterized by elevated blood levels of the amino acid lysine, a building block of most proteins. Pipecolic acid can also be increased in serum and urine, while ornithine is typically decreased. Clinical symptoms of hyperlysinemia are highly variable. The descriptions range from symptom-free to severe developmental delay, spastic diplegia, seizures, rigidity, coma, episodic vomiting, and diarrhea. For the vast majority of people, hyperlysinemia typically causes no health problems, and most people with elevated lysine levels are unaware that they have this condition.

Dopamine beta-hydroxylase deficiency (or norepinephrine deficiency) is caused by mutation in the gene encoding dopamine beta-hydroxylase. Clinical features include orthostatic hypotension, ptosis, nasal stuffiness, and a neonatal history of delayed eye opening. Noradrenaline and adrenaline are generally not detectable in plasma, urine, and cerebrospinal fluid, but dopamine is increased 7- to 12-fold in plasma, 4-fold in urine, and 20-fold in CSF. Treatment with dihydroxyphenylserine has been shown to reduce symptoms and signs of postural hypotension and increase plasma levels of noradrenaline.

Prolinemia Type II is caused by mutation in the pyrroline-5-carboxylate dehydrogenase gene (P5CDH) mitochondrial matrix NAD-dependent dehydrogenase. This dehydrogenase is a catalyst for converting pyrroline-5-carboxylate to glutamate in the proline degradation pathway. An enzyme defect causes accumulation of glycine, hydroxyproline and proline in the urine, ornithine in the serum and proline in plasma. Symptoms include mental retardation, acute and chronic renal failure, and seizures.

Lysosomal Acid Lipase Deficiency, also known as Wolman disease, is predictably enough the result of a specific defect in lysosomal acid lipase. The defect results from a mutation on the 10th chromosome to the LIPA gene. Of interest is that the nature of the particular defect to the LIPA gene can result in two major, and distinct disorders. The first and more severe is the infantile-onset Wolman disease, whereas the other less severe disorder is late-onset cholesteryl ester storage diseas, also known as CESD. These two disorders are the product of mutations to different regions 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, vomiting, failure to thrive, enlarged liver, malabsorption, steatorrhea and abdominal pain.

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.

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.

Ocular non-nephropathic cystinosis, also known as adult-onset cystinosis, is a rare inborn error of metabolism (IEM) and autosomal recessive disorder of the cysteine metabolism pathway. It is caused by a defect in the CTNS gene, which encodes the protein cystinosin, which acts as a cystine/H+ symporter that transports L-cysteine out of the lysosome. Ocular non-nephropathic cystinosis is characterized by a buildup of cysteine in cells, in the case of this form in the cornea. Symptoms include photophobia and damage to the cornea due to crystals forming from the excess cysteine. However, unlike other forms of cystinosis, no or minimal kidney damage occurs. Treatment with cysteamine, a drug that can convert cysteine into a form that can be secreted by the lysosome, can be effective in all of the forms of cystinosis. It is estimated that ocular non-nephropathic cystinosis affects less than 1 in 100,000 to 200,000 individuals, which is the rate of the more severe nephropathic cystinosis.