Browsing Pathways

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.

Glucose-6-phosphate dehydrogenase deficiency, also called G6PDD, is a very common inherited inborn error of metabolism (IEM) that is characterized by a defect in the glucose-6-phosphate dehydrogenase gene. Glucose-6-phosphate dehydrogenase (G6PD) is an enzyme in the pentose phosphate pathway. G6PD converts glucose-6-phosphate into 6-phosphoglucono-delta-lactone. This reaction supplies reducing energy to cells by maintaining high levels of NADPH inside cells, especially red blood cells. NADPH helps maintain the supply of reduced glutathione that is used to eliminate free radicals that cause oxidative damage in red blood cells. G6PDD is an X-linked genetic disorder that primarily affects males and predisposes affected individuals to red blood cell breakdown, which is called hemolysis. About 400 million people (1 in 20) have G6PDD globally and it is particularly common in certain parts of Africa, Asia, the Mediterranean, and the Middle East. Carriers of the G6PDD allele may be partially protected against malaria, which explains the higher incidence of this genetic defect in people coming from countries that have or historically had malaria. While the vast majority of affected individuals are male, females can be clinically affected due to unfavourable lyonization, where random inactivation of an X-chromosome in certain cells creates a population of G6PD-deficient red blood cells coexisting with unaffected red blood cells. As noted above, G6PDD mainly affects the redox capacity of red blood cells, which carry oxygen from the lungs to tissues throughout the body. The most common medical problem associated with G6PDD is hemolytic anemia, which occurs when red blood cells are destroyed faster than the body can replace them. This type of anemia leads to paleness, yellowing of the skin and whites of the eyes (jaundice), dark urine, shortness of breath, fatigue, and a rapid heart rate. In individuals with G6PDD, hemolytic anemia is most often triggered by bacterial or viral infections or by certain drugs (such as some antibiotics, aspirin, quinine and other antimalarials derived from quinine). Hemolytic anemia can also occur after inhaling fava plant pollen or consuming fava beans (a reaction called favism). In newborns, G6PDD is also a significant cause of mild to severe jaundice. Many people with G6PDD, however, are asymptomatic.

Short Chain Acyl CoA Dehydrogenase Deficiency (SCAD Deficiency) is caused by mutation in the gene encoding short-chain acyl-CoA dehydrogenase, an enzyme which normally breaks down short chain fatty acids. SCADD causes accumulation of ammonia in blood; butyrylcarnitine(C4) in plasma; adipic acid, butyrylglycine, ethylmalonic acid; hexanoylglycine and methylsuccinic acid in urine. Symptoms include hypoglycemia, hypotonia, microcephaly, failure to thrive, lactic acidosis, peripheral neuropathy, and vomiting.

Carnitine palmitoyltransferase I deficiency, which is also known as CPT I deficiency, is a very rare inherited inborn error of metabolism (IEM) leading to muscle weakness. Fewer than 50 people have been identified with this condition. It is an autosomal recessive disorder associated with a mutation in the enzyme carnitine palmitoyltransferase I. Carnitine palmitoyltransferase I (CPT1) is also known as carnitine acyltransferase I (CAT1), CoA:carnitine acyl transferase (CCAT), or palmitoylCoA transferase I. CPT I is a mitochondrial enzyme. It is responsible for the formation of acylcarnitines by catalyzing the transfer of the acyl group of a long-chain fatty acyl-CoA from CoA to carnitine. Carnitine, a natural substance acquired mostly through the diet, is used by cells to process fats and produce energy. Defects in CPT I prevents the body from using certain fats for energy, particularly during periods of fasting. Affected individuals often have increased carnitine levels along with low blood sugar (hypoglycemia) and a low level of ketones (hypoketosis), which are produced during fat metabolism as an energy source. Together these signs are termed hypoketotic hypoglycemia. The condition's severity varies greatly among affected individuals and many of the signs and symptoms manifest during early childhood. People with CPT I deficiency can also have an enlarged liver (hepatomegaly) and liver malfunction. CPT I deficienct individuals are at risk for liver failure, nervous system damage, seizures, coma, and sudden death. Affected individuals should eat a high-carbohydrate, low-fat diet and avoid fasting.

Trifunctional protein deficiency is a condition caused by mutations in the genes HADHA and HADHB. The enzyme affected is required to metabolize long-chain fatty acids, which makes a patients ability to convert fats to energy very difficult. This is exacerbated by periods without food. The symptoms associated with this disorder differ depending on when they appear in a patient. In infancy, symptoms would include lethargy, hypoglycaemia and hypotonia. Infants are also at higher risk for sudden death and heart problems. Later onset trifunctional protein deficiency symptoms also include hypotonia, but also include breakdown of muscle tissue and peripheral neuropathy. Treatment includes a low-fat, high-carbohydrate diet and avoiding fasting, as this can induce symptoms of this condition.

Type I primary hyperoxaluria (Glycolicaciduria) is caused by mutation in the gene encoding alanine-glyoxylate aminotransferase (AGXT). AGXT normally catalyzes the reaction from L-serine and pyruvate to 3-hydroxypyruvate and L-alanine and the reaction from L-alanine and glyoxylate to pyruvate and glycine. A defect in AGXT results in accumulation of glycolic acid, glyoxylic acid, and oxalate in urine. Symptoms include hematuria, myocarditis, nephrocalcinosis, peripheral neuropathy, and renal failure.

Adult Refsum Disease (Classic Refsum Disease; Phytanic Acid Oxidase Deficiency; Heredopathia Atactica Polyneurtiformis; Hereditary Motor and Sensory Neuropathy IV; HSMN4; Adult Refsum Disease I; Adult Refsum Disease II), can be caused by mutations in the PHYH (or PAHX) gene, which encodes Phytanoyl-CoA hydroxylase (, the first enzyme in the Phytanic Acid Peroxisomal Oxidation pathway) on chromosome 10 (adult Refsum disease I), and by mutation of the PEX7 gene. A defect in phytanoyl-CoA hydroxylase results in accumulation of phytanic acid in the plasma, as well as low levels of pristanic acid due to the inability for phytanic acid to undergo alpha and beta oxidation. Symptoms include anosmia, ataxia, nystagmus, neurological deterioration and peripheral neuropathy. Adult Refsum disease is distinctly different from Infantile Refsum disease both genetically and phenotypically. Infantile Refsum disease involves mutations of the PEX1, PEX2 and PEX26 genes.

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.

In Wolman's disease excessive amounts of cholesterol ester in the liver are present mainly in the macrophages of the reticuloendo- thelial system. The livler in Wiolman's disease contains triglyceride at 10 to 20 times the normal concentratlon, most of whilch is present in hepatocytes. The first case of Wolman's disease was published in 1956 by M. Wolman, M.D., reporting a case of a 2 month old girl who had been admitted to the Hadassah University Hospital. Lysosomal acid lipase/acid cholesteryl ester hydrolase (LAL/ACEH) plays an important role in cellular processing of plasma lipoproteins and thus contributes to both the homeostatic control of plasma lipoprotein levels and the prevention of cellular lipid overload. Wolman's Disease results from severely reduced levels of the enzyme lysosomal acid lipase/acid cholesteryl ester hydrolase.

Isobutyryl-CoA dehydrogenase deficiency, also called IBDD, is an extremely rare inherited inborn error of metabolism (IEM) of valine metabolism. It is an autosomal recessive disorder that is caused by a defective isobutyryl-coenzyme A dehydrogenase. Approximately 30 people have been identified with this condition, although the frequency may be much higher since it is relatively asymptomatic. Isobutyryl-coenzyme A dehydrogenase is a mitochondrial protein that belongs to the acyl-CoA dehydrogenase family of enzymes. Its main function is to catalyze the dehydrogenation of acyl-CoA derivatives in the metabolism of branched-chain amino acids, specifically valine. This enzyme is responsible for the third step in the breakdown of valine and converts isobutyryl-CoA into methylacrylyl-CoA. Defects in the IBD enzyme function lead to elevated levels of valine in blood and other biofluids (valinemia). IBDD can be identified by elevated levels of C4-acylcarnitine via newborn screening. Most people with IBDD are asymptomatic. Some individuals with IBDD have developed features such as a weakened and enlarged heart (dilated cardiomyopathy), weak muscle tone (hypotonia), and developmental delay. This condition may also result in low numbers of red blood cells (anemia) and very low levels of carnitine in the blood, which is a compound that plays a role in converting certain foods into energy. Symptoms may be worsened by long periods of fasting or infections that increase the body's demand for energy. Treatment may include the use of L-carnitine supplements, frequent meals, and a low-valine diet.