Browsing Pathways

2-Ketoglutarate dehydrogenase complex deficiency, also known as alpha-ketoglutarate dehydrogenase deficiency or oxoglutaric aciduria, is an autosomal recessive disorder of the Krebs cycle caused by a defective oxoglutarate dehydrogenase complex (OGDC). OGDC catalyzes the conversion of 2-ketoglutarate into succinyl-CoA. This disorder is characterized by a large accumulation of 2-ketoglutarate in the urine. Symptoms of the disorder include opisthotonus, ataxia, developmental delay, and seizures.

Mitochondrial complex II deficiency, which is also known as CII deficiency, is a rare form of an inherited inborn error of metabolism (IEM). CII deficiency is an autosomal recessive disorder that arises from mutations in the succinate dehydrogenase (SDH) genes (SDHA, SDHB, SDHC and SDHD). These genes code for the mitochondrial enzyme known as succinate dehydrogenase, a multicomponent, membrane-bound enzyme, which is also known as SDH, succinate-coenzyme Q reductase (SQR), or respiratory complex II. SDH is found in the inner mitochondrial membrane and catalyzes the oxidation of succinate to fumarate with the reduction of ubiquinone to ubiquinol. SDH or complex II is assembled via the action of two assembly factors (SDHAF1 and SDHAF2). Mutations in SDHA and SDHAF1 are most commonly found in patients with CII deficiency. Because complex II is found in the mitochondria, CII deficiency is technically considered a mitochondrial disease. CII deficiency accounts for between 2%-23% of all respiratory chain deficiency diagnoses. The signs and symptoms of mitochondrial complex II deficiency can vary greatly from severe life-threatening symptoms in infancy to muscle disease beginning in adulthood. The symptoms are very much dependent on the mutations to the SDH components. SDHA gene mutations cause myoclonic seizures and Leigh’s syndrome, a severe neurological disorder that is characterized by progressive loss of mental and movement abilities (psychomotor regression) and typically results in death within 1-2 years. SDHB gene mutations can cause leukodystrophy which affects the myelin sheath, the material surrounding and protecting nerve cells. Damage to the myelin sheath slows down or blocks messages between the brain and the rest of the body, which leads to problems with movement, speech, vision, hearing, and mental and physical development. SDHAF1 gene mutations can cause severe progressive leukoencephalopathy, which is characterized by the degeneration of the white matter of the brain. Interestingly, complex II deficiency gene mutation carriers may be at an increased risk for certain cancers.

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.

Congenital lactic acidosis, also known as CLA, is an inherited inborn error of metabolism (IEM) characterized by the build-up of lactic acid in the body (lactic acidosis). The incidence of congenital lactic acidosis is unknown. One estimate places the incidence at 250-300 live births per year in the United States. CLA is typically caused by a mutation in the genes encoding the pyruvate dehydrogenase complex (PDC) leading to deficiencies in the function and efficiency of pyruvate dehydrogenase complex proteins, which are located in the mitochondria. Collectively the PDC converts pyruvate, NAD+, coenzyme A into acetyl-CoA, CO2, and NADH. While CLA-associated defects have been identified in all 3 enzymes of the PDC complex, the E1-alpha subunit is the most commonly mutated form. Defects in the citric acid cycle due to PDC deficiency deprives the body of energy and leads to an abnormal build-up of lactic acid in tissues and biofluids. CLA has either an autosomal recessive or X-linked mode of inheritance. There are two forms of CLA: severe and mild. Severe cases of CLA manifest in the neonatal period while milder cases may not manifest until early adulthood. Symptoms may be persistent or brought on by an event causing stress, such as an asthma attack, seizure, or infection. Symptoms in the neonatal form of CLA include hypotonia, lethargy, vomiting, and tachypnea. As the disease progresses, it can cause developmental delays, cognitive disabilities, abnormal development of the face and head, and organ failure. Treatments for CLA that are occasionally used include the ketogenic diet and dichloroacetate.

Increased lactic acid concentrations in urine or serum can be a result of many metabolic disorders but also of other origin (infections, etc.). Respiratory chain defects account for most of the metabolic causes of lactic acid accumulation. Often alanine is also high. A urine spectrum indicating an increased lactic acid and alanine concentration is shown.

Pyruvate carboxylase deficiency is caused by mutation in the pyruvate carboxylase gene. Serine—pyruvate aminotransferase catalyzes the reaction of serine and pyruvate to produce 3-hydroxypyruvate and L-alanine, as well as the reaction from L-alanine and glyodxylate to pyruvate and glycine. A defect in this results in accumulation of ammonia, glucose and pyruvate in blood; proline, lysine, citrulline, and alanine in plasma; and 2-oxoglutaric acid, fumaric acid, ketone bodies and succinate in urine. Symptoms include ataxia, lactic acidosis, mental retardation, metabolic acidosis, siezures, and dyspnea.

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.

Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency, which is also known LCHADD, is a rare inherited inborn error of metabolism (IEM) of long-chain fatty acid metabolism. The estimated birth prevalence of LCHADD is 1 in 62 000 in Northern European individuals. The worldwide birth prevalence is estimated at 1 in 250 000. MCADD is an autosomal recessive disorder associated with a mutation in the enzyme known as hydroxyacyl-CoA dehydrogenase (HADHA). HADHA catalyzes the last three steps of mitochondrial beta-oxidation of long chain fatty acids. HADHA converts medium- and long-chain 2-enoyl-CoA compounds into the corresponding 3-ketoacyl-CoA compounds when NAD is present, and acetyl-CoA when NAD and CoASH are present. Deficiencies in this enzyme prevent the body from converting certain fats to energy, particularly during periods without food (fasting). Signs and symptoms of LCHAD deficiency typically manifest during infancy or early childhood and can include feeding difficulties, hypoglycemia, hypotonia, lethargy, liver problems, and retinal abnormalities. During late childhood, people may experience muscle pain and peripheral neuropathy. LCHAD-deficiency individuals are also at risk for breathing difficulties, serious heart problems, coma, and sudden death. Fasting or illnesses (e.g. viral infections) can trigger related problems. LCHADD is associated with some pregnancy-specific disorders, including preeclampsia, HELLP syndrome (hemolysis, elevated liver enzymes, low platelets), hyperemesis gravidarum, acute fatty liver of pregnancy, and maternal floor infarction of the placenta.

Hereditary folate malabsorption, also known as folic acid transport defect, is an extremely rare inborn error of metabolism (IEM) and autosomal recessive disorder of the folate metabolism pathway. It is caused by a defect in the SLC46A1 gene that encodes the proton-coupled folate transporter protein which is responsible for folate uptake from the intestines. Hereditary folate malabsorption is characterized by low concentrations of folate in the serum and cerebrospinal fluid. Symptoms include feeding difficulties and failure to thrive and anemia, as well as potential neurological issues such as seizures and developmental delays. When infants are born with hereditary folate malabsorption, there are initially few signs, as folate is provided across the placenta, but after birth, folate absorption is inhibited and these symptoms begin to be exhibited. Treatment for hereditary folate malabsorption includes intramuscular or oral doses of reduced folates to bring cerebrospinal fluid folate levels to a normal range, as well as blood transfusions if severe anemia is present. It is estimated that hereditary folate malabsorption affects less than 1 in 1,0000,000 people, with only approximately 30 reported cases.

Carnitine-acylcarnitine translocase deficiency, also called CACT deficiency, is an extremely rare inherited inborn error of metabolism (IEM) of fatty acid oxidation. It is an autosomal recessive disorder caused by a defective carnitine-acylcarnitine translocase gene. Carnitine-acylcarnitine translocase is a transporter protein that is responsible for transporting carnitine-fatty acid complexes and carnitine across the inner mitochondrial membrane. Defects in the CACT enzyme prevent the shuttle-like action of carnitine from moving fatty acids across the mitochondrial membrane and therefore there is decreased fatty acid catabolism. As a result, CACT deficiency prevents the body from using certain fats for energy, particularly during periods without food (fasting). Individuals with CACT may have extremely low levels of ketones (hypoketosis) and low blood sugar (hypoglycemia). Together these signs are called hypoketotic hypoglycemia. Signs and symptoms of this disorder usually begin soon after birth and may include breathing problems, seizures, and an irregular heartbeat (arrhythmia). Individuals with CACT deficiency also usually have excess ammonia in the blood (hyperammonemia), an enlarged liver (hepatomegaly), and a weakened heart muscle (cardiomyopathy). Many CACT-deficient newborns do not survive. Others who are afflicted with a milder form of the disorder develop signs and symptoms in early childhood and are at risk for nervous system damage, liver failure, coma, and death.