Browsing Pathways

Methylenetetrahydrofolate reductase deficiency (MTHFRD; Homocystinuria due to defect of n(5,10)-methylene THF deficiency) is caused by a defect in the MTHFR gene which codes for methylenetetrahydrofolate reductase. Methylenetetrahydrofolate reductase catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a co-substrate for homocysteine remethylation to methionine. A defect in this enzyme results in accumulation of homocysteine and methionine in both plasma and urine. Some of the symptoms and signs include mental retardation, withdrawal, hallucinations, delusions, muscle weakness. Some patients remain asymptomatic until adulthood.

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.

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.

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.

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.

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.

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.

Dihydrolipoamide dehydrogenase deficiency, which is also known as DLDD, DLD, E3 deficiency, pyruvate dehydrogenase E3 deficiency, DLD deficiency, E3-deficient maple syrup urine disease, is a rare inherited inborn error of metabolism. DLD deficiency occurs in an estimated 1 in 35 000 to 48 000 individuals of Ashkenazi Jewish descent. DLDD is an autosomal recessive metabolic disorder characterized by mutations to the DLD gene, which codes for dihydrolipoamide dehydrogenase (DLD). DLD is a flavoprotein enzyme that oxidizes dihydrolipoamide to lipoamide. The DLD homodimer functions as the E3 component of the pyruvate, alpha-ketoglutarate, and branched-chain amino acid-dehydrogenase complexes and the glycine cleavage system, all of which are located in the mitochondrial matrix. DLDD is a combined deficiency of the branched-chain alpha-keto acid dehydrogenase complex (BCKDC), pyruvate dehydrogenase complex (PDC), and alpha-ketoglutarate dehydrogenase complex (KGDC). A common feature of dihydrolipoamide dehydrogenase deficiency is a potentially life-threatening buildup of lactic acid in tissues (lactic acidosis), which can cause nausea, vomiting, severe breathing problems, and an abnormal heartbeat. Neurological problems are also common in this condition; the first symptoms in affected infants are often decreased muscle tone (hypotonia) and extreme tiredness (lethargy). E3 deficiency is often associated with increased urinary excretion of alpha-keto acids, such as pyruvate. E3 deficiency can also be associated with increased concentrations of branched-chain amino acids, as observed in maple syrup urine disease (MSUD) and is sometimes referred to as MSUD type III, although patients with E3 deficiency have additional biochemical defects.

Pyruvate Dehydrogenase (PDH) Deficiency is an X linked disease where individuals have a reduced number of functioning PDH complexes ultimately affecting the mitochondria’s energy metabolism. In a healthy individual, PDH complex catalyzes the conversion of pyruvate to acetyl coenzyme A, therefore PDH deficiency can cause the accumulation of excess pyruvate and lactic acid. PDH deficiency presents itself in a variety of ways, however since the brain obtains most of it’s energy from aerobic oxidation of glucose, all PDH deficient individuals have some degree of neurological impairment. Other symptoms range from fatal lactic acidosis in the newborns, chronic neurodegenerative conditions, brain lesions, cerebral atrophy and much more. Due to the fatal nature of the disease many with this condition do not live past childhood, however there are some that survive to adolescents and adulthood. Treatments have tried to minimize systemic lactic acid accumulation by feeding patients high fat/low carbohydrate diets. However, this does not reverse neurological structural damage already present and therefore does little to influence the end results.

Glycogen storage disease, also called glycogenosis and dextrinosis, is a rare inborn error of metabolism (IEM) and recessive disorder, which is caused by a defective glycogen synthase. Glycogen synthase catalyzes the conversion of uridine diphosphate glucose into amylose and uridine 5'-diphosphate which amylose is the substrate of 1,4-alpha-glucan-branching enzyme and glycogen debranching enzyme. This disorder is characterized by a large accumulation of glycogen in the liver or muscles. Symptoms of the disorder depends on the type of glycogen storage disease (e.g. GSD I, GSD III, etc.). Treatments are also depend on the type of glycogen storage disease.