Browsing Pathways

Homocystinuria, Cystathionine beta-Synthase Deficiency, also known as homocystinuria, is a inherited disorder of amino acid methionine metabolism caused by a defective cystathionine beta-Synthase. Cystathionine beta-Synthase catalyzes the conversion of homocysteine and L-Serine into L-Cystathionine which is the substrate of cystathionine gamma-lyase. This disorder is characterized by a large accumulation of homocysteine in the cell. Symptoms of the disorder include thromboembolism, ectopia lentis and/or severe myopia, skeletal system deficiency and developmental delay. Treatment with homocystinuria aims at correct the biochemical abnormalities through disorder management (e.g. surveillance, circumstances to avoid, prevention of primary manifestations, etc.

Adrenoleukodystrophy (ALD) is an X-linked recessive transmission disease. Central nervous system signs and symptoms have been consistently more prominent than signs of adrenal involvement. Behavioral changes are the most common initial finding and range from aggressive outbursts to withdrawal. Such behavior is generally accompanied by a gradually failing memory and poor school performance. Loss of vision is an early finding in some patients and is a prominent feature at some stage in most affected individuals. The initial visual loss appears as homonomous hemianopsia in some individuals and is usually associated with intact pupillary reflexes. Optic atrophy is less common as an initial finding but eventually develops in almost all cases. Gait disturbance is also an early finding and as is stiff-legged, unsteady and accompanied by hyperreflexia. In almost all cases there is spastic quadraplegia and a variable degree of decorticate posturing. Hearing loss, dysarthria and dysphagia develop at about the same time as gait disturbance. Seizures are a typical symptom in many affected individuals in the the end stages of the disease progression.

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.

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.

Ribose-5-phosphate isomerase (RPI) deficiency, is a genetic disorder caused by mutations in the RPIA gene that codes for RPI. RPI is an enzyme that is involved in the pentose phosphate pathway as part of carbohydrate degradation. It reversibly converts D-ribulose 5-phosphate into D-ribose 5-phosphate. In the case of this disorder, RPI functions partially in tissues, because if the gene was simply non-functional, it would likely be lethal. This means that a specific type of mutation needs to occur for this disorder to occur, leading to it being the rarest disease in the world, with only three confirmed cases. In the first known case, the patient had one allele containing a frameshift mutation, which led to a truncated protein, while the other allele contained a missense mutation. This combination meant that activity of RPI was found to vary across tissues and cell types. Characteristics of the RPI deficiency include higher ribitol and arabitol levels in a metabolic profile, as well as differences in polyol profiles. There are other symptoms, including leukoencephalopathy and neuropathy, which may be caused by a toxic accumulation of ribitol and arabitol, or a potential lack of ribose-5-phosphate in RNA synthesis.

Transaldolase deficiency, also known as Eyaid syndrome or TALDO deficiency, is a desease caused by homozygous or compound heterozygous mutations in the TALDO1 gene that encodes for transaldolase. The mutation found in one study was a base pair deletion leading to a premature truncation of the protein, preventing its activity in the cell. Other mutations reported in other studies include other deletions or homozygous base pair substitutions that cause a misfolded and non-functional protein. Transaldolase is an enzyme that reversibly converts D-erythrose 4-phosphate and fructose 6-phosphate to D-sedoheptulose 7-phosphate and D-glyceraldehyde 3-phosphate, as a part of the pentose phosphate pathway. Almost all affected patients show hepatosplenomegaly, liver dysfunction, low counts for all blood cell types, cardiac defects, and come from consanguinous families. They also show dysmorphic features, including a triangular face, low set ears, and a wide mouth with thin lips. Other signs include abnormal concentrations of polyols in urine and plasma, as well as ribose-, xylulose-, and ribulose-5-phosphate being elevated in urine.

3-Hydroxyisobutyric acid dehydrogenase deficiency (3-hydroxyisobutyric aciduria) is an extremely rare inborn error of metabolism (IEM), potentially caused by numerous mechanisms. It is currently thought to be autosomal recessively inherited. At least two cases of 3-hydroxyisobutyric aciduria were determined to be caused by a mutation in the ALDH6A1 gene, which encodes acylating methylmalonate-semialdehyde dehydrogenase. This enzyme converts 2-methyl-3-oxopropanoate, CoA and water into propanoyl-CoA, using NAD+ as an oxidizing agent, and producing a hydrogen ion and hydrogencarbonate as byproducts. Other forms of 3-hydroxyisobutyric aciduria may be caused by a mutation in the gene encoding 3-hydroxyisobutyrate dehydrogenase, which forms (S)-methylmalonic acid semialdehyde from (S)-3-hydroxyisobutyric acid. This mutation leads to an accumulation of (S)-3-hydroxyisobutyric acid, as no other processes in the pathway use it. 3-hydroxyisobutyric aciduria is characterized by elevated levels of 3-hydroxyisobutyric acid excreted in the urine. Symptoms of the disorder include dysmorphic features, developmental delays and intellectual disabilities. Treatments are not currently well researched due to the rarity of the condition, but protein-restricted diets may be helpful. It is estimated that 3-hydroxyisobutyric aciduria affects less than 1 in 1,000,000 people, with only 12 cases having been reported by 2006.

3-Hydroxyisobutyric aciduria, also called HIBA, is an extremely rare inherited inborn error of metabolism (IEM) of valine metabolism. Only 12-13 patients have been identified with this condition. It is an autosomal recessive disorder that may be caused, in some cases, by a defective aldehyde dehydrogenase 6 family member A1 (ALDH6A1) gene which codes for methylmalonate semialdehyde dehydrogenase (MMSDH). MMSDH is a mitochondrial methylmalonate semialdehyde dehydrogenase that plays a role in the valine and pyrimidine catabolism. This protein catalyzes the irreversible oxidative decarboxylation of malonate and methylmalonate semialdehydes to acetyl- and propionyl-CoA. Another possible cause of the disorder is a mutation in 3-hydroxyisobutyrate dehydrogenase, a mitochondrial enzyme which catalyzes the conversion of 3-hydroxyisobutyrate into methylmalonic semialdehyde, or in the conversion of the semialdehyde to propionyl-CoA. Individuals with this disorder have very high levels of 3-hydroxyisobutyric acid secreted in their urine. Other indications of organic acidemia are also present. Signs and symptoms of 3-hydroxyisobutyric aciduria include developmental delay, dysmorphic facial features, and brain abnormalities. The excretion of 3-hydroxyisobutyric acid in the urine can range from 170 to 390 mmol/mol of creatinine. Concentrations of free carnitine are also low, and esterified carnitine can be elevated in patients. Protein-restricted diets and carnitine supplementation have been tried with varying degrees of success.

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.

Isovaleric academia, also called IVA, is an extremely rare inherited inborn error of metabolism (IEM) of leucine metabolism. It is an autosomal recessive disorder that is caused by a deficiency of isovaleryl-CoA dehydrogenase. It is characterized by a build-up of isovaleric acid in the blood and other biofluids. High levels of isovaleric acid lead to a rancid cheese odour. There are two major phenotypes of IVA: (1) an acute form and (2) a late-onset form. The acute form manifests as catastrophic disease in the newborn period and infants become extremely sick in the first week of life. There is usually a history of poor feeding, vomiting, lethargy, and seizures. In the acute form, metabolic acidosis is present, usually with an elevated anion gap and ketosis. There may be secondary hyperammonemia, thrombocytopenia, neutropenia, and sometimes anemia. The late-onset form is characterized by chronic, intermittent episodes of metabolic decompensation. The degree of isovaleryl-CoA dehydrogenase deficiency and the mutations differ between the two extreme presentations. The acute form of IVA is reasonably treatable. Administration of glycine has been shown to reduce isovaleric acidemia in neonates. Glycine is readily conjugated with isovaleric acid, which leads to urinary excretion of the conjugate. A diet that is also restricted in leucine consumption is also useful in treating the disorder.