Browsing Pathways

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.

Fabry disease, also called Anderson-Fabry disease is an X-linked inherited condition that begins in childhood. The symptoms are caused by the buildup of a substance called globotriaosylceramide in cells in the body, due to a mutation in the GLA gene, that causes a malfunction in the production of an enzyme called alpha-galactosidase A, which, when functioning properly, breaks down globotriaosylceramide. The symptoms include angiokeratomas, tinnitus, episodes of pain in the hands and feet and corneal opacity. This condition can also lead to severe complications such as heart attack, stroke and kidney damage.

Krabbe disease, also called globoid cell leukodystrophy, is an extremely rare inherited inborn error of metabolism (IEM). It is a degenerative disorder that affects the nervous system. It has an estimated prevalence of 1/100,000 in the Northern European population and a worldwide incidence of 1/100,000-1/250,000 live births. Krabbe disease is an autosomal recessive disorder that is caused by a deficiency of an enzyme called galactosylceramidase. Galactosylceramidase is a lysosomal protein that hydrolyzes the galactose ester bonds of ceramides and ceramide derivatives including galactocerebroside, galactosylsphingosine (psychosine), lactosylceramide, and monogalactosyldiglyceride. More specifically, galactosylceramidase is an enzyme that is involved in the catabolism (via the removal of galactose) of galactosylceramide, a major lipid in myelin, kidney, and epithelial cells of the small intestine and colon. Defects in galactosylceramidase lead to the accumulation of cytotoxic psychosine, which ultimately leads to apoptosis of oligodendrocytes and demyelination. As a result, this enzyme deficiency impairs the growth and maintenance of myelin, the protective sheath around nerve cell axons that ensures that electrical impulses are rapidly transmitted. Krabbe disease is part of a group of disorders known as leukodystrophies, which result from the loss of myelin (demyelination). Krabbe disease is also characterized by the abnormal presence of globoid cells, which are globe-shaped cells that often have multiple nuclei. There are three different phenotypes for Krabbe disease: infantile, juvenile, and late-onset. Neurodegeneration and early death (at age 2-3) occur in most infantile cases. In juvenile patients, the disease is often fatal 2-7 years after the symptoms begin. Adult-onset patients can survive many years after symptoms first manifest. The symptoms of infantile Krabbe disease usually begin during the first year of life. Typically, the initial signs and symptoms include feeding difficulties, episodes of fever without any sign of infection, irritability, stiff posture, muscle weakness, and slowed mental and physical development. Muscles continue to weaken as the disease progresses which decreases the infant's ability to move, chew, swallow, and breathe. It is also common for affected infants to experience vision loss and seizures. Treatment is limited to hematopoietic stem cell transplantation in pre-symptomatic infantile patients and mildly affected late-onset patients. Stem cell transplants have been shown to slow the progression of the disease.

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.

Saccharopinuria (also known as: saccharopinemia, saccharopine dehydrogenase deficiency, and alpha-aminoadipic semialdehyde synthase deficiency, hyperlysinemia type II) is an autosomal recessive disease characterized by high concentrations of saccharopine in the plasma and urine.It is caused by the deficiency of the enzyme alpha-aminoadipic semialdehyde synthase (AASS). AASS contains a lysine ketoglutarate reductase (LKR) domain which catalyzes the conversion of lysine to saccharopine, and a saccharapine dehydrogenase (SDH) domain which catalyzes the conversion of saccharopine to alpha-aminoadipic semialdehyde. Hyperlysinemia type II is categorized by the loss in SDH activity but the preservation of significant amounts of LKR activity. This leads to the accumulation of saccharopine. The loss of both enyzmatic functions is categorized as hyperlysinemia type I.

D-Glyceric aciduria is an extremely rare inherited inborn error of metabolism (IEM) of serine and fructose metabolism. It is an autosomal recessive disorder that is caused by a defect in the D-glycerate kinase (GLYCTK) gene. GLYCTK codes for D-glycerate kinase, an enzyme that is responsible for phosphorylating D-glyceric acid into phosphoglycerate. D-Glycerate kinase is an enzyme that participates in 3 metabolic pathways: (1) serine/glycine/threonine metabolism, (2) glycerolipid metabolism, and (3) glyoxylate-dicarboxylate metabolism (which is a minor pathway in fructose metabolism). Defects in the enzyme will lead to accumulations of D-glyceric acid in tissues and biofluids. D-Glyceric aciduria was first described in 1974 and is characterized by elevated levels of D-glyceric acid in the urine. Clinical symptoms of D-glyceric aciduria are highly variable. Some patients have neurological symptoms, with severe mental retardation, seizures, microcephaly, and sometimes early death, whereas others have a mild phenotype with only mild speech delay or even normal development.

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.

Glycogen storage disease, Type VII, also called GSD VII and Tarui Disease, is an inborn error of metabolism (IEM) and metabolic disorder caused by a defective 6-phosphofructokinase. 6-phosphofructokinase catalyzes the conversion of fructose 6-phosphate into fructose 1,6-bisphosphate which is the substrate of fructose-bisphosphate aldolase A. This disorder is characterized by a large accumulation of fructose 6-phosphate. Symptoms of the disorder include anemia, increased muscle glycogen content and myotonia. Currently, the major treatment for Glycogen storage disease, Type VII is associated with diet management.

Sulfite oxidase deficiency (SOD) is a disorder, an autosomal recessive disease. In classic SOD, it is usually identified a few days after the birth of an affected individual, and is recognizable through characteristic dysmorphic features, seizures, and other signs of progressive encephalopathy. Patients also have ocular lenses that are dislocated, and usually die within a few months of being born. In late- onset SOD, the disorder is identified only in the later months, usually 6-18 months, of the child’s life by a delay or regression of neurological progress. This disorder is very rare, but the actual prevalence is not known. It can be diagnosed through a sulfite test strip in urine or by a skin fibroblast culture, which will indicate an absence of sulfite oxidase.