Browsing Pathways

The BCR-ABL fusion protein is a cytoplasm-targeted constitutively active tyrosine kinase that causes uninhibited cell proliferation via signalling cascades. This fusion protein is the result of a genetic abnormality known as the Philadelphia chromosome in which Abelson Murine Leukemia viral oncogene homolog 1 (ABL1) translocates within the Breakpoint Cluster Region (BCR) gene on chromosome 22. The action of BCR-ABL produces chronic myelogenous leukemia (CML), a cancer characterized by increased and unregulated growth of white blood cells in the bone marrow and the accumulation of these cells in the blood. Physiologically, ABL is a tyrosine kinase involved with cell growth that moves between the nucleus and the cytoplasm. Upon fusion with BCR, the oncoprotein is constitutively activated due to a preference for dimerization or tetramerization promoting subsequent autophosphorylation, and it is retained in the cytoplasm. BCR-ABL activates several oncogenic pathways which promote increased cell proliferation and survival including the MAPK/ERK Pathway, the JAK-STAT Pathway, and the PI3K/Akt pathway. BCR-ABL forms a complex with GRB2, GAB2, and SOS that activates Ras (converted from its inactive GDP-bound state to the active GTP-bound state). Ras signalling triggers the MAPK/ERK pathway which stimulates abnormal cell proliferation through regulation of transcription and translation. The BCR-ABL/GRB2/GAB2/SOS complex also activates STAT5 either through direct phosphorylation or indirectly through JAK2 kinase to promote survival. Additionally, JAK2 kinase activates the MYC transcription factor for growth-related genes. The PI3K/Akt pathway can be activated either via the BCR-ABL/GRB2/GAB2/SOS complex or the BCR-ABL/CRK/CRKL/CBL/PI3K complex. Akt functions in: (1) increasing cell proliferation by promoting the degradation of p27 (CDKN1B) through the upregulation of SKP2; (2) enhancing protein translation (and subsequently increasing cell proliferation) by activating mTOR kinase; (3) and preventing apoptosis to ensure survival by inhibiting both FOXO transcription factors and the protein Bcl2-associated agonist of cell death (BAD) as well as activating MDM2 which inhibits the tumour suppressor p53.

Chondrodysplasia Punctata 2, X Linked Dominant (CDPX2; CPDXD; CPXD; Conradi-Hunermann Syndrome; Happle Syndrome; Conradi-Hunermann-Happle Syndrome is caused by a mutation in the gene encoding delta(8)-delta(7) sterol isomerase emopamil-binding protein (EBP). EBP contains the code for the enzyme 3-beta-hydroxysteroid-Delta(8),Delta(7)-isomerase, which normally catalyzes the conversion of Delta(8)-sterols to their corresponding Delta(7)-isomers. A defect in this enzyme causes accumulation of 8-dehydrocholesterol and 8(9)cholestenol in the plasma. Symptoms include alopecia, dysmorphism, hyperkeratosis, ichthyosis, kyphoscoliosis, limb abnormalities and deformities, and mental retardation.

Carnitine palmitoyltransferase II deficiency, which is also known as CPT II deficiency, is an inherited inborn error of metabolism (IEM) of fatty acid oxidation leading to muscle weakness. It is the most common inherited disorder of lipid metabolism affecting the skeletal muscle of adults. It is an autosomal recessive disorder associated with a mutation in the enzyme carnitine palmitoyltransferase II. Carnitine palmitoyltransferase II (CPT2) is a peripheral inner mitochondrial membrane protein found in all tissues that oxidize fatty acids. It catalyzes the transesterification of palmitoylcarnitine back into palmitoyl-CoA which is a substrate for beta-oxidation inside the mitochondrial matrix. CPT2 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. Deficiencies or mutations in the CPT2 gene lead to disorders of long-chain fatty acid oxidation. There are three forms of CPT II deficiency: (1) lethal neonatal form, (2) severe infantile hepatocardiomuscular form, and (3) the myopathic form. More than 300 CPT II deficiency cases have been described with the myopathic form being the most common (myopathic form: 86%, severe infantile form: 8%, neonatal form: 6% of cases). The myopathic form is usually mild and can manifest from infancy to adulthood. The infantile and neonatal forms are severe multisystemic diseases characterized by liver failure with hypoketotic hypoglycemia, cardiomyopathy, seizures, and early death. The adult-onset myopathic form is characterized by exercise-induced muscle pain and weakness, sometimes associated with myoglobinuria. The most common cause of hereditary myoglobinuria is the myopathic form of CPT II deficiency and affects men more than women.

Ethylmalonic Encephalopathy (Epema Syndrome; EE) is a rare autosomal recessive disorder caused by a mutation in the ETHE1 gene which codes for protein ETHE1. A deficiency of this protein inhibits proper energy production in mitochondria and a deficiency in cytochrome c oxidase. This results in accumulation of 2-methylbutyrylglycine, N-butyrylglycine, isobutyrylglycine, isovalerylglycine, and methylsuccinic acid in urine. Concentrations of L-carnitine are reduced in plasma. Symptoms, which present at birth, include peripheral neuropathy, seizures, microcephaly, and hypotonia lead to premature death. Treatment includes riboflavin and L-carnitine.

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.

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.

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.

Propionic acidemia (Ketotic hyperglycinemia) is caused by mutation in the genes encoding propionyl-CoA carboxylase, PCCA or PCCB. The break down of Propionyl-CoA is catalyzed by Propionyl-CoA carboxylase (PCC). Propionyl-CoA plays an important role in amino acid metabolism. A mutation in this enzyme causes accumulation of ammonia and propionylcarnitine (C3) in the blood; carnitine , glutamine, glycine, and propionic acid in the plasma; 3-hydroxypropionic acid, 3-hydroxyvaleric acid, 5-oxoproline, acylcarnitin, glycine, methylcitric acid, propionylglycine and tiglylcine in the urine. Symptoms include cardio myopathy, growth retardation, hypothermia, ketosis, neutropenia, strokelike episodes, pyloric stenosis and spastic diplegia/quadriplegia.

3-Methylglutaconic Aciduria Type IV, also called MGA, Type IV and MGA4, is a rare inborn error of metabolism (IEM) and autosomal recessive disorder and caused by a defective methylglutaconyl-CoA hydratase. Methylglutaconyl-CoA hydratase catalyzes the conversion of 3-Methylglutaconyl-CoA into 3-Hydroxy-3-methylglutaryl-CoA which is the substrate of hydroxymethylglutaryl-CoA lyase. This disorder is characterized by increased urinary excretion of 3-methylglutaconic acid. Symptoms of the disorder include poor growth and neurological degression. Currently, there is no effective treatment for 3-MGA type IV.

3-Methylglutaconic aciduria type 3 (Costeff syndrome; Optic atrophy plus syndrome) is an autosomal recessive disease caused by a deficiency in the OPA3 code which does for optic atrophy 3 protein. A deficiency of this enzyme results in accumulation of 3-methylglutaconic acid and methylglutaric acid. Symptoms include ataxia, dysarthria, optic atrophy, and neurological deterioration.