Imipramine Action Pathway,Drug Action

Imipramine is a tricyclic antidepressant that exerts its therapeutic effects by inhibiting norepinephrine and serotonin reuptake in the brain. It does so by competing for the same binding site as norepinephrine on the sodium-dependent noradraneline transporter (SLC6A2) and by competing with serotonin for binding to the sodium-dependent serotonin transporter (SLC6A4). This increases the concentrations of both norepinephrine and serotonin in their respective synapses and reverses the state of low concentrations of both neurotransmitters found in depression. Higher concentrations of norepinephrine and serotonin have also been shown to have long-term neuromodulatory effects. Binding of these neurotransmitters to their respective receptors activate adenylate cyclase, which produces cAMP. cAMP activates protein kinase A which activates cAMP-responsive binding protein 1 (CREB-1). CREB-1 enters the nucleus and affects transcription of brain-derived neurotrophic factor (BDNF). BDNF subsequently stimulates neurogenesis, which may contribute to the long-term reversal of depression.  Imipramine is metabolized in the liver mostly through N-demethylation by CYP2C19 into desipramine. Desipramine is an active metabolite and also has similar actions to imipramine on norepinephrine and serotonin reuptake.


Desipramine Action Pathway,Drug Action

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Desipramine is a tricyclic antidepressant that exerts its therapeutic effects by inhibiting norepinephrine and serotonin reuptake in the brain. It does so by competing for the same binding site as norepinephrine on the sodium-dependent noradraneline transporter (SLC6A2) and by competing with serotonin for binding to the sodium-dependent serotonin transporter (SLC6A4). This increases the concentrations of both norepinephrine and serotonin in their respective synapses and reverses the state of low concentrations of both neurotransmitters found in depression. Higher concentrations of norepinephrine and serotonin have also been shown to have long-term neuromodulatory effects. Binding of these neurotransmitters to their respective receptors activate adenylate cyclase, which produces cAMP. cAMP activates protein kinase A which activates cAMP-responsive binding protein 1 (CREB-1). CREB-1 enters the nucleus and affects transcription of brain-derived neurotrophic factor (BDNF). BDNF subsequently stimulates neurogenesis, which may contribute to the long-term reversal of depression.


Citalopram Action Pathway,Drug Action

Citalopram is a selective serotonin reuptake inhibitor that exerts antidepressive effects by selectively inhibiting serotonin reuptake in the brain. It does so by competing for the same binding site as serotonin on the the sodium-dependent serotonin transporter (SLC6A4). This increases the concentrations of serotonin in the synaptic cleft and reverses the state of low concentration seen in depression. Higher concentration of serotonin has also been shown to have long-term neuromodulatory effects. Binding of serotonin to certain serotonin receptors activate adenylate cyclase, which produces cAMP. cAMP activates protein kinase A which activates cAMP-responsive binding protein 1 (CREB-1). CREB-1 enters the nucleus and affects transcription of brain-derived neurotrophic factor (BDNF). BDNF subsequently stimulates neurogenesis, which may contribute to the long-term reversal of depression.


Escitalopram Action Pathway,Drug Action

Escitalopram is a selective serotonin reuptake inhibitor that exerts antidepressive effects by selectively inhibiting serotonin reuptake in the brain. It does so by competing for the same binding site as serotonin on the the sodium-dependent serotonin transporter (SLC6A4). This increases the concentrations of serotonin in the synaptic cleft and reverses the state of low concentration seen in depression. Higher concentration of serotonin has also been shown to have long-term neuromodulatory effects. Binding of serotonin to certain serotonin receptors activate adenylate cyclase, which produces cAMP. cAMP activates protein kinase A which activates cAMP-responsive binding protein 1 (CREB-1). CREB-1 enters the nucleus and affects transcription of brain-derived neurotrophic factor (BDNF). BDNF subsequently stimulates neurogenesis, which may contribute to the long-term reversal of depression.


Fluoxetine Action Pathway,Drug Action

Fluoxetine is a selective serotonin reuptake inhibitor that exerts antidepressive effects by selectively inhibiting serotonin reuptake in the brain. It does so by competing for the same binding site as serotonin on the the sodium-dependent serotonin transporter (SLC6A4). This increases the concentrations of serotonin in the synaptic cleft and reverses the state of low concentration seen in depression. Higher concentration of serotonin has also been shown to have long-term neuromodulatory effects. Binding of serotonin to certain serotonin receptors activate adenylate cyclase, which produces cAMP. cAMP activates protein kinase A which activates cAMP-responsive binding protein 1 (CREB-1). CREB-1 enters the nucleus and affects transcription of brain-derived neurotrophic factor (BDNF). BDNF subsequently stimulates neurogenesis, which may contribute to the long-term reversal of depression.


Thioguanine Action Pathway,Drug Action

Thioguanine is a purine antimetabolite prodrug closely related to mercaptopurine and similarly inhibits purine metabolism. The thioguanine pathway is shown as a part of the mercaptopurine pathway. Thioguanine exerts cytotoxic effects via incorporation of thiodeoxyguanosine triphosphate into DNA and thioguanosine triphosphate into RNA and inhibition of Ras-related C3 botulinum toxin substrate 1, which induces apoptosis of activated T cells. Once in a cell, thioguanine is converted to thioguanosine monophosphate by hypoxanthine-guanine phosphoribosyltransferase. Thioguanosine monophosphate is then phosphorylated to thioguanosine diphosphate, which is converted via a thiodeoxyguanosine diphosphate intermediate to thiodeoxyguanosine triphosphate. Thiodeoxyguanosine triphosphate is incorporated into DNA causing cytotoxicity. Thioguanosine diphosphate is also converted to thioguanosine triphosphate which is incorporated into RNA. The thioguanosine triphosphate metabolite also inhibits Ras-related C3 botulinum toxin substrate 1, a plasma membrane-associated small GTPase that regulates cellular processes, inducing apoptosis in activated T cells.


Nicotine Action Pathway,Drug Action

Nicotine is a stimulant drug that acts as an agonist at nicotinic acetylcholine receptors. These are ionotropic receptors composed of five homomeric or heteromeric subunits. In the brain, nicotine binds to nicotinic acetylcholine receptors on dopaminergic neurons in the cortico-limbic pathways. This causes the channel to open and allow conductance of multiple cations including sodium, calcium, and potassium. This leads to depolarization, which activates voltage-gated calcium channels and allows more calcium to enter the axon terminal. Calcium stimulates vesicle trafficking towards the plasma membrane and the release of dopamine into the synapse. Dopamine binding to its receptors is responsible the euphoric and addictive properties of nicotine.Nicotine also binds to nicotinic acetylcholine receptors on the chromaffin cells in the adrenal medulla. Binding opens the ion channel allowing influx of sodium, causing depolarization of the cell, which activates voltage-gated calcium channels. Calcium triggers the release of epinephrine from intracellular vesicles into the bloodstream, which causes vasoconstriction, increased blood pressure, increased heart rate, and increased blood sugar.


Disulfiram Action Pathway,Drug Action

Disulfiram is a drug used in the treatment of cocaine addiction and chronic alcoholism. With regards to cocaine addiction, cocaine inhibits dopamine reuptake by blocking dopamine transporter 1 (DAT1). This increases dopamine concentrations in the synapse and dopamine binding to its receptors induces euphoria. Disulfiram inhibits dopamine beta-hydroxylase, which metabolizes dopamine into norepinephrine.  This causes more dopamine to accumulate in the axon terminal and more dopamine is released. When used concomitantly with cocaine, this causes an extremely high concentration of dopamine in the synapse that does not increase the euphoric effects of cocaine, but rather induces an unpleasant sensation of anxiety. This serves to discourage the patient from using cocaine while taking disulfiram. Disulfiram can prevent alcohol metabolism by inhibiting acetaldehyde dehydrogenase in mitochondria, which lead to increased level of acetaldehyde, and eventually result in hangover (e.g. flushing, vomiting, headache, etc.) as the main symptoms. Therefore, disulfiram is not suggested to take while patient consuming alcohol.


Nateglinide Action Pathway,Drug Action

Nateglinide is a non-sulfonylurea insulin secretagogue used in the treatment of type 2 diabetes. As the name of the drug class suggests, nateglinide acts on pancreatic beta-cells to stimulate insulin secretion. Under physiological conditions, insulin secretion from beta-cells is mediated by elevated glucose concentration in the blood. Glucose enters the cell via GLUT2 (SLC2A2) transporters. Once inside the cell, glucose is metabolized to produce ATP. High concentration of ATP will inhibit ATP-dependent potassium channels (ABCC8), which depolarizes the cell. Depolarization causes opening of voltage-gated calcium channels, allowing calcium to enter cell. High intracellular calcium subsequently stimulate vesicle exocytosis and insulin secretion. Nateglinide stimulate insulin secretion in a glucose-sensitive manner by inhibiting ATP-dependent potassium channels. As a result, there tends to be a lesser likelihood of hypoglycemia with nateglinide therapy compared to sulfonylureas.


Repaglinide Action Pathway,Drug Action

Repaglinide is a non-sulfonylurea insulin secretagogue used in the treatment of type 2 diabetes. As the name of the drug class suggests, repaglinide acts on pancreatic beta-cells to stimulate insulin secretion. Under physiological conditions, insulin secretion from beta-cells is mediated by elevated glucose concentration in the blood. Glucose enters the cell via GLUT2 (SLC2A2) transporters. Once inside the cell, glucose is metabolized to produce ATP. High concentration of ATP will inhibit ATP-dependent potassium channels (ABCC8), which depolarizes the cell. Depolarization causes opening of voltage-gated calcium channels, allowing calcium to enter cell. High intracellular calcium subsequently stimulate vesicle exocytosis and insulin secretion. Repaglinide stimulate insulin secretion in a glucose-sensitive manner by inhibiting ATP-dependent potassium channels. As a result, there tends to be a lesser likelihood of hypoglycemia with repaglinide therapy compared to sulfonylureas.


Glibenclamide Action Pathway,Drug Action

Glibenclamide is a sulfonylurea drug used in the treatment of type 2 diabetes. Glibenclamide acts on pancreatic beta-cells to stimulate insulin secretion. Under physiological conditions, insulin secretion from beta-cells is mediated by elevated glucose concentration in the blood. Glucose enters the cell via GLUT2 (SLC2A2) transporters. Once inside the cell, glucose is metabolized to produce ATP. High concentration of ATP will inhibit ATP-dependent potassium channels (ABCC8), which depolarizes the cell. Depolarization causes opening of voltage-gated calcium channels, allowing calcium to enter cell. High intracellular calcium subsequently stimulate vesicle exocytosis and insulin secretion. Glibenclamide stimulates insulin secretion by directly inhibiting ATP-dependent potassium channels.


Gliclazide Action Pathway,Drug Action

Gliclazide is a sulfonylurea drug used in the treatment of type 2 diabetes. Gliclazide acts on pancreatic beta-cells to stimulate insulin secretion. Under physiological conditions, insulin secretion from beta-cells is mediated by elevated glucose concentration in the blood. Glucose enters the cell via GLUT2 (SLC2A2) transporters. Once inside the cell, glucose is metabolized to produce ATP. High concentration of ATP will inhibit ATP-dependent potassium channels (ABCC8), which depolarizes the cell. Depolarization causes opening of voltage-gated calcium channels, allowing calcium to enter cell. High intracellular calcium subsequently stimulate vesicle exocytosis and insulin secretion. Gliclazide stimulates insulin secretion by directly inhibiting ATP-dependent potassium channels.


Adefovir Dipivoxil  Action Pathway,Drug Action

Adefovir dipivoxil is an ester prodrug of adefovir, a nucleotide analogue used in the treatment of chronic hepatitis B. Adefovir dipivoxil is taken up into the liver cell and is cleaved into adefovir by intracellular esterases. Adefovir is subsequently phosphorylated first by adenylate kinases and then by nucleoside diphosphate kinases into adefovir diphosphate. Adefovir diphosphate is an analogue of deoxyadenosine triphosphate (dATP) and competes with dATP for binding to the viral DNA polymerase and subsequent incorporation into the growing DNA strand. Once incorporated into the DNA, adefovir causes chain termination, thus preventing viral replication.


Tenofovir  Action Pathway,Drug Action

Tenofovir is a nucleotide analogue used in the treatment of HIV and chronic hepatitis B. It is taken up into the cell and is subsequently phosphorylated first by adenylate kinases and then by nucleoside diphosphate kinases into tenofovir diphosphate. Tenofovir diphosphate is an analogue of deoxyadenosine triphosphate (dATP) and competes with dATP for binding to the viral DNA polymerase and subsequent incorporation into the growing DNA strand. Once incorporated into the DNA, tenofovir causes chain termination, thus preventing viral replication.


Prednisone Action Pathway,Drug Action

Prednisone is a synthetic glucocorticoid that is used clinically for its anti-inflammatory properties. Prednisone is converted to the active metabolite prednisolone in the liver. Prednisolone can diffuse passively across the cell membrane, where it binds to glucocorticoid receptors in the cytoplasm. Upon binding, the glucocorticoid receptor (GR) dissociates from heat shock protein 90, and translocate into the nucleus. In the nucleus, GR dimers can bind to glucocorticoid response element (GRE) in the promoter region of anti-inflammatory genes, which activates their transcription. GRs also inhibit transcription of inflammatory mediators by binding to negative GRE (nGRE). GRs further interact with the transcription factors cAMP-responsive element binding protein and NF-kappa-B, and inihibit their activation of inflammatory gene transcription. GRs also recruit histone deacetylase 2 to inflammatory genes, which leads to DNA condensation at those loci, thus suppressing expression of those genes.


Prednisolone Action Pathway,Drug Action

Prednisolone is a synthetic glucocorticoid that is used clinically for its anti-inflammatory properties. Prednisolone diffuses passively across the cell membrane, where it binds to glucocorticoid receptors in the cytoplasm. Upon binding, the glucocorticoid receptor (GR) dissociates from heat shock protein 90, and translocate into the nucleus. In the nucleus, GR dimers can bind to glucocorticoid response element (GRE) in the promoter region of anti-inflammatory genes, which activates their transcription. GRs also inhibit transcription of inflammatory mediators by binding to negative GRE (nGRE). GRs further interact with the transcription factors cAMP-responsive element binding protein and NF-kappa-B, and inihibit their activation of inflammatory gene transcription. GRs also recruit histone deacetylase 2 to inflammatory gene loci on DNA, which leads to DNA condensation and suppression of gene expression.


Dopamine Activation of Neurological Reward System,Signaling

In the nervous system, dopamine acts as a neurotransmitter with roles in motor control, motivation, arousal, cognition, and reward. The mesolimbic pathway is the main pathway associated with reward, and the dopaminergic neurons of this pathway are found in the substantia nigra (SNc) and  ventral tegmental area (VTA) of the midbrain. Dopamine acts on different G protein-coupled receptor subtyes. The D1-class (D1 and D5) receptors stimulate cAMP production by activating adenylyl cyclase, which activates the reward pathway. The D2-class (D2, D3, and D4) subtypes act oppositely, inhibiting cAMP production by inhibiting adenylyl cyclase. The differing distributions of the receptor subtypes mean that complex outputs often produce a synergistic effect, despite the receptor subtypes having opposite molecular effects (PMID: 20925949, 21303898).


Excitatory Neural Signalling Through 5-HTR 4 and Serotonin,Protein

The 5-HT4 receptor is primarily found in the CNS, GI tract, and PNS. Peripheral receptors have important roles in the function of many organ responses (alimentary tract, urinary bladder, heart, and adrenal gland). Alimentary tract receptors have a role in smooth muscle tone, mucosal electrolyte secretion, and the peristaltic reflex. Urinary bladder receptors control cholinergic/purinergic transmission. Atrial heart receptors produce positive inotropy and tachycardia that can precipitate arrhythmias. This receptor is also thought to have roles in anxiety, appetite, GI motility, learning, memory, mood, and respiration. The 5-HT4 receptor activates G(s) proteins which lead to the activation of adenylyl cyclase which produces the secondary messenger cAMP. cAMP activates PKA (protein kinase A) which phosphorylates downstream effectors that lead to a specific cellular response.


Corticotropin Activation of Cortisol Production,Protein

Corticotropin (ACTH or adrenocorticotropic hormone) is a polypeptide tropic hormone produced and secreted by the anterior pituitary gland. It is produced from the cleavage of pre-pro-opiomelanocortin by various endopeptidases, along with other physiologically active peptide fragments such as β-lipotropin, γ-lipotropin, melanocyte stimulating hormone (MSH), and β-endorphin. It is an important component of the hypothalamic-pituitary-adrenal axis and is often produced in response to biological stress. Its principal effects are increased production of androgens and cortisol from the adrenal cortex. The ACTHR receptor activates G(s) proteins which lead to the activation of adenylyl cyclase which produces the secondary messenger cAMP. cAMP activates PKA (protein kinase A) which phosphorylates downstream effectors that lead to androgen and cortisol production.


Excitatory Neural Signalling Through 5-HTR 7 and Serotonin,Protein

The 5-HT7 receptor is primarily found in the CNS, GI tract, and blood vessels. Serotonin is the primary ligand of the 5-HT7 receptor, which activates G(s) proteins associated with the receptor and leads to the activation of adenylyl cyclase and production of the secondary messenger cyclic adenosine monophosphate (cAMP). cAMP activates protein kinase A, phosphorylating downstream effectors that lead to specific cellular responses which mediate physiological functions such as thermoregulation, circadian rhythm, learning and memory, sleep, and potentially mood.


Excitatory Neural Signalling Through 5-HTR 6 and Serotonin,Protein,The 5-HT6 receptor is primarily expressed in the brain and is involved in glutamatergic and cholinergic neuronal activity.  The 5-HT6 receptor activates G(s) proteins which lead to the activation of adenylyl cyclase which produces the secondary messenger cAMP. cAMP activates PKA (protein kinase A) which phosphorylates downstream effectors that lead to a specific cellular response.


Intracellular Signalling Through Adenosine Receptor A2a and Adenosine,Protein

A member of the G-coupled protein receptor family, the adenosine A2A receptor regulates blood flow to myocardial tissues through the action of vasodilating the coronary arteries, which can potentially lead to hypotension. The adenosine receptor A2a activates G(s) proteins which lead to the activation of adenylyl cyclase which produces the secondary messenger cAMP. cAMP activates PKA (protein kinase A) which phosphorylates downstream effectors that lead to a specific cellular response. This occurs through activation of the MAPK/ERK signaling cascade. The A2A receptor has also been demonstrated to play a role in dopamine and glutamate release in the CNS.


Intracellular Signalling Through Adenosine Receptor A2b and Adenosine,Protein,Adenosine is thought to play a role in the pathophysiology of asthma. Stimulation of A2B can induce production of interleukin-8 mast cells. The adenosine receptor A2b activates G(s) proteins which lead to the activation of adenylyl cyclase which produces the secondary messenger cAMP. cAMP activates PKA (protein kinase A) which phosphorylates down stream effectors that lead to a specific cellular response. This occurs though activation of the MAPK/ERK signaling cascade.


Vasopressin Regulation of Water Homeostasis,Protein

The vasopressin V2 receptor is found in the kidneys. It serves a role in maintaining corporal water homeostasis. Malfunction of this receptor can lead to Nephrogenic Diabetes Insipidus.Vasopressin (aka Antidiuretic hormone) activates both follicle-stimulating hormone receptor as well as the V2 receptor G protein complex. From this complex, Guanine nucleotide binding protein G(s) protein reacts with Adenylate Cyclase Type 2, Adeonsine Triphosphate, as well as GTP and magnesium to produce cAMP and Pyrophosphate. cAMP then activates PKA (protein kinase A) which leads to changes in the concentration of water in urine.


Intracellular Signalling Through FSH Receptor and Follicle Stimulating Hormone,Protein

In the ovary, the FSH receptor is necessary for follicular development and is expressed on the granulosa cells. In the male the FSH receptor has been identified on the Sertoli cells that are critical for spermatogenesis.  The FSH receptor activates G(s) proteins which lead to the activation of adenylyl cyclase which produces the secondary messenger cAMP. cAMP activates PKA (protein kinase A) which phosphorylates downstream effectors that lead to a specific cellular response.


Intracellular Signalling Through Histamine H2 Receptor and Histamine,Signaling

Histamine is an organic nitrogenous compound that is involved in local immune responses and it is a neurotransmitter for brain. Histamine can mediate various actions by interacting with histamine receptors (H1, H2, H3 and H4). The H2 receptor activates G(s) proteins which lead to the activation of adenylyl cyclase which produces the secondary messenger cAMP. cAMP activates PKA (protein kinase A) which phosphorylates downstream effectors that lead to a specific cellular response.


Intracellular Signalling Through LHCGR Receptor and Luteinizing Hormone/Choriogonadotropin,Protein

Its activation is necessary for the hormonal functioning during reproduction. LHCGRs are found in the ovary, testis, and many extragonadal tissues.In the ovary, the LHCG receptor is necessary for follicular maturation and ovulation, as well as luteal function. In the male the LHCGR has been identified on the Leydig cells that are critical for testosterone production, and support spermatogenesis. The LHCGRs receptor activates G(s) proteins which lead to the activation of adenylyl cyclase which produces the secondary messenger cAMP. cAMP activates PKA (protein kinase A) which phosphorylates downstream effectors that lead to a specific cellular response.


Intracellular Signalling Through PGD2 receptor and Prostaglandin D2,Signaling,PGD is the major prostanoid released from human mast cells upon immunological challenge. Prostaglandin D2 (PGD2) can trigger asthmatic responses by acting as a cell-derived mediator in mice. The PGD receptor activates G(s) proteins which lead to the activation of adenylyl cyclase which produces the secondary messenger cAMP. cAMP activates PKA (protein kinase A) which phosphorylates downstream effectors that lead to a specific cellular response.


Intracellular Signalling Through Prostacyclin Receptor and Prostacyclin,Signaling

Cyclooxygenase is the major producer of prostacyclin. Prostacyclin binding to its receptor increases vasodilation and decreases platelet aggregation. The receptor is a G-protein coupled receptor, upon its binding it activates G proteins causing the activation of adenylyl cyclase and production of cAMP messenger molecules. cAMP activates PKA (protein kinase A) which phosphorylates downstream effectors that lead to a specific cellular response.In vasodilation, the PKA activity causes phosphorylation of MLCK, decreasing its activity, resulting in dephosphorylation of MLC of myosin. This leads to smooth muscle relaxation resulting in vasodilation.


Fc Epsilon Receptor I Signaling in Mast Cells,Protein

Fc epsilon receptor 1 (Fc epsilon RI) is a high-affinity receptor for the Fc region of immunoglobulin E (IgE), an antibody isotope involved in allergies. The antigens of allergens bind to IgE antibodies, which then interact with Fc epsilon RIs on the surface of mast cells. This activates the mast cells and results in degranulation, a process by which preformed granules containing histamine, proteoglycans, and serine proteases, are released. Activated mast cells also synthesize and secrete lipid-derived mediators (such as prostaglandins, leukotrienes, and platelet-activating factor) and cytokines (notably tumor necrosis factor-alpha, interleukin-4, and interleukin-5). The release of these compounds results in the inflammatory response.


Insulin Signalling,Protein

Insulin is responsible for the regulation of glucose levels in the body. It stimulates the storage of energy and inhibits the breakdown of high energy metabolites. Glycogen and lipid biosynthesis are upregulated, and conversely, glycogen and fatty acid metabolism are down-regulated. Insulin also modulates transcription and translation. Binding of insulin to the insulin receptor (IR) results in the activation of its tyrosine kinase activity leading to IR autophosphorylation. IR then phosphorylates several substrates that lead to the activation of an intracellular signalling cascade. IR activation leads to the activation of H-Ras, MAPK1-3, and PI3-kinase pathways. The activation of these pathways leads to modulation of key proteins in glycogen metabolism/lipid metabolism and transcription/translation.


DNA Replication Fork,Metabolic

DNA is composed of two long and complementary strands, with a backbone on the outside and nucleotides in the middle. During replication the two strands of DNA separate; the resulting structure is called the replication fork. The replication fork forms because enzymes called helicases surround the DNA strands and break the hydrogen bonds which hold them together. The result is that two long branches, almost like fork prongs, each of which is a DNA strand. Replication of DNA has two main different processes. Because DNA is replicated in the 5' to 3' direction, and because both DNA strands in the replication fork are negative mirror images of each other, and because the replication fork is created on only one direction down the length of the DNA, two types of replication strands are formed: the leading and the lagging strand. These strands are so named by the way in which DNA polymerase reads the original DNA strand and attaches the complementary nucleotides as it makes its way along the chain. Because the direction of the movement of the replication fork, and the direction of the addition of nucleotides in the leading strand is the same, the process is continuous.That is, a polymerase is able to read the DNA and add the matching nucleotide bases to it continuously. In prokaryotes DNA polymerase III is responsible for creating the leading strand. The lagging strand is oriented in the opposite direction to the leading strand. Thus, replication of the lagging strand occurs in the opposing direction to that of the leading strand and the replication fork. As a result, replication of the lagging strand is a slower and more complicated process than that of the leading strand. Thus it is seen to lag behind the leading strand (hence the name).


Nucleotide Excision Repair ,Metabolic

In order to pass genetic information from one generation to the next, all organisms must accurately replicate their genomes during each cell division. This includes the nuclear genome and mitochondrial and chloroplast genomes. These are normally replicated with high fidelity that is achieved through the action of accurate DNA repair. Nucleotide Excision Repair is one os several mechanisms of DNA repair.  Nucleotide excision repair (NER) operates on base damage caused by exogenous agents (such as mutagenic and carcinogenic chemicals and photoproducts generated by sunlight exposure) that cause alterations in the chemistry and structure of the DNA duplex . Such damage is recognized by a protein called XPC, which is stably bound to another protein called HHRAD23B (R23). The binding of the XPC–HHRAD23 heterodimeric subcomplex is followed by the binding of several other proteins (XPA, RPA, TFIIH and XPG). Of these, XPA and RPA are believed to facilitate specific recognition of base damage. TFIIH is a subcomplex of the RNA polymerase II transcription initiation machinery which also operates during NER. It consists of six subunits and contains two DNA helicase activities (XPB and XPD) that unwind the DNA duplex in the immediate vicinity of the base damage. This local denaturation generates a bubble in the DNA, the ends of which comprise junctions between duplex and single-stranded DNA. The subsequent binding of the ERCC1–XPF heterodimeric subcomplex generates a completely assembled NER multiprotein complex. XPG is a duplex/single-stranded DNA endonuclease that cuts the damaged strand at such junctions 3’ to the site of base damage. Conversely, the ERCC1–XPF heterodimeric protein is a duplex/single-stranded DNA endonuclease that cuts the damaged strand at such junctions 5’ to the site of base damage. This bimodal incision generates an oligonucleotide fragment 27–30 nucleotides in length which includes the damaged base. This fragment is excised from the genome, concomitant with restoring the potential 27–30 nucleotide gap by repair synthesis. Repair synthesis requires DNA polymerases or , as well as the accessory replication proteins PCNA, RPA and RFC. The covalent integrity of the damaged strand is then restored by DNA ligase. Collectively, these biochemical events return the damaged DNA to its native chemistry and configuration. ERCC1, excision repair cross-complementing 1; PCNA, proliferating cell nuclear antigen; POL, polymerase; RFC, replication factor C; RPA, replication protein A; TFIIH, transcription factor IIH; XP, xeroderma pigmentosum.


Dimethylglycine Dehydrogenase Deficiency (DMGDH deficiency; Dimethylglycinuria) phenotype in the catabolism of choline, catalyzing the oxidative demethylation of dimethylglycine (DMG) to form sarcosine. A defect in DMGDH results in the accumulation of N,N-dimethylglycine and creatinine kinase in serum, and N,N-dimethylglycine in urine. Symptoms of this disease include an unusual odor and muscle weakness.


DOPA-Responsive Dystonia,Disease

Dopa-responsive dystonia is a disorder that involves involuntary muscle contractions, tremors, and other uncontrolled movements (dystonia). The features of this condition range from mild to severe. This form of dystonia is called dopa-responsive dystonia because the signs and symptoms typically improve with sustained use of a medication known as L-Dopa. Over time, affected individuals often develop a group of movement abnormalities called parkinsonism. These abnormalities include unusually slow movement (bradykinesia), muscle rigidity, tremors, and an inability to hold the body upright and balanced (postural instability). Mutations in the GCH1 gene are the most common cause of dopa-responsive dystonia. Less often, mutations in the TH or SPR gene cause this condition.


Hyperphenylalaninemia Due to Guanosine Triphosphate Cyclohydrolase Deficiency,Disease

Hyperphenylalaninemia is the high presence of phenylalanine in the system/blood caused by a genetic mutation. In this case a missense error in the gene which encodes GTP cyclohydrolase. Consequently, this form of hyperphenylalaninemia is also called GTP cyclohydrolase I deficiency and/or dopa-responsive dystonia. It is an autosomal recessive mutation.The mutation results in a reduction in the production of BH4 which is a necessary component in the reaction which transforms phenylalanine to other products in the body.Common symptoms include: abnormality of eye mpvement, choreoathetosis, dysphagia, dystonia, excessive salivation, hypekinesis, lethargy, limb hyptertonia, seizures, tremor, among others.


Hyperphenylalaninemia Due to 6-Pyruvoyltetrahydropterin Synthase Deficiency (ptps),Disease

BH4-deficient hyperphenylalaninemia has several causes. One such cause is a PTS deficiency resultant from a genetic mutation. (In particular, a mutation in the gene encoding 6-pyruvoyl-tetrahydropterin synthase.)  The mutation is autosomal recessive. Common symptoms include: muscular hypotonia, ataxia, bradykinesia, choreoathetosis, depressivity, dysphagia, hyperkinesis, hypsarrhythmia, myoclonus, and others. BH4 is a cofactor involved in many things and associated with neurotransmitter synthesis. In short, the reduction of levels of BH4 creates issues in the metabolism of phenylalanine. This cascade of reactions produces the aforementioned symptoms.


Hyperphenylalaninemia Due to DHPR-Deficiency,Disease

Hyperphenylalaninemia due to dihydropteridine reductase deficiency (DHPR) is the high presence of phenylalanine in the system/blood caused by a genetic mutation. More specificially, mutations in the QDPR gene are the root cause of the condition. One observes that such a mutation results in an error encoding a reductase enzyme, and from there a chain reaction of effects lead to the observed effects of the disease. The mutation is autosomal recessive. When tetrahydrobiopterin levels drop, the breakdown of many several amino acids, such as phenylalanine, is reduced and as a result their levels in the blood augment. Symptoms of hyperphenylalaninemia due to dihydropteridine reductase deficiency include: dysphagia, global development delay, microcephaly, and intellectual disability (among others). Treatment consists of BH4 supplements as well as other medical treatments.


Segawa Syndrome,Disease

Dopa-responsive dystonia (autosomal dominant Segawa syndrome) is caused by heterozygous mutation in the gene encoding GTP cyclohydrolase I. GTP cyclohydrolase I is rate-limiting in the conversion of GTP to tetrahydrobiopterin (BH4), the cofactor for tyrosine hydroxylase, which in turn is the rate-limiting enzyme for dopamine synthesis. Patients are characterized by childhood onset dystonia of the legs, progressing to parkinsonism and pseudo-pyramidal deficits, or in adult life with parkinsonism and pseudo-pyramidal signs.  Treatment with levodopa typically resolves the symptoms.


Sepiapterin reductase deficiency results from a metabolic disorder; namely, the underproduction of Sepiapterin. The cause of this underproduction is an autosomal recessive genetic mutation in the SPR gene. This gene is responsible for Sepiapterin production, and naturally, when the gene malfunctions the production of this metabolite is altered leading to a range of effects on the body. In this case, some symptoms of Sepiapterin Deficiency are: motor and speech delay, axial hypotonia, dystonia, weakenss microcephaly, dysarthria, autonomic dysfunction, oculogyric crises, drowsiness, among others.


Galactosemia II (GALK),Disease,Galactokinase deficiency or Galactosemia type II is caused by mutation in the GALK1 gene on chromosome 17q24. Galactokinase deficiency is an autosomal recessive disorder which causes cataract formation in children not maintained on a lactose-free diet. Cataract formation is the result of osmotic phenomena caused by the accumulation of galactitol in the lens.


Galactosemia III,Disease

Galactosemia III (GALE deficiency or UDP-Galactose-4-Epimerase deficiency) is caused by homozygous or compound heterozygous mutation in the UDP-galactose-4-epimerase gene (GALE).  Patients with GALE deficiency may be at increased risk for cataracts. Patients also exhibit symptoms similar to classic galactosemia, including jaundice, vomiting, hypotonia, failure to thrive, hepatomegaly, moderate generalized amino aciduria and marked galactosuria. Although a galactose-free diet is recommended in galactokinase deficiency and in classic galactosemia patients with galactose epimerase deficiency cannot utilize the endogenous pathway for synthesis of UDP-galactose, making them dependent on exogenous galactose; thus, a galactose-restricted rather than a galactose-free diet is recommended in the management of this disorder.


Tyrosine Hydroxylase Deficiency,Disease

Mutations in the Tyrosine hydroxylase (TH) gene cause TH deficiency. The TH gene provides instructions for making the enzyme tyrosine hydroxylase, which takes part in the pathway that produces a group of chemical messengers called catecholamines, namely dopamine, norepinephrine and epinephrine. Dopamine transmits signals to help the brain control physical movement and emotional behavior. Norepinephrine and epinephrine are involved in the autonomic nervous system. Mutations in the TH gene result in reduced activity of the tyrosine hydroxylase enzyme. As a result, the body produces less dopamine, norepinephrine and epinephrine. These catecholamines are necessary for normal nervous system function, and changes in their levels contribute to the abnormal movements, autonomic dysfunction, and other neurological problems seen in people with TH deficiency.


Dopamine beta-hydroxylase deficiency (or norepinephrine deficiency) is caused by mutation in the gene encoding dopamine beta-hydroxylase. Clinical features include orthostatic hypotension, ptosis, nasal stuffiness, and a neonatal history of delayed eye opening. Noradrenaline and adrenaline are generally not detectable in plasma, urine, and cerebrospinal fluid, but dopamine is increased 7- to 12-fold in plasma, 4-fold in urine, and 20-fold in CSF. Treatment with dihydroxyphenylserine has been shown to reduce symptoms and signs of postural hypotension and increase plasma levels of noradrenaline.


Metcaptolactate-cysteine disulfiduria (MCDU) is an autosomal disorder that leads to the loss of function of the enzyme mercaptopyruvate sulfurtransferase. The condition is characterized by the urinary excretion of large amounts of a sulfur-containing amino acid, which is beta-mercaptolactate-cysteine disulfide. Patients exhibit a low IQ, grand mal seizures, flattened nasal bridge, and an excessively arched palate.


5-Oxoprolinase Deficiency,Disease,5-oxoprolinase deficiency can be caused by heterozygous or homozygous mutation in the OPLAH gene (5-Oxoprolinase).  Patients are relatively asymptomatic but they do exhibit high levels of urinary excretion of 5-oxoproline. Patients also exhibit plasma 5-oxoproline levels of about 0.18 mM or higher.  Patients tend to exhibit transient hypoglycemia.


Gamma-glutamyltranspeptidase deficiency is characterized by glutathionemia and glutathionuria. Gamma-glutamyltranspeptidase acts as a glutathionase and catalyzes the transfer of the glutamyl moiety of glutathione to a variety of amino acids and dipeptide acceptors. Patients with this disorder may exhibit mild mental retardation, asthma and easy bruising.


Malonyl CoA decarboxylase deficiency is an autosomal disorder is caused by mutation in the malonyl-CoA decarboxylase gene. The characteristic phenotype of this condition is quite variable, but may include developmental delay in early childhood, seizures, hypotonia, diarrhea, vomiting, metabolic acidosis, hypoglycemia, ketosis, abnormal urinary compounds, lactic acidemia, and hypertrophic cardiomyopathy.


Hypophosphatasia,Disease

Infantile hypophosphatasia is caused by homozygous or compound heterozygosity mutation in the gene encoding tissue-nonspecific alkaline phosphatase. It is an inborn error of metabolism characterized clinically by defective bone mineralization that can be fatal early in infancy.  Three more or less distinct types can be identified: (1) type 1 with onset in utero or in early postnatal life, craniostenosis, severe skeletal abnormalities, hypercalcemia, and death in the first year or so of life; (2) type 2 with later, more gradual development of symptoms, moderately severe 'rachitic' skeletal changes and premature loss of teeth; (3) type 3 with no symptoms, the condition being determined on routine studies. Heterozygotes excrete phosphoethanolamine in the urine and suffer early loss of teeth. Serum and urinary phosphoethanolamine are typically elevated and serum pyridoxal-PO4 concentrations are often markedly elevated.


Hyperornithinemia with Gyrate Atrophy (HOGA),Disease

Gyrate atrophy of the choroid and retina (also called Gyrate atrophy, OAT deficiency, ornithine aminotransferase deficiency, ornithine keto acid aminotransferase deficiency) is an autosomal recessive disorder caused by homozygous or compound heterozygous mutation in the OAT gene (Ornithine aminotransferase).  It is clinically characterized by progressive chorioretinal degeneration, early cataract formation, and type II muscle fiber atrophy.  Ornithine levels are typically 10 to 20 times higher than normal in plasma, urine, spinal fluid, and aqueous humor.  Some cases of OAT deficiency are vitamin B6 (pyridoxine) -responsive.


Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome is an autosomal recessive disorder caused by a mutation in the SLC25A15 gene, which encodes the mitochondrial ornithine transporter. It is clinically characterized by mental retardation, spastic paraparesis and myoclonic seizures associated with hyperornithinemia, hyperammonemia, and homocitrullinemia. Ornithine supplementation and restricted protein intake appears to be useful in the treatment of HHH syndrome.


Arginine:glycine amidinotransferase deficiency is an inherited disorder that primarily affects the brain. People with this disorder have mild to moderate intellectual disability and delayed speech development. Some affected individuals develop autistic behaviors that affect communication and social interaction. They may experience seizures, especially when they have a fever. Children with arginine:glycine amidinotransferase deficiency may not gain weight and grow at the expected rate (failure to thrive), and have delayed development of motor skills such as sitting and walking. Affected individuals may also have weak muscle tone and tend to tire easily.


Cholesteryl Ester Storage Disease,Disease

Lysosomal acid lipase deficiency (also known as LIPA deficiency or cholesteryl ester storage disease [CESD] or Wolman disease) is an autosomal recessive disorder caused by homozygous or compound heterozygous mutations in the LIPA gene (lysosomal acid lipase) on chromosome 10q24-q25.  Wolman disease is an early-onset fulminant disorder of infancy with massive infiltration of the liver, spleen, and other organs by macrophages filled with cholesteryl esters and triglycerides.  Death occurs early in life.  CESD is a milder, later-onset disorder with primary hepatic involvement by macrophages engorged with cholesteryl esters.  This slowly progressive visceral disease has a very wide spectrum of involvement ranging from early onset with severe cirrhosis to later onset of more slowly progressive hepatic disease with survival into adulthood.


Hyper-IgD Syndrome,Disease

Hyperimmunoglobulinemia D with recurrent fever (commonly abbreviated as HIDS) is a periodic fever syndrome originally described in 1984 by the internist Prof. Jos van der Meer, then at Leiden University Medical Centre. No more than 300 cases have been described worldwide. HIDS is one of a number of periodic fever syndromes. It is characterised by attacks of fever, arthralgia, skin lesions including cyclical mouth ulcers, and diarrhea. Laboratory features include an acute phase response (elevated CRP and ESR) and markedly elevated IgD (and often IgA), although cases with normal IgD have been described. (Wikipedia)


Mevalonic Aciduria,Disease

Mevalonate kinase deficiency is a condition characterized by recurrent episodes of fever, which typically begin during infancy. Each episode of fever lasts about 3 to 6 days, and the frequency of the episodes varies among affected individuals. In childhood the fevers seem to be more frequent, occurring as often as 25 times a year, but as the individual gets older the episodes occur less often. Mevalonate kinase deficiency has additional signs and symptoms, and the severity depends on the type of the condition. There are two types of mevalonate kinase deficiency: a less severe type called hyperimmunoglobulinemia D syndrome (HIDS) and a more severe type called mevalonic aciduria (MVA).


Wolman Disease,Disease

In Wolman's disease excessive amounts of cholesterol ester in the liver are present mainly in the macrophages of the reticuloendo- thelial system. The livler in Wiolman's disease contains triglyceride at 10 to 20 times the normal concentratlon, most of whilch is present in hepatocytes. The first case of Wolman's disease was published in 1956 by M. Wolman, M.D., reporting a case of a 2 month old girl who had been admitted to the Hadassah University Hospital. Lysosomal   acid   lipase/acid   cholesteryl   ester   hydrolase (LAL/ACEH) plays an important role in cellular processing of plasma lipoproteins and thus contributes to both the homeostatic control of plasma lipoprotein levels and the prevention of cellular lipid overload. Wolman's Disease results from severely reduced levels of the enzyme lysosomal   acid   lipase/acid   cholesteryl   ester   hydrolase.


Xanthinuria Type I,Disease

Xanthinuria Type I is a condition caused by an autosomal recessive mutation. The condition was discovered (though not diagnosed) in 1817, when stones formed of almost pure xanthine were first identified by Marcet. The symptoms arise because of a malfunction in the production of xanthine oxidase. It is a rare . It is characterized by a loss of oxidase  such as in serum and the uric acid found in peepee. As a result, the opposite is true for the presence of xanthine and hypoxanthine. They will be found in the latter and former in increased quantities. Although the condition can cause a wide range of symptoms including renal xanthine stones, what occurs most of the time is that xanthinuria is asymptomatic and diagnosis is product of chance.


Xanthinuria Type II,Disease

Xanthinuria, also known as xanthine oxidase deficiency, is a rare genetic disorder causing the accumulation of xanthine. It is caused by a deficiency of the enzyme xanthine oxidase. Classic xanthinuria is a rare metabolic defect concerning the final reactions of purine catabolism. There are two types of the disorder: type I results from xanthine dehydrogenase (XDH) deficiency, while type II is characterized by lack of both XDH and aldehyde oxidase activity. Both types are clinically similar and are characterized by elevated xanthine concentration in body fluids that can lead to xanthine crystallisation. The most common manifestation of the disease is urolithiasis, but in most cases xanthinuria remains asymptomatic and the diagnosis is accidental.


Cystathioninuria, also called cystathionase deficiency, is an autosomal recessive metabolic disorder that results in an excess of cystathionine in the urine. It is associated with a congenital dysfunction of the enzyme cystathionase, or acquired deficiency of vitamin B6 which is essential for the function of this enzyme. The latter is usually related to an overall deficiency of all the B-complex vitamins.


Carnitine-acylcarnitine translocase (CACT) deficiency is a condition that prevents the body from using certain fats for energy, particularly during periods without food (fasting). Signs and symptoms of this disorder usually begin soon after birth and may include breathing problems, seizures, and an irregular heartbeat (arrhythmia). Affected individuals typically have low blood sugar (hypoglycemia) and a low level of ketones, which are produced during the breakdown of fats and used for energy. Together these signs are called hypoketotic hypoglycemia. People with CACT deficiency also usually have excess ammonia in the blood (hyperammonemia), an enlarged liver (hepatomegaly), and a weakened heart muscle (cardiomyopathy). Many infants with CACT deficiency do not survive the newborn period. Some affected individuals have a less severe form of the condition and do not develop signs and symptoms until early childhood. These individuals are at risk for liver failure, nervous system damage, coma, and sudden death.


Glucose-6-phosphate dehydrogenase deficiency is a genetic disorder that occurs most often in males. This condition mainly affects red blood cells, which carry oxygen from the lungs to tissues throughout the body. In affected individuals, a defect in an enzyme called glucose-6-phosphate dehydrogenase causes red blood cells to break down prematurely. This destruction of red blood cells is called hemolysis. The most common medical problem associated with glucose-6-phosphate dehydrogenase deficiency 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, fatigue, shortness of breath, and a rapid heart rate. In people with glucose-6-dehydrogenase deficiency, hemolytic anemia is most often triggered by bacterial or viral infections or by certain drugs (such as some antibiotics and medications used to treat malaria). Hemolytic anemia can also occur after eating fava beans or inhaling pollen from fava plants (a reaction called favism). Glucose-6-dehydrogenase deficiency is also a significant cause of mild to severe jaundice in newborns. Many people with this disorder, however, never experience any signs or symptoms.


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,Disease

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,Disease,3-Hydroxyisobutyric aciduria  (3-hydroxyisobutyric acid dehydrogenase deficiency) is a rare entity and affected individuals display a range of clinical manifestations including dysmorphic features and neurodevelopmental problems in the majority of patients.


3-Hydroxyisobutyric Aciduria,Disease

3-Hydroxyisobutyric aciduria, a disorder of valine metabolism, has been found in a boy in whom the clinical picture was that of a typical organic acidemia with repeated episodes of ketoacidosis requiring admission to hospital and parenteral fluid therapy, along with impressive failure to thrive and chronic lactic acidemia. The excretion of 3-hydroxyisobutyric acid ranged from 170 to 390 mmol/mol of creatinine. The administration of valine increased this to 18,700 mmol/mol of creatinine and reproduced the clinical picture of ketoacidosis. Concentrations of free carnitine were low, and esterified carnitine was elevated. Treatment with carnitine and a diet restricted in protein appeared to be beneficial.


Isobutyryl-CoA dehydrogenase (IBD) deficiency is a condition that disrupts the breakdown of certain proteins. Normally, proteins from food are broken down into parts called amino acids. Amino acids can be further processed to provide energy for growth and development. People with IBD deficiency have inadequate levels of an enzyme that helps break down a particular amino acid called valine. Most people with IBD deficiency are asymptomatic, which means they do not have any signs or symptoms of the condition. A few children with IBD deficiency have developed features such as a weakened and enlarged heart (dilated cardiomyopathy), weak muscle tone (hypotonia), and developmental delay. This condition may also cause low numbers of red blood cells (anemia) and very low blood levels of carnitine, which is a natural substance that helps convert certain foods into energy. The range of signs and symptoms associated with IBD deficiency remains unclear because very few affected individuals have been reported.


Isovaleric Acidemia,Disease

Isovaleric acidemia is a rare disorder in which the body is unable to process certain proteins properly. It is classified as an organic acid disorder, which is a condition that leads to an abnormal buildup of particular acids known as organic acids. Abnormal levels of organic acids in the blood (organic acidemia), urine (organic aciduria), and tissues can be toxic and can cause serious health problems. Mutations in the IVD gene cause isovaleric acidemia.


Fabry Disease,Disease

Fabry disease is an inherited disorder that results from the buildup of a particular type of fat, called globotriaosylceramide, in the body's cells. Beginning in childhood, this buildup causes signs and symptoms that affect many parts of the body. Characteristic features of Fabry disease include episodes of pain, particularly in the hands and feet (acroparesthesias); clusters of small, dark red spots on the skin called angiokeratomas; a decreased ability to sweat (hypohidrosis); cloudiness of the front part of the eye (corneal opacity); problems with the gastrointestinal system; ringing in the ears (tinnitus); and hearing loss. Fabry disease also involves potentially life-threatening complications such as progressive kidney damage, heart attack, and stroke. Some affected individuals have milder forms of the disorder that appear later in life and affect only the heart or kidneys. Fabry disease is caused by mutations in the GLA gene.


Krabbe Disease,Disease

Krabbe disease (also called globoid cell leukodystrophy) is a degenerative disorder that affects the nervous system. It is caused by the shortage (deficiency) of an enzyme called galactosylceramidase. This enzyme deficiency impairs the growth and maintenance of myelin, the protective covering around certain nerve cells that ensures the rapid transmission of nerve impulses. Krabbe disease is part of a group of disorders known as leukodystrophies, which result from the loss of myelin (demyelination). This disorder is also characterized by the abnormal presence of globoid cells, which are globe-shaped cells that usually have more than one nucleus. The symptoms of Krabbe disease usually begin before the age of 1 year (the infantile form). Initial signs and symptoms typically include irritability, muscle weakness, feeding difficulties, episodes of fever without any sign of infection, stiff posture, and slowed mental and physical development. As the disease progresses, muscles continue to weaken, affecting the infant's ability to move, chew, swallow, and breathe. Affected infants also experience vision loss and seizures.


Hyperlysinemia II or Saccharopinuria,Disease

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 Acidura,Disease

D-glyceric aciduria is a rare inborn error of serine and fructose metabolism that was first described in 1974. Most affected individuals have presented with neurological symptoms. The molecular basis of D-glyceric aciduria is largely unknown; possible causes that have been discussed are deficiencies of D-glycerate dehydrogenase, triokinase, and D-glycerate kinase. In 1989, van Schaftingen has reported decreased D-glycerate kinase activity in the liver of a single patient with D-glyceric aciduria. Mutations in the GLYCTK gene are reported to be the cause of D-glycerate kinase deficiency.


Familial Lipoprotein Lipase Deficiency,Disease

Hyperlipidemia, hyperlipoproteinemia, or hyperlipidaemia (British English) involves abnormally elevated levels of any or all lipids and/or lipoproteins in the blood. It is the most common form of dyslipidemia (which also includes any decreased lipid levels). Hyperlipidemias are divided in primary and secondary subtypes. Primary hyperlipidemia is usually due to genetic causes (such as a mutation in a receptor protein), while secondary hyperlipidemia arises due to other underlying causes such as diabetes. Lipid and lipoprotein abnormalities are common in the general population, and are regarded as a modifiable risk factor for cardiovascular disease due to their influence on atherosclerosis. In addition, some forms may predispose to acute pancreatitis.


Sulfite Oxidase Deficiency,Disease

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.


Monoamine Oxidase-A Deficiency (MAO-A),Disease

Momoamine oxidase A (MAO-A) deficiency, or Brunner syndrome, is an X-linked recessive genetic disorder caused by a mutation in the MAOA gene that encodes for monoamine oxidase A. As such it is almost exclusively found in men.MAO-A is an enzyme that catalyzes the deamination of amines such as epinephrine, dopamine and tyramine, as part of the tyrosine metabolism pathway. In this disorder, some neurotransmitters such as serotonin and dopamine build up in the brain due to their inability to be properly metabolized. Since serotonin helps to regulate emotions and mood, with epinephrine and norepinephrine regulating stress, the unnecessary presence of the chemicals in the brain can lead to poor impulse control, aggression and other effects. The buildup of chemicals may also damage the brain, leading to a lower IQ in individuals with this disorder. In addition, foods containing the compounds that cannot be broken down, such as tyramine, can cause episodes of increased symptoms in the patients.In the subpathway that converts dopamine to homovanillic acid, there are two instances of MAO-A that are inactivated in this disorder, both in different branches. The first reaction converts dopamine to 3,4-dihydroxyphenylacetaldehyde, while the second converts 3-methoxytyramine to homovanillin. With the inactivation of MAO-A, 3-methoxytyramine builds up as there are no reactions that use it, and both of these paths lead to a decrease in the concentration of homovanillic acid, as there are no other reactions present that produce it. Another reaction, this time converting tyramine to homovanillin, is also prevented by the lack of MAO-A, which leads to an accumulation of tyramine in the body.In another branch of tyrosine metabolism, the absence of MAO-A prevents the oxidation of norepinephrine and epinephrine into 3,4-dihydroxymandelaldehyde. Its absence also prevents the oxidative deamination of metanephrine and normetanephrine into 3-methoxy-4-hydroxyphenylglycolaldehyde. As this is no longer produced, it leads to a decrease in the concentration of vanillylmandelic acid, which is produced from 3-methoxy-4-hydroxyphenylglycolaldehyde in a reaction catalyzed by aldehyde dehydrogenase.


Adenine Phosphoribosyltransferase Deficiency (APRT),Disease

Adenine phosphoribosyltransferase (APRT) deficiency is an inherited condition that affects the kidneys and urinary tract. The most common feature of this condition is recurrent kidney stones; urinary tract stones are also a frequent symptom. Kidney and urinary tract stones can create blockages in the urinary tract, causing pain during urination and difficulty releasing urine.


Mitochondrial DNA Depletion Syndrome,Disease

Mitochondrial DNA depletion syndromes are a group of autosomal recessive disorders. They are characterized by decreased levels of mitochondrial DNA (mtDNA), resulting in decreased energy production. Mitochondrial DNA depletion syndrome-3 is caused by a mutation in the gene coding for deoxyguanosine kinase (DGUOK). DGUOK aids in maintaining the levels of available deoxyguanosine triphosphate (dGTP), thus the deficiency of DGUOK impairs the synthesis of dGTP. Symptoms of DGUOK deficiency can arise in the form of a multi-system disease in neonates or an isolated hepatic disease in infancy, with the former being more common. The most common cause of death in both forms is progressive hepative disease.


Adenosine monophosphate (AMP) deaminase deficiency is a condition that can affect the muscles used for movement (skeletal muscles). People with this condition do not make enough of an enzyme called AMP deaminase. In most people, AMP deaminase deficiency does not cause any symptoms. People who do experience symptoms typically have muscle pain (myalgia) or weakness after exercise or prolonged physical activity. They often get tired more quickly and stay tired longer than would normally be expected. Some affected individuals have more severe symptoms, but it is unclear whether these symptoms are due solely to a lack of AMP deaminase or additional factors. Muscle weakness is typically apparent beginning in childhood or early adulthood. Researchers have proposed three types of AMP deaminase deficiency, which are distinguished by their symptoms and genetic cause.


Carnitine Palmitoyl Transferase Deficiency I,Disease

Carnitine palmitoyltransferase I (CPT I) deficiency is a condition that prevents the body from using certain fats for energy, particularly during periods without food (fasting). The severity of this condition varies among affected individuals. Signs and symptoms of CPT I deficiency often appear during early childhood. Affected individuals usually have low blood sugar (hypoglycemia) and a low level of ketones, which are produced during the breakdown of fats and used for energy. Together these signs are called hypoketotic hypoglycemia. People with CPT I deficiency can also have an enlarged liver (hepatomegaly), liver malfunction, and elevated levels of carnitine in the blood. Carnitine, a natural substance acquired mostly through the diet, is used by cells to process fats and produce energy. Individuals with CPT I deficiency are at risk for nervous system damage, liver failure, seizures, coma, and sudden death. Mutations in the CPT1A gene cause CPT I deficiency.


Long Chain Acyl-CoA Dehydrogenase Deficiency (LCAD),Disease

Very Long Chain Acyl CoA Dehydrogenase Deficiency (VLCADD) is a rare disorder that is inherited through an autosomal recessive trait, and prevents the body from properly metabolizing very long chain fatty acids. This disorder occurs in the mitochondria, where the metabolization of fatty acids takes place. Early-onset VLCADD patients usually begin to exhibit symptoms just days or weeks after birth. Hypoglycemia, lethargy and irritability are symptoms associated with this disorder. Patients will also be at risk for hypertrophic cardiomyopathy and other heart conditions from age two months to two years. It can be diagnosed through a research of family history and generally a urine analysis will reveal that the patient has reduced of absent ketone bodies. To help control acute episodes, treatment includes maintaining a high carbohydrate and low fat diet, and avoiding fasting for more than 12 hours.


Very-Long-Chain Acyl-CoA Dehydrogenase Deficiency (VLCAD),Disease

Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency is a condition that prevents the body from converting certain fats to energy, particularly during periods without food (fasting). Signs and symptoms of VLCAD deficiency typically appear during infancy or early childhood and can include low blood sugar (hypoglycemia), lack of energy (lethargy), and muscle weakness. Affected individuals are also at risk for serious complications such as liver abnormalities and life-threatening heart problems. When symptoms begin in adolescence or adulthood, they tend to be milder and usually do not involve the heart. Problems related to VLCAD deficiency can be triggered by periods of fasting, illness, and exercise. This disorder is sometimes mistaken for Reye syndrome, a severe disorder that may develop in children while they appear to be recovering from viral infections such as chicken pox or flu. Most cases of Reye syndrome are associated with the use of aspirin during these viral infections.


Carnitine Palmitoyl Transferase Deficiency II,Disease

Carnitine palmitoyltransferase II (CPT II) deficiency is a disorder of long-chain fatty-acid oxidation. The three clinical presentations are: lethal neonatal form, severe infantile hepatocardiomuscular form, and myopathic form that is usually mild and can manifest from infancy to adulthood. While the former two are severe multisystemic diseases characterized by liver failure with hypoketotic hypoglycemia, cardiomyopathy, seizures, and early death, the latter is characterized by exercise-induced muscle pain and weakness, sometimes associated with myoglobinuria. The myopathic form of CPT II deficiency is the most common disorder of lipid metabolism affecting skeletal muscle and is the most frequent cause of hereditary myoglobinuria. Males are more likely to be affected than females.


Medium Chain Acyl-CoA Dehydrogenase Deficiency (MCAD),Disease

Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is a condition that prevents the body from converting certain fats to energy, particularly during periods without food (fasting). Signs and symptoms of MCAD deficiency typically appear during infancy or early childhood and can include vomiting, lack of energy (lethargy), and low blood sugar (hypoglycemia). In rare cases, symptoms of this disorder first appear during adulthood. People with MCAD deficiency are at risk for serious complications such as seizures, breathing difficulties, liver problems, brain damage, coma, and sudden death.Problems related to MCAD deficiency can be triggered by periods of fasting or by illnesses such as viral infections. This disorder is sometimes mistaken for Reye syndrome, a severe disorder that may develop in children while they appear to be recovering from viral infections such as chicken pox or flu. Most cases of Reye syndrome are associated with the use of aspirin during these viral infections.


Methylenetetrahydrofolate Reductase Deficiency (MTHFRD),Disease

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 (LCHAD),Disease

Long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency is a rare condition that prevents the body from converting certain fats to energy, particularly during periods without food (fasting). Signs and symptoms of LCHAD deficiency typically appear during infancy or early childhood and can include feeding difficulties, lack of energy (lethargy), low blood sugar (hypoglycemia), weak muscle tone (hypotonia), liver problems, and abnormalities in the light-sensitive tissue at the back of the eye (retina). Later in childhood, people with this condition may experience muscle pain, breakdown of muscle tissue, and a loss of sensation in their arms and legs (peripheral neuropathy). Individuals with LCHAD deficiency are also at risk for serious heart problems, breathing difficulties, coma, and sudden death. Problems related to LCHAD deficiency can be triggered by periods of fasting or by illnesses such as viral infections. This disorder is sometimes mistaken for Reye syndrome, a severe disorder that may develop in children while they appear to be recovering from viral infections such as chicken pox or flu. Most cases of Reye syndrome are associated with the use of aspirin during these viral infections. Mutations in the HADHA gene cause LCHAD deficiency.


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,Disease

Mitochondrial DNA depletion syndrome-9 is a severe autosomal recessive disorder characterized by infantile onset of hypotonia, lactic acidosis, severe psychomotor retardation, progressive neurologic deterioration, and excretion of methylmalonic acid. Some patients die in early infancy (summary by Rouzier et al., 2010).


Fumarase Deficiency,Disease

Fumarase deficiency (or fumaric aciduria), also known as "Polygamist Down's", is an autosomal recessive metabolic disorder characterized by a deficiency of the enzyme fumarate hydratase, which is indicated by a build up of fumaric acid in the urine. (Wikipedia) Fumarase deficiency is a severe autosomal recessive metabolic disorder characterized by early-onset hypotonia, profound psychomotor retardation, and brain abnormalities, such as agenesis of the corpus callosum, gyral defects, and ventriculomegaly. Many patients show neonatal distress, metabolic acidosis, and/or encephalopathy (summary by Kerrigan et al., 2000 and Mroch et al., 2012).


Mitochondrial Complex II Deficiency,Disease

Mitochondrial complex II deficiency is a rare form of mitochondrial disease, accounting for approximately 2% of all respiratory chain deficiency diagnoses. The succinate dehydrogenase (SDH) genes (SDHA, SDHB, SDHC and SDHD) are autosomally-encoded and transcribe the conjugated heterotetramers of complex II via the action of two known assembly factors (SDHAF1 and SDHAF2). Only a handful of reports describe inherited SDH gene defects as a cause of paediatric mitochondrial disease, involving either SDHA (Leigh syndrome, cardiomyopathy) or SDHAF1 (infantile leukoencephalopathy). However, all four SDH genes, together with SDHAF2, have known tumour suppressor functions, with numerous germline and somatic mutations reported in association with hereditary cancer syndromes, including paraganglioma and pheochromocytoma.


2-Ketoglutarate Dehydrogenase Complex Deficiency,Disease

2-Ketoglutarate dehydrogenase complex deficiency is a rare autosomal recessive disease. 2-ketoglutarate dehydrogenase is an enzyme of the Krebs cycle that catalyzes the oxidation of alpha-ketoglutarate to succinyl CoA. The deficiency of 2-Ketoglutarate dehydrogenase complex results in the disorder of Krebs cycle with accumulation of succinyl CoA. The primary manifestations include developmental delay, ataxia, opisthotonus, seizure and other neurological symptoms.


Pyruvate Dehydrogenase Deficiency (E3),Disease

DLD deficiency is an autosomal recessive metabolic disorder characterized biochemically by a combined deficiency of the branched-chain alpha-keto acid dehydrogenase complex (BCKDC), pyruvate dehydrogenase complex (PDC), and alpha-ketoglutarate dehydrogenase complex (KGDC). This is the result of E3 being a common component of all 3 mitochondrial multienzyme complexes. Clinically, affected individuals have lactic acidosis and neurologic deterioration due to sensitivity of the central nervous system to defects in oxidative metabolism. E3 deficiency is often associated with increased urinary excretion of alpha-keto acids, such as pyruvate (summary by Hong et al., 1996). E3 deficiency can also be associated with increased concentrations of branched-chain amino acids, as observed in maple syrup urine disease (MSUD; 248600), and is sometimes referred to as 'MSUD type III,' although patients with E3 deficiency have additional biochemical defects (Chuang and Shih, 2001; Robinson, 2001).


Pyruvate Dehydrogenase Deficiency (E2),Disease

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 Synthetase Deficiency,Disease

Glycogen storage disease (GSD, also glycogenosis and dextrinosis) is the result of defects in the processing of glycogen synthesis or breakdown within muscles, liver, and other cell types.[1] GSD has two classes of cause: genetic and acquired. Genetic GSD is caused by any inborn error of metabolism (genetically defective enzymes) involved in these processes. In livestock, acquired GSD is caused by intoxication with the alkaloid castanospermine.


Mucopolysaccharidosis VII. Sly Syndrome,Disease

Mucopolysaccharidosis type VII (MPS VII), also known as Sly syndrome, is a progressive condition that affects most tissues and organs. The severity of MPS VII varies widely among affected individuals. The features of MPS VII include a large head (macrocephaly), a buildup of fluid in the brain (hydrocephalus), distinctive-looking facial features that are described as "coarse," and a large tongue (macroglossia). Affected individuals also frequently develop an enlarged liver and spleen (hepatosplenomegaly), heart valve abnormalities, and a soft out-pouching around the belly-button (umbilical hernia) or lower abdomen (inguinal hernia). MPS VII causes various skeletal abnormalities that become more pronounced with age, including short stature and joint deformities (contractures) that affect mobility. Mutations in the GUSB gene cause MPS VII.


Sucrase-Isomaltase Deficiency,Disease

Congenital sucrase-isomaltase deficiency is a disorder that affects a person's ability to digest certain sugars. People with this condition cannot break down the sugars sucrose and maltose. Sucrose (a sugar found in fruits, and also known as table sugar) and maltose (the sugar found in grains) are called disaccharides because they are made of two simple sugars. Disaccharides are broken down into simple sugars during digestion. Sucrose is broken down into glucose and another simple sugar called fructose, and maltose is broken down into two glucose molecules. People with congenital sucrase-isomaltase deficiency cannot break down the sugars sucrose and maltose, and other compounds made from these sugar molecules (carbohydrates). Congenital sucrase-isomaltase deficiency usually becomes apparent after an infant is weaned and starts to consume fruits, juices, and grains. After ingestion of sucrose or maltose, an affected child will typically experience stomach cramps, bloating, excess gas production, and diarrhea. These digestive problems can lead to failure to gain weight and grow at the expected rate (failure to thrive) and malnutrition. Most affected children are better able to tolerate sucrose and maltose as they get older.


Pyruvate Kinase Deficiency,Disease

Pyruvate kinase deficiency is a genetic disorder. It affects red blood cells in the body. Patients are affected by a condition called chronic hemolytic anemia, which is where red blood cells undergo hemolysis before they are meant to which causes anemia in the patient. Symptoms of this condition can include jaundice, fatigue, dyspnea and splenomegaly. Gallstones are also common to patients with this disorder. This disorder is diagnosed through genetic testing. In mild cases, no treatment is required. Patients with more severe cases may require blood transfusions, and occasionally the spleen is removed to aid with the reduction of red blood cell destruction.


Phosphoenolpyruvate Carboxykinase Deficiency 1 (PEPCK1),Disease

Phosphoenolpyruvate carboxykinase deficiency 1 (pepck1) is a rare congenital metabolic disease caused by mutation of the phosphoenolpyruvate carboxykinase gene. Phosphoenolpyruvate carboxykinase (PEPCK) is an enzyme in the lyase family used in the metabolic pathway of gluconeogenesis. It converts oxaloacetic acid into phosphoenolpyruvate and carbon dioxide. Deficiency of Phosphoenolpyruvate carboxykinase results in metabolic disorder with impaired gluconeogenesis. The clinical characteristics include hypotonia, failure to thrive, hepatomegaly, lactic acidosis and hypoglycemia.


Fructosuria,Disease

Essential fructosuria is a benign, asymptomatic defect of intermediary metabolism characterized by the intermittent appearance of fructose in the urine (summary by Bonthron et al., 1994). Essential fructosuria caused by a deficiency of the enzyme hepatic fructokinase is a clinically benign condition characterized by the incomplete metabolism of fructose in the liver, leading to its excretion in urine. Essential fructosuria is a genetic condition that is inherited in an autosomal recessive manner.Mutations in the KHK gene, located on chromosome 2p23.3-23.2 are responsible.


Triosephosphate isomerase deficiency is a genetic disorder caused by a mutation in the TPI1 gene. The mutation of this gene causes the production of enzymes that are unstable or enzymes that have reduced activity. This means that cells have reduced energy supplies as glycolysis is compromised. This disorder causes anemia, movement problems and muscle weakness. As a result of the lack of red blood cells to carry oxygen through the body, patients may experience fatigue and shortness of breath. Movement problems appear in early infancy, typically before the age of 2 in patients with this disorder. Treatment includes blood transfusions.


Aromatase Deficiency,Disease

Aromatase deficiency is a rare autosomal recessive disorder caused by mutations in the CYP19A1 gene and characterized by lack of conversion of androgens to estrogens. It presents with virilization of pregnant mothers during the antenatal period, and virilization of female fetuses at birth. Affected subjects of either gender later manifest with features of estrogen deficiency and androgen excess.


Congenital adrenal hyperplasia (CAH) refers to any of several autosomal recessive diseases resulting from mutations of genes for enzymes mediating the biochemical steps of production of cortisol from cholesterol by the adrenal glands (steroidogenesis). Most of these conditions involve excessive or deficient production of sex steroids and can alter development of primary or secondary sex characteristics in some affected infants, children, or adults.


Succinic Semialdehyde Dehydrogenase Deficiency,Disease

Succinic Semialdehyde Dehydrogenase (SSADH) deficiency is a rare autosomal recessive inherited disorder affecting the metabolism of γ-aminobutyric acid (GABA). With reduced GABA activity, oxidation of succinic semialdehyde (SSA) to succinic acid is impaired causing a build up of SSA and ultimately it’s downstream metabolite γ-hydroxybutyric acid (GHB). Symptoms of SSADH deficiency are primarily neuropsychiatric including developmental delays, hypotonia, expressive language impairment, seizures, difficulty coordinating movements (ataxia), decreased reflexes (hyporeflexia), and other behavioral issues. Patients with SSADH deficiency have elevated levels of GHB in urine, however this method is not a definitive diagnosis due to the potential volatilization of acidified urine and the use of GHB as a drug. Instead SSADH can be confirmed suing enzyme analysis in leukocytes and molecular genetic analysis of the Aldh5a1 gene at chromosome 6p22.


Short-Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency (SCHAD),Disease

3-hydroxyacyl-CoA dehydrogenase deficiency is an inherited condition that prevents the body from converting certain fats to energy, particularly during prolonged periods without food (fasting). Initial signs and symptoms of this disorder typically occur during infancy or early childhood and can include poor appetite, vomiting, diarrhea, and lack of energy (lethargy). Affected individuals can also have muscle weakness (hypotonia), liver problems, low blood sugar (hypoglycemia), and abnormally high levels of insulin (hyperinsulinism). Mutations in the HADH gene cause 3-hydroxyacyl-CoA dehydrogenase deficiency.


Succinyl CoA: 3-Ketoacid CoA Transferase Deficiency,Disease

Succinyl CoA: 3-Ketoacid CoA Transferase (SCOT) deficiency is a rare inherited metabolic disorder causing reduction of ketone body utilization. In normal functioning patients, ketone bodies such as Acetoacetate (AcAc) and 3‐hydroxybutyrate (3HB) are metabolized inside the liver from free fatty acids. Next, ketone bodies are transported to extrahepatic tissues via the blood stream. Once in extrahepatic tissues, SCOT converts AcAc to acetoacetyl‐CoA and T2 cleaves acetoacetyl‐CoA into acetyl‐CoA. This process is crucial for producing alternative energy sources to glucose in order to maintain blood glucose levels. Patients with SCOT deficiency have this process disturbed and ketoacidosis which is the acidification of the bloodstream due to excess ketone body accumulation, can occur. Current treatments include avoiding actions that could onset ketoacidosis such as fasting and early infusion of glucose.The severity of SCOT deficiency differs from patient to patient. Some exhibit severe genotypes where ketones are always in abundance in the body, while others could have mild genotypes with no preeminent ketosis however both could exhibit ketoacidotic episodes.


Pyridoxine Dependency with Seizures,Disease

Pyridoxine-dependent epilepsy is a condition that involves seizures beginning in infancy or, in some cases, before birth. Those affected typically experience prolonged seizures lasting several minutes (status epilepticus). These seizures involve muscle rigidity, convulsions, and loss of consciousness (tonic-clonic seizures). Additional features of pyridoxine-dependent epilepsy include low body temperature (hypothermia), poor muscle tone (dystonia) soon after birth, and irritability before a seizure episode. In rare instances, children with this condition do not have seizures until they are 1 to 3 years old. Anticonvulsant drugs, which are usually given to control seizures, are ineffective in people with pyridoxine-dependent epilepsy. Instead, people with this type of seizure are medically treated with large daily doses of pyridoxine (a type of vitamin B6 found in food). If left untreated, people with this condition can develop severe brain dysfunction (encephalopathy). Even though seizures can be controlled with pyridoxine, neurological problems such as developmental delay and learning disorders may still occur.


Fanconi-Bickel Syndrome,Disease

Fanconi-Bickel syndrome (FBS) is a rare autosomal recessive disorder of carbohydrate metabolism recently demonstrated to be caused by mutations in Glut2, the gene for the glucose transporter protein 2 expressed in liver, pancreas, intestine and kidney. The disease was first described in a 3-year-old Swiss boy in 1949.


Congenital adrenal hyperplasia (CAH) due to 11-beta-hydroxylase deficiency is one of a group of disorders (collectively called congenital adrenal hyperplasia) that affect the adrenal glands. The adrenal glands are located on top of the kidneys and produce a variety of hormones that regulate many essential functions in the body. In people with CAH due to 11-beta-hydroxylase deficiency, the adrenal glands produce excess androgens, which are male sex hormones. There are two types of CAH due to 11-beta-hydroxylase deficiency, the classic form and the non-classic form. The classic form is the more severe of the two types.


Congenital adrenal hyperplasia (CAH) refers to any of several autosomal recessive diseases resulting from mutations of genes for enzymes mediating the biochemical steps of production of cortisol from cholesterol by the adrenal glands (steroidogenesis). 21-hydroxylase deficiency is an inherited disorder that affects the adrenal glands. The adrenal glands are located on top of the kidneys and produce a variety of hormones that regulate many essential functions in the body. In people with 21-hydroxylase deficiency, the adrenal glands produce excess androgens, which are male sex hormones. There are three types of 21-hydroxylase deficiency. Two types are classic forms, known as the salt-wasting and simple virilizing types. The third type is called the non-classic type. The salt-wasting type is the most severe, the simple virilizing type is less severe, and the non-classic type is the least severe form.


Corticosterone Methyl Oxidase I Deficiency (CMO I),Disease

Corticosterone methyloxidase type I (CMO-I) deficiency is an autosomal recessively inherited disorder causing congenital hypoaldosteronism due to defects in aldosterone synthase (P450aldo), the enzyme that converts 11-deoxycorticosterone to corticosterone, 18-hydroxycorticosterone, and aldosterone.


Corticosterone Methyl Oxidase II Deficiency (CMO II),Disease

CMO type II deficiency is an autosomal recessive disorder caused by a defect in the final biochemical step of aldosterone biosynthesis, the 18-hydroxylation of 18-hydroxycorticosterone (18-OHB) to aldosterone. This enzymatic defect results in decreased aldosterone and salt-wasting associated with an increased serum ratio of 18-OHB to aldosterone. In CMO II deficiency, aldosterone can be low or normal, but at the expense of increased secretion of 18-OHB. These patients have a low ratio of corticosterone to 18-OHB (Portrat-Doyen et al., 1998). The CYP11B2 gene product also catalyzes an earlier step in aldosterone biosynthesis: the 18-hydroxylation of corticosterone to 18-OHB. A defect in that enzymatic step results in CMO type I deficiency (204300), an allelic disorder with an overlapping phenotype but distinct biochemical features. In CMO I deficiency, aldosterone is undetectable, whereas its immediate precursor, 18-OHB, is low or normal (Portrat-Doyen et al., 1998).


Congenital Disorder of Glycosylation CDG-IId,Disease

Congenital disorders of glycosylation (CDGs) are a genetically heterogeneous group of autosomal recessive disorders caused by enzymatic defects in the synthesis and processing of asparagine (N)-linked glycans or oligosaccharides on glycoproteins. These glycoconjugates play critical roles in metabolism, cell recognition and adhesion, cell migration, protease resistance, host defense, and antigenicity, among others. CDGs are divided into 2 main groups: type I CDGs (see, e.g., CDG1A, 212065) comprise defects in the assembly of the dolichol lipid-linked oligosaccharide (LLO) chain and its transfer to the nascent protein, whereas type II CDGs refer to defects in the trimming and processing of the protein-bound glycans either late in the endoplasmic reticulum or the Golgi compartments. The biochemical changes of CDGs are most readily observed in serum transferrin (TF; 190000), and the diagnosis is usually made by isoelectric focusing of this glycoprotein (reviews by Marquardt and Denecke, 2003; Grunewald et al., 2002).


GLUT-1 Deficiency Syndrome,Disease

GLUT1 deficiency syndrome is a disorder that primarily affects the brain. Affected individuals generally have seizures beginning in the first few months of life. Babies with GLUT1 deficiency syndrome have a normal head size at birth, but growth of the brain and skull is often slow, in severe cases resulting in an abnormally small head size (microcephaly). People with GLUT1 deficiency syndrome may have developmental delay or intellectual disability. They may also have other neurological problems, such as stiffness caused by abnormal tensing of the muscles (spasticity), difficulty in coordinating movements (ataxia), and speech difficulties (dysarthria). Some experience episodes of confusion, lack of energy (lethargy), headaches, muscle twitches (myoclonus), or involuntary irregular eye movements, particularly before meals.


Joubert Syndrome,Disease

Joubert syndrome is a disorder that affects many parts of the body. The signs and symptoms of this condition vary among affected individuals, even among members of the same family. The hallmark feature of Joubert syndrome is a brain abnormality called the molar tooth sign, which can be seen on brain imaging studies such as magnetic resonance imaging (MRI). This sign results from the abnormal development of regions near the back of the brain called the cerebellar vermis and the brainstem. The molar tooth sign got its name because the characteristic brain abnormalities resemble the cross-section of a molar tooth when seen on an MRI.


Blue Diaper Syndrome,Disease

Blue diaper syndrome is a rare, autosomal recessive metabolic disorder characterized in infants by bluish urine-stained diapers. It is caused by a defect in tryptophan absorption. Bacterial degradation of tryptophan in the intestine leads to excessive indole production and thus to indicanuria which, on oxidation to indigo blue, causes a peculiar bluish discoloration of the diaper. Symptoms typically include digestive disturbances, fever and visual problems.


Lysinuric Protein Intolerance (LPI),Disease

Lysinuric protein intolerance is a disorder caused by the body's inability to digest and use certain protein building blocks (amino acids), namely lysine, arginine, and ornithine. Because the body cannot effectively break down these amino acids, which are found in many protein-rich foods, nausea and vomiting are typically experienced after ingesting protein. Mutations in the SLC7A7 gene cause lysinuric protein intolerance. The SLC7A7 gene provides instructions for producing a protein called y+L amino acid transporter 1 (y+LAT-1), which is involved in transporting lysine, arginine, and ornithine between cells in the body.


Coagulation ,Protein

Blood coagulation can be initiated by either an extrinsic or an intrinsic pathway, resulting in a cascade of serine protease activation that ultimately leads to the formation of thrombin, which converts soluble fibrinogen to an insoluble fibrin clot. The extrinsic, or tissue factor, pathway is initiated upon vascular injury, when the membrane-bound protein tissue factor (TF) comes into contact with factor VII or VIIa in plasma. The TF-VIIa complex is the strongest known activator of the coagulation cascade, and converts factors IX and X to IXa and Xa, respectively. Factors VII, IX, and X are vitamin-K-dependent proteins produced in the liver. In the intrinsic, or contact, pathway, injury exposes collagen to the bloodstream where is binds to factor XII and activates it to XIIa. Factor XIIa converts prekallikrein to kallikrein and factor XI to XIa. Both the extrinsic and intrinsic pathways result in the activation of factor IX to IXa, which forms the 'tenase' complex with factor VIIIa, calcium and phospholipids. This complex converts factor X to Xa and is important in haemostasis. Factor Xa complexes with factor Va (which functions as a non-enzymatic cofactor), calcium and a phospholipid membrane surface to form what is called the prothrombinase complex, which converts prothrombin to thrombin. Thrombin converts soluble fibrinogen to insoluble fibrin polymer, which is stabilized by cross-linking by coagulation factor XIIIa.