Browsing Pathways

Gamma-cystathionase deficiency, also called cystathionase deficiency, is an autosomal recessive metabolic disorder caused by a defective cystathionine gamma-lyase. Cystathionine gamma-lyase catalyzes the conversion of L-Serine and homocysteine into L-Cystathionine which is the substrate of cystathionine gamma-lyase. This disorder is characterized by a large accumulation of L-Cystathionine in the cell. Symptoms of the disorder include mental deficiency and seizure. Since there is currently no cure forGamma-cystathionase deficiency, treatment involves managing the disorder's symptoms.

Adult Refsum Disease (Classic Refsum Disease; Phytanic Acid Oxidase Deficiency; Heredopathia Atactica Polyneurtiformis; Hereditary Motor and Sensory Neuropathy IV; HSMN4; Adult Refsum Disease I; Adult Refsum Disease II), can be caused by mutations in the PHYH (or PAHX) gene, which encodes Phytanoyl-CoA hydroxylase (, the first enzyme in the Phytanic Acid Peroxisomal Oxidation pathway) on chromosome 10 (adult Refsum disease I), and by mutation of the PEX7 gene. A defect in phytanoyl-CoA hydroxylase results in accumulation of phytanic acid in the plasma, as well as low levels of pristanic acid due to the inability for phytanic acid to undergo alpha and beta oxidation. Symptoms include anosmia, ataxia, nystagmus, neurological deterioration and peripheral neuropathy. Adult Refsum disease is distinctly different from Infantile Refsum disease both genetically and phenotypically. Infantile Refsum disease involves mutations of the PEX1, PEX2 and PEX26 genes.

3-beta-hydroxysteroid dehydrogenase (HSD) deficiency is an extremely rare inborn error of metabolism (IEM) and autosomal recessive disorder of the steroidogenesis pathway. It is caused by an defect in the HSD3B2 gene which encodes for the 3 beta-hydroxysteroid dehydrogenase enzyme, which is responsible for forming cortisol from 11b,17a,21-trihydroxypregnenolone. When the enzyme is not correctly produced, cortisol levels in the cell are lowered, and as cortisol is used in the production of other steroids, it may affect their levels as well. 3-beta-HSD deficiency is characterized by low levels of cortisol produced in the adrenal glands. Symptoms include abnormal genitalia for both males and females, as well as infertility. There is also a more severe salt-wasting form of this deficiency, characterized by dehydration. Treatment for 3-beta-HSD deficiency includes steroid replacement, as well as sex hormone replacement during puberty to allow proper development. Surgery can also be used to correct any genital abnormalities that may occur. It is estimated that 3-beta-HSD deficiency affects less than 1 in 1,000,000 individuals, with around 60 cases reported.

Apparent mineralocorticoid excess (AME), also known as cortisol 11-beta-ketoreductase deficiency, is an extremely rare inborn error of metabolism (IEM) and autosomal recessive disorder of the steroidogenesis pathway. It is caused by a mutation in the HSD11B2 gene which encodes for corticosteroid 11-beta-dehydrogenase isozyme 2, and enzyme that converts cortisol to cortisone in the cell. Without this enzyme being functional, an accumulation of tetrahydrocortisol builds up, while tetrahydrocortisone levels dissipate. AME is characterized excessive thirst and urination, and along with this, symptoms include low levels of aldosterone, failure to thrive and hypertension. Treatment with corticoids that suppress the secretion of cortisol within the body can affect blood pressure and aldosterone levels. Antihypertensive agents are also effective. It is estimated that AME affects less than 1 in 1,000,000 individuals, with less than 100 reported cases as of 2019.

Corticosterone methyloxidase type II (CMO-II) deficiency, also called 18-oxidase defiency or aldosterone deficiency II among other names, is a genetic disorder that is autosomally linked. It is caused by a mutation in the cytochrome P450 11B2 gene, whose protein product is responsible for the formation of aldosterone from 18-hydroxycorticosterone (18-OHB), as well as converting progesterone to 11b-hydroxyprogesterone. The conversion of 18-OHB to aldosterone is the only reaction that uses 18-OHB, and due to the enzyme not being entirely functional, it builds up in the cell, while aldosterone levels will be lowered. However, since progesterone and 11b-hydroxyprogesterone are both produced and used by other reactions, their levels in the cell are not changed as drastically. Compared to the CMO-I deficiency, the CMO-II deficiency has less severe mutations in the gene, which cause it to have less severe changes in aldosterone and 18-OHB concentrations. The CMO-II deficiency, and its resulting aldosterone deficiency can cause a salt-wasting phenotype in children, due to aldosterone being responsible for the resorption of sodium in the body, as well as secretion of potassium. With levels of aldosterone being lower due to this deficiency, excess sodium is excreted in the urine, and higher than average levels of potassium in the serum. Aside salt-wasting and potential failure to thrive as an infant due to this, there are no symptoms, such as genital abnormalities, that are seen in similar salt-wasting disorders like CYP21 deficiency.

Corticosterone methyloxidase type I (CMO-I) deficiency, also known as 18-hydroxylase deficiency or aldosterone deficiency among other names, is a genetic disorder that is autosomally linked and caused by a defective CYP11B2 gene. This gene encodes the cytochrome P450 11B2 mitochondrial protein, also called aldosterone synthase, which is used to catalyze the conversion of 18-hydroxycorticosterone to aldosterone. This leads to a decrease in the amount of aldosterone present in the cells, which is responsible for an increased amount of salt excreted in the urine, known as salt wasting. In CMO-I deficiency, aldosterone levels are so low that they are undetectable in plasma.

11-beta-Hydroxylase Deficiency, also called congenital adrenal hyperplasia (CAH), is an autosomal recessive disorder and caused by a defective 11-beta-hydroxylase. 11-beta-hydroxylase catalyzes the conversion of cortexolone into cortisol which is useful for maintaining blood sugar levels and suppressing inflammation. This disorder is characterized by a large accumulation of cortexolone in the endoplasmic reticulum (ER). Symptoms of the disorder include abnormality of hair growth rate and menstrual cycle. It is estimated that 11-beta-hydroxylase deficiency affects 1 in 100,000 to 200,000 newborns.

Adrenal hyperplasia type 5 (AH5) also known as Congenital Adrenal Hyperplasia Due to 17 alpha-Hydroxylase Deficiency is a rare inborn error of metabolism (IEM) and autosomal recessive disorder of cortisol and sex steroids synthesis caused by a defect in the CYP17A1 gene which codes for Steroid 17-alpha-hydroxylase/17,20 lyase. These 2 enzymes catalyze pregnenolone and progesterone to their 17-hydroxy forms in steroidogenesis and mediate three key transformations in cortisol and sex steroid synthesis. This disorder is characterized by a decrease in both cortisol and sex steroids and increase in mineralocorticoids. Symptoms of the disorder include mild hypocortisolism, ambiguous genitalia in genetic males or failure of the ovaries to function at puberty in genetic females, and hypertension. Treatments for Hypertension and mineralocorticoid excess is done with glucocorticoid replacement. Genetically female patients need female hormone replacement to induce puberty and regulate menses. Surgery may be needed for males with ambiguous genitalia. Testosterone must be replaced for genetically males (XY) to induce puberty and continued throughout adult life. It is estimated that Adrenal hyperplasia type 5 affects 1 in 1 million individuals worldwide.

Congenital Lipoid Adrenal Hyperplasia (CLA),also called steroid 20-22 desmolase deficiency and lipoid CAH, is an autosomal recessive disorder and caused by a defective cholesterol side-chain cleavage enzyme. Cholesterol side-chain cleavage enzyme catalyzes the conversion of cholesterol into 20α-Hydroxycholesterol which is also a substrate of cholesterol side-chain cleavage enzyme. This disorder is characterized by a large accumulation of cholesterol in the mitochondrial. Symptoms of the disorder is not clear. Extra glucocorticoid and mineral replacement could be the potential treatments.

Adrenal hyperplasia type 3, also called Congenital adrenal hyperplasia due to 21-hydroxylase deficiency, is caused by a defect in the CYP21A2 gene which codes for Steroid 21-hydroxylase (21-hydroxylase). Steroid 21-hydroxylase catalyzes hydroxylation of 17-hydroxyprogesterone to 11-deoxycortisol in the glucocorticoid pathway from pregnenolone to cortisol. It also catalyzes hydroxylation of progesterone to 11-deoxycorticosterone (DOC) in the mineralocorticoid pathway on its way from pregnenolone to aldosterone. A defect in this enzyme results in accumulation of 17-Hydroxyprogesterone, progesterone and 17a-Hydroxypregnenolone, androstenedione, and testosterone; decreased levels of cortexolone, deoxycorticosterone, aldosterone and cortisol. Symptoms include salt-wasting crises in infancy due to the lack of aldosterone, like spitting, poor weight gain, vomiting, severe dehydration, and circulatory collapse. The high level of testosterone results in virilization and genital ambiguity of female infants.