SMP0000516
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Adrenoleukodystrophy, X-Linked
Adrenoleukodystrophy (ALD) is an X-linked recessive transmission disease. Central nervous system signs and symptoms have been consistently more prominent than signs of adrenal involvement. Behavioral changes are the most common initial finding and range from aggressive outbursts to withdrawal. Such behavior is generally accompanied by a gradually failing memory and poor school performance. Loss of vision is an early finding in some patients and is a prominent feature at some stage in most affected individuals. The initial visual loss appears as homonomous hemianopsia in some individuals and is usually associated with intact pupillary reflexes. Optic atrophy is less common as an initial finding but eventually develops in almost all cases. Gait disturbance is also an early finding and as is stiff-legged, unsteady and accompanied by hyperreflexia. In almost all cases there is spastic quadraplegia and a variable degree of decorticate posturing. Hearing loss, dysarthria and dysphagia develop at about the same time as gait disturbance. Seizures are a typical symptom in many affected individuals in the the end stages of the disease progression.
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SMP0125745
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Adrenoleukodystrophy, X-Linked
Adrenoleukodystrophy (ALD) is an X-linked recessive transmission disease. Central nervous system signs and symptoms have been consistently more prominent than signs of adrenal involvement. Behavioral changes are the most common initial finding and range from aggressive outbursts to withdrawal. Such behavior is generally accompanied by a gradually failing memory and poor school performance. Loss of vision is an early finding in some patients and is a prominent feature at some stage in most affected individuals. The initial visual loss appears as homonomous hemianopsia in some individuals and is usually associated with intact pupillary reflexes. Optic atrophy is less common as an initial finding but eventually develops in almost all cases. Gait disturbance is also an early finding and as is stiff-legged, unsteady and accompanied by hyperreflexia. In almost all cases there is spastic quadraplegia and a variable degree of decorticate posturing. Hearing loss, dysarthria and dysphagia develop at about the same time as gait disturbance. Seizures are a typical symptom in many affected individuals in the the end stages of the disease progression.
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Disease
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SMP0000168
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AICA-Ribosiduria
AICA-ribosiduria is a metabolic disease caused by a defect in final steps of purine de novo biosynthesis. This defect is caused by a mutation in the ATIC which codes for bifunctional purine biosynthesis protein PURH. A deficiency in this enzyme results in accumulation of 5-aminoimidazole-4-carboxamide in urine. Symptoms include mental retardation, epilepsy, dysmorphic features, and congenital blindness.
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SMP0000169
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Alkaptonuria
Alkaptonuria (Homogentisic acid oxidase deficiency) is an autosomal recessive disease caused by a mutation in the HGD gene which codes for homogentisate 1,2-dioxygenase. A mutation in this enzyme results in accumulation of homogentisic acid in urine. Symptoms, which present in adulthood, include arthritis, black or brown urine, and urolithiasis. Treatment includes a low-protein diet with vitamin C.
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SMP0125485
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Anti-inflammatory pathway
As the bacteria are cleared, tryptophan levels continue to drop as the indole
dioxygenase (IDO) enzyme becomes more active. IDO activation results in the generation (from
tryptophan) of kynurenine (and its other metabolites) through a self-stimulating autocrine
process. Kynurenine binds to the arylhydrocarbon receptor (AhR) found in most immune cells
[5-7]. In addition to increased kynurenine production via IDO mediated synthesis,
hyopalbuminemia can also lead to the release of bound kynurenine (and other
immunosuppressive LysoPCs) into the bloodstream to fuel this kynurenine-mediated
immunosuppression process. Regardless of the source of kynurenine, the kynurenine-bound
AhR will migrate to the nucleus to bind to NF-kB which leads to more production of the IDO
enzyme, which leads to more production of kynureneine and more loss of tryptophan. High
kynurenine levels and low tryptophan levels leads to a shift in T-cell differentiation from a TH1
response (pro-inflammatory) to the production of Treg cells and an anti-inflammatory response
[5-7]. This often marks the beginning of the body’s return to normal and the impending end of
the bacterial infection. High kynurenine levels also lead to the production of more IL10R (the
interluekin-10 receptor) via binding of kynurenine to the arylhydrocarbon receptor (AhR).
Activated AhR effectively increases the anti-inflammatory response from interleukin 10 (an
anti-inflammatory cytokine). Low tryptophan levels also lead to the activation of the general
control non-depressible 2 kinase (GCN2K) pathway, which inhibits the mammalian target of
rapamycin (mTOR), and protein kinase C signaling. This leads to T cell autophagy and anergy.
High levels of kynurenine also lead to the inhibition of T cell proliferation through induction of T
cell apoptosis [5-7].
After bacterial clearance, the anti-inflammatory pathway is further activated and the
pro-inflammatory process further deactivated. With the bacteria cleared, the production of
pro-inflammatory cytokines are reduced due to lack of activity from TLR4 and other TLR
stimulation. Additionally, anti-inflammatory cytokines (IL-10 and IL-4) are induced leading to a
shift in the T-cells from a pro-inflammatory TH1 response to an anti-inflammatory Treg
response. Likewise, with this T-cell shift, levels of cortisol and epinephrine drop, as do levels of
glucose and NO. Blood pressure begins to rise to normal. Kynurenine levels fall due to
continued kynurenine metabolism and uptake by serum albumin. More tryptophan is released
or produced to arrest the IDO synthesis (which reduces kynurenine levels) which further
reduces activation of the arylhydrocarbon receptor (AhR) which leads to the de-activation of
the NF-κB pathway, which leads to lower levels of pro-inflammatory cytokines. Itaconate,
accumulated by pro-inflammatory B-cells and T-cells, promotes the post-transcriptional
modification of KEAP1, which induces the expression of the antioxidant response and PPARγ.
PPARγ inhibits the NF-κB pathway and induces the expression of anti-inflammatory genes while
at the same time increasing fatty-acid β-oxidation and glutaminolysis. Glutamine and fatty acids
fuel the TCA cycle to support oxidative-phosphorylation. Aerobic glycolysis stops. The
accumulated lactate and α-Ketoglutarate promote cysteine modifications that induce the
expression of anti-inflammatory genes. Lactate levels in the blood drop as do glucose levels.
Macrophages and other T-cells and B-cells begin to die or apoptose, the number of white blood
cells drops and the body returns to normal.
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SMP0000717
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Apparent Mineralocorticoid Excess Syndrome
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.
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Disease
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- 11-Dehydrocorticosterone
- 11b,17a,21-Trihydroxypreg-neno...
- 11b,21-Dihydroxy-3,20-oxo-5b-p...
- 11b,21-Dihydroxy-5b-pregnane-3...
- 11b-Hydroxyprogesterone
- 17-Hydroxyprogesterone
- 17a,20a-Dihydroxycholesterol
- 17a,21-Dihydroxy-5b-pregnane-3...
- 17a-Hydroxypregnenolone
- 17α,21-Dihydroxypregnenolone
- 18-Hydroxycorticosterone
- 20a,22b-Dihydroxycholesterol
- 20α-Hydroxycholesterol
- 21-Deoxycortisol
- 21-Hydroxy-5b-pregnane-3,11,20...
- 21-Hydroxypregnenolone
- 22b-Hydroxycholesterol
- 3a,11b,21-Trihydroxy-20-oxo-5b...
- 3a,21-Dihydroxy-5b-pregnane-11...
- 3a-Hydroxy-5b-pregnane-20-one
- 4-Methylpentanal
- 5a-Pregnane-3,20-dione
- Aldosterone
- Cholesterol
- Cortexolone
- Corticosterone
- Cortisol
- Cortisone
- Deoxycorticosterone
- Dihydrocortisol
- Heme
- Hydrogen Ion
- NAD
- NADH
- NADP
- NADPH
- Oxygen
- Pregnenolone
- Progesterone
- Tetrahydrocorticosterone
- Tetrahydrocortisol
- Tetrahydrocortisone
- Water
- (
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SMP0125623
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Arginine: Glycine Amidinotransferase Deficiency (AGAT Deficiency)
Arginine: Glycine Amidinotransferase Deficiency (AGAT Deficiency, Creatine Deficiency Syndrome, Creatine Deficiency due to AGAT Deficiency, GATM Deficiency) is caused by mutation in the GATM gene, which codes for L-arginine:glycine amidinotransferase, which catalyzes the reaction between L-arginine and glycine, transferring an amidino group from L-arginine to glycine, producing L-ornithine and guanidinoacetate, a precursor of creatine. A defect in this enzyme causes a decrease in concentration of creatine and guanidinoacetate in plasma and urine. Symptoms include mental and motor retardation, seizures, and delayed or abnormal speech development.
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SMP0000362
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Arginine: Glycine Amidinotransferase Deficiency (AGAT Deficiency)
Arginine: Glycine Amidinotransferase Deficiency (AGAT Deficiency, Creatine Deficiency Syndrome, Creatine Deficiency due to AGAT Deficiency, GATM Deficiency) is caused by mutation in the GATM gene, which codes for L-arginine:glycine amidinotransferase, which catalyzes the reaction between L-arginine and glycine, transferring an amidino group from L-arginine to glycine, producing L-ornithine and guanidinoacetate, a precursor of creatine. A defect in this enzyme causes a decrease in concentration of creatine and guanidinoacetate in plasma and urine. Symptoms include mental and motor retardation, seizures, and delayed or abnormal speech development.
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SMP0125765
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Argininemia
Argininemia is caused by a mutation in the gene ARG, encoding liver arginase, which hydrolyses arginine to urea and ornithine in the last step of the urea cycle. A defect in liver arginase causes accumulation of ammonia in blood; arginine, creatine, guanidinoacetate, and homoarginine in plasma; urea nitrogen in serum; arginine and homoarginine in spinal fluid; and arginiosuccinate orotic acid, and uracil in urine. Symptoms include ataxia, cerebral atrophy, chorea, jaundice, and seizures.
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Disease
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SMP0000357
View Pathway
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Argininemia
Argininemia is caused by a mutation in the gene ARG, encoding liver arginase, which hydrolyses arginine to urea and ornithine in the last step of the urea cycle. A defect in liver arginase causes accumulation of ammonia in blood; arginine, creatine, guanidinoacetate, and homoarginine in plasma; urea nitrogen in serum; arginine and homoarginine in spinal fluid; and arginiosuccinate orotic acid, and uracil in urine. Symptoms include ataxia, cerebral atrophy, chorea, jaundice, and seizures.
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