Browsing Pathways

Short Chain Acyl CoA Dehydrogenase Deficiency (SCAD Deficiency) is caused by mutation in the gene encoding short-chain acyl-CoA dehydrogenase, an enzyme which normally breaks down short chain fatty acids. SCADD causes accumulation of ammonia in blood; butyrylcarnitine(C4) in plasma; adipic acid, butyrylglycine, ethylmalonic acid; hexanoylglycine and methylsuccinic acid in urine. Symptoms include hypoglycemia, hypotonia, microcephaly, failure to thrive, lactic acidosis, peripheral neuropathy, and vomiting.

Sarcosinemia (SAR), also known as hypersarcosinemia, sarcosine dehydrogenase complex deficiency, SARDH deficiency, SARDHD or SARD deficiency, is an autosomal recessive metabolic disorder leading to increased levels of the amino acid sarcosine in blood plasma, as well as increased levels of sarcosine excreted in urine. SAR can be caused by a mutation, either homozygous or compound heterozygous, in the SARDH gene which codes for the sarcosine dehydrogenase enzyme. This enzyme converts sarcosine to glycine, and its absence leads to an increase in the amount of sarcosine in the body. It can also potentially be caused by a lack of folate, as folate is used in the sarcosine dehydrogenase reaction, and even with a working enzyme, the lack of substrates can prevent the conversion from occurring, leading to the same effects. The condition has been associated with mental and motor retardation, visual impairment, however other cases have been detected with no mental or physical abnormalities other than increased sarcosine levels, so it is possible that the defect is benign, or that there exist some phenotypes that are more severe than others, or unknown disorders present in the cases showing symptoms. Sarcosine can be formed from a series of reactions starting with trimethylglycine. This, along with homocysteine, react using betaine-homocysteine S-methyltransferase to form L-methionine, as well as dimethylglycine. The dimethylglycine then enters the mitochondrial matrix, and interacts with dimethylglycine dehydrogenase along with a water molecule, forming formadehyde and sarcosine. Sarcosine can also be formed in a reversible reaction from S-adenosylmethionine and glycine, using glycine N-methyltransferase as the enzyme, and forming S-adenosylhomocysteine as another product. Normally, sarcosine can interact with sarcosine dehydrogenase in the mitochondria, forming both formaldehyde and glycine. However, in this disorder, the gene encoding sarcosine dehydrogenase has been mutated and the protein is not produced, preventing this reaction from occurring. This leads to an increased concentration of sarcosine, which leads to the effects of the condition.

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.

Methylmalonate Semialdehyde Dehydrogenase Deficiency (MMSDH Deficiency; Aldehyde Dehydrogenase 6 Family, Member A1; ALDH6A1 Deficiency)is caused by a defect in methylmalonate semialdehyde dehydrogenase, which catalyzes the irreversible oxidative decarboxylation of malonate and methylmalonate semialdehydes to acetyl- and propionyl-CoA, respectively. A defect in methylmalonate semialdehyde dehydrogenase causes accumulation of 3-Aminoisobutyric acid, 3-Hydroxyisobutyric acid, 3-hydroxypropionic acid, beta-Alanine, lactate, and methylmalonic acid in urine. Symptoms inclue failure to thrive, large liver, mental and motor retardation and vomiting.

Salla disease, also called sialic acid storage disease, is a rare inborn error of metabolism (IEM) and autosomal recessive disorder of lysosomal storage caused by a defective SLC17A5 gene. SLC17A5 codes for the lysosomal transporter sialin which exports sialic acid from the lysosome into the cytoplasm. This disorder is characterized by a large accumulation of sialic acid in the urine. Symptoms of the disorder include seizures, intellectual disability, developmental delay, nystagmus, hypotonia, ataxia, spasticity, and athetosis. There are three forms of Salla disease: infantile free sialic acid storage disease (ISSD), Salla disease, and intermediate severe Salla disease. Since there is currently no cure for Salla disease, treatment involves managing the disorder's symptoms. Salla disease has been reported in approximately 150 people (mostly from Finland and Sweden) and ISSD has been reported in a few dozen infants.

Methylmalonic acidemia cause defects (Methylmalonaciduria due to methylmalonic CoA mutase; Acidemia, methylmalonic; MMA) in the metabolic pathway where methylmalonyl-coenzyme A (CoA) is converted into succinyl-CoA by the enzyme methylmalonyl-CoA mutase. Defects in the enzyme Methylmalonyl-CoA mutase causes accumulation of ammonia in blood; methylmalonic acid in plasma; creatinine and uric acid in serum; 3-Aminoisobutyric acid, 3-Hydroxypropionic acid, 3-Hydroxyvaleric acid, glycine, methylcitric acid and methylmalonic acid in urine; and methylmalonic acid in spinal fluid. Symptoms include anemia, dehydration, growth retardation, nephrosis, respiratory distress and metabolic acidosis.

Saccharopinuria (also known as: saccharopinemia, saccharopine dehydrogenase deficiency, and alpha-aminoadipic semialdehyde synthase deficiency) is caused by a partial deficiency of aminoadipic semialdehyde synthase (AASS) enzyme and causes an increase in saccharopine in the urine. Saccharopinuria is another form of hyperlysinemia. AASS has lysine ketoglutarate reductase (LKR) and saccharopine dehydrogenase (SDH) activity. AASS acts in the first 2 steps in lysine degradation. A defect in this enzyme results in accumulation of citrulline, lysine and saccharopin in the plasma; lysine in the spinal fluid; and citrulline, lysine and saccharopine in the urine. Symptoms include growth and mental retardation.

S-Adenosylhomocysteine hydrolase deficiency, also known as AdoHcy hydrolase deficiency or adenosylhomocysteinase (AHCY) deficiency, is an autosomal recessive disorder characterized by a defective AHCY gene. AHCY codes for the enzyme S-adenosylhomocysteine hydrolase (AdoHcyase) which efficiently eliminates S-adenosylhomocysteine (SAH) by catalyzing its hydrolysis into adenosine and homocysteine. SAH is both a byproduct of S-adenosylmethionine-dependent methyltransferases and a powerful methyltransferase inhibitor. For these reasons, AdoHcyase is thought to play an essential role in regulating methylations. AdoHcyase deficiency causes a buildup of homocysteine which may be then converted into methionine or cysteine. The accumulation of methionine as a result of AHCY deficiency may lead to signs and symptoms associated with hypermethioninemia, including mental and motor retardation, dysmorphism (unusual facial features), and abnormalities in liver function.

Methylcobalamin (MeCbl) is the cofactor of methionine synthase and involved in the conversion of homocysteine to methionine. Adenosylcobalamin (AdoCbl) is a cofactor for methylmalonyl CoA mutase converting methylmalonic acid into succinic acid. Methylmalonyl-CoA mutase is involved in key metabolic pathways, catalyzing the isomerization of methylmalonyl-CoA to succinyl-CoA. It requires its Vitamin B12 derived prosthetic group, adenosylcobalamin, to function.It catalyzes the isomerization of methylmalonyl-CoA to succinyl-CoA. It requires its Vitamin B12 derived prosthetic group, adenosylcobalamin, to function. Defects in these cofactors for methylmalonyl CoA mutase cause accumulation of ammonia in blood; methylmalonic acid in plasma; creatinine and uric acid in serum; 3-Aminoisobutyric acid, 3-Hydroxypropionic acid, 3-Hydroxyvaleric acid, glycine, methylcitric acid and methylmalonic acid in urine; and methylmalonic acid in spinal fluid. Symptoms include anemia, dehydration, growth retardation, nephrosis, respiratory distress and metabolic acidosis.

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.