Browsing Pathways

Glycine N-methyltransferase deficiency, also called GNMT deficiency, is an autosomal recessive disorder of methionine metabolism caused by a defective glycine N-methyltransferase (GNMT). GNMT catalyzes the conversion of glycine into N-methylglycine (sarcosine) using S-adenosylmethionine (SAM or AdoMet). This disorder is characterized by a large accumulation of methionine in the plasma and transaminases in the serum. Symptoms of the disorder include hepatomegaly.

Fabry disease, also called Anderson-Fabry disease is an X-linked inherited condition that begins in childhood. The symptoms are caused by the buildup of a substance called globotriaosylceramide in cells in the body, due to a mutation in the GLA gene, that causes a malfunction in the production of an enzyme called alpha-galactosidase A, which, when functioning properly, breaks down globotriaosylceramide. The symptoms include angiokeratomas, tinnitus, episodes of pain in the hands and feet and corneal opacity. This condition can also lead to severe complications such as heart attack, stroke and kidney damage.

D-Glyceric aciduria is an extremely rare inherited inborn error of metabolism (IEM) of serine and fructose metabolism. It is an autosomal recessive disorder that is caused by a defect in the D-glycerate kinase (GLYCTK) gene. GLYCTK codes for D-glycerate kinase, an enzyme that is responsible for phosphorylating D-glyceric acid into phosphoglycerate. D-Glycerate kinase is an enzyme that participates in 3 metabolic pathways: (1) serine/glycine/threonine metabolism, (2) glycerolipid metabolism, and (3) glyoxylate-dicarboxylate metabolism (which is a minor pathway in fructose metabolism). Defects in the enzyme will lead to accumulations of D-glyceric acid in tissues and biofluids. D-Glyceric aciduria was first described in 1974 and is characterized by elevated levels of D-glyceric acid in the urine. Clinical symptoms of D-glyceric aciduria are highly variable. Some patients have neurological symptoms, with severe mental retardation, seizures, microcephaly, and sometimes early death, whereas others have a mild phenotype with only mild speech delay or even normal development.

Galactosemia (GALT Deficiency; GALT; Galactose-1-Phosphate Uridylyltransferase Deficiency) is a rare genetic disorder caused by a mutation in the GALT gene which codes for galactose-1-phosphate uridylyltransferase. A deficiency in this enzyme results in accumulation of D-galactose and galactitol in plasma and urine; bilirubin, chloride, and galactose-1-phosphate, and transaminases in serum. Symptoms, which present at birth, include jaundice, enlarged liver, anemia, weight loss, and vomiting. Treatment includes galactose-free diet, antibiotics, and vitamin K.

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.

Hyperinsulinism-hyperammonemia syndrome (HHS; Glutamate dehydrogenase 1; GLUD1), an inherited condition, is caused by a defect in the GLUD1 gene which codes for mitochondrial glutamate dehydrogenase 1. It is a mitochondrial matrix enzyme, with a key role in the nitrogen and glutamate (Glu) metabolism and the energy homeostasis. An excessive activity of this enzyme results in high insulin and ammonia levels in blood; decrease level of glucose in blood. Symptoms and signs include shakiness, weakness, seizure, rapid pulse and confusion. Maintain normoglycemia is essencial to prevent neurologic damage. Some medications can be used to suppress insulin secretion.

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.

Hypoacetylaspartia, also known as N-acetylaspartate (NAA) deficiency is an extremely rare autosomal recessive inborn error of metabolism (IEM) caused by a mutation in the NAT8L gene. This gene encodes the N-acetylaspartate synthase protein, which catalyzes the formation of N-acetyl-L-aspartate from L-aspartate and acetyl-CoA, with CoA and a hydrogen ion being byproducts. This reaction occurs as part of the aspartate metabolism pathway. This disorder is characterized by a deficiency of NAA in the brain, as shown by magnetic resonance spectroscopy (MRS). Symptoms of the disorder include microcephaly, developmental delays, ataxia and seizures, which have been shown to worsen the ataxia. So, only one patient has been diagnosed with Hypoacetylaspartia.

Glycogenosis, Type IB, also called von Gierke disease or GSDI, is a rare inborn error of metabolism (IEM) and autosomal recessive disorder which caused by a defective glucose-6-phosphate translocase. Glucose-6-phosphate translocase transports glucose 6-phosphate from endoplasmic reticulum (ER) to cell, which glucose 6-phosphate is required for various pathways as the substrate. This disorder damages the ability of converting glycogen into glucose. Symptoms of the disorder include longer sleeping time through night, tiredness and seizures due to low blood sugar. Treatment with diet management is very effective.

Fructose-1,6-bisphosphatase deficiency (FBP1D) is an autosomal recessive inborn error of metabolism (IEM) caused by a mutation in the FBP1 gene which encodes for fructose-1,6-bisphosphatase-1. This enzyme is responsible for catalyzing the conversion of fructose 1,6-bisophosphate into fructose 5-phosphate by removing a phosphate group from it as part of the gluconeogenesis pathway. FBP1D is characterized by hypoglycemia and acidosis after fasting, caused by the impairment of gluconeogenesis. Symptoms can also include hyperventilation. Treatment includes feeding more often with foods enriched with glucose, as well as avoiding foods high in fructose and sucrose, as well as avoiding fasting for longer than overnight. It is estimated that FBP1D affects between 1 in 350,000 and 1 in 900,000 individuals.