Browsing Pathways

Galactosemia III also called GALE deficiency or UDP-Galactose-4-Epimerase deficiency, is a rare inborn error of metabolism (IEM) and autosomal recessive disorder caused by either a homozygous or compound heterozygous mutation in the UDP-galactose-4-epimerase (GALE) gene. GALE catalyses the reversible conversion of UDP-galactose to UDP-glucose in galactose metabolism. Symptoms are similar to classic galactosemia, including jaundice, vomiting, hypotonia, failure to thrive, hepatomegaly, moderate generalized amino aciduria and marked galactosuria. Treatment usually includes galactose restricted diets instead of galactose free diets in the management of this disorder because unlike patients with galactokinase deficiency and classic galactosemia, patients with galactose epimerase deficiency cannot utilize the endogenous pathway for synthesis of UDP-galactose. This makes patients dependent on exogenous galactose.

Lysosomal acid lipase deficiency, also called cholesteryl ester storage disease [CESD], LIPA deficiency or Wolman disease, is a rare autosomal recessive inborn error of metabolism. It's caused by not enough lysosomal acid lipase enzyme is produced at lysosome, which act to break down the fatty material. Lysosomal acid lipase enzyme catalyzes the conversion of cholesterol and fatty acid into cholesterol ester. This disorder is characterized by a large accumulation of cholesterol in the endoplasmic reticulum (ER). Symptoms of the disorder include vomiting, diarrhea, weight loss (i.e. feeding difficulties) and swelling of the abdomen. Lysosomal acid lipase deficiency can be treated with sebelipase alfa.

Desmosterolosis is caused by a mutation in the DHCR24 gene, which codes for the enzyme 24-dehydrocholesterol reductase, which catalyzes the reduction of the delta-24 double bond of sterol intermediates. A defect in 24-dehydrocholesterol reductase causes accumulation of desmosterol in plasma. Symptoms include cleft palate, clubfoot, dysmorphism, mental and motor retardation, and speech development.

Acute intermittent porphyria (AIP), also called Swedish porphyria, is a rare inborn error of metabolism (IEM) and autosomal dominant disorder of heme biosynthesis caused by a defective HMBS gene. The HMBS gene codes for the protein hydroxymethylbilane synthase (porphobilinogen deaminase) which catalyzes the synthesis of porphobilinogen into hydroxymethylbilane. This disorder is characterized by a large accumulation of 5-aminolevulinic acid or porphobilinogen in both urine and serum. Most patients are asymptomatic between attacks. Symptoms of the disorder include abdominal pain, constipation, vomiting, hypertension, muscle weakness, seizures, delirium, coma, and depression. Treatment involves undertaking a high-carbohydrate diet and, during severe attacks, a glucose 10% infusion. It is estimated that AIP affects 5.9 per 1 000 000 people.

2-Methyl-3-hydroxybutyryl CoA dehydrogenase deficiency (Hydroxyl-CoA dehydrogenase deficiency; MHBD) is a rare inborn disease of metabolism caused by a mutation in the HSD17B10 gene which codes for 3-hydroxyacyl-CoA dehydrogenase type-2. A deficiency in this enzyme results in accumulation of L-lactic acid in blood, spinal fluid, and urine; 2-ethylhydracrylic acid, 2-methyl-3-hydroxybutyric acid, and tiglylglycine in urine. Symptoms include cerebal atrophy, motor and mental retardation, overactivity and behavior issues, seizures and progressive neurological defects leading to early death. Treatment includes a high carbohydrate and low protein diet.

3-Methylglutaconic aciduria type 1 (3-Methylglutaconicaciduria; Aciduria, 3-methylglutaconic type I) is an autosomal recessive disease caused by a mutation in the AUH gene which codes for methylglutaconyl-CoA hydratase. A deficiency in this enzyme results in accumulation of 3-hydroxyisovaleric acid, 3-methylglutaconic acid, and methylglutaric acid in urine. Symptoms include hypoglycemia, low birth weight, coma, seizures, and mental retardation. Treatment includes a low protein diet.

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.

Cystathionine Beta-Synthase Deficiency (CBS Deficiency; Homocystinuria) is an autosomal recessive disease caused by a mutation in the CBS gene which codes for cystathionine beta-synthase. A deficiency in this enzyme results in accumulation of L-cystathionine, homocysteine, and L-homocystine in plasma and urine; and L-methionine and ornithine in plasma. Symptoms include osteoporosis, myopia, fatty-liver, mental retardation, and early death. Treatment includes folic acid, vitamin B6, vitamin B12, and a methionine-restricted diet.

Methionine adenosyltransferase (MAT; Hypermethioninemia; MAT I/III deficiency) deficiency is caused by mutations in the MAT1A gene which causes isolated hypermethioninemia. MAT catalyzes the formation of adenosylmethionine from methionine and ATP. Adenosylmethionine is an important methyl donor in most transmethylation reactions. MAT dificiency is characterized by increased homocysteine and methionine levels in plasma; and accumulation of methionine in urine. Symptoms include dystonia, mental retardation and unusual odor.

Gaucher disease, also known as glucocerebrosidase deficiency, acid beta-glucosidase deficiency or GBA deficiency, refers to a group of autosomal recessively inherited rare inborn error of metabolism (IEM) that affect the sphingolipid metabolism pathway. All forms of Gaucher disease is caused by a mutation in the GBA gene that encodes lysosomal acid glucosylceramidase, an enzyme that is responsible for catalyzing the formation of ceramide and glucose from glucosylceramide via a hydrolysis reaction. Gaucher disease is characterized by the intracellular buildup of glucosylceramides, particularly in phagocytes, forming what are known as Gaucher cells. Symptoms include anemia, fatigue, hepatomegaly and splenomegaly, however these may vary based on the type of Gaucher disease. For example, type 1 (GD1) involves hepato- and splenomegaly, and types 2 and 3 (GD2 and GD3) also typically affect the brain and spinal cord, and as such tend to be more severe and more likely to become lethal. Treatment for Gaucher disease includes enzyme replacement therapy for type 1, which also helps treat types 2 and 3, but as the enzymes cannot cross the blood-brain barrier, cannot help with the brain damage associated with these types. A drug called miglustat, sold as Zavesca, can also be used to treat the symptoms of type 1 Gaucher disease in individuals who cannot have enzyme replacement therapy. It is estimated that Gaucher disease affects 1 in 100,000 individuals, with the rates being higher in certain populations such as Ashkenazi Jews. GD1 is the most common in most populations representing around 90% of cases of Gaucher disease, with GD2 and GD3 representing roughly 5% each.