Galactose epimerase deficiency
Encyclopedia
Galactose epimerase deficiency, also known as GALE deficiency, Galactosemia III and UDP-galactose-4-epimerase deficiency, is a rare, autosomal
recessive form of galactosemia
associated with a deficiency of the enzyme
galactose epimerase.
.
Galactose epimerase deficiency is an autosomal recessive disorder, which means the defective gene
is located on an autosome
, and two copies of the defective gene - one from each parent - are required to inherit the disorder. The parents of an individual with an autosomal recessive disorder both carry one copy of the defective gene, but usually do not experience any signs or symptoms of the disorder.
, glycogen phosphorylase
, UDP-glycopyrophosphorylase, and inositol monophosphatase
activity in bacterial models and in vitro, yet in vivo mechanisms toxicity have yet to be confirmed. Regardless, median galactose-1-phosphate levels act as the most accurate predictors of the severity of symptoms associated with Type III galactosemia.
Blockage of the Leloir pathway by GALE deficiency or dysfunction activates alternate pathways of glucose metabolism and leads to galactitol and galactonate formation. Galactonate is metabolized by the pentose phosphate pathway
, and is not considered toxic. Galactitol, however, may accumulate in lens fibers, perturbing lens epithelial cell permeability and leading to cell death and cataract formation. GALE deficiency also perturbs glycolipid and glycoprotein biosynthesis due to decreased production of UDP-GalNAc from UDP-GlcNAc.
Studies of Type III galactosemia symptoms are mostly descriptive, and precise pathogenic mechanisms remain unknown. This is largely due to a lack of functional animal models of classic galactosemia. The recent development of a Drosophila melanogaster GALE mutant exhibiting galactosemic symptoms may yield a promising future animal model.
Autosome
An autosome is a chromosome that is not a sex chromosome, or allosome; that is to say, there is an equal number of copies of the chromosome in males and females. For example, in humans, there are 22 pairs of autosomes. In addition to autosomes, there are sex chromosomes, to be specific: X and Y...
recessive form of galactosemia
Galactosemia
Galactosemia is a rare genetic metabolic disorder that affects an individual's ability to metabolize the sugar galactose properly. Although the sugar lactose can metabolize to galactose, galactosemia is not related to and should not be confused with lactose intolerance...
associated with a deficiency of the enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
galactose epimerase.
Classification
There are 2 forms of epimerase deficiency: benign RBC deficiency and Severe liver deficiency. Severe form is similar to galactosemiaGalactosemia
Galactosemia is a rare genetic metabolic disorder that affects an individual's ability to metabolize the sugar galactose properly. Although the sugar lactose can metabolize to galactose, galactosemia is not related to and should not be confused with lactose intolerance...
.
Genetics
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
is located on an autosome
Autosome
An autosome is a chromosome that is not a sex chromosome, or allosome; that is to say, there is an equal number of copies of the chromosome in males and females. For example, in humans, there are 22 pairs of autosomes. In addition to autosomes, there are sex chromosomes, to be specific: X and Y...
, and two copies of the defective gene - one from each parent - are required to inherit the disorder. The parents of an individual with an autosomal recessive disorder both carry one copy of the defective gene, but usually do not experience any signs or symptoms of the disorder.
Genetic basis
Various human GALE mutations resulting in Type III galactosemia have been identified. Functional analysis of these mutant GALE isoforms suggests that reduced catalytic efficiency and increased likelihood of proteolytic digestion act causatively in Type III galactosemia.| Mutated Residue | Biochemical Effect | Clinical Manifestation |
|---|---|---|
| V94M, K257R, L313M, R335H | Strongly impaired turnover number Turnover number Turnover number has two related meanings:In enzymology, turnover number is defined as the maximum number of molecules of substrate that an enzyme can convert to product per catalytic site per unit of time and can be calculated as follows: kcat = Vmax/[E]T... and specificity constant |
Severe generalized galactosemia. |
| S81R, T150M, P293L | Mild turnover number impairment | Intermediate galactosemia. |
| L183P, D103G, G90E, N34S | Strongly impaired turnover number and specificity constant; increased proteolytic digestion. | Severe generalized galactosemia. |
Biochemical basis
GALE deficiency inhibits UDP-glucose regeneration, preventing the formation of glucose-1-phosphate and leading to the accumulation of galactose and galactose-1-phosphate. High galactose-1-phosphate levels have been shown to interfere with phosphoglucomutasePhosphoglucomutase
Phosphoglucomutase is an enzyme that transfers a phosphate group on an α-D-glucose monomer from the 1' to the 6' position in the forward direction or the 6' to the 1' position in the reverse direction....
, glycogen phosphorylase
Glycogen phosphorylase
Glycogen phosphorylase is one of the phosphorylase enzymes . Glycogen phosphorylase catalyzes the rate-limiting step in the degradation of glycogen in animals by releasing glucose-1-phosphate from the terminal alpha-1,4-glycosidic bond...
, UDP-glycopyrophosphorylase, and inositol monophosphatase
Inositol monophosphatase
Inositol monophosphatase , commonly referred to as IMPase, is an enzyme found in all cells and is thought to be key in bipolar disorder...
activity in bacterial models and in vitro, yet in vivo mechanisms toxicity have yet to be confirmed. Regardless, median galactose-1-phosphate levels act as the most accurate predictors of the severity of symptoms associated with Type III galactosemia.
Blockage of the Leloir pathway by GALE deficiency or dysfunction activates alternate pathways of glucose metabolism and leads to galactitol and galactonate formation. Galactonate is metabolized by the pentose phosphate pathway
Pentose phosphate pathway
The pentose phosphate pathway is a process that generates NADPH and pentoses . There are two distinct phases in the pathway. The first is the oxidative phase, in which NADPH is generated, and the second is the non-oxidative synthesis of 5-carbon sugars...
, and is not considered toxic. Galactitol, however, may accumulate in lens fibers, perturbing lens epithelial cell permeability and leading to cell death and cataract formation. GALE deficiency also perturbs glycolipid and glycoprotein biosynthesis due to decreased production of UDP-GalNAc from UDP-GlcNAc.
Symptoms
Symptoms of congenital Type III Galactosemia are apparent from birth, but vary in severity depending on whether the peripheral or generalized disease form is present. Symptoms may include:- Infantile jaundiceJaundiceJaundice is a yellowish pigmentation of the skin, the conjunctival membranes over the sclerae , and other mucous membranes caused by hyperbilirubinemia . This hyperbilirubinemia subsequently causes increased levels of bilirubin in the extracellular fluid...
- Infantile hypotoniaHypotoniaHypotonia is a state of low muscle tone , often involving reduced muscle strength. Hypotonia is not a specific medical disorder, but a potential manifestation of many different diseases and disorders that affect motor nerve control by the brain or muscle strength...
- Dysmorphic features
- Sensorineural hearing loss
- Impaired growth
- Cognitive deficiencies
- Depletion of cerebellar Purkinje cells
- Ovarian failure (POI) and hypertrophic hypergonadism
- Liver failure
- Renal failure
- SplenomegalySplenomegalySplenomegaly is an enlargement of the spleen. The spleen usually lies in the left upper quadrant of the human abdomen. It is one of the four cardinal signs of hypersplenism, some reduction in the number of circulating blood cells affecting granulocytes, erythrocytes or platelets in any...
- Cataracts
Studies of Type III galactosemia symptoms are mostly descriptive, and precise pathogenic mechanisms remain unknown. This is largely due to a lack of functional animal models of classic galactosemia. The recent development of a Drosophila melanogaster GALE mutant exhibiting galactosemic symptoms may yield a promising future animal model.
Detection and treatment
Screening for elevated galactose levels may detect GALE deficiency or dysfunction in infants, and mutation studies for GALE are clinically available. Individuals presenting with Type III galactosemia must consume a lactose- and galactose-restricted diet devoid of dairy products and mucilagenous plants. Dietary restriction is the only current treatment available for GALE deficiency. As glycoprotein and glycolipid metabolism generate endogenous galactose, however, Type III galactosemia may not be resolved solely through dietary restriction.External Links
- GeneReviews/NCBI/NIH/UW entry on Epimerase Deficiency Galactosemia
- OMIM entries on Epimerase Deficiency Galactosemia
- http://dwb.unl.edu/Teacher/NSF/C11/C11Links/web.indstate.edu/thcme/mwking/non-glucose-metabolism.html