Galactose epimerase deficiency, also known as GALE deficiency, Galactosemia III and UDP-galactose-4-epimerase deficiency, is a rare,

autosomal An autosome is any chromosome that is not a sex chromosome. The members of an autosome pair in a diploid cell have the same morphology, unlike those in allosomal (sex chromosome) pairs, which may have different structures. The DNA in autosom ...

recessive form of

galactosemia Galactosemia (British galactosaemia, from Greek γαλακτόζη + αίμα, meaning galactose + blood, accumulation of galactose in blood) is a rare genetic metabolic disorder that affects an individual's ability to metabolize the sugar galacto ...

associated with a deficiency of the

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...

'' galactose epimerase''.

Symptoms and signs

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 jaundice * Infantile

hypotonia Hypotonia is a state of low muscle tone (the amount of tension or resistance to stretch in a muscle), often involving reduced muscle strength. Hypotonia is not a specific medical disorder, but a potential manifestation of many different diseases ...

* Dysmorphic features * Sensorineural hearing loss * Impaired growth * Cognitive deficiencies * Depletion of cerebellar

Purkinje cells Purkinje cells, or Purkinje neurons, are a class of GABAergic inhibitory neurons located in the cerebellum. They are named after their discoverer, Czech anatomist Jan Evangelista Purkyně, who characterized the cells in 1839. Structure T ...

* Ovarian failure (POI) and hypertrophic hypergonadism * Liver failure * Renal failure *

Splenomegaly Splenomegaly is an enlargement of the spleen. The spleen usually lies in the left upper quadrant (LUQ) of the human abdomen. Splenomegaly is one of the four cardinal signs of ''hypersplenism'' which include: some reduction in number of circulatin ...

Cataracts A cataract is a cloudy area in the lens of the eye that leads to a decrease in vision. Cataracts often develop slowly and can affect one or both eyes. Symptoms may include faded colors, blurry or double vision, halos around light, trouble w ...

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.

Genetics

Galactose epimerase deficiency is an autosomal recessive disorder, which means the defective

gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...

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.

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.

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

phosphoglucomutase 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. More precisely, it facilitates the interconve ...

glycogen phosphorylase Glycogen phosphorylase is one of the phosphorylase enzymes (). Glycogen phosphorylase catalyzes the rate-limiting step in glycogenolysis in animals by releasing glucose-1-phosphate from the terminal alpha-1,4-glycosidic bond. Glycogen phosphor ...

, UDP-glycopyrophosphorylase, 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 The pentose phosphate pathway (also called the phosphogluconate pathway and the hexose monophosphate shunt and the HMP Shunt) is a metabolic pathway parallel to glycolysis. It generates NADPH and pentoses (5-carbon sugars) as well as ribose 5-pho ...

, 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.

Diagnosis

Screening for elevated galactose levels may detect GALE deficiency or dysfunction in infants, and mutation studies for GALE are clinically available.

Classification

There are 2 forms of epimerase deficiency: benign RBC deficiency and Severe liver deficiency. Severe form is similar to

Treatment

Individuals presenting with Type III galactosemia must consume a lactose- and galactose-restricted diet devoid of dairy products and mucilaginous 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.

References

External links

{{Carbohydrate metabolic pathology Autosomal recessive disorders Rare diseases