In fructose bisphosphatase deficiency, there is not enough fructose bisphosphatase for

gluconeogenesis Gluconeogenesis (GNG) is a metabolic pathway that results in the generation of glucose from certain non- carbohydrate carbon substrates. It is a ubiquitous process, present in plants, animals, fungi, bacteria, and other microorganisms. In verteb ...

to occur correctly.

Glycolysis Glycolysis is the metabolic pathway that converts glucose () into pyruvate (). The free energy released in this process is used to form the high-energy molecules adenosine triphosphate (ATP) and reduced nicotinamide adenine dinucleotide (NADH ...

(the breakdown of

glucose Glucose is a simple sugar with the molecular formula . Glucose is overall the most abundant monosaccharide, a subcategory of carbohydrates. Glucose is mainly made by plants and most algae during photosynthesis from water and carbon dioxide, u ...

) will still work, as it does not use this enzyme.

History

Early research into the disorder was conducted by a team led by Anthony S. Pagliara and

Barbara Illingworth Brown Barbara Illingworth Brown was an American biochemist. She worked primarily at Washington University in St. Louis. Education and career Brown was born in Hartford, Connecticut and later moved to Pennsylvania when her father's job in insurance mo ...

Washington University Medical Center The Washington University Medical Center (WUMC), located in St. Louis, Missouri, is a large scale health-care focused commercial development located in St. Louis' Central West End neighborhood. The Washington University Medical Center Redevelopme ...

, based on the case of an infant girl from

Oak Ridge, Missouri Oak Ridge is a village in the southern part of Apple Creek Township in Cape Girardeau County, Missouri, United States. The population was 237 at the 2020 census. It is part of the Cape Girardeau–Jackson, MO- IL Metropolitan Statistical Are ...

Presentation

Without effective gluconeogenesis (GNG),

hypoglycaemia Hypoglycemia, also called low blood sugar, is a fall in blood sugar to levels below normal, typically below 70 mg/dL (3.9 mmol/L). Whipple's triad is used to properly identify hypoglycemic episodes. It is defined as blood glucose bel ...

will set in after about 12 hours of fasting. This is the time when liver

glycogen Glycogen is a multibranched polysaccharide of glucose that serves as a form of energy storage in animals, fungi, and bacteria. The polysaccharide structure represents the main storage form of glucose in the body. Glycogen functions as one of ...

stores have been exhausted, and the body has to rely on GNG. When given a dose of

glucagon Glucagon is a peptide hormone, produced by alpha cells of the pancreas. It raises concentration of glucose and fatty acids in the bloodstream, and is considered to be the main catabolic hormone of the body. It is also used as a medication to tre ...

(which would normally increase blood glucose) nothing will happen, as stores are depleted and GNG doesn't work. (In fact, the patient would already have high glucagon levels.) There is no problem with the metabolism of glucose or galactose, but

fructose Fructose, or fruit sugar, is a ketonic simple sugar found in many plants, where it is often bonded to glucose to form the disaccharide sucrose. It is one of the three dietary monosaccharides, along with glucose and galactose, that are absorb ...

and

glycerol Glycerol (), also called glycerine in British English and glycerin in American English, is a simple triol compound. It is a colorless, odorless, viscous liquid that is sweet-tasting and non-toxic. The glycerol backbone is found in lipids known ...

cannot be used by the liver to maintain blood glucose levels. If fructose or glycerol are given, there will be a buildup of phosphorylated three-carbon sugars. This leads to

phosphate In chemistry, a phosphate is an anion, salt, functional group or ester derived from a phosphoric acid. It most commonly means orthophosphate, a derivative of orthophosphoric acid . The phosphate or orthophosphate ion is derived from phosph ...

depletion within the cells, and also in the blood. Without phosphate, ATP cannot be made, and many cell processes cannot occur. High levels of glucagon will tend to release

fatty acid In chemistry, particularly in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated or unsaturated. Most naturally occurring fatty acids have an unbranched chain of an even number of carbon atoms, f ...

s from

adipose tissue Adipose tissue, body fat, or simply fat is a loose connective tissue composed mostly of adipocytes. In addition to adipocytes, adipose tissue contains the stromal vascular fraction (SVF) of cells including preadipocytes, fibroblasts, vascular ...

, and this will combine with

that cannot be used in the liver, to make

triacylglyceride A triglyceride (TG, triacylglycerol, TAG, or triacylglyceride) is an ester derived from glycerol and three fatty acids (from ''tri-'' and ''glyceride''). Triglycerides are the main constituents of body fat in humans and other vertebrates, as w ...

s causing a

fatty liver Fatty liver disease (FLD), also known as hepatic steatosis, is a condition where excess fat builds up in the liver. Often there are no or few symptoms. Occasionally there may be tiredness or pain in the upper right side of the abdomen. Complica ...

. As three carbon molecules cannot be used to make glucose, they will instead be made into

pyruvate Pyruvic acid (CH3COCOOH) is the simplest of the alpha-keto acids, with a carboxylic acid and a ketone functional group. Pyruvate, the conjugate base, CH3COCOO−, is an intermediate in several metabolic pathways throughout the cell. Pyruvic a ...

and

lactate Lactate may refer to: * Lactation, the secretion of milk from the mammary glands * Lactate, the conjugate base of lactic acid Lactic acid is an organic acid. It has a molecular formula . It is white in the solid state and it is miscible with w ...

. These acids cause a drop in the pH of the blood (a

metabolic acidosis Metabolic acidosis is a serious electrolyte disorder characterized by an imbalance in the body's acid-base balance. Metabolic acidosis has three main root causes: increased acid production, loss of bicarbonate, and a reduced ability of the kidneys ...

Acetyl CoA Acetyl-CoA (acetyl coenzyme A) is a molecule that participates in many biochemical reactions in protein, carbohydrate and lipid metabolism. Its main function is to deliver the acetyl group to the citric acid cycle (Krebs cycle) to be oxidized for ...

(acetyl co-enzyme A) will also build up, leading to the creation of

ketone bodies Ketone bodies are water-soluble molecules that contain the ketone groups produced from fatty acids by the liver ( ketogenesis). Ketone bodies are readily transported into tissues outside the liver, where they are converted into acetyl-CoA (acet ...

Diagnosis

Diagnosis is made by measurement of FDPase in cultured lymphocytes and confirmed by detection of mutation of FBP1, encoding FDPase.

Treatment

To treat people with a deficiency of this enzyme, they must avoid needing gluconeogenesis to make glucose. This can be accomplished by not fasting for long periods, and eating high-carbohydrate food. They should avoid fructose containing foods (as well as

sucrose Sucrose, a disaccharide, is a sugar composed of glucose and fructose subunits. It is produced naturally in plants and is the main constituent of white sugar. It has the molecular formula . For human consumption, sucrose is extracted and refine ...

which breaks down to fructose). As with all single-gene metabolic disorders, there is always hope for genetic therapy, inserting a healthy copy of the gene into existing liver cells.

References

External links