Carbohydrate metabolism

Carbohydrate metabolism denotes the various biochemical processes responsible for the formation, breakdown and interconversion of carbohydrates in living organisms.

The most important carbohydrate is glucose, a simple sugar (monosaccharide) that is metabolized by nearly all known organisms. Glucose and other carbohydrates are part of a wide variety of metabolic pathways across species: plants synthesize carbohydrates from atmospheric gases by photosynthesis storing the absorbed energy internally, often in the form of starch or lipids. Plant components are eaten by animals and fungi, and used as fuel for cellular respiration. Oxidation of one gram of carbohydrate yields approximately 4 kcal of energy and from lipids about 9 kcal. Energy obtained from metabolism (e.g. oxidation of glucose) is usually stored temporarily within cells in the form of ATP. Organisms capable of aerobic respiration metabolize glucose and oxygen to release energy with carbon dioxide and water as byproducts.

Carbohydrates are a superior short-term fuel for organisms because they are simpler to metabolize than fats or those amino acid portions of proteins that are used for fuel. In animals, the most important carbohydrate is glucose; so much so, that the level of glucose is used as the main control for the central metabolic hormone, insulin. Starch, and cellulose in a few organisms (eg, termites, ruminants, and some bacteria), both being glucose polymers, are disassembled during digestion and absorbed as glucose. Some simple carbohydrates have their own enzymatic oxidation pathways, as do only a few of the more complex carbohydrates. The disaccharide lactose, for instance, requires the enzyme lactase to be broken into its monosaccharides components; many animals lack this enzyme in adulthood.

Carbohydrates are typically stored as long polymers of glucose molecules with glycosidic bonds for structural support (e.g. chitin, cellulose) or for energy storage (e.g. glycogen, starch). However, the strong affinity of most carbohydrates for water makes storage of large quantities of carbohydrates inefficient due to the large molecular weight of the solvated water-carbohydrate complex. In most organisms, excess carbohydrates are regularly catabolised to form acetyl-CoA, which is a feed stock for the fatty acid synthesis pathway;

1

fatty acids, triglycerides, and other lipids are commonly used for long-term energy storage. The hydrophobic character of lipids makes them a much more compact form of energy storage than hydrophilic carbohydrates. However, animals, including humans, lack the necessary enzymatic machinery and so do not synthesize glucose from lipids.

All carbohydrates share a general formula of approximately CnH2nOn; glucose is C6H12O6. Monosaccharides may be chemically bonded together to form disaccharides such as sucrose and longer polysaccharides such as starch and cellulose.

Catabolism

Oligo/polysaccharides are typically cleaved into smaller monosaccharides by enzymes called glycoside hydrolases. The monosaccharide units then enter monosaccharide catabolism. Organisms vary in the range of monosaccharides they can absorb and use, and also in the range of more complex carbohydrates they are capable of disassembling.

Metabolic pathways

Carbon fixation , or photosynthesis, in which CO2 is reduced to carbohydrate.

Glycolysis - the oxidation metabolism of glucose molecules to obtain ATP and

pyruvate Pyruvate from glycolysis enters the Krebs cycle, also known as the citric acid cycle, in aerobic organisms after moving through pyruvate dehydrogenase complex.

The pentose phosphate pathway, which acts in the conversion of hexoses into pentoses and in NADPH regeneration.

Glycogenesis - the conversion of excess glucose into glycogen as a cellular storage mechanism; this prevents excessive osmotic pressure buildup inside the cell

Glycogenolysis - the breakdown of glycogen into glucose, which provides a glucose supply for glucose-dependent tissues.

Gluconeogenesis - de novo synthesis of glucose molecules from simple organic compounds. an example in humans is the conversion of a few amino acids in cellular protein to glucose.

Metabolic use of glucose is highly important as an energy source for muscle cells and in the brain, and red blood cells.

2

Glucoregulation

Glucoregulation is the maintenance of steady levels of glucose in the body; it is part of homeostasis, and so keeps a constant internal environment around cells in the body.

The hormone insulin is the primary regulatory signal in animals, suggesting that the basic mechanism is very old and very central to animal life. When present, it causes many tissue cells to take up glucose from the circulation, causes some cells to store glucose internally in the form of glycogen, causes some cells to take in and hold lipids, and in many cases controls cellular electrolyte balances and amino acid uptake as well. Its absence turns off glucose uptake into cells, reverses electrolyte adjustments, begins glycogen breakdown and glucose release into the circulation by some cells, begins lipid release from lipid storage cells, etc. The level of circulatory glucose (known informally as "blood sugar") is the most important signal to the insulin producing cells. Because the level of circulatory glucose is largely determined by the intake of dietary carbohydrates, diet controls major aspects of metabolism via insulin. In humans, insulin is made by beta cells in the pancreas, fat is stored in adipose tissue cells, and glycogen is both stored and released as needed by liver cells. Regardless of insulin levels, no glucose is released to the blood from internal glycogen stores from muscle cells.

The hormone glucagon, on the other hand, has an effect opposite to that of insulin, forcing the conversion of glycogen in liver cells to glucose, which is then released into the blood. Muscle cells, however, lack the ability to export glucose into the blood. The release of glucagon is precipitated by low levels of blood glucose. Other hormones, notably growth hormone, cortisol, and certain catecholamines (such as epinepherine) have glucoregulatory actions similar to glucagon.

Human diseases of carbohydrate metabolism

Diabetes mellitus

Diabetes mellitus, often simply referred to as diabetes—is a group of metabolic diseases in which a person has high blood sugar, either because the body does not produce enough insulin, or because cells do not respond to the insulin that is produced. This high blood sugar

3

produces the classical symptoms of polyuria (frequent urination), polydipsia (increased thirst) and polyphagia (increased hunger).

There are three main types of diabetes:

Type   1 diabetes : results from the body's failure to produce insulin, and presently requires the person to inject insulin. (Also referred to as insulin-dependent diabetes mellitus, IDDM for short, and juvenile diabetes.)

Type   2 diabetes : results from insulin resistance, a condition in which cells fail to use insulin properly, sometimes combined with an absolute insulin deficiency.

Gestational diabetes : is when pregnant women, who have never had diabetes before, have a high blood glucose level during pregnancy. It may precede development of type 2 DM.

Other forms of diabetes mellitus include congenital diabetes, which is due to genetic defects of insulin secretion, cystic fibrosis-related diabetes, steroid diabetes induced by high doses of glucocorticoids, and several forms of monogenic diabetes.

Definition

The term diabetes, without qualification, usually refers to diabetes mellitus, which roughly translates to excessive sweet urine (known as "glycosuria"). Several rare conditions are also named diabetes. The most common of these is diabetes insipidus in which large amounts of urine are produced (polyuria), which is not sweet (insipidus meaning "without taste" in Latin).

The term "type 1 diabetes" has replaced several former terms, including childhood-onset diabetes, juvenile diabetes, and insulin-dependent diabetes mellitus (IDDM). Likewise, the term "type 2 diabetes" has replaced several former terms, including adult-onset diabetes, obesity-related diabetes, and non-insulin-dependent diabetes mellitus (NIDDM). Beyond these two types, there is no agreed-upon standard nomenclature. Various sources have defined "type 3 diabetes" as: gestational diabetes,[4] insulin-resistant type 1 diabetes (or "double diabetes"), type 2 diabetes which has progressed to require injected insulin, and latent autoimmune diabetes of adults (or LADA or "type 1.5" diabetes)

4

Classification

Most cases of diabetes mellitus fall into three broad categories: type 1, type 2, and gestational diabetes. A few other types are described.

Type 1 diabetes

Type 1 diabetes mellitus is characterized by loss of the insulin-producing beta cells of the islets of Langerhans in the pancreas leading to insulin deficiency. This type of diabetes can be further classified as immune-mediated or idiopathic. The majority of type 1 diabetes is of the immune-mediated nature, where beta cell loss is a T-cell mediated autoimmune attack.[6] There is no known preventive measure against type 1 diabetes, which causes approximately 10% of diabetes mellitus cases in North America and Europe. Most affected people are otherwise healthy and of a healthy weight when onset occurs. Sensitivity and responsiveness to insulin are usually normal, especially in the early stages. Type 1 diabetes can affect children or adults but was traditionally termed "juvenile diabetes" because it represents a majority of the diabetes cases in children.

Type 2 diabetes

Type 2 diabetes mellitus is characterized by insulin resistance which may be combined with relatively reduced insulin secretion. The defective responsiveness of body tissues to insulin is believed to involve the insulin receptor. However, the specific defects are not known. Diabetes mellitus due to a known defect are classified separately. Type 2 diabetes is the most common type.

In the early stage of type 2 diabetes, the predominant abnormality is reduced insulin sensitivity. At this stage hyperglycemia can be reversed by a variety of measures and medications that improve insulin sensitivity or reduce glucose production by the liver.

Gestational diabetes

Gestational diabetes mellitus (GDM) resembles type 2 diabetes in several respects, involving a combination of relatively inadequate insulin secretion and responsiveness. It occurs in about 2%–5% of all pregnancies and may improve or disappear after delivery. Gestational diabetes is fully treatable but requires careful medical supervision throughout the pregnancy. About 20%–50% of affected women develop type 2 diabetes later in life.

5

Even though it may be transient, untreated gestational diabetes can damage the health of the fetus or mother. Risks to the baby include macrosomia (high birth weight), congenital cardiac and central nervous system anomalies, and skeletal muscle malformations. Increased fetal insulin may inhibit fetal surfactant production and cause respiratory distress syndrome. Hyperbilirubinemia may result from red blood cell destruction. In severe cases, perinatal death may occur, most commonly as a result of poor placental perfusion due to vascular impairment. Labor induction may be indicated with decreased placental function. A cesarean section may be performed if there is marked fetal distress or an increased risk of injury associated with macrosomia, such as shoulder dystocia.

Other types

Pre-diabetes indicates a condition that occurs when a person's blood glucose levels are higher than normal but not high enough for a diagnosis of type 2 diabetes. Many people destined to develop type 2 diabetes spend many years in a state of pre-diabetes

Following is a comprehensive list of other causes of diabetes:

Genetic defects of β-cell Function

o Maturity onset diabetes of the young (MODY)

o Mitochondrial DNA mutations

Genetic defects in insulin processing or insulin action

o Defects in proinsulin conversion

o Insulin gene mutations o Insulin receptor

mutations Exocrine Pancreatic Defects

o Chronic pancreatitis o Pancreatectomy o Pancreatic neoplasia o Cystic fibrosis o Hemochromatosis

Endocrinopathies o Growth hormone

excess (acromegaly) o Cushing syndrome o Hyperthyroidism o Pheochromocytoma o Glucagonoma

Infections o Cytomegalovirus

infection o Coxsackievirus B

Drugs o Glucocorticoids o Thyroid hormone

o β-adrenergic agonists

6

o Fibrocalculous pancreatopathy

Signs and symptoms

Overview of the most significant symptoms of diabetes.

The classical symptoms of diabetes are polyuria (frequent urination), polydipsia (increased thirst) and polyphagia (increased hunger).[11] Symptoms may develop rapidly (weeks or months) in type 1 diabetes while in type 2 diabetes they usually develop much more slowly and may be subtle or absent.

Prolonged high blood glucose causes glucose absorption, which leads to changes in the shape of the lenses of the eyes, resulting in vision changes; sustained sensible glucose control usually returns the lens to its original shape. Blurred vision is a common complaint leading to a diabetes diagnosis; type 1 should always be suspected in cases of rapid vision change, whereas with type 2 change is generally more gradual, but should still be suspected.

People (usually with type 1 diabetes) may also present with diabetic ketoacidosis, a state of metabolic dysregulation characterized by the smell of acetone; a rapid, deep breathing known as Kussmaul breathing; nausea; vomiting and abdominal pain; and an altered states of consciousness.

A rarer but equally severe possibility is hyperosmolar nonketotic state, which is more common in type 2 diabetes and is mainly the result of dehydration. Often, the patient has been drinking extreme amounts of sugar-containing drinks, leading to a vicious circle in regard to the water loss.

A number of skin rashes can occur in diabetes that are collectively known as diabetic dermadromes.

Causes

7

The cause of diabetes depends on the type. Type 2 diabetes is due primarily to lifestyle factors and genetics.

Type 1 diabetes is also partly inherited and then triggered by certain infections, with some evidence pointing at Coxsackie B4 virus. There is a genetic element in individual susceptibility to some of these triggers which has been traced to particular HLA genotypes (i.e., the genetic "self" identifiers relied upon by the immune system). However, even in those who have inherited the susceptibility, type 1 diabetes mellitus seems to require an environmental trigger.

Diagnosis

See also: Glycosylated hemoglobin and Glucose tolerance test2006 WHO Diabetes diagnosis criteria[13]  edit

Condition 2 hour glucose Fasting glucosemmol/l(mg/dl) mmol/l(mg/dl)

Normal <7.8 (<140) <6.1 (<110)Diabetes mellitus ≥11.1 (≥200) ≥7.0 (≥126)

Diabetes mellitus is characterized by recurrent or persistent hyperglycemia, and is diagnosed by demonstrating any one of the following:[9]

Fasting plasma glucose level ≥ 7.0 mmol/L (126 mg/dL). Plasma glucose ≥ 11.1 mmol/L (200 mg/dL) two hours after a

75 g oral glucose load as in a glucose tolerance test. Symptoms of hyperglycemia and casual plasma glucose

≥ 11.1 mmol/L (200 mg/dL). Glycated hemoglobin (Hb A1C) ≥ 6.5%.

A positive result, in the absence of unequivocal hyperglycemia, should be confirmed by a repeat of any of the above-listed methods on a different day. It is preferable to measure a fasting glucose level because of the ease of measurement and the considerable time commitment of formal glucose tolerance testing, which takes two hours to complete and offers no prognostic advantage over the fasting test. According to the current definition, two fasting glucose measurements above 126 mg/dL (7.0 mmol/L) is considered diagnostic for diabetes mellitus.

People with fasting glucose levels from 100 to 125 mg/dL (5.6 to 6.9 mmol/L) are considered to have impaired fasting glucose. Patients

8

with plasma glucose at or above 140 mg/dL (7.8 mmol/L), but not over 200 mg/dL (11.1 mmol/L), two hours after a 75 g oral glucose load are considered to have impaired glucose tolerance. Of these two pre-diabetic states, the latter in particular is a major risk factor for progression to full-blown diabetes mellitus as well as cardiovascular disease.

MedicationsOral medications

Routine use of aspirin has not been found to improve outcomes in uncomplicated diabetes.

Insulin

Type 1 treatments usually include combinations of regular or NPH insulin, and/or synthetic insulin analogs.

Glucose tolerance progressively declines with age, leading to a high prevalence of type 2 diabetes and postchallenge hyperglycemia in the older population. Age-related glucose intolerance in humans is often accompanied by insulin resistance, but circulating insulin levels are similar to those of younger people. Treatment goals for older patients with diabetes vary with the individual, and take into account health status, as well as life expectancy, level of dependence, and willingness to adhere to a treatment regimen. Glycated hemoglobin is better than fasting glucose for determining risks of cardiovascular disease and death from any cause.

Glycogen Storage Disease

*The underlying problem in all of the glycogen storage diseases is the use and storage of glycogen.

9

Glycogen is the storage form of glucose (sugar). To briefly review metabolism, a simple form of sugar

(glucose) is our bodies’ main source of energy .After we eat, we have too much glucose in our blood, so our bodies store the extra glucose in the form of glycogen (much like we deposit our extra money in a bank). When our bodies need more energy, certain enzymes convert the glycogen back to glucose and withdraw it from the liver and the muscles (just like we withdraw spending money from the bank). Glycogen is a complex material made of individual glucoses linked together in long chains with many branches off the chains (just like a tree). Sometimes GSDs are also referred to as glycogenoses because they are caused by difficulty in glycogen metabolism.

A person with a Glycogen Storage Disease (GSD) has an absence or deficiency of one of the enzymes responsible for making or breaking down glycogen in the body. This is called an enzyme deficiency. The enzyme deficiency causes either abnormal tissue concentrations of glycogen (too much or too little) or incorrectly or abnormally formed glycogen (shaped wrong). Depending on the type of GSD a person has, their enzyme deficiency may be important in all parts of the body, or only in some parts of the body, like the liver or muscle. Typically, the forms of GSD are described by the part of the body that has trouble because of the enzyme deficiency. The categories most often are: the liver only, the muscles only, or both the liver and the muscles.

Other systems that may be involved include blood cells (red blood cells, white blood cells, and platelets), heart, and kidneys amongst others.

All types of GSD cause the body to either not be able to make enough glucose, or not be able to use glucose as a form of energy. Determining what type of GSD a person has (diagnosis) depends on an individual's symptoms. Typically a doctor will do a physical examination and some blood and urine testing. Occasionally, a muscle and/or liver biopsy will be needed to measure the amount of a certain enzyme in that part of the

10

body.

There are about eleven known types of GSD, which are classified by a number, by the name of the defective enzyme, or by the name of the doctor who first described the condition. For example, Glycogen Storage Disease type Ia, caused by a defect in the enzyme glucose-6-phosphatase, was originally known as “von Gierke's Disease” but is also referred to as “Glucose-6-Phosphatase Deficiency Glycogen Storage Disease.

GSDs are genetic disorders. This means that they are caused by a change in a part of an individual’s genetic information. Our genetic information is stored on genes. Genes serve as the instruction manual for our bodies. They tell our bodies how to grow and function. They also determine our physical features, such as hair color and eye color. We have around 30,000 genes in every cell of our body. We get two sets of every gene, one set from our mother and one set from our father. This is why we appears to be a combination of our parents. Our parents have no control over which genes they pass on to us. The genes we inherit from our parents happen purely by chance.

If there is a change in the genetic information contained on one of these genes, our bodies are unable to read its instructions. Therefore, it may cause a difference in the way our body functions. This is similar to having a page missing out of an instruction manual for putting an appliance together. Without that page, we would be unable to properly assemble the appliance and it would not be able to work. Almost all forms of GSD occur when a child inherits an incorrect genetic instruction from both their mother and their father (autosomal recessive inheritance). Some forms of GSD are caused by a genetic change that is passed from mother to son (sex or X-linked inheritance).

Approximately 2.3 children per 100 000 births (1 in 43,000) have some form of glycogen storage disease.

Since glycogen storage diseases are hereditary, the primary risk factor for is having a family member with this disease.

11

Symptoms:

The symptoms of a glycogen storage disease depend on its type. The following is a list of common glycogen storage disease symptoms:

Low blood sugar

Enlarged liver

Slow growth

Muscle cramps

Symptoms of specific types of glycogen storage diseases include : Type I - Von Gierke Disease:

Enlarged liver and kidneys

Low blood sugar

High levels of lactate, fats, and uric acid in the blood

Impaired growth and delayed puberty

Bone thinning from osteoporosis

Increased mouth ulcers and infection

Type II - Pompe's Disease:

Enlarged liver and heart

In severe cases, muscle weakness and heart problems develop

In severe cases, infants may suffer heart failure by the age of 18 months

Milder forms of type II may not cause heart problems

Type III - Cori's Disease:

Swollen abdomen due to an enlarged liver

Growth delay during childhood

Low blood sugar

Elevated fat levels in blood

Possible muscle weakness

12

Type IV - Anderson's Disease:

Growth delay in childhood

Enlarged liver

Progressive cirrhosis of the liver (which may lead to liver failure)

May affect muscles and heart in late-onset type

Type V - McArdle's Disease:

Muscle cramps during exercise

Extreme fatigue after exercise

Burgundy-colored urine after exercise

Types VI, IX - Hers' Disease:

Liver enlargement occurs, but diminishes with age

Low blood sugar

Type VII- Tarui's Disease:

Muscle cramps with exercise

Anemia

Type VIII:

Muscle weakness

Anemia

Increased levels of uric acid

Diagnosis: Biopsy of the affected organs

Blood and urine samples

MRI scan – a test that uses magnetic waves to make pictures of the inside of the body

Treatment: Treatment will depend on the type of glycogen storage disease and the symptoms.

The goal of treatment is to maintain normal blood glucose levels. This may be done with:

13

A nasogastric infusion of glucose in infants and children under age two

Dietary changes, including:

o In children over age two, frequent small carbohydrate feedings are given throughout the day. This may include uncooked cornstarch. (Uncooked cornstarch provides a steady slow-release form of glucose.)

o Elimination of foods that are high in fructose or lactose (type I only)

o Allopurinol (Aloprim, Zyloprim) may be prescribed to reduce uric acid levels in the blood. This is done to prevent gout and kidney stones.

The goal of treatment is to avoid muscle fatigue and/or cramps induced by exercise. This is done by:

1. Regulating or limiting strenuous exercise to avoid fatigue symptoms

2. Improving exercise tolerance by oral intake of glucose or fructose (fructose must be avoided in people with type I), or an injection of glucagon

3. Eating a high protein diet

There is no way to prevent glycogen storage diseases. However, early treatment can help control the disease once a person has it. If you have a glycogen storage disease or a family history of the disorder, you can talk to a genetic counselor when deciding to have children.

GLYCOGENOLYSIS PATHWAY:

14

Galactosemia

Galactosemia is a rare, hereditary disorder of carbohydrate that means too much galactose(a sugar contained in milk, including human mother’s milk) in the bloodThere are many variants of the disease but most affect one of three enzymes:

GALT deficiency is the most common abnormality. The enzyme converts:

15

galactose-1-phosphate and UDP glucose to UDP galactose and glucose-1-phosphate. Patients with GALT deficiency have abnormal galactose tolerance. Galactokinase converts galactose to galactose-1-

phosphate and deficiency is rather more uncommon. Uridine diphosphate (UDP) galactose-4-epimerase

epimerises UDP galactose to UDP glucose and deficiency is also less common.

* This accumulation of galactose is a poison to the body and can cause serious complications such as the following and if untreated, as high as 75% of infants will die.

1. an enlarged liver2. kidney failure3. cataract4. brain damage

Because milk is the staple of an infant's diet, early diagnosis and treatment of this disorder is absolutely essential to avoid serious lifelong disability..Genetics of GalactosemiaA person unaffected by galactosemia (neither carrier nor galactosemic) inherits two ‘normal' genes for the production of the GALT enzyme. This person's genotype would be N/N and their enzyme activity would be normal.A person who is a carrier of classic galactosemia inherits one normal gene from one parent and one gene containing the error that leads to classic galactosemia from the other parent. This person's genotype would be G/N and their enzymeactivity would be less than normal, but not so much so as to cause medicalcomplications or require dietary management. A person who is classic galactosemic inherits two genes with the error, one from each of his/her parents.This person's genotype would be G/G and their enzyme activity would be essentially zero.Genotypes involving the Duarte variant gene include:D/N = carrier of Duarte galactosemia (about 75% enzyme activity)D/D = homozygous carrier of Duarte galactosemia (about 50% enzyme activity)D/G = Duarte galactosemia (about 25 - 50% enzyme activity ??)

16

Duarte Galactosemia is a variant of classic galactosemia. Patients with this genetic make-up are frequently referred to as D/G galactosemics.Diagnosis of Duarte galactosemia is made usually within the first weeks of life by the same blood test used to diagnose classic galactosemia.Classic galactosemia is the most severe form.PresentationThis may be rather variable and not all features listed below will be found. It almost invariably presents in the neonatal period. Variant disease can presentlater in life.

There is often feeding difficulty, with vomiting and failure to gain weight,

with poor growth in the first few weeks of life. Lethargy and hypotonia occur. Jaundice and hepatomegaly develop. There are often associated coagulation defects. Sepsis (often with E. coli) can be fatal. Cataracts may be apparent even in the early days of life. Ascites may even be apparent in early life. Developmental delay may affect speech, language and

general learning. In adults there is often short stature and there may be

ataxia and tremor. Hypergonadotrophic hypogonadism is common and in

women, prematureovarian failure. Prenatal diagnosis by amniocentresis is also available.Investigations If the child is having milk, and hence lactose that will be

split to glucoseand galactose, there will be galactose in the urine. This is a reducing sugarand so gives a positive test with Fehling's or Benedict's reagent but anegative test with glucose oxidase test strips. Galactose may appear in theurine of any patient with liver disease and in galactosaemia it can swiftly disappear. Liver function tests should be performed If there is doubt about cataracts, slit lamp examination by

an

17

ophthalmologist may be required. It should be performed as a routinescreening test every 6 months until the age of 3 and annually thereafter. The Beutler test involves a fluorescent spot test for GALT

activity. It is now widely used for the diagnosis of galactosaemia but will give false positives

with glucose-6-phosphate dehydrogenase deficiency. A quantitative erythrocyte analysis for GALT is required. A GALT isoelectric-focusing electrophoresis test helps

distinguish variant forms such as the Duarte defect. GALT genotyping may provide a specific molecular diagnosis if available.

Management# As soon as the diagnosis is made, milk should be discontinued to remove the lactose load. This will have some immediate benefit but will not halt all aspects of the disease. If an infant is to be fed without milk, the advice of a dietician should be sought. A certain amount of galactose is present even in fruit and vegetables and so total elimination is very difficult. As thepatient matures, the ability to tolerate lactose improves but milk should be restricted throughout life.# Antibiotics, intravenous fluids and vitamin K are often required.#Developmental delay will benefit from special attention to education and schooling. The help of speech and language therapy may be required as the problems of speech appear to be greater than would be expected merely from the reduced intelligence. .#The help of an endocrinologist may be required with hypergonadotrophic hypogonadism. Fertility is unlikely. With premature ovarian failure the use of HRT to prevent osteoporosis should be considered and androgendeficiency may well merit attention in men; however, the risk ofhypogonadism in men with the condition is much less than in affected women.# There are no drugs that are known to benefit this condition.# Puberty in girls may be induced by supervised gradual introduction of ethinylestradiol before moving to a low-dose combined oral contraceptive such as Loestrin®.# Sepsis and liver disease are treated as in any other situation. It is important to make the diagnosis early to implement lactose

18

avoidance to reduce long-term problems before such conditions as cirrhosis and cataracts develop; however, most patients will still develop at least one major complication.# If a woman with galactosaemia does become pregnant, the high level of galactose does not seem to have an adverse effect on the fetus. where the diet must be strictly observed in pregnancy.

TypeDiseases Database

OMIM Gene Locus Enzyme Name

Type 1

5056 230400 GALT 9p13

galactose-1-phosphate uridyl transferase

classic galactosemia

Type 2

29829 230200 GALK1 17q24 galactokinasegalactokinase deficiency

Type 3

29842 230350 GALE1p36-p35

UDP galactose epimerase

galactose epimerase deficiency, UDP-Galactose-4-epimerase deficiency

19