Major Inborn Errors of Metabolism

The following points highlight the seven major inborn errors of metabolism. The inborn errors are: 1. Phenylketonuria (PKU) 2. Galactosemia 3. Refsum’s Disease 4. Maple-Syrup Urine Disease 5. Fructose Intolerance 6. Von Gierke’s Disease 7. Hyperlipidemia.

Metabolism: Inborn Error # 1. Phenylketonuria (PKU):

PKU occurs due to a defect in the metabolism of amino acid phenylalanine. The affected children show normal physical development but impaired mental development to a varying degree. The un­treated children become mentally defective adults.

i. The Biochemical and Genetic Defects:

a. PKU had been named by the finding of a ketone, phenyl pyruvic acid in the urine. The primary defect is in the phenylalanine hydroxylating system which converts the amino acid into tyrosine.

b. This system when cannot convert all of the phenylalanine derived from the pro­tein in a mother’s milk, the level in the blood rises and this causes the impaired development of the nervous system. Some of the excess phenylalanine is deaminated to phenyl pyruvic acid which is excreted in the urine.

c. Hydroxylation is effected by phenylala­nine hydroxylase (PH) and a coenzyme 5, 6, 7, 8-tetra-hydrobiopterin (BH₄). The coenzyme is oxidized to BH₂ from which it is reformed by another enzyme, di-hydrobiopterin reductase (DHPR). Hydroxylation may be impaired by genetic defects in production of pH of DHPR and of an enzyme responsible for the formation of BH₂.

d. The genes responsible for the control of the hydroxylation are not closely linked and may be on different chromosomes. The defects are transmitted by autosomal recessive inheritance. Unaffected hetero­zygous individuals act as carriers.

ii. Classical Phenylketonuria:

a. When the baby is at the age of 8 to 10 months, the parents may become anxious because their child is slow in learning to sit and handle things and is generally un­responsive.

b. About 25 p.c. of the affected children de­velop eczema.

c. The retarded development becomes obvi­ous and there may be signs of severe birth damage, such as myoclonic epilepsy and marked hyperactivity.

d. Most affected children grow up to become physically sound but are mentally defec­tive.

iii. Variant Forms:

Besides classical PKU, other forms of hyper-phenyl-alanemia are known and at least nine types have been recorded.

iv. Dietary Management:

a. Clinical symptoms do not arise in case the affected infant is put on a low phenyla­lanine diet soon after birth and kept on it for a long period.

b. A severe emotional strain is imposed on a young child on an entirely artificial diet.

c. As soon as the diagnosis is made, breast feeding should be stopped and the infant is bottle-fed with a low phenylalanine milk substitute.

d. Greater difficulty arises when the baby has to be weaned. A mother then has to pre­pare a low phenylalanine diet for her child from five lists of foods. Therefore, she needs continuing help from a dietician.

The lists are:

(i) Basic foods containing negligible phenylalanine which can be used freely (these include sugar, sweets, jams, solid vegetable oils and cook­ing oils).

(ii) Fruits and vegetables which can be taken freely since they provide neg­ligible phenylalanine and protein in a normal helping.

(iii) A basic list of 59 mg phenylalanine ex­changes of foods.

(iv) Manufacturer’s foods of negligible phe­nylalanine content.

(v) Exchanges of foods containing 50 mg of phenylalanine (by calculation taking one gram of protein as 50 mg phenylalanine).

Metabolism: Inborn Error # 2. Galactosemia:

This hereditary defect due to reduced activity of glucose-1 -phosphate uridyl transferase impairs the metabolism of galactose raising its concentration in the blood. Toxic signs appears soon after birth when an infant begins to take milk and are due to accumulation of galactose-1-phosphate within the cells. This defect is less common than phenylke­tonuria.

1. Clinical Features:

a. In infants in its se­vere form within two or three weeks after birth with the manifestation of vomiting, difficulty in feeding, loss of weight and the onset of jaundice.

b. The spleen may be palpable and the liver greatly enlarged and very firm, and ascites may be present.

c. Sugar (galactose) and protein are found in urine.

d. If not treated properly, cataracts may de­velop which may lead to blindness.

e. Mental and physical retardation are likely to occur.

f. Without immediate dietetic treatment of such severe cases death rapidly occurs.

g. Lack of galactokinase also causes rarer form of this disorder in which mental de­velopment is normal and the liver is not damaged but severe cataracts leading to blindness occur early in childhood.

ii. Diagnosis:

The raised blood galactose and the reduced glu­cose-l-phosphate uridyl transferase activity in erythrocytes confirm the disorder.

iii. Treatment:

a. Breast feeding should be stopped imme­diately and the infant should be given a milk powder in which lactose has been replaced by dextrin, dextrose and maltose.

b. Milk, milk products and food preparations containing these should be excluded from the diet. It is necessary to continue these restrictions throughout life.

c. The intake of galactosides, present in small quantities in most foods, and widely used in the food industry as a filler or flavouring agent, should be reduced.

d. Lactose is used in the pharmaceutical in­dustry in the formulation of many drug products. Such preparations can normally be taken with safety but when a patient requires large doses for a long time it may be wise to use an alternative drug.

Metabolism: Inborn Error # 3. Refsum’s Disease:

This is due to a defect in the enzyme systems re­sponsible for the metabolism of phytanic acid (3, 7, 1, 15-tetramethyl-hexadecanoic acid) which ac­cumulates in the plasma and tissues. Phytanic acid is derived from phytol, a product of the hydrolysis of chlorophyll.

i. Clinical Features:

a. The main features are peripheral neuropa­thy, cerebellar ataxia, nerve deafness and retinitis pigmentosa.

b. Symptoms usually first appear in child­hood and progress slowly, patients become severely disabled between the age of 20 to 30 years.

ii. Treatment:

a. Great improvement is possible by remov­ing phytanic acid by plasma exchange and by a diet low in chlorophyll.

b. There should be restriction of many fruits and vegetables, butter and ruminant fat.

Metabolism: Inborn Error # 4. Maple-Syrup Urine Disease:

A defect in the oxidative deamination of the branched-chain amino acids, leucine, isoleucine and valine, leads to accumulation of their oxyacid’s in the blood and these are excreted in the urine imparting an odour of maple syrup.

i. Clinical Features:

1. Soon after birth the infant has difficulty in feeding; loss of reflexes, convulsions and coma follow and in severe cases, death within a month.

b. Long survivors are mentally defective un­less fed with a formula diet low in leucine, isoleucine and valine.

c. A few children have been reared success­fully and when they are older, require a low protein diet based on gelatin, gluten- free flour, butter, sugar and fruits.

Metabolism: Inborn Error # 5. Fructose Intolerance:

The lack of the enzyme aldolase which converts fructose-l-phosphate to dihydroxyacetone phos­phate, and glyceraldehyde cause this disorder. When fructose is ingested, fructose-l-phosphate ac­cumulates in the liver. This interferes with release of glucose from the liver and leads to severe hypoglycemia.

i. Clinical Features:

a. There may be vomiting and hypoglycemic fits.

b. A series of episodes may lead to jaundice and enlargement of the liver.

c. The teeth of the patient do not show car­ies.

ii. Treatment:

Sucrose and fruit should be excluded from the diet.

Metabolism: Inborn Error # 6. Von Gierke’s Disease:

This is due to a defect in the low activity of glucose-6-phosphatase for which glycogen is not mo­bilised and large amounts accumulate in the liver. Most patients survive into adult life in this rare disorder.

i. Clinical Features:

a. Growth is retarded and there is marked en­largement of the liver so that the abdo­men is protruded.

b. Hypoglycemia and ketoacidosis may oc­cur in the new born and attacks may con­tinue throughout life, often brought on by an infection or temporary starvation.

c. Mental development is retarded only if episodes of hypoglycemia have been fre­quent and severe.

d. As the child grows up attacks of hypoglycemia become less severe.

ii. Treatment:

a. A diet high in protein accelerates gluconeogenesis from amino acids and so helps to maintain blood sugar.

b. In severe cases, frequent feeds every 3 to 4 hours may be required.

c. A moderate amount of carbohydrate is nec­essary, but this should be in the form of glucose or starch.

d. Both sucrose and lactose should be avoided, because fructose and galactose are readily converted to glycogen in the liver.

Metabolism: Inborn Error # 7. Hyperlipidemia:

Hyperlipidemia may arise from an increased con­centration of either cholesterol or triglycerides and frequently both are raised.

There is slow rise of cholesterol with age start­ing at 20 years but ceasing at about 60 years when it may be followed by a slight fall. The rise is less steep in women until the menopause when it may increase abruptly. After 60 years there is little or no difference between the sexes.

A high fasting plasma triglyceride is often as­sociated with a high plasma cholesterol, but is not by itself a risk factor for CHD.

Dietary cholesterol has little effect on plasma cholesterol over the range of intake since increas­ing intake inhibits endogenous production. Very high intakes, only obtainable by eating two or more eggs daily, raise plasma concentration and this can be lowered by eliminating the diets—eggs, meat, etc. Dietary cholesterol is much less important than dietary fat in determining plasma cholesterol.

People who subsist on diets high in starchy foods, like rice or maize, do not have high plasma triglycerides unless they are obese. Sucrose in large amounts may have a greater effect than starch in raising plasma triglycerides. Plasma cholesterol usually falls with increasing carbohydrate in the diet.

Alcohol favours hepatic lipogenesis and this stimulates the synthesis of VLDL as well as lead­ing to a fatty liver.

Familial Hypercholesterolemia:

This disorder consists of an increase in low density lipoproteins (LDL), the main carrier of cholesterol in the blood, and is due to genetic failure of LDL receptors.

i. Clinical Features:

a. There is a greatly increased risk of coro­nary heart disease. A heart attack due to myocardial infarction before the age of 30 is not uncommon and 50 p.c. of patients present evidence of CHD before they are 50 years old. Thus, it greatly reduces life expectancy.

b. Xanthomata, swellings or small tumours containing cholesterol and sometimes triglycerides, commonly occur. Common sites are tendons, especially the Achilles tendon and tendons on the back of the hands and skin, and around the eye where they are known as Xanthelasmata.

c. Corneal arcus occurs early and when seen in someone under 40 years is probably due to the disorder.

ii. Risk Factors of Hyperlipidemia:

iii. Management:

a. The coronary heart disease (CHD) may be prevented by lowering plasma LDL cho­lesterol level throughout life and begin­ning in early childhood. This needs life-long dietary restriction and the use of drugs.

b. Since clinical symptoms rarely arise be­fore the patient is an adult, early diagno­sis depends on the examination of the blood. Whenever the diagnosis is made in a new adult patient, a biochemical exami­nation of the blood should be made on as many of the near relatives as possible, es­pecially the children.

All affected mem­bers of the family should then be advised to begin life-long dietary restrictions to reduce plasma cholesterol and often pro­longed periods on a drug.

c. The diet should be low in saturated fats and cholesterol, but polyunsaturated fats from vegetable oils and in other foods are permitted.

d. Two drugs lower plasma cholesterol ef­fectively. Cholestyramine is an anion ex­change resin that absorbs bile salts and increases their excretion in the stools. Al­though this leads to increased synthesis of cholesterol, plasma cholesterol falls, gastrointestinal side effect may be severe.

Nicotinic acid in pharmacological doses (3-6 g/day) inhibits lipolysis and mobili­zation of free fatty acids from adipose tis­sue and also reduces plasma VLDL. Both drugs have been shown to be very safe in the short term. Nicotinic acid has vasodi­lator effects which cause hot flushing’s in some individuals but these are not seri­ous.

Reduction of plasma cholesterol for long periods increases the risk of stone formation in the bile and the incidence of gall bladder disease. A third drug, clofibrate, that lowers plasma cholesterol is no longer prescribed since its continued use has been associated with an increased number of deaths from a variety of causes.