Inborn errors of metabolism are genetic disorders involving defects in metabolic pathways. Common types include disorders of carbohydrate metabolism like glycogen storage disease, amino acid metabolism like phenylketonuria, and organic acid metabolism. Symptoms result from substrate accumulation or product deficiency. Treatment focuses on dietary management to control metabolite levels and prevent complications like hypoglycemia, organ damage, and neurological decline. Strict dietary therapy and monitoring are needed lifelong for many of these inherited metabolic diseases.

1. z
INBORN
ERRORS OF
METABOLISM
Mrs.Keerthi Samuel
Asst.Professor,
VMCON

2. - Inborn errors of metabolism comprise a large
class of genetic diseases involving disorders
of metabolism.
- The majority are due to defects of single genes
that code for enzymes that facilitate
conversion of various substances (substrates)
into others (products).
- In most of the disorders, problems arise due to
accumulation of substances which are toxic or
interfere with normal function, or to the effects
of reduced ability to synthesize essential
compounds.
2

3. Inborn errors of metabolism
are now often referred to as
congenital metabolic
diseases or inherited
metabolic diseases
3

4. Garrod’s
hypothesis
A B
substrateexcess
Cproductdeficiency
Dtoxicmetabolite
4

5. z
CLASSIFICATION

6. Disorders of carbohydrate metabolism
• E.g., glycogen storage disease
Disorders of amino acid metabolism
• E.g., phenylketonuria , maple syrup urine disease
Disorders of organic acid metabolism (organic
acidurias)
• E.g., alcaptonuria
Disorders of porphyrin metabolism
• E.g., acute intermittent porphyria
Disorders of steroid metabolism
• E.g., congenital adrenal hyperplasia
• Lysosomal storage disorders
• E.g., Gaucher's disease
6

7. 7

9. z
Glycogen storage
disease
9
• Glycogen storage disease (GSD, also
glycogenosis and dextrinosis) is the result of
defects in the processing of glycogen synthesis
or breakdown within muscles, liver, and other cell
types. GSD has two classes of cause: genetic
and acquired.
• Genetic GSD is caused by any inborn error of
metabolism (genetically defective enzymes)
involved in these processes.

10. • Symptoms:
Hypoglycemia, Hyperlipidemia, Hepatomegaly,
Lactic
acidosis, and Hyperuricemia.
• Progression: Growth failure
• Enzyme deficiency:
(glucose-6-phosphatase)
which
is an
enzymethat hydrolyzesglucose-6-phosphate
resulting
in the
10
creation of a phosphate group and free glucose. This
deficiency impairs the ability of the liver to produce
free glucose from glycogen and from
gluconeogenesis. Since these are the two principal
metabolic mechanisms by which the liver supplies
glucose to the rest of the body during periods of
fasting, it causes severe hypoglycemia.

11. z
Treatment:
11
• The essential treatment goal is prevention of hypoglycemia
and the secondary metabolic derangements by frequent
feedings of foods high in glucose or starch (which is
readily digested to glucose). To compensate for the inability
of the liver to provide sugar, the total amount of dietary
carbohydrate should approximate the 24-hour glucose
production rate. The diet should contain approximately 65-
70% carbohydrate, 10-15% protein, and 20-25% fat. At
least a third of the carbohydrates should be supplied
through the night, so that a young child goes no more than
3–4 hours without carbohydrate intake
• Two methods have been used to achieve this goal in
young children:
(1) continuous nocturnal gastric infusion of glucose or
starch; and(2)

12. • Is an autosomal recessive metabolic disorder, which
damages muscle and nerve cells throughout the body. It
is caused by an accumulation of glycogen in the
lysosome due to deficiency of the lysosomal acid
alpha-glucosidase enzyme that transforms glycogen
into glucose in lysosomes.
• The build-up of glycogen causes progressive muscle
weakness (myopathy) throughout the body and affects
various body tissues, particularly in the heart, skeletal
muscles, and weakness facial and oral muscles.
Pompe's disease is one of the infiltrative causes of
restrictive cardiomyopathy and hepatomegaly.
• caused by a mutation in a gene (acid alpha-glucosidase:
also known as acid maltase) on long arm of chromosome
17. 12

14. Nutrition & Weight Maintenance
• Because of weakened facial and oral muscles, patients of all
ages, from infants to adults, may experience difficulties eating.
Trouble with sucking, chewing, and/or swallowing can lead to
insufficient caloric intake, problems maintaining a healthy
weight, and a general failure to thrive. Inadequate nutrition
may even lead to endogenous muscle protein breakdown.
Several approaches can address these issues:
• Physical therapy to help strengthen muscles and allow for
independent feeding.
• Modification of food texture to facilitate swallowing and reduce
the risk of aspiration.
• Carefully balanced diets to maximize nutrients and provide
protein to
muscles.
• Tube feeding, most commonly in severely ill infants.
14

15. Treatment:
• In 2006, the European Medicines Agency (EMEA) and
the U.S. Food and Drug Administration (FDA) both
granted marketing approval for the drug Myozyme
(alglucosidase alfa) for treatment of Pompe disease.
Myozyme replaces the enzyme missing in the disease,
which helps break down glucose.
• Early diagnosis and early treatment leads to much better
outcomes.
• Progression: Death by age ~2 years.
15

16. • Is a metabolic disorder, caused by a deficiency of enzyme
Myophosphorylase, which is the muscle isoform of the
enzyme glycogen phosphorylase.
• This enzyme helps break down glycogen into glucose-1-
phosphate, so that it can be utilized within the muscle
cell.
• Symptoms: The onset of this disease is usually noticed
in childhood, but often not diagnosed until the third or
fourth decade of life. Symptoms include exercise
intolerance with myalgia, early fatigue, painful cramps,
weakness of exercising muscles and myoglobinuria.
Myoglobinuria, the condition where myoglobin is present
in urine, may result from serious damage to the muscles,
or rhabdomyolysis, where skeletal muscle cells
breakdown rapidly, sending their contents into the16

17. Treatment/Thera
py
• Oral vitamin
B6
appears
t
o
impart
greate
r
resistance
t
o
fatigue. No
specific
therapy exists, but combined
aerobicexercise programs and high-protein diets may help. Some
patients learn the limits of their exercise and work within
their restrictions, going on to live fairly normal lives.
• Supervised exercise programs have
been recommended to lessen the risks of
extended inactivity.
• Sucrose treatment is now being recommended prior to
exercise.
• Progression: Renal failure due to muoglobinuria.
17

19. Vit B6 rich food High proteins food
Spinach
Red bell
peppers Garlic
Carrots
Peas
Potatoe
s Milk
Egg
Fis
h
Live
r
Meat (red)
Broccoli
Soy protein
isolate Gelatin
Egg,
white
Fish
meat
Milk
Chicken
Nuts
Peanut
butter
Steak
Cheese
Hamburger
Broccoli 19

20. Type
of
GSD
Eponym Enzyme deficiency Progression
and
Complication
s
GSD III Cori’s or Forbes
disease
Glycogen
debrancher
Hypoglycemia and
myopathy
GSD IV Andersen
disease
Glycogen
branching
Enzyme
Liver cirrhosis,
death at age ~5 years
GSD VI Hers disease Liver glycogen
phosphorylase
Hypoglycemia and
Hepatomegaly
GSD IX Phosphorylase
kinase
Delayed motor
development, Growth
retardation
GSD XI Fanconi-
Bickel
syndrome
Glucose
transporter,
GLUT2
Hypoglycemia
and
Hepatomegaly
GSD XII Red Cell
Aldolase
Aldolase A Exercise intolerance,
and muscle cramps

21. 21

22. • (PKU) is an autosomal recessive metabolic genetic
disorder characterized by a deficiency in the hepatic
enzyme phenylalanine hydroxylase (PAH). This enzyme
is necessary to metabolize the phenylalanine (Phe) to
the tyrosine. When PAH is deficient, phenylalanine
accumulates and is converted into phenylpyruvate, which
is detected in the urine.
• It can cause problems with brain development, leading to
progressive mental retardation, brain damage, and
seizures.
• Optimal treatment involves lowering blood (Phe) levels to
a safe range and monitoring diet and cognitive
development.
22

23. Signs and Symptoms:
• the disease may present clinically with seizures, albinism
(excessively fair hair and skin), and a "musty odor" to the
baby's sweat and urine (due to phenylacetate, one of the
ketones produced).
• Treatment: by managing and controlling (Phe) levels through
diet, or
a combination of diet and medication.
• All PKU patients must adhere to a special diet low in
phenylalanine for at least the first 16 years of their lives. This
requires severely restricting or eliminating foods high in
phenylalanine, such as meat, chicken, fish, eggs, nuts,
cheese, legumes, cow milk and other dairy products. Starchy
foods such as potatoes, bread, pasta, and corn must be
monitored.
• Infants require a commercial formula of milk that free from
23

25. • Tyrosine, which is normally derived from phenylalanine,
must be
supplemented.
• The sweetener of aspartame must be avoided, as
aspartame consists of two amino acids: phenylalanine
and aspartic acid.
• The oral administration of tetrahydrobiopterin (or BH4) (a
cofactor for the oxidation of phenylalanine) can reduce
blood levels of this amino acid in certain patients.
• For childhood, we can add some fruits and vegetables the
low in (Phe) which provide essential vitamins and
minerals.
25

26. 26

27. • Also called branched-chain ketoaciduria, is an autosomal
recessive metabolic disorder affecting branched-chain amino
acids. It is one type of organic acidemia.
• MSUD is caused by a deficiency of the branched-chain alpha-
keto acid dehydrogenase complex (BCKDH), leading to a
buildup of the branched-chain amino acids (leucine,
isoleucine, and valine) and their toxic by-products in the blood
and urine.
• The disease is characterized in an infant by the presence of
sweet- smelling urine, with an odor similar to that of maple
syrup. Infants with this disease seem healthy at birth but if left
untreated suffer severe brain damage and eventually die.
• From early infancy, symptoms of the condition include poor
feeding, vomiting, dehydration, lethargy, seizures,
hypoglycaemia, ketoacidosis, pancreatitis, coma and
neurological decline.
27

29. Management:
• Keeping MSUD under control requires careful monitoring
of blood chemistry and involves both a special diet and
frequent testing.
• A diet with minimal levels of the amino acids leucine,
isoleucine, and valine must be maintained in order to
prevent neurological damage. As these three amino
acids are required for proper metabolic function in all
people, specialized protein preparations containing
substitutes and adjusted levels of the amino acids have
been synthesized and tested, allowing MSUD patients to
meet normal nutritional requirements without causing
harm.
29

30. Leucine (Food) Isoleucine (Food) Valine (Food)
Soybeans
Lentils
Cowpea ‫ال‬‫ل‬‫و‬‫ب‬‫ي‬‫ا‬
Beef (lean and trimmed)
Peanuts
Salmon
fish
Shrimp
Nuts
Eggs
Eggs
Soy
protein
Seeweed
Milk
Cheese
Sesame
seeds
Sunflower
seeds Cod
liver
Closed to Isoleucine
sources
30

31. 31

32. • Alkaptonuria (black urine disease) is a rare inherited
genetic disorder of phenylalanine and tyrosine
metabolism. This is an autosomal recessive condition
that is due to a defect in the enzyme homogentisate 1,2-
dioxygenase, which participates in the degradation of
tyrosine.
• As a result, a toxic tyrosine byproduct called
homogentisic acid (or alkapton) accumulates in the
blood and is excreted in urine in large amounts.
Excessive homogentisic acid causes damage to cartilage
(leading to osteoarthritis) and heart valves as well as
precipitating as kidney stones.
32

34. • No treatment modality has been demonstrated to
reduce the
complications of alkaptonuria.
• Commonly recommended treatments include dietary
restriction of phenylalanine and tyrosine and large doses
of ascorbic acid (vitamin C).
• Dietary restriction may be effective in children, but
benefits in adults have not been demonstrated.
34

35. 35

36. • Congenital adrenal hyperplasia (CAH) refers to any of
several autosomal recessive diseases resulting from
mutations of genes for enzymes mediating the
biochemical steps of production of cortisol from
cholesterol by the adrenal glands (steroidogenesis).
• Most of these conditions involve excessive or deficient
production of sex steroids and can alter development of
primary or secondary sex characteristics in some affected
infants, children, or adults. Approximately 95% of cases of
CAH are due to 21-hydroxylase deficiency.
• Steroid 21-hydroxylase is one of a cytochrome P450
enzymes that is involved with the biosynthesis of the
steroid hormones aldosterone and cortisol.
36

38. Treatment:
• Supplying enough glucocorticoid to reduce hyperplasia
and overproduction of androgens or mineralocorticoids.
• Providing replacement mineralocorticoid and extra salt.
• Providing replacement testosterone or estrogen at puberty.
Diet:
• Patients with congenital adrenal hyperplasia should be on
an unrestricted diet.
• Patients should have ample access to salt because salt
wasting.
• Infants who have salt wasting generally benefit from
supplementation with NaCl (2-4 g/d) added to their formula.
• Caloric intake may need to be monitoredand restrictedif
excess
weight gain occurs because glucocorticoids stimulate appetite.
Activity: restriction is not necessary if appropriate glucocorticoid.
38

39. 39

40. • Gaucher's disease is a genetic disease in which a fatty
substan
ce
accumulates in cells and certain organs.
40
• It is caused by a hereditary
deficiency
glucocerebrosidase. The enzyme
acts on
of the
enzyme a
fatty
substance
glucocerebroside (also known as glucosylceramide).
• When the enzyme is defective, glucocerebroside
accumulates, particularly in white blood cells (mono &
lymphocyte).
• Glucocerebroside can collect in the spleen, liver, kidneys,
lungs, brain
and bone marrow.
Sign and Symptoms:
• Painless hepatomegaly, splenomegaly, mental retardation, and
rapid and premature destruction of blood cells, leading to

41. Treatment:
• The enzyme replacement therapy is essential for the
treatment.
• Osteoporosis can be reduced by Vit D.
• Gaucher patients have increased caloric requirements
because
they have higher-than-normal metabolism.
• Despite the need for more food, patients with pronounced
liver and/or spleen enlargement can frequently have a
suppressed appetite. The enlarged organs leave little
room in the body cavity for a full stomach, so patients
often report a sensation of feeling full, even after having
only a few bites of food.
41

43. • Galactosemia is an inherited disorder characterized by
an inability of the body to utilize galactose.
• Galactosemia means "galactose in the blood".
• The main source of galactose in the diet is milk products.
• The deficient enzyme that is responsible of galactosemia
is called galactose-1-phosphate uridyl transferase
(GALT). The GALT enzyme enables the body to break
down galactose into glucose for energy.
• Galactosemia is treated by removing foods that contain
galactose from the diet. Untreated galactosemia will
result in a harmful build-up of galactose and galactose-1-
phosphate in the bloodstream and body tissues.
43

44. • Infants with unrecognized galactosemia usually have
problems with feeding and do not grow as they should.
• If galactosemia is not treated, infants can develop
cataracts, liver disease, kidney problems, brain damage,
and in some cases, can lead to death.
Diet:
• The diet should allow most protein-containing foods other
than milk and milk products.
• Lactose is often used as a filler or inactive ingredient in
medicines, and might not be listed on the package.
44

46. z
Some foods contain galactose and are
unacceptable:
46
• Sherbet: Traditional cold drink prepared of species of
cherries,
rose, licorice or Hibiscus with diary products.
Butter Buttermilk and solids
Calcium caseinate Casein
Nonfat milk Cream
Dry milk and milk protein beans
Hydrolyzed protein made from casein Ice cream
Lactalbumin (milk albuminate) Lactose
Milk and milk solids Milk chocolate
Nonfat dry milk & solids Cheese
Organ meats (liver, heart, etc.) Sherbet
Sodium caseinate Sour cream
Whey ‫ال‬‫ل‬‫ب‬‫ن‬‫لصم‬ and wheysolids Yogurt

47. • Is a disorder characterized by the presence of a higher level of
methemoglobin in the blood.
• Methemoglobin is an oxidized form of hemoglobin, {the iron
within hemoglobin is oxidized from the ferrous (Fe2+) state to
the ferric (Fe3+) state}, that has no affinity for oxygen,
resulting in no oxygen delivery to the tissue, so hypoxia can
occur.
• Clinically, this condition causes cyanosis.
• The major cause of inborn is glucose-6-phosphate
dehydrogenase [G6PD] deficiency and cytochrome b5 oxidase
deficiency) or severe acidosis, which impairs the function of
cytochrome b5 oxidase.
• This is particularly evident in young infants with diarrhea, in
whom excessive stool bicarbonate loss leads to metabolic
acidosis.
47

48. • Ascorbic acid is an antioxidant that may also be
administered in
patients with methemoglobin levels of more than 30%.
• Oral ascorbic acid (200-500 mg) has been found to be
partially effective, some authors recommend using higher
doses of up to 1000 mg/d.
• Some vegetables (beets ‫بال‬‫ن‬‫ج‬‫,ر‬ spinach, and carrots) are
high in nitrite content, may need to be avoided in
susceptible patients as well as contaminated water of
nitrates and nitrites.
48

49. 6
8
Food Sources of Vit C
(adapted from world healthiest food; WHFood’s)
Food Serving size Calories Vit-C (mg)
Bell peppers, red, raw, slices 1 cup 24.8 174.8
Broccoli, steamed 1 cup 43.7 123.4
Strawberries 1 cup 43.2 81.70
Lemon juice, fresh ¼ cup 15.3 28.06
Grapefruit ½ each 36.9 46.86
Kiwifruit 1 each 46.4 57.00
Cantaloupe 1 cup 56.0 67.52
Oranges 1 each 61.6 69.70
Tomato, ripe 1 cup 37.8 34.38
Banana 1 each 108.1 10.75
Apples 1 each 81.4 7.87
Grapes 1 cup 61.6 3.68
Avocado, slices 1 cup 235 11.53

50. • Celiac Disease (CD) is a lifelong inherited autoimmune
condition affecting children and adults.
• When people with CD eat foods that contain gluten, it
creates an immune-mediated toxic reaction that causes
damage to the small intestine and does not allow food to
be properly absorbed. (For children, growth failure is the
biggest challenge)
• Even small amounts of gluten in foods can affect those
with CD and cause health problems.
• Damage occur to small bowel even when no symptoms
present
.
• Gluten can find in wheat, barley, and rye.
• Sensitivity of gluten is to Gliadin portion of
50

52. Gluten free diet (Accepted) Have Gluten (Not-Accepted)
•Fresh meats, fish and poultry
•Most dairy products (due to
Lactase deficiency, milk may be
restricted)
•Fruits
•Vegetables
•Rice
•Potatoes
•Gluten-free flours (soy, corn)
•Breads (bran, germ, & semolina)
•Cereals
•Crackers
•Pasta
•Cookies
•Cakes and pies
•Sauces
52
Reading food labels is important.
Actually, No treatment for celiac
disease.