Inborn errors of carbohydrate metabolism, Inborn errors, carbohydrate metabolism, glycogen storage disorders, glycogen storage diseases, congenital galactosemia, von gierkes disease, lactose intolerance, essential pentosuria

1. INBORN ERRORS OF
CARBOHYDRATE
METABOLISM
DR. UMOH, OFONMBUK

2. OUTLINE
• INTRODUCTION
• BRIEF OVERVIEW
• GLYCOGEN STORAGE DISEASES
• LACTOSE INTOLERANCE
• DISORDERS OF GALACTOSE
• DISORDERS OF FRUCTOSE
• ESSENTIAL PENTOSURIA
• SUMMARY & CONCLUSION
• REFERENCES 2

3. INTRODUCTION
• Inborn errors of metabolism are single gene
disorders resulting in enzymatic defects in the
biochemical pathways of the body.
• Although IEMs are individually rare, their
collective incidence is approximately 1 in 10,000.
• Most of them are inherited as autosomal recessive
disorders.
3

4. BRIEF OVERVIEW
• Sometimes, inborn errors may occur in the metabolism of
biomolecules, usually due to a defective enzyme. The
affected enzyme may either be absent or deficient.
4

5. • When such abnormalities occurs in metabolic pathways
involving the catabolism and anabolism of carbohydrates,
the resulting diseases are termed Inborn Errors of
Carbohydrate Metabolism.
• Glycogen Storage Disease (GSD), lactose intolerance,
galactosemia and hereditary disorders of fructose
metabolism are the common representatives of inborn
errors of carbohydrate metabolism.
5

6. GLYCOGEN STORAGE DISEASES
• Glycogen, although present in most tissue, is stored
principally in the liver and skeletal muscle to a larger
degree. During fasting, these muscle or liver glycogen is
converted to glucose to provide energy for the whole body.
• Glycogen storage disease are a group of diseases in which
enzyme deficiencies impair glycogen synthesis, glycogen
degradation and its resulting glycolysis.
6

7. • Glycogen storage diseases that affect the liver typically
cause hepatomegaly and hypoglycemia; those that affect
skeletal muscle cause exercise intolerance, progressive
weakness and cramping.
• Glycogen Storage Disease (GSD) is usually inherited as an
autosomal recessive disorder.
7

8. 8
GLYCOGEN STORAGE DISEASES CAN BE
CLASSIFIED INTO:
• Type I (Von Gierke’s disease)
• Type II (Pompe’s disease)
• Type III (Cori’s disease)
• Type IV (Andersen’s disease)
• Type V (McArdle’s disease)
• Type VI (Her’s disease)
• Type VII (Tarui’s disease)
• Type IX (Phosphorylase kinase deficiency)

9. INTERMEDIARY METABOLISM PATHWAYS
9

10. GLYCOGEN STORAGE DISEASE TYPE I (GSD-I)
• Also known as von Gierke’s disease.
• This is the most common type of glycogen storage disease,
and accounts for 90% of all glycogen storage disease cases.
• It is due to absence or severe deficiency of glucose-6-
phosphatase in liver and kidneys.
• Conversion of glucose-6-phosphate into glucose does not
occur.
10

11. …GSD-1
Clinical features in GSD-1 includes:
• Fasting Hypoglycemia
• Massive hepatomegaly
• Growth retardation
• Lactic acidosis
• Hyperlipidemia
• Failure of blood glucose to increase in response to oral or
intravenous galactose administration is diagnostic.
• Also, low Gluc-6-phosphatase activities can be assayed in liver
biopsy.
11

12. GLYCOGEN STORAGE DISEASE TYPE II
• Also known as Pompe’s disease
• There is lysosomal alpha-1,4-glucosidase deficiency
• Glycogen accumulates in lysosomes of skeletal and cardiac
muscles
• There is progressive muscle weakness and hypotonia,
cardiomegaly and CCF.
• Involvement of respiratory muscles my cause difficulty in
breathing
• Serum CK and LDH will be elevated. 12

13. GLYCOGEN STORAGE DISEASE TYPE III
• Also known as Cori’s disease.
• There is deficiency of the debranching enzyme amylo-1,6-
glucosidase
• Glycogenolysis stops at the branch point, producing Limit
Dextrins, of which excess gets deposited in tissues.
• Therefore, this disease is also known as limit dextrinosis.
• Clinical features include: hypoglycemia, hepatomegaly, muscle
weakness/atrophy, growth retardation.
13

14. GLYCOGEN STORAGE DISEASE TYPE IV
• Also known as Andersen’s disease
• There is deficiency of the branching enzyme: amylo-1,4
1,6 -transglucosidase
• Therefore, glycogen having very few branches, resembling
amylopectins, accumulates in the liver and muscles tissues.
• There is growth retardation, hepatomegaly, liver cirrhosis
and liver failure, as well as hypotonia, muscle weakness and
atrophy.
14

15. GLYCOGEN STORAGE DISEASE TYPE V
• This is also known as McArdle’s disease.
• There is deficiency of muscle phosphorylase enzyme.
Hence, glycogen accumulates in the muscles.
• It manifests in adulthood as exercise intolerance and
cramps on exercise. Avoiding strenuous exercise helps to
prevent the symptoms.
• Serum CK is highly elevated with physical activity.
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16. GLYCOGEN STORAGE DISEASE TYPE VI
• Also known as Her’s disease.
• There is deficiency of liver phosphorylase enzyme, causing
glycogen accumulation in the liver.
• Hypoglycemia and hepatomegaly are the usual clinical
abnormalities. Though mild ketosis also occurs.
• The condition improves with age.
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17. GLYCOGEN STORAGE DISEASE TYPE VII
• This is also known as Tarui’s disease.
• There is deficiency of the enzyme phosphofructokinase (PFK) in
the muscles.
• PFK is a glycolytic enzyme with 4 isoforms M, B and L.
• The muscles have the M form only, which is defective in this
disease.
• The clinical features include cramps on exercise and easy
fatigability, and severe exercise may cause myoglobinuria.
• Some degree of hemolysis is present, from PFK deficiency in RBCs 17

18. GLYCOGEN STORAGE DISEASE TYPE IX
• This is due to phosphorylase kinase deficiency in the liver.
• Therefore, hypoglycemia occurs due to decreased
glycogenolysis in the liver. 18

19. DIAGNOSIS OF GLYCOGEN STORAGE DISEASES
• The presenting symptom of GSD with liver involvement is
usually a marked hepatomegaly.
• A careful history, clinical findings with a tendency for
hypoglycemia (fasting/stressor) can help to differentiate
these GSDs from other types of GSD.
• Today, definite diagnosis is usually established by
measurement of enzyme activity in blood cells or mutational
analysis, if possible. If these investigations are not
conclusive, a biopsy is done to measure enzyme activity in
liver/muscle tissue, as well as assay for glycogen
19

20. • Biotinidase activity has been proposed for use, as a useful
screening parameter with a sensitivity of about 100% for
patients with GSD I, III, IV, VI & IX. However,
conformational diagnostic investigations for the specific
type are always necessary.
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21. 21

22. 22

23. LACTOSE INTOLERANCE
• This is due to the congenital absence or deficiency of lactase.
• The enzyme lactase is located in the brush border (microvilli)
of the small intestine. It hydrolyzes dietary lactose into the
monosaccharides: glucose and galactose, for transport across
epithelial cell membranes.
• When lactase is absent or deficient, unhydrolyzed lactose
remains in the intestinal lumen. Fluid is osmotically driven into
the intestine, increasing the volume and fluidity of the
gastrointestinal contents, allowing undigested lactose to enter
the colon.
23

24. • The fermentation of lactose by colonic microflora produces
lactic acid and hydrogen. In the presence of methanogenic
bacteria, hydrogen and carbon dioxide combine together to
form methane gas in the colon.
• Bloating, abdominal distension, flatulence and non-specific
abdominal pains as well as diarrhea may occur.
• The most accurate test for the diagnosis of lactose
intolerance is an intestinal biopsy to measure the mucosal
lactase activity.
24
…Lactose intolerance

25. • The lactose hydrogen breath test, which is non-invasive and
cost effective, is currently considered to be the best
diagnostic test for identifying lactose intolerance. After
fasting for at least 12hrs, lactose, at a concentration of 1
gm/kg body weight dissolved into a 20% solution with water,
and given to the patient.
• Breath samples are collected at 20-minute intervals for 2
hours. An increase in breath hydrogen or methane in three
consecutive samples confirms the diagnosis of lactose
intolerance. A meta-analysis found that the overall sensitivity
for the breath test to be 0.88 and the specificity 0.85.
25
…Lactose intolerance

26. • The mainstay of treatment for lactose intolerance is
avoidance of all lactose containing food especially milk
products, but that is typically not necessary.
• Yogurt is an option for patients diagnosed with lactose
intolerance, because lactose is digested by yoghurt bacteria,
improving absorption compared with other dairy products.
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Treatment

27. DISORDERS OF GALACTOSE
• Deficiency of galactose-1-phosphate uridyl
transferase (GALT) in the liver…most common form.
• Deficiency of Galactokinase (GALK), which catalyzes
the conversion of galactose to galactose-1-
phosphate.
• Deficiency of galactose-6-phosphate epimerase
(GALE).
27
There are 3 forms of the Congenital
galactosemia
Diagnosis is clinical, and by assessment of these deficient
enzymes in blood.

28. • NOTE: Galactosemia and galactosuria
occurs after ingestion of milk.
• Here, galactose ingested as this milk
sugar cannot be metabolized. Hence
accumulates.
• Galactose is excreted in urine, even soon
after birth. Also, there is hypoglycemia,
hepatomegaly jaundice, growth
retardation, convulsion, premature
cataract, mental retardation.
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Congenital galactosemia …contd

29. DISORDERS OF FRUCTOSE
1. Essential Fructosuria – a rare, benign elevation of
fructose level in blood and eventually urine, due to
deficiency of fructokinase.
•Usually asymptomatic, and diagnosed accidentally
when a non-glucose reducing substrate is detected by
routine screening for reducing sugars in urine.
29

30. 2. Fructose-1,6-bisphosphatase 1 deficiency. (FBPase, or
FBP1) is a key enzyme of the gluconeogenic pathway. Its
deficiency impairs glucose production from all
gluconeogenic precursors, including dietary fructose,
leading to fasting hypoglycemia, ketosis and acidosis.
• Diagnosis can be made by DNA analysis of enzyme activity
from EDTA-anticoagulated blood, or in a liver biopsy.
30

31. 3. Hereditary fructose intolerance (HFI) – caused by
deficiency of the enzyme aldolase B which splits fructose-1-
phosphate into dihydroxyacetone phosphate and
glyceraldehyde.
31

32. •Accumulation of fructose-1-phosphate inhibits both
hepatic glycogenolysis and gluconeogenesis, hence
inducing hypoglycemia, and results in depletion of
ATP.
•The best non invasive approach for confirmation of
diagnosis is carried out by DNA analysis for Aldolase
from EDTA-anticoagulated blood.
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33. ESSENTIAL PENTOSURIA
• This is a benign condition common in the Jews.
• It is due to the absence of L-Xylulose reductase. L-Xylulose
is excreted in urine, and identified by serendipity.
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34. MANAGEMENT OF INBORN ERRORS OF
CARBOHYDRATE METABOLISM
• Clinically, the diagnosis of inborn errors of carbohydrates requires a
careful nutritional history. Specific enzyme assay can be done for
definitive diagnosis of the disorder.
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The management of inborn errors of
metabolism has traditionally been
dietary and supportive therapy, but
recently other treatment options have
become available, including enzyme
and coenzyme replacement, removal
of harmful substances, cell and organ
transplantation, and gene therapy.

35. SUMMARY
•Inborn errors of carbohydrate metabolisms are
usually autosomal recessive disorders resulting from
the deficiency or absence of an enzyme involved in
an intermediary metabolic pathway.
•While clinical diagnosis is often used, routine
biochemistry tests for reducing substances can
sometimes elicit the presence of disorders of
carbohydrate metabolism.
•However, definitive diagnosis is usually achieved by
measurement of the activity of the affected enzyme
in tissues.
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36. CONCLUSION
• Newborn screening does not identify all metabolic
disorders, and some patients can be missed during this
screening. Therefore a symptomatic patient, at any age,
should be investigated despite normal newborn screening
results.
• Treatment approaches such as special diets have been
widely used for IEMs, while long term approaches includes
enzyme replacement therapy, substrate inhibition, and
organ transplantation. 36

37. REFERENCES
• Tietz Clinical Chemistry and Molecular Diagnostics, 5th Ed
• Bishops Clinical Chemistry – Principles, Techniques, Correlations, 7th Ed.
• Rake JP, Visser G, Labrune P, Leonard JV, Ullrich K, Smit GP. Glycogen
storage disease type I: diagnosis, management, clinical course and
outcome. Eur J Pediatr 2000;159:322–30
• Results of the European Study on Glycogen Storage Disease Type I (ESGSD
I). Eur J Pediatr 2002;161(Suppl. 1):S20–34.
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38. THANK YOU
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