Definition: Many childhood conditions are caused by gene mutations that encode specific proteins. These mutations can result in the alteration of primary protein structure or the amount of protein synthesized. The functional ability of protein, whether it is an enzyme, receptors, transport vehicle, membrane, or structural element, may be relatively or seriously compromised. These hereditary biochemical disorders are collectively termed as ‘’Inborn errors of metabolism’’

1. INBORN ERRORS OF LIPID
METABOLISM
Tapeshwar Yadav
(Lecturer)
BMLT, DNHE,
M.Sc. Medical Biochemistry

2. Definition:
 Many childhood conditions are caused by gene
mutations that encode specific proteins. These
mutations can result in the alteration of primary protein
structure or the amount of protein synthesized.
 The functional ability of protein, whether it is an
enzyme, receptors, transport vehicle, membrane, or
structural element, may be relatively or seriously
compromised.
 These hereditary biochemical disorders are collectively
termed as ‘’Inborn errors of metabolism’’

3. Classifications:
1. Disorders of F.A-oxidation:-
A. Defects in Beta-oxidation:-
a) Sudden infant death syndrome(SIDS)
b) Zellweger’s Syndrome.
c) Carnitine deficiency.
d) Carnitine palmitoyl transferese deficiency.
B. Defect in Alpha-oxidation:-
Refsum’s disease.

4. 2) Lipid Storage diseases:-
A. Niemann-pick disease
B. Farber’s disease
C. Gaucher’s disease
D. Krabbe’s disease
E. Tay- sachs disease
F. Fabry’s disease

5. 3) Disorders associated with Lipoprotein Metabolism
A. Hyper-Lipoproteinaemias :-
a) Type-I: familial lipoprotein lipase deficiency.
b) Type-II: familial hypercholesterolaemia.
c) Type-III: familial dys-beta Lipoproteinaemia.
d) Type-IV: familial hypertriglyceridaemia.
e) Type-V: Combined hyperlipidaemias.
B. Hypolipo-proteinaemias:-
a) A-beta- Lipoproteinaemia.
b) Familial alpha-Lipoprotein deficiency (Tangier’s
disease).

6. Defects in Beta-oxidation:-
1) Sudden infant death Syndrome:- (SIDS)
 Disorder due to blockage in beta-oxidation.
 Unexpected death of healthy infants, usually
overnight.
 Real cause of SIDS is not known.

7.  Now estimated that at least 10% of SIDS is due to
deficiency of medium chain acyl-CoA
dehydrogenase.
 Frequency- 1 in 10,000 births.
 More prevalence than phenylketonuria.
 Occurrence:- hypoglycemia.

10. 2) Zellweger’s Syndrome:-
 Also called Hepato renal syndrome
 Rare inherited disorder
 Due to the absence of peroxisomes and its enzymes in
all tissues, fail to oxidize long chain FA in
peroxisomes.
 As a result there is accumulation of FA C26 – C38
chain length in brain tissues and other tissues like
Liver and Kidney.

11. 3) Carnitine Deficiency:-
It occurs in
a)In newborns:- Specially premature infants, owing to
inadequate synthesis or renal leakage.
b) In adults:-
 Can occur in hemodialysis.
 Patients with organic acidurias, carnitine is lost in
urine being conjugated with organic acid.
Clinical features:- Hypoglycemia.
Treatment:- oral therapy with Carnitine.

12. 4) Carnitine- palmitoyl transferase deficiency:-
Features:
a) Hepatic deficiency of the enzyme results in
hypoglycemia and low plasma ketone bodies.
b) Muscular deficiency of these enzyme produces
impaired FA-oxidation which results in recurrent
muscle weakness and myoglobinuria.

13. 5) Jamaican Vomiting Sickness:-
 Caused by eating the unripe akee fruits, which
contains a toxin, hypoglycin that inactivates medium
and short chain acyl-coA dehydrogenase.
 Inhibits β-oxidation.
Clinical Features:- Hypoglycemia with excretion of
medium and short chain mono and dicarboxylic acids.

14. Defect in Alpha-oxidation:-
1) Refsum’s disease:-
Enzyme deficiency:- “Phytanate alpha-oxidase’’.
Inheritance:- autosomal recessive.
Age:- from childhood to adult life.
Biochemical Defect:-
Phytanic acid Pristanic acid
 Accumulates in tissues & blood.
 Blood shows increase up to 20% of the total FA.

15. Clinical manifestations:-
 Neurological signs & symptoms
 Sensory disturbances
 Eye manifestations
 Mental development:- Usually normal
 CS-Fluid:- Increased protein & cell count normal.
Diagnosis:- Increased phytanic acid in plasma.
Treatment:- Omit intake of dietary phytols which is the
precursor of phytanic acid

16. Lipid storage diseases:-
 Also known as sphingolipidoses.
 Genetically acquired.
 Group of inherited diseases that are caused by a
genetic defect in the catabolism of lipids containing
sphingosine.
 They are part of a larger group of lysosomal disorders.

17. Features are:
a) Complex lipids containing ceramide accumulate in
cells, particularly neurons, causing
neurodegeneration and shortening the life span.
b) The rate of synthesis of the stored lipid is normal.
c) The enzymatic defect is in the lysosomal
degradation pathway of sphingolipids.
d) The extent to which the activity of the affected
enzyme is decreased is similar in all tissues.

18. 1) Niemann-Pick disease:-
Sphingomyelin Ceramide
 Caused by deficiency of sphingomyelinase.
 Principal storage substance: sphingomyelin which
accumulates in reticuloendothelial cells.
 Liver and spleen enlargement, mental retardation.

19. 2) Fabry’s disease:-
 Caused by deficient in lysosomal α-galactosidase.
 Accumulation of ceramide trihexoside in kidneys of
these patients.
 Sometimes referred to as ceramide trihexosidase.
 Skin rash, kidney failure, pains in the lower
extremities.
 Now treated with enzyme replacement therapy:
agalsidase beta (Fabrazyme).

20. 3) Gaucher’s disease:-
Glucocerebroside Ceramide
 Caused by a deficiency of lysosomal glucocerebrosidase.
 Increase content of glucocerebroside in the spleen and
liver.
 Erosion of long bones and pelvis.
 Enzyme replacement therapy is available for the Type I
disease (Imiglucerase or Cerezyme).
 Also miglustat (Zavesca) – an oral drug which inhibits the
enzyme glucosylceramide synthase, an essential enzyme
for the synthesis of most glycosphingolipids.

21. 4) Krabbe’s disease:-
Galactocerebroside Ceramide
 Also known as globoid leukodystrophy.
 Caused by a deficiency in the lysosomal enzyme
galactocerebrosidase
 Increased amount of galactocerebroside in the white matter
of the brain.

22. 5)Tay-Sachs disease:-
 A fatal disease which is due to the deficiency of
hexosaminidase -A activity.
 Accumulation of ganglioside GM2 in the brain of
infants.
 Mental retardation, blindness, inability to swallow.
 A “cherry red “ spot develops on the macula (back of
the the eyes).
 Tay-Sachs children usually die by age 5 and often
sooner.

23. Disease Defective
Enzyme
Major Storage
comp
Symptoms
Niemann-
pick
Disease
Sphingomyelinase Sphingomyelins Hepatomegaly,
Splenomegaly &
mental retardation.
Farber’s
Disease
Ceramidase Ceramide Painful & deformed
joints.
Gaucher’s
Disease
β-glucosidase Glucocerebrosides Hepatomegaly,
Splenomegaly,
Osteoporosis &
mental retardation.
Krabbe’s
Disease
β-galactosidase Galactocerebrosides Absence of Myelin
formation,
Hepatomegaly,
Splenomegaly &
mental retardation.

24. Tay-Sachs
Disease
Hexosaminidase-A Ganglioside GM2 Blindness, mental
retardation, death
within
2-3yrs.
Fabry’s
Disease
α-galactosidase Ceramidase
trihexoside
Renal failure, skin
rash, pain in
lower extremities.

25. Is there any treatment?
 Currently there is no specific treatment available for
most of the lipid storage disorders, although Gaucher
and Fabry diseases have highly effective enzyme
replacement therapies.
 There is currently no cure for Niemann-Pick disease.
 Treatment is supportive.
 Doctors often prescribe corticosteroids to relieve the
pain of Farber’s disease.
 Anticonvulsant medications are often used to control
seizures in Tay-Sachs disease.

26. What is the prognosis?
 The prognosis for a lipid storage disorder is determined by
the type of disease, the age of onset, and the severity of
symptoms.
 Children with Gaucher disease may live well into
adulthood, while children with Niemann-Pick disease most
often die at a young age from infection or progressive
neurological loss.

27.  Children with Fabry disease often die prematurely of
complications from heart disease, renal failure, or stroke.
 Most children with Farber’s disease die by age 2, usually
from lung disease.
 Children with Tay-Sachs disease may eventually need a
feeding tube and they often die by age 4 from recurring
infection.

28. What research is being done?
 The National Institute of Neurological Disorders and
Stroke (NINDS) and other institutes of the National
Institutes of Health (NIH) conduct research related to lipid
storage diseases in laboratories at the NIH and also support
additional research through grants to major medical
institutions across the country.

29.  NINDS researchers were responsible for developing highly
effective enzyme replacement therapies for Gaucher and
Fabry diseases.
 Scientists at the NINDS continue to study how lipids
accumulate in cells and why they cause harm to the body.
 The goal of this research is to develop novel approaches to
the treatment of these disorders.

30. Clinical Disorders associated with Lipoprotein
Metabolism:-
A. Hyper-lipoproteinaemia:-
Frederickson et al(1967) proposed 5 types
based on changes in plasma lipoprotein.
1. Type-I: familial lipoprotein lipase deficiency:-
 Rare disorder characterized by hypertriglyceridaemia
& hyperchylomicronaemia.
 VLDL(Pre-beta Lipoproteins) also increased.
 Alpha Lipoprotein(HDL) & Beta-Lipoproteins(LDL)
is decreased.
Inheritance:- Autosomal recessive.
Enzyme deficiency:- “Lipoprotein lipase”

31. Clinical features:-
 Recurrent abdominal pain.
 Eruptive xanthomas.
 Hepatomegaly.
Lab.diagnosis:-
 Refrigeration Test:-
If serum of suspected patients is taken in a narrow small
tube & kept in refrigerator temp. for 24hrs undisturbed,
a clean zone of chylomicrons is seen to float on the top
and make a distinct separate layer.
Management:-
 Restriction of fat intake.
 Medium Chain Triglyceride.

32. 2) Type-II: familial hypercholesterolaemia(FHC):-
 Common disorder.
 Characterized by:-
o Increased Total Cholesterol & HDL.
o May be high TG & VLDL.
Inheritance:- Autosomal dominant
Frequency:- 1:500(0.2%)
Metabolic defect:- No enzyme deficiency but defect of LDL
receptors.
Clinical features:-Atherosclerosis, CAD,Corneal arcus &
Tuberous xanthoma.
Management:-
 Low cholesterol diet decreased intake of saturated fat.
 Give PUFA & drug like statins.

33. 3) Type-III: familial dys-beta Lipoproteinaemia:-
Synonyms:- Broad beta disease & Remnant removal disease.
Characterised by:-
 Increased LDL & VLDL.
 Rise in IDL
 Hypercholesterolemia & hypertriglyceridaemia
Inheritance:- Autosomal dominant
Frequency:- 1:5000(0.02%)
Metabolic defect:-
 Increased apo-E & apo-B
 Conversion of normal VLDL to IDL & its degradation
without conversion of LDL.
 Defect is in “Remnant” metabolism

34. Clinical Features:-
 Palmar xanthoma.
 High incidence of vascular disease.
Management-
 Reduction of weight.
 Restriction of fat & chol.
 Give PUFA & drugs.

35. 4) Type-IV: familial hypertriglyceridaemia:-
Characterised by:-
 Increased TG & VLDL.
 Chol. May be normal or increased.
 Decreased HDL & LDL.
Inheritance:- Autosomal dominant
Metabolic defects:-over production of VLDL & Apo-CII
Clinical features:- Associated with diabetes mellitus, IHD &
Obesity.
Management:-
 Reduction of weight.
 Restriction of Carbohydrate & chol.
 Hypolipidaemic drugs.

36. 5) Type-V: Combined hyperlipidaemias:-
 Hypercholesterolemia & hypertriglyceridaemia.
 Decreased HDL & LDL.
Inheritance:- Autosomal dominant
Metabolic defects:-Secondary to other causes
Clinical features:-
 Manifested only in adulthood.
 Xanthomas.
 Abnormal glucose tolerance.
 Frequency Associated with diabetes mellitus & Obesity.
Management:-
 Reduction of weight.
 High PUFA intake & Hypocholipidemic drugs.

37. Wolman’s Disease:-
 Also called cholesteryl ester storage disease.
 Hyper-cholesterolaemia.
Enzyme deficiency:-
“Cholesteryl ester hydrolase” in lysosomes;
such deficiency in cells of fibroblasts have been
demonstrated.

38. B)Hypolipo-proteinaemias:-
1) A-Beta Lipoproteinaemia:-
 Rare inherited disorder.
Characterized by:-
 Decreased plasma cholesterol due to absence of LDL.
 Low TG.
 No Chylomicrons & VLDL formed.
Clinical features:-
 Malabsorption.
 Mental & physical retardation.
 Acanthocytosis.
Metabolic defect:- Defect in “Synthesis of apo-B” leading
to gross deficiency of apo-B resulting to deficiency of
lipoproteins containing apo-B i.e mainly Chylomicrons,
VLDL & LDL.

39. 2) Familial Alpha-Lipoprotein deficiency:-
 Also called Tangier’s disease
Characterized by:-
 Deficiency of HDL.
 In homozygous patients plasma HDL may be nearly
completed absent.
Inheritance:- Autosomal recessive
Metabolic defect:-
 Reduction in apo-AI & apo-AII
 Leading to accumulation of cholesteryl esters in diff.
tissues.
Clinical features-
 Increased risk of CAD.
 Adenoids.

40. All these Disease can be diagnosed
Prenatally by:-
 Amniocentesis
 Chorionic Villi Sampling
 Ultrasonography
 Fetal blood Sampling
 Maternal blood Sampling

43. THANK U