The document discusses inborn errors of metabolism, specifically focusing on genetic disorders that affect fat metabolism, leading to various conditions such as lipid storage diseases and fatty acid oxidation defects. It outlines different types of metabolic disorders, their causes, and symptoms, including conditions like Tay-Sachs disease, Gaucher's disease, and familial hypercholesterolemia. Additionally, it highlights the importance of enzymatic functions and the impact of these metabolic errors on physiological homeostasis.

1. NUTRITION IN INBORN
ERRORS OF METABOLISM - FAT
submitted by,
. SWETHA M ANIL
SUBMITTED TO,
RENU MISS

2. INTRODUCTION
• Inborn errors of metabolism are a heterogeneous group of
disorders that may be inherited or may occur as the result
of spontaneous mutations.
• These diseases involve failure of the metabolic pathways
involved in either the break-down or storage of
carbohydrates, fatty acids, and proteins.
• Although any given inborn error of metabolism is very
rare, taken as a group, inborn errors of metabolism occur
in 1 in 2500 births.

3. INBORN ERRORS OF METABOLISM
• The name ‘inborn’ error signifies that the symptoms of
disorders/defects can be detected in child after birth.
• Pointed out that there are certain features in common in
all these disorders like it occurred with high frequency
Among the offspring of consanguineous marriages; the
symptoms appeared mostly to early days or weeks of
Neonatal life with familial occurrence in substantial
number of cases with overall benign conditions.
• The original Four metabolic disorders have now been
amplified to many disorders.

4. • Thus, dysregulation of developmental and Homeostatic metabolic
networks commonly known as ‘Inborn errors of metabolism’
comprises an important Increasing group of genetic disorders.
• Therefore, it may be defined as an enzymopathy and
genetotrophic Disease which is genetically based biochemical
problem where an enzyme defect obstructs a defined metabolic
Pathway accumulating the substrate causing disastrous pathologic
effect at birth (e.g phenylketonuria) or Afterwards in life (e.g.
diabetes mellitus).

5. • An assortment of symptoms include vomiting, diarrhoea,
seizures,encephalopathy, hepatomegaly, hypotonia and failure
to thrive.
• The concept of inborn error signifies the aspect of disturbance
in the physiological homeostasis.
• The metabolic pathway is dependent on anabolic (synthetic)
and catabolic (degradation) pathway which are balanced.
• All the pathway-dependent metabolic reactions (endergonic or
exergonic) are catalyzed by enzymes.

7. INBORN ERRORS OF FAT METABOLISM
• Numerous genetic disorders are caused by errors in fatty acid
metabolism. These disorders may be described as fatty oxidation
disorders or as a lipid storage disorders, and are any one of
several inborn errors of metabolism that result from enzyme
defects affecting the ability of the body to oxidize fatty acids in
order to produce energy within muscles, liver, and
other cell types.

8. TYPES

9. 1.Lipid storage disease or Lipidoses
• Lipidoses (or lipid storage diseases) are a collection of
hereditary metabolic inborn errors in which detrimental
quantity of lipids (fats) mount up in several of the body’s
cells and tissues.
• Lipidoses are inborn metabolic errors, leading to the
accumulation of various lipids in the nervous system and
in the reticulo-endothelial system.

10. • These metabolic disorders can occur because of mainly two
reasons, first is that enough enzyme production or improper
functioning of enzymes.
• Therefore, unnecessary storage of fats can cause everlasting
cellular and tissue harm, chiefly in the peripheral nervous system,
brain, liver, bone marrow and spleen.

12. Types of Lipidoses
A.Sphingolipidoses
• Sphingolipidoses are the sphingolipid storage diseases
essentially an autosomal recessive disease except Fabry
Disease which is X-linked.
• Broadly, Sphingophospholipids and Glycosphingolipids
are the main groups of Sphingolipidoses. Ceramides are
the precursors of both phosphorylatred and glycosylated
sphingolipids.

13. a)Sphingophospholipidoses
• The most important sphingophospholipid in human is
sphingomyelin which is an important constituent of the
Myelin of nerve fibres and have a structure in which an
alcohol group at carbon 1 of sphingosine is esterified
tophosphorylcholine.
• Ceramide is the immediate precursor of sphingomyelin
and it is the major constituent of skin and regulates skin`s
water permeability.
• Eg: Niemann-Pick Disease

14. b)Glycosphingolipidoses
• Transformed cells with dysregulated cell growth and
division leads to a dramatic change in the
Glycosphingolipid composition of the plasma membrane.
• They are antigenic (blood group antigens or embryonic
Antigens specific for particular stages of fetal
development and tumor antigens).
• Glycosphingolipids consists of neutral and acidic types.
Further within acidic glycosphingolipids, there are two
types: Gangliosides and Sulfatides

15. 1.GM1 Gangliosidoses
• GM1 gangliosidosis, also called beta-galactosidase-1 deficiency,
is a genetic disorder that progressively destroys nerve cells in the
brain and spinal cord.
• The disorder is one of about 50 diseases classified as lysosomal
storage disorders (LSD), where a genetic variation disrupts the
normal activity of lysosomes in human cells.

16. • In this there is an accumulation of gangliosides
(GM1) and keratin sulphate.
• Neurologic deterioration
• Hepatosplenomegaly
• Skeletal deformaties
• Cherry-red macula

17. 2.Tay-Sachs Disease
• The most common form of Tay-Sachs disease, known as
infantile Tay-Sachs disease, becomes apparent early in life.
Infants with this disorder typically develop normally until
they are 3 to 6 months old.
• During this time, their development slows and muscles
used for movement weaken.
• Affected infants stop achieving normal developmental
milestones and begin to lose previously acquired skills
such as turning over, sitting, and crawling.

18. • Accumulation of gangliosides (GM2)
• Rapid, progressive and fatal neurogeneration
• Blindness
• Cherry-red macula
• Muscular weakness
• Seizures

20. 3.Gaucher`s Disease
• Gaucher disease is an inherited genetic disorder.
• It causes bone pain, anemia, enlarged organs, a swollen,
painful belly, and bruising and bleeding problems.
• There are three types of the disease. Some types of
Gaucher disease can lead to severe brain damage and
death.

21. • Accumulation of glucocerebrosides
• Most common lysosomal storage disease
• Hepatosplenomegaly
• Osteoporosis of long bones
• CNS involvement in rare infantile and
juvenile forms

22. • Gaucher disease type 1
• The most common type in the U.S., Gaucher disease type
1 affects your spleen, liver, blood and bones.
• It doesn’t affect your brain or spinal cord.
• Gaucher disease type 1 is treatable, but there’s no cure. For
some people, symptoms are mild. Other people experience
severe bruising, fatigue and pain, especially in their bones
and belly (abdomen). Symptoms can appear at any age,
from early childhood to late adulthood.

23. • Gaucher disease type 2
• A rare form of the disorder, Gaucher disease
type 2 appears in babies younger than 6
months old.
• It causes an enlarged spleen, movement
problems and severe brain damage. There’s no
treatment for Gaucher disease type 2.
• Babies with this condition usually pass away
within two to three years.

24. • Gaucher disease type 3
• Worldwide, Gaucher disease type 3 is the most common form, but
it’s rare in the U.S.
• It appears before age 10 and causes bone and organ abnormalities
and neurological (brain) problems.
• Treatments can help many people with Gaucher disease type 3
live into their 20s or 30s.

25. 4.Sandhoff Disease
• Sandhoff disease is a rare, inherited disease that progressively
destroys nerve cells in the brain and spinal cord.
• It occurs when fatty materials called lipids accumulate in brain
cells (and in other parts of the body), forcing them to malfunction
and die.
• Sandhoff disease is caused by a deficiency of the enzyme beta-
hexosaminidase and is a severe form of the neurological disorder
called Tay-Sachs disease.

27. 5.Fabry Disease
• Fabry disease (also known as alpha-galactosidase-A deficiency)
is an inherited neurological disorder that occurs when the
enzyme alpha-galactosidase-A cannot efficiently break down
fatty materials known as lipids into smaller components that
provide energy to the body.
• The mutated gene allows lipids to build up to harmful levels in
the body's autonomic nervous system (the part of the nervous
system that controls involuntary functions such as breathing and
heartbeat), as well as in the eyes, kidneys, and cardiovascular
system

28. • Accumulation of globosides
• Reddish purple skin rash
• Kidney and heart failure
• Burning pain in lower extremities

29. 6.Metachromatic leukodystrophy
• Accumulation of sulfatides
• Cognitive deterioration
• Demyelination
• Progressive paralysis and dementia in infantile
form
• Nerves stain yellowish-brown with cresyl violet
(metachromasia)
• Multiple sulfatase deficiency due to defect in post-
translational modification of several sulfatases

30. 7.Niemann-Pick Disease (A+B)
• Niemann-Pick is a rare, inherited disease that affects the body's
ability to metabolize fat (cholesterol and lipids) within cells. These
cells malfunction and, over time, die. Niemann-Pick disease can
affect the brain, nerves, liver, spleen, bone marrow and, in severe
cases, lungs.
• People with this condition experience symptoms related to
progressive loss of function of nerves, the brain and other organs.
• Niemann-Pick can occur at any age but mainly affects children. The
disease has no known cure and is sometimes fatal.

31. Accumulation of sphingomyelin
Hepatosplenomegaly
Neurodegenerative course (Type A)
• Cherry-red macula

32. Wolman’s disease
• It is an autosomal recessive disorder lipid storage disease
in which cholesteryl esters and triglycerides are
accumulated.
• Appear normal at birth but quickly develop progressive
mental deterioration.
• Hardened adrenal glands because of calcium deposits
• Enlarged liver and spleen with gastrointestinal problems
like anaemia, jaundice and vomiting
• Low muscle tone

34. Cholesteryl ester storage disease (CESD)
• It is an exceedingly uncommon disorder where cells of
blood and lymph accumulate cholesteryl esters and
triglycerides.
• Enlarged liver and problems associated with like
cirrhosis and thus before adulthood chronic liver
failure most probably occur.
• Jaundice as well as calcium deposits occurs in the
adrenal glands.

35. C. Neuronal ceroid lipofuscinoses
• Neuronal ceroid lipofuscinoses (NCL) results from unnecessary
accretion of lipofuscin (lipopigments) which are made up of
coloured proteins (greenish-yellow color when viewed under an
ultraviolet light microscope) and lipids in the body’s tissues
mostly in the neuronal cells while it is also present in
myocardium, spleen, liver and kidneys.

37. Diagnoses of Lipid Storage Disease
• 1. Clinical examination of urine analysis: discover the existence of
stored material
• 2. Genetic testing and molecular enzymatic analysis of cells of
affected tissues or blood or body fluids.
• 3. Genotyping is a process in which some specific tests can done
which verify the person carrying the defective gene that can be
passed on to her or his children.
• 4. Biopsy for lipid storage disorders involves study of cells and
tissues like liver by removing a small amount of tissue done
through surgery or by needle biopsy.

38. 2.Fatty acid oxidation defects
• The trio, i.e. mitochondrial fatty acid oxidation (mFAO), tri-
carboxylic acid cycle (TCA) and oxidative phosphorylation
(OXPHOS) which occurs in mitochondria are processes which are
interlinked.
• Problems in fatty acid oxidation leads to increased energy demand
and consequently low production of ketone bodies which is
abnormal.

39. • Fatty acids oxidation defects mostly β-oxidation occurs in
mitochondria, are mainly of three main types:
• 1. Carnitine uptake defect which is the primary carnitine
deficiency can because of three enzyme defects which are
important in the carnitine shuttle.
• 2. Problems associated with the processing of long chain
fatty acids in which problem is because of main protein
complex [Trifunctional protein] which is a trimer and thus
are of two types

40. • (a) Trifunctional protein deficiency type 1
• (b) Trifunctional protein deficiency type 2
• 3. Medium chain acyl –CoA dehydrogenase deficiency : Most
common fatty acid oxidation defect

41. Long chain fatty acid oxidation
• Long chain fatty acid oxidation defects can be due to defect in one
of the enzyme of protein trimer complex, i.e. Trifunctional
protein. This protein complex is made up of three proteins:
• 1. Long chain enoyl-CoA hydratase
• 2. Long-chain 3-hydroxyacyl-coenzyme A dehydrogenase
• 3. Long chain 3-ketothiolase

42. Median chain fatty acid oxidation
• Similarly for median chain fatty acid oxidation, there is no
trifunctional complex but separate enzymes doing their function.
• This is the most common type of fatty acid oxidation present in
childhood and the symptoms appeared by trigerring via a period
of catabolic stress like exercise, fasting or illness ultimately it
leads to neurological problems.

43. Short chain fatty acid oxidation
• Very uncommon fatty acid oxidation defect is short chain
fatty acid oxidation defect.
• The outline of after effects of short chain fatty acid
oxidation leads to lactic academia and gluconeogenesis
and inhibits oxidative phosphorylation.

44. Carnitine uptake defect
• Carnitine is mostly present in meat and it is obtained from
the diet and distributed by the blood. It can also be
synthesized inherently from the lysine and methionine.
• Carnitine deficiencies resulted from limited ability of
various organs and tissues to use long chain fatty acids as a
metabolic fuel. It is because of many reasons like food
intake which consists of least carnitine mostly present in
persons suffering from malnutrition or people strictly
taking vegetarian diet deficency in hereditary carnitine
deficiency

45. 3.Peroxisomal disorders
• The peroxisomal disorders represent defects in peroxisomal
functions leading to genetic diseases in man.
• The peroxisomal enzyme deficit group comprises seven different
disorders of which phytanoyl-CoA hydroxylase (adult Refsum
disease) and D-bifunctional protein deficiencies are the most
recurrent.
• X-linked adrenoleukodystrophy is the only disease of peroxisomal
substrate transport deficiency group.

47. Neonatal adrenoleukodystrophy
• NALD is an inheritable disorder that affects
multiple organs, including the adrenal glands
and the white matter of the brain.
• Some of the symptoms for this disorder
include seizures, hyperactivity, crossed eyes,
paralysis, hearing loss, and muscular
weakness

48. Zellweger syndrome
• Zellweger spectrum disorder, also known as
cerebrohepatorenal syndrome, is a rare inherited
disorder characterized by the absence or reduction of
functional peroxisomes.
• It is autosomal recessive due to a defect in the PEX
gene. It is a rapidly progressive disorder with a high
mortality rate.
• With no curative treatment available, treatment options
are limited to supportive care to improve quality of life.

49. Infantile Refsum disease
• Infantile Refsum disease (IRD) is a medical condition
within the Zellweger spectrum of perixisome
biogenesis disorders (PBDs), which are inherited
genetic disorders that damage the white matter of the
brain and affect motor movements.
• PBDs are part of a larger group of disorders called the
leukodystrophies.

50. Rhizomelic chondrodysplasia punctata
• Rhizomelic chondrodysplasia punctata (RCDP) is a type of
peroxisomal disorder which impairs the normal development of
many parts of the body.
• It is characterized by shortening of the bones in the upper arms
and thighs (rhizomelia).
• People with RCDP have very poor growth and often develop joint
deformities (contractures) that make the joints stiff and painful.
Other major features include distinctive facial features, intellectual
disability, clouding of the lenses of the eyes (cataracts), heart
defects, and respiratory problems

52. 4.Inborn errors of cholesterol biosynthesis
• The cholesterol biosynthesis disorders have lately emerged
as imperative IEM which have taught us a lot of new
Genetic and biochemical edifications.
• Despite the fact that most of the metabolic diseases are
exemplified by Exclusively or largely post-natal
biochemical deficiencies or toxicities, cholesterol
biosynthesis disorders are Prominent for their relentless
effects on pre-natal development.

53. Familial hypercholesterolemia
• Familial hypercholesterolemia also known as spelled familial
hypercholesterolaemia (FH or SFH) is a genetic disorder portrayed
by high cholesterol levels, exclusively very high levels of LDL (low
density lipoprotein or bad cholesterol) in the blood and untimely
cardiovascular illness.
• Individuals with FH or SFH displayed Different body biochemistry
and their elevated cholesterol levels are less responsive to the control
methods of Cholesterol frequently more efficient in people without
FH or SFH (e.g. dietary modification and statin tablets).

54. Symptoms
• Chest pain (angina)
• Coronary artery disease
• Fatty deposits around the body
(xanthomas)
• Cholesterol deposits on the eyelid
(xanthelasmas)
• Sores on the toes that do not heal

55. Smith-Lemli-Opitz syndrome
• Smith-Lemli-Opitz syndrome (SLOS) is a manifold
congenital anomalies (MCA) / mental retardation (MR)
Syndrome caused by a deficiency in the synthesis of
cholesterol.
• SLOS is an autosomal recessive genetic state Caused by
the deficiency of 3 β-hydroxysterol-δ 7-reductase(7-
dehydrocholesterol-δ 7-reductase [DHCR7] EC
1.3.1.21), the ultimate enzyme in the sterol biosynthetic
pathway that converts 7-dehydrocholesterol to
Cholesterol.

56. Other lipid disorders
Carotenemia
• Carotenemia is a clinical condition depicted by the yellow pigmentation
of the skin (xanthoderma) and augmented β-carotene levels in the
blood.
• In most of the cases, the situation pursues extended and too much
consumption of carotene-rich foods (e.g. carrots, sweet potatoes and
squash). It is a frequent finding in children.
• The condition of carotenemia is undisruptive, but it can show the way
to a mistaken diagnosis of jaundice.

58. Lipodystrophy
• Greek: Lipo for fat and dystrophy for abnormal or
degenerative condition] is a condition in Which adipose
tissues are degraded.
• Specifically, Lipoatrophy signifies loss of fat from one
specific area mostly Face.
• It is also notified by a absence of circulating leptin which
may lead to osteosclerosis.

59. NUTRITION
• Diet is a key element to prevent complications, especially
neurological ones.
• The precise treatment in the metabolism of proteins, lipids
and carbohydrates in these patients is essential to avoid
metabolic decompensation, which can have serious
consequences at the multi-organ level and even death.
Dietary adherence must be sought.

60. • At the same time, the diets prescribed for IEM must be
personalized, considering the greater or lesser severity of
the disease, the clinical status of the patient, their
tolerance, age, and neurodevelopment.
• However, despite the advances in recent years, this diet
and nutritional therapy is sometimes very complex and
difficult to comply with, requiring strict evolutionary
control that is not always well known.

61. • Low-Fat Diet: Individuals with these disorders often need to follow
a low-fat diet to minimize the intake of long-chain fatty acids,
which their bodies may struggle to metabolize. This involves
restricting foods high in long-chain fats, such as certain oils, dairy
products, and fatty meats.
• Medium-Chain Triglycerides (MCTs): MCTs are more easily
metabolized than long-chain fats. Including MCTs in the diet
provides an alternative energy source. Foods like coconut oil and
MCT oil may be incorporated, and special MCT-enriched formulas
might be recommended.

62. • Protein Intake: Adequate protein intake is essential for growth and
development. Protein can also serve as an alternative energy source.
Monitoring amino acid profiles may be necessary, and medical
formulas or supplements may be required to ensure proper protein
balance.
• Essential Fatty Acids (EFAs): Since the body can't synthesize EFAs,
they need to be supplied through the diet. Special attention is given
to ensuring an adequate intake of essential fatty acids like omega-3
and omega-6, possibly through supplementation.

63. • Caloric Intake: Maintaining a proper balance of calories is
crucial for overall health. Nutritionists work to ensure
individuals receive enough energy from sources other than
fats to support growth, development, and daily activities.
• Micronutrient Monitoring: Regular monitoring of vitamin
and mineral levels is essential. Deficiencies can occur due
to dietary restrictions, and supplements may be prescribed
to address specific needs.

64. • Hydration: Adequate hydration is important, especially if
individuals are on specialized diet or formulas. This helps
support overall well-being and metabolic processes.
• Individualized Plans: Nutrition plans are highly
individualized based on the specific inborn error of fat
metabolism. Close collaboration between healthcare
professionals, including dietitians and metabolic
specialists, is crucial to tailor nutrition interventions to
each person’s needs.

65. CONCLUSION
• Inborn errors of metabolism are rare, but the diseases with which
they are associated often have a significant impact on growth,
development, and long-term health of affected children.
• Early recognition and intervention (when possible) are essential to
avoiding disastrous consequences associated with these diseases.
• Some disorders arise as a result of mutations to catabolic pathways
involving lysosomal storage and macromolecule degradation.