Disorders of lipid metabolism case studies-1

Disorders of
chemistry
and
metabolism
of Lipids -I
Namrata Chhabra
Professor Biochemistry
SSR Medical College,
Mauritius
02-Mar-20 Disorders of lipid metabolism 1

Learning objectives
To understand:
• Basic characteristics of lipids
• Clinical implications of non- degradation of complex lipids
• Types of oxidation of fatty acids
• Clinical implications of impaired fatty acid oxidation

What are Lipids ?

Lipids
Simple
Fats Waxes
Compound
Phospholipids Glycolipids Lipoproteins
Derived
Fatty acids,
Steroids,
Cholesterol,
Eicosanoids

Fats
Fats are esters of fatty acids with
glycerol.
❑Mono- and Diacylglycerol are also
found in the tissues.
❑If all the OH groups are esterified to
same fatty acids- It is Simple
Triglyceride
❑If different fatty acids are esterified-
it is known as Mixed triglyceride.

Fats versus Oils
• Fats are solid at room temperature
and contain saturated long chain fatty
acids.
• Oils are fats in the liquid state at 200C.
• They contain higher proportion of
Unsaturated fatty acids.
• They are insoluble in water
• Specific gravity is less than 1.0,
consequently all fats float in water.
02-Mar-20

Disorders of lipid metabolism 02-Mar-20 8

Waxes
• Waxes: Esters of fatty acids with
higher molecular weight
monohydric alcohols.
• Have very long straight chain of 60-
100 carbon atoms.
• Can take up water without getting
dissolved in it
• Used as bases for the preparation of
cosmetics, ointments, polishes,
lubricants and candles.
• In nature, they are found on the
surface of plants and insects.

Phospholipids

Glycolipids

Glycolipids
Glycolipids
Neutral
Cerebrosides Globosides
Acidic
GM, GD, GT
& GQ

Lipoproteins
Water insoluble lipids are transported
in the aqueous plasma by associating
nonpolar lipids (triacylglycerols and
cholesteryl esters) with amphipathic
lipids (phospholipids and cholesterol)
and proteins to make water-miscible
lipoproteins.

Derived Lipids
Derived
Lipids
Fatty acids
Fat soluble
vitamins
Cholesterol
Hydrocarb
ons
Ketone
bodies

Fatty acids
• Fatty acids are aliphatic carboxylic acids
• Have the general formula R-(CH2)n-COOH
• Occur mainly as esters in natural fats and
oils but do occur in the unesterified form
as free fatty acids, a transport form found
in the plasma.

Cholesterol
• Widely distributed in all cells of
the body but particularly in
nervous tissue.
• A major constituent of the plasma
membrane and of plasma
lipoproteins.
• Synthesized in many tissues from
acetyl-CoA.
• Precursor of all other steroids in
the body, including
corticosteroids, sex hormones,
bile acids, and vitamin D.

Case study-1

Case study-1
A 25 –year-old woman presents, with
a history that includes:
a) Hepatosplenomegaly with eventual
removal of spleen
b) Bone and joint pains with several
fractures of femur.
02-Mar-20

Case study
(contd.)
c) A liver biopsy that
shows wrinkled looking
cells with accumulation
of Glucosyl ceramide.
What might be the
likely diagnosis for this
patient?

Case discussion
• The patient is suffering from Gaucher disease,
• an inherited disorder of Cerebroside
metabolism,
• the commonest Lysosomal storage disease,
and
• the most common genetic disorder among
Ashkenazi Jews.

Cerebrosides
Disorders of lipid metabolism
• Cerebrosides contain a
carbohydrate which is
generally galactose or
glucose,
• a high molecular weight
fatty acid,
• an alcohol which is
sphingosine or Dihydro
sphingosine
• no glycerol, no
phosphoric acid and no
nitrogenous base
02-Mar-20 22

What are cerebrosides ?
Individual cerebrosides are differentiated by the type of fatty acid present in them
Kerasin- Lignoceric acid
Cerebron- Cerebronic acid
Nervon- Nervonic acid
Oxynervon- Hydroxy-Nervonic acid

Cerebrosides- Occurrence
• Cerebrosides occur in large
amount in the white matter of
brain and
• in the myelin sheath of nerves.

Gaucher disease
Hematological
changes
Organomegaly
Multiple
fractures
Bone pains
Gaucher
disease

Gaucher disease- defect
• Inheritance- Autosomal
recessive
• Biochemical defect-
deficient activity of
lysosomal hydrolase, β-
Glucocerebrosidase.

Gaucher
disease-
Pathophysiology
• The enzyme defect
results in accumulation
of undegraded glycolipid
in the form of Glucosyl
ceramide in the cells of
reticuloendothelial
system.
• This progressive
accumulation results in
infiltration of bone
marrow,
hepatosplenomegaly
and skeletal
complications.

Gaucher disease- Clinical manifestations
• There are three clinical sub types depending upon the presence of,
absence of or progression of neurological complications
99% of cases
Type 1
Less common
Type 2
Intermediate
Type 3

Type-1- Gaucher
disease
29
• Variable age of onset, from early
childhood to late adulthood.
• The patients present with :
oeasy bruising due to
thrombocytopenia,
ochronic fatigue due to anemia,
oclinical bone involvement,
manifested in the form of bone
pains, or pathological fractures
ohepatomegaly with or without
impaired liver functions.
oprogressive enlargement of spleen,
which can become massive.

Type-1- Gaucher
disease
• The hall-mark of Gaucher’s disease is
Gaucher cells in the reticuloendothelial
system, particularly in the bone
marrow.
• These cells have a typical appearance,
they are 20-100μm in diameter,
wrinkled looking due to the presence
of intracytoplasmic inclusion bodies.
• The presence of these cells is highly
diagnostic of Gaucher’s disease.
30

Type 2- Gaucher disease
• Less common,
• Characterized by neurodegeneration,
• Extreme visceral involvement and
death within 2 years of life.
• Death is due to respiratory
compromise.

Type 3- Gaucher disease
• Intermediate in presentation
to type 1 and 2.
• Neurological involvement but
occurs later in life with
decreased severity as
compared to Type 2.

Gaucher disease- Laboratory Diagnosis
•Measurement of Glucocerebrosidase activity in peripheral blood
leukocytes- A finding of less than 15% of mean normal activity is
diagnostic.
•Genotype testing: Molecular diagnosis can be helpful, especially in
Ashkenazi patients, in whom 6 GBA mutations account for most disease
alleles.
•CBC count and differential to assess the degree of cytopenia.
•Liver function enzyme testing: Minor elevations of liver enzyme levels
are common, even in patients who are mildly affected with Gaucher
disease; however, the presence of jaundice or impaired hepatocellular
synthetic function merits a full hepatic evaluation.

Gaucher disease-Imaging
Studies
• Ultrasonography
• MRI
• Radiography- Skeletal and
Chest
• Bone marrow examination
• Liver Biopsy

Gaucher disease- Management
1) Enzyme replacement
therapy(ERT) by recombinant β-
Glucocerebrosidase.
2) Surgical Care
3) Bone marrow transplant
4) Gene Replacement

Gaucher disease- prognosis
•Individuals with Gaucher disease having few manifestations have a
normal life expectancy without any intervention.
•The prognosis for symptomatic patients with type 1 or type 3 Gaucher
disease who receive treatment is very good, with a decrease in
organomegaly and an eventual rise in hemoglobin levels and platelet
counts.
•Skeletal disease is slow to respond to ERT, a much longer period of
ERT is required to achieve a radiologic response.

Case study-2

Case study-2
• A boy was born normal but started flinching at loud noises (enhanced
startle response) at the age of 6 months.
• The child initially could sit up,
• but then regressed so that he could not roll over or recognize his
parents.
• Ophthalmological examination revealed a central red area of the
retina surrounded by white tissue (Cherry red spot).
• What might be the probable diagnosis ?

Chief symptoms

Case discussion
• The child is suffering from Tay-
Sachs disease (GM2
Gangliosidosis).
• The disease is named after the
British ophthalmologist Warren
Tay who first described the red
spot on the retina of the eye, and
• the American neurologist Bernard
Sachs who described the cellular
changes of Tay-Sachs and noted an
increased prevalence in the
Eastern European Jewish
(Ashkenazi) population

Basic
concept
Gangliosides have been isolated from the ganglion cells,
neuronal bodies, dendrites, spleen and RBC stroma.
The highest concentration is found in the grey matter of
brain.
Four important types of Gangliosides are GM-1, GM-2, GM-3
and GD-3.GM-1 is more complex ganglioside and is known
to be the receptor for cholera toxin in human intestine.
Gangliosides are mainly components of membranes.
They also serve as receptors for circulating hormones and
thereby influence various biochemical processes in the cells.

Structure of Gangliosides
• Structurally they contain:
• a long chain fatty acid,
• alcohol sphingosine,
• a carbohydrate moiety
which is usually glucose/
and or galactose, and
• at least one molecule of N-
acetyl –Neuraminic acid
(NANA).

Tay-Sachs disease
• Biochemical defect-deficiency of ß hexosaminidase A enzyme.
• This Lysosomal enzyme removes amino hexose groups from
Gangliosides, Subsequently the other components are hydrolyzed by
other specific enzymes.
• In its deficiency the gangliosides are not degraded thus accumulate
in various tissues especially nervous tissue.

Tay-Sachs disease
• Inheritance- inherited as an autosomal recessive traits,
• with a predilection in the Ashkenazi Jewish population,
• where the carrier frequency is about 1/25.
Classification- Tay-Sachs disease is classified in three forms, based on
the time of onset of neurological symptoms.
oInfantile
oJuvenile
oAdult /Late onset

Tay-Sach ’s disease-
Clinical Manifestations
• Infantile TSD
• Children with this disease are born
normal,
• Develop normally till the age of 5-6
months, later develop:
oloss of motor skills,
oincreased startle reaction,
odecreased eye contact,
omacular pallor and
oretinal cherry red spot

Tay-Sachs disease-
46
• Infantile TSD
o Progressive development of idiocy
and blindness are diagnostic of this
disease and they are due to wide-
spread injury to ganglion cells, in
brain and retina.
o Macrocephaly not associated with
hydrocephalus may be there.
o Convulsions are seen in severe
cases.

Tay-Sach ’s disease-
• Juvenile TSD
• Extremely rare,
• Presents itself in children between 2
and 10 years of age.
• Cognitive, motor, speech difficulties
(dysarthria), swallowing difficulties
(dysphagia), unsteadiness of gait
(ataxia), and spasticity are commonly
observed.
• Death occurs between 5–15 years

Tay-Sach’s disease- Clinical Manifestations
• Adult Onset Tay-Sachs disease or Late Onset Tay-Sachs disease
(LOTS)
• Occurs in patients in their 20s and early 30s.
• Characterized by unsteadiness of gait and progressive neurological
deterioration.
• Speech and swallowing difficulties,
• Spasticity, cognitive decline, and
• Psychiatric illness, particularly schizophrenic-like psychosis.

Adult Onset Tay-Sachs disease

Tay-Sachs disease- Diagnosis
• The diagnosis of infantile Tay-Sachs disease is usually suspected in an
infant with neurologic features and a cherry-red spot.
• Enzymatic Assays-Definitive diagnosis is by determination of the level
of ß-hexosaminidase A in isolated blood leukocytes.
• Fine needle Aspiration Cytology of brain tissue – can show the
degree of neuronal degeneration.
• FNAC has a great potential for diagnosis and follow-up of Tay-Sachs
disease

Tay-Sachs disease- Diagnosis
• Prenatal screening-Future at-risk pregnancies for both disorders can
be monitored by prenatal diagnosis by amniocentesis or chorionic
villus sampling.
• Carrier screening- Identification of carriers within families is also
possible by ß-hexosaminidase A determination.

Tay Sachs disease- Diagnosis

Tay-Sachs disease- Treatment
• No cure for this disease.
• Symptomatic treatment is given.
• Enzyme replacement therapy and Gene therapy are under trial.
• Patients receive palliative care to ease the symptoms.
• Infants are given feeding tubes when they can no longer swallow.
• No current therapy is able to reverse or delay the progress of the
disease.
• Prognosis is bad and death occurs in early years of life.

Lipid storage diseases

Sphingolipidoses (lipid storage diseases)
• A group of inherited diseases that are caused by a genetic defect in
the catabolism of lipids containing sphingosine.
• They exhibit several constant features:
(1) Complex lipids containing ceramide accumulate in cells, particularly
neurons, causing neurodegeneration and shortening the lifespan.
(2) The rate of synthesis of the stored lipid is normal.
(3) The enzymatic defect is in the lysosomal degradation pathway of
sphingolipids.
(4) The extent to which the activity of the affected enzyme is decreased
is similar in all tissues.

Lipid storage diseases(Sphingolipidosis)
Disease Enzyme deficiency Nature of lipid
accumulated
Clinical Symptoms
Tay Sach’s Disease Hexosaminidase A GM2 Ganglioside Mental retardation,
blindness, muscular
weakness
Fabry's disease α-Galactosidase Globo-triaosylceramide Skin rash, kidney
failure (full symptoms
only in males; X-linked
recessive).
Metachromatic
leukodystrophy
Aryl-sulfatase A Sulfo-galactosylceramide Mental retardation
and Psychological
disturbances in
adults; demyelination.
02-Mar-20 57Disorders of lipid metabolism

Lipid storage diseases(Sphingolipidosis)- contd.
Disease Enzyme deficiency Nature of lipid
accumulated
Clinical symptoms
Krabbe's disease β-Galactosidase Galactosyl ceramide Mental retardation;
myelin almost absent.
Gaucher's disease β -Glycosidase Glucosyl ceramide Enlarged liver and spleen,
erosion of long bones,
mental retardation in
infants.
Niemann-Pick disease Sphingomyelinase Sphingomyelin Enlarged liver and spleen,
mental retardation; fatal
in early life.
Farber's disease Ceramidase Ceramide Hoarseness, dermatitis,
skeletal deformation,
mental retardation; fatal
in early life02-Mar-20 58Disorders of lipid metabolism

Case study-3

Case study-3
• A teenage girl was brought to the medical
center because of her complaints that she
used to get too tired when asked to
participate in gym classes.
• A consulting neurologist found muscle
weakness in girl’s arms and legs.
• When no obvious diagnosis could be
made, biopsies of her muscles were taken
for test.

Case study-3
• Biochemistry revealed greatly
elevated amounts of
triglycerides esterified with
primary long chain fatty acids.
• Pathology reported the
presence of significant numbers
of lipid vacuoles in the muscle
biopsy.

Case study-3 (contd.)
• A chest X-ray showed moderate
enlargement of her heart.
• Her liver was moderately enlarged and
palpable.
• She was slightly hypoglycemic, and her
non-esterified fatty acids were slightly
higher than would be expected for an
overnight fast.
• Ketone bodies were not detectable.
• What is the probable diagnosis?
• What might be the cause of her
symptoms?

Case details
• The most likely cause of these symptoms is carnitine deficiency.
• Carnitine is required for the transport of long-chain fatty acyl
coenzyme esters into myocyte mitochondria, where they are oxidized
for energy.
• Carnitine is obtained from foods, particularly animal-based foods, and
via endogenous synthesis.
• Carnitine deficiency results from inadequate intake of or inability to
metabolize the amino acid carnitine.

Role of Carnitine in fatty acid oxidation
• Fatty acids are activated on the
outer mitochondrial membrane,
whereas they are oxidized in the
mitochondrial matrix.
• A special transport mechanism is
needed to carry long-chain acyl
CoA molecules across the inner
mitochondrial membrane.
• Activated long-chain fatty acids
are transported across the
membrane by conjugating them
to carnitine.

Type of fatty acid oxidation affected by
Carnitine deficiency
1) It’s the Beta oxidation which is affected- Major mechanism, occurs
in the mitochondria matrix. 2-C units are released as acetyl CoA
per cycle.
Other types of fatty oxidation:
2) Alpha oxidation- Predominantly takes place in brain and liver, one
carbon is lost in the form of CO2 per cycle.
3) Omega oxidation- Minor mechanism, but becomes important in
conditions of impaired beta oxidation

Overview of Beta
oxidation
A saturated acyl Co A is
degraded by a recurring
sequence of four
reactions:
1) Oxidation by flavin
adenine dinucleotide
(FAD)
2) Hydration,
3) Oxidation by NAD+,
and
4) Thiolysis by Co A

Causes of carnitine deficiency
• Inadequate intake
• Inability to metabolize carnitine due to enzyme deficiencies.
• Decreased endogenous synthesis of carnitine due to a severe liver
disorder
• Excess loss of carnitine due to diarrhea, diuresis, or hemodialysis
• Carnitine leak from renal tubules (Primary carnitine deficiency)
• Increased requirements for carnitine when ketosis is present or
demand for fat oxidation is high.

Clinical manifestations of Carnitine deficiency
Carnitine
deficiency
Myoglobin
uria
Muscle
necrosis
Muscle
aches
Fatty liver

Diagnosis of Carnitine deficiency
1) Extremely reduced carnitine levels in plasma and
muscle (1–2% of normal).
2) Fasting ketogenesis may be normal if liver carnitine
transport is normal, but it may be impaired if dietary
carnitine intake is interrupted.
3) Hypoglycemia is a common finding. It is precipitated by
fasting and strenuous exercise.
4) Muscle biopsy reveals significant lipid vacuoles.

Treatment
• Pharmacological doses of oral carnitine is highly effective in
correcting the cardiomyopathy and muscle weakness as well as any
impairment in fasting ketogenesis.
• All patients must avoid fasting and strenuous exercise.
• Some patients require supplementation with medium-chain
triglycerides and essential fatty acids (e.g., Linoleic acid, Linolenic
acid).
• Patients with a fatty acid oxidation disorder require a high-
carbohydrate, low-fat diet.

Case study-4

Case study-4
72
• A three-month-old male infant
presented with facial
dysmorphism, hypotonia,
psychomotor retardation, and
hepatomegaly.
• He had an elder brother with the
same facial features and
hypotonia who died of hepatic
failure at four months of age.

Case study-4
• Biochemical studies revealed elevation of
blood VLCFAs, compatible with
peroxisomal disorder.
• Electron microscopy of liver biopsy
revealed absence of peroxisomes.
• What might be the most probable
diagnosis ?

Case details
• Zellweger syndrome, also called
cerebrohepatorenal syndrome is a
rare, congenital disorder (present at
birth),
• characterized by the reduction or
absence of peroxisomes in the cells
of the liver, kidneys, and brain.

Biochemical Defect
• Zellweger syndrome is a peroxisome
biogenesis disorders (PBD), component
of large group of disorder:
Adrenoleukodystrophy.
• It is characterized by an individual’s
inability to beta-oxidize very-long chain
fatty acids in the peroxisomes of the
cell, due to a genetic disorder in one of
the several genes involved with
peroxisome biogenesis.

• Enlarged liver, vision disturbances(glaucoma) and
prenatal growth failure.
• Symptoms at birth may include a lack of muscle tone,
an inability to move.
• Other symptoms may include mental retardation,
seizures, and an inability to suck and/or swallow.

• Jaundice and gastrointestinal
bleeding may also occur.
• Of central diagnostic importance
are the typical facial
appearance(high forehead,
unslanting palpebral fissures,
hypoplastic supraorbital ridges,
and epicanthal folds.

Laboratory
Diagnosis
• Several noninvasive
laboratory tests
permit precise and
early diagnosis of
peroxisomal
disorders.
• The abnormally high
levels of VLCFA (Very
long chain fatty acids),
are most diagnostic.

Treatment
• There is no cure for Zellweger syndrome, nor is there a standard
course of treatment.
• Since the metabolic and neurological abnormalities that cause the
symptoms of Zellweger syndrome are caused during fetal
development, treatments to correct these abnormalities after birth
are limited.
• Most treatments are symptomatic and supportive.

Prognosis
• The prognosis for infants with Zellweger syndrome is poor.
• Most infants do not survive past the first 6 months, and usually
succumb to :
• respiratory distress,
• gastrointestinal bleeding, or
• liver failure.

Case study-5

Case study-5
• A 6-year-old child with progressive hearing loss was brought for
consultation.
• History revealed that the child was born normal but progressively
developed loss of hearing and loss of smell.
• From the past few months the child was finding it difficult to locate
the things at night time.

Case study-5
• The child had dysmorphic
features,
• a flat bridge of nose, and
• low-set ears.

Case study-5
• On examination, pulse was irregular and the liver was enlarged.
• Laboratory investigations revealed low levels of plasma cholesterol,
HDL and LDL.
• A diagnosis and Refsum disease was made.
• What is the defect in Refsum disease?

Review of clinical and lab profile
Hearing loss
Visual
impairment
Loss of
smell
Irregular pulse
Enlarged
liver
Dysmorphic
features
Low Cholesterol
Low LDL
Low HDL

Refsum disease (RD)
• A neurocutaneous syndrome that is characterized biochemically by the
accumulation of phytanic acid in plasma and tissues.
• Refsum first described this disease.
• The symptoms evolve slowly and insidiously from childhood through
adolescence and early adulthood.
• Peripheral polyneuropathy, cerebellar ataxia, retinitis pigmentosa, and
ichthyosis are the major clinical components.
• Phytanic acid replaces other fatty acids, including such essential ones as
Linoleic and Arachidonic acids, in lipid moieties of various tissues leading to
an essential fatty acid deficiency, which is associated with the development
of ichthyosis.

Biochemical Defect
• Refsum disease is a recessive disorder characterized by defective
peroxisomal alpha-oxidation of phytanic acid.
• Phytanic acid is almost exclusively of exogenous origin and is delivered
mainly from dietary plant chlorophyll and, to a lesser extent, from
animal sources.

Alpha oxidation
• Phytanic acid is metabolized by an
initial α- hydroxylation followed by
dehydrogenation and
decarboxylation.
• Beta oxidation can not occur
initially because of the presence of
4- methyl groups, but it can
proceed after decarboxylation.
• The whole reaction produces three
molecules of propionyl co A, three
molecules of Acetyl co A, and one
molecule of iso butyryl co A

Clinical manifestations
• Classic Refsum disease manifests
in children aged 2-7 years;
however, diagnosis usually is
delayed until early adulthood.
• Infantile Refsum disease makes its
appearance in early infancy.
• Symptoms develop progressively
and slowly with neurologic and
ophthalmic manifestations.

Clinical
manifestations
91
• Night blindness due to degeneration
of the retina (retinitis pigmentosum)
• Concentric constriction of the visual
fields
• Cataract
• Loss of the sense of smell (anosmia)
• Deafness

Clinical manifestations
• Signs resulting from cerebellar ataxia –
oProgressive weakness
oFoot drop
oLoss of balance
• Some individuals will have shortened
bones in their fingers or toes.
• The children usually have moderately
dysmorphic features that may include
epicanthal folds, a flat bridge of the
nose, and low-set ears.
• Ichthyosis

Laboratory Diagnosis
• Blood levels of phytanic acid are increased, 10 to 50 mg/dL (normal
values ≤ 0.2 mg/dL, and account for 5 to 30 percent of serum lipids.
• Cerebrospinal fluid (CSF) shows a protein level of 100-600 mg/dL.
• Phytanic oxidase activity estimation in skin fibroblast cultures is
important
• Imaging
• Skeletal radiography shows bone changes.

Treatment • Eliminate all sources of chlorophyll from
the diet.
• The major dietary exclusions are
green vegetables (source of phytanic
acid) and animal fat (phytol).
• The aim of such dietary treatment is
to reduce daily intake of phytanic
acid from the usual level of 50 mg/d
to less than 5 mg/d.

Treatment
Plasmapheresis – Patients may
also require plasma exchange
(Plasmapheresis) in which blood
is drawn, filtered, and reinfused
back into the body, to control the
buildup of phytanic acid.

Prognosis
• In early diagnosed and treated cases, phytanic acid decreases slowly,
followed by improvement of the skin scaling and, to a variable degree,
reversal of recent neurological signs. Retention of vision and hearing
are reported.
• Prognosis in untreated patients generally is poor.
• Pharmacological up regulation of the omega-oxidation of phytanic
acid may form the basis of the new treatment strategy for adult
Refsum disease in the near future.

Thank you

Disorders of lipid metabolism case studies-1

Recommended

Recommended

More Related Content

What's hot

What's hot (20)

Similar to Disorders of lipid metabolism case studies-1

Similar to Disorders of lipid metabolism case studies-1 (20)

More from Namrata Chhabra

More from Namrata Chhabra (20)

Recently uploaded

Recently uploaded (20)

Disorders of lipid metabolism case studies-1