zamil INBORN ERRORS OF METABOLISM 23122020 Outlines Definition genetic disorders that cause disruption of a metabolic pathway Disease accumulation of a toxic substrate proximal to the metabolic block ID: 916382
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Slide1
Slide2By
Noha
nageh
Brihan
zamil
INBORN ERRORS OF METABOLISM
23/12/2020
Slide3Outlines :
Slide4Definition:
genetic disorders that cause disruption of a metabolic pathway
Disease
accumulation of a toxic
substrate proximal to the metabolic block
deficiency of the a product
distal to the block
diversion of the substrate to an alternative pathway
Slide5General pathophysiology in inborn errors of metabolism (IEMs) :
Slide6Inborn Errors
of
Carbohydrates Metabolism
Slide7Carbohydrates account for a major portion of the human diet and are metabolized into three principal
monosaccharides
: glucose,
galactose
and
fructose•The failure to effectively use these molecules accounts for the majority of the inborn errors of carbohydrates metabolism
Slide8Galactosemia
:
*
galactose
is metabolised
by the Leloir pathway*Galactosemia is an autosomal recessive disorder, results from failure to metabolise galactose*
Three types of galactosemia are recognized.:**Type I or classical galactosemia
most common, mutation in the gene encoding galactose
1-phosphateUridylyltransferase:**Type II galactosemiamildest form, mutation in thegene encoding galactokinase**Type III galactosemia:
rarest form, mutation in the geneencoding UDP-galactose
4’-epimerase
Slide9Type I or classical
galactosemia
:
Reduction
in the rate
of galactose 1-phosphate Uridylyltransferase (GALT) -catalyzed utilization of galactose 1-P
Accumulation of
gal 1-P
toxic
to cells
*
depletion
of
cellular
phosphate
(leading
to
decreased
production of
ATP
)
*
stimulation
of
ATPases
in brain cells by
galactose
*
accumulation
of
galactose
metabolites
causes
ER stress
and
accumulation
of
unfolded proteins
Slide10*Affected
newborns
are apparently healthy, then develop
serious morbidity
upon consuming milk
.*The most common signs are failure to thrive, hepatic insufficiency, cataract and developmental delay.
*Long term disabilities include mental retardation, and ovarian failure in females.
Slide11Type II
galactosemia
(mild galactosemia
):
*also
known as galactokinase (GALK) deficiency.
*GALK deficient patients are biochemically characterized by galactosemia and elevated levels of galactitol.
Bilateral cataract,
characterized by central lens opacities with the appearance of an oil droplet, is a consistent manifestationPseudotumor cerebri has also been described due to the accumulation of galactitol in the brain cells with subsequent cerebral edema
Slide12hypergalactosemia
high amounts of
galactose
are transported to the lens cells
Aldose
reductase
is
abundantly present in the epithelial cells, located at the anterior side of the lenshigh levels of galactose are reduced to galactitol
creating
high
osmotic
pressure
with
lens swelling,
lysis
, and
cataract
Slide13Type III
galactosemia
Mutations in
the gene encoding
UDP-
galactose 4-epimerase (GALE).
Exist in two forms:**severe (generalized) form; low GALE activity in all tissues
**mild (peripheral) form; GALE activity is reduced in blood
GALE is responsible for the interconversion ofUDP-galactose and UDP-glucose
UDP-N-acetylgalactosamine and UDP-N-acetylglucosamine
Slide14GALE deficiency
galactose-1 phosphate
disturbance of amino-sugar metabolism
Cataract within
the first few months of
life
followed by
liver, kidney
and brain damage
Slide15Newborn screening:
Galactose
level:
Primary
screening by assessment of total blood galactoseBut
it carries high false-positive and false-negative resultsGalactose-1-P level:
more than 10 mg%
is suggestive of galactosemia RBC enzyme activity: GAL-1-P urydil transferase activity assessment combined with gal-1-phosphate in a blood spot, is adopted for neonatal screening in many nations
The presence of elevated galactose
together
with
normal GALT
activity suggests a deficiency of
either GALK or GALE
Slide16Early identification affords prompt treatment, which consists
of
eliminating dietary galactose
and
its precursor lactose
Slide17Inborn Errors of
Fructose
Metabolism
(
1) Essential
or benign fructosuria (2) Hereditary fructose intolerance These disorders are
autosomal recessive disorders
Slide18Essential or benign
fructosuria
:
•
caused
by mutations in the gene encoding hepatic fructokinase,
that catalyzes the first step in the metabolism of dietary fructose•Inactivation of the hepatic fructokinase results in asymptomatic fructosuria.
*Ingested fructose is partly excreted unchanged in the urine and the rest
is converted to fructose-6-phosphate by hexokinase in muscle.
Slide19Hereditary Fructose
Intolerance (HFI):
deficiency of
aldolase
B
Accumulation of
fructose 1-P and
trapping of phosphateThis has two major effectsInhibition of glucose production by inhibiting of gluconeogenesis and glycogenolysis
Hypoglycemia within 3-4 hours after fructose rich diet
diminished regeneration of ATP
*increased
production of uric
acid
*impaired
protein
synthesis
*hepatic
and renal dysfunction
Slide20Symptoms
appear only when
fructose either as the monosaccharide, or in sucrose or sorbitol is
introduced in diet
Early symptoms are nausea, vomiting
followed by hypoglycemia, hemorrhage, hepatomegaly, liver damage and hyperuricaemiaDiagnosis of HFI is suspected from a detailed
nutritional history and the clinical picture.Diagnosis is confirmed by :molecular analysis of the ALDOB gene
If no mutation can be found despite a strong clinical and nutritional history suggestive of HFI, demonstration of deficient aldolase
B activity in liver sample will confirm the diagnosis.As soon as HFI is suspected, all fructose, sucrose, and sorbitol must be eliminated from the diet and medications. Prognosis is excellent and recovery within a few days after fructose elimination.
Slide21GLUCOSE-6-PHOSPHATE DEHYDROGENASE (G6PD)
DEFICIENCY
*
G6PD
is a housekeeping enzyme, expressed in all cells of the
body *Prime physiologic role of G6PD is the production of NADPH.*In most cells of the human body NADPH is the key electron donor required for many
biosynthetic processes*In most cells there are
several enzymes catalyzing dehydrogenase reactions that produce NADPH
Slide22The situation is
different
in
RBCs
HMP pathway
is the source of NADPHThe major function of NADPH: defense against oxidative stress or oxidative attack. This defense is mediated through the
glutathione cycleThe steady regeneration of reduced glutathione (GSH) depends on a steady supply of NADPH
Slide23G6PD deficiency
*
X-linked inherited
disorder
*never complete; if it were complete, it would be lethal
*in the steady state, the consequences of G6PD deficiency are not noticeable *NADPH produced by the
residual G6PD activity is just enough to keep the RBCs intigrity,
with marginal reduction of its life span.
Slide24G6PD deficiency
exogenous
oxidative
stress
G6PD-deficient RBCs
NADPH
is not sufficient to cope with the excess
of reactive oxygen species.
GSH is rapidly depleted hemoglobin and other proteins are damaged and RBCs are
hemolyzed
Slide25Clinical Manifestations:
G6PD-deficient individuals remain
asymptomatic
till they exposed to triggering factors:
*Ingestion
of fava beans (vicine and convicine; produce free radicals)*Infection *primaquine (super oxide free radicle ) *
Aspirin, Sulfadiazine, Chloramphenicol
Acute hemolytic anemia and
Jaundice typically occurs24 to 72 hours after ingestion
Slide26Diagnosis:
*estimation of enzyme
activity by quantitative
spectrophotometric analysis of the rate of NADPH
production from NADP *rapid fluorescent spot test : detecting the generation of NADPH from NADP (test is positive if the bloodspot fails to fluoresce under UV light; semiquantitative ).In patients with acute hemolysis,
testing for G6PD deficiency give false negative resultbecause older erythrocytes with a higher enzyme deficiency have been
hemolyzedYoung erythrocytes and
reticulocytes have normal or near-normal enzyme activity.
Slide27According to residual enzyme activity :
Slide28Other inborn errors causing Hemolytic anemia
Hexokinase deficiency
:
Decrease in ATP production
Hemolysis 2,3-BPG are low in RBCPyruvate kinase deficiency:
PK deficiency in RBCs results in Inadequate ATP generation leads to hemolysis2,3-BPG in RBC is high
Slide29Pyruvate dehydrogenase (PDH) deficiency:
Deficiency of
E1
enzyme account
for the great majority of cases of PDH
deficiency
PDH deficiency results in lactic acidosis that manifest during neonatal period Tissues with a high demand for ATP are most affected, with the
nervous system being particularly vulnerable
Slide30Glycogen storage diseases
*Are
also
known as
glycogenosis
*The inheritance of glycogen storage diseases is autosomal recessive*It is a group of diseases in which synthesis or breakdown of glycogen is impaired
*Abnormally large amounts of glycogen accumulate in the affected tissues*The glycogen that accumulates may be normal or
abnormal in structure
Slide31Glycogen storage diseases
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 VIII (
Phosphorylase kinase deficiency)
Slide32Symptoms
Deficient
enzyme/ organ affected
Glycogen Storage Disease
Fasting
hypoglycaemiaLactic acidosis
HyperlipidaemiaHyperuricaemia
Enlargement of liver
Retardation of growthglucose-6-phosphatase in liverType I (von Gierke’s disease)Muscular weaknessHypotonia
Cardiomegaly
Congestive heart failure
Lysosomal
α
-1,4-glucosidase (acid maltase) in lysosomes in skeletal and cardiac muscles
Type II (
Pompe’s
disease)
Mild
Hypoglycaemia
Hepatomegaly
Muscle weakness
Muscle atrophy
Retardation of growth
α
1,6-glucosidase (
debranching
enzyme) in liver and muscle
Type III (Cori’s disease)
Hepatomegaly (abnormal fibrous glycogen)
Cirrhosis
Growth retardation
Branching enzyme in liver
Type IV (Andersen’s disease)
Slide33Symptoms
Deficient
enzyme/ organ affected
Glycogen Storage Disease
cramps on exercise
Serum CK is elevated after physical activityMyoglobinuria
after sever exerciseGlycogen Phosphorylase
in muscle Type V (McArdle’s disease)
Hypoglycaemia HepatomegalyGlycogen Phosphorylase in liverType VI (Her’s disease)cramps on exercise
Myoglobinuria
after sever exercise
Haemolysis
Sever deficiency of Phosphofructokinase1 in muscle
Moderate deficiency of phosphofructokinase1
in erythrocytes
Type VII (
Tarui’s
disease)
Hypoglycaemia
glycogen
phosphorylase
kinase in liver
Type VIII (
Phosphorylase
kinase deficiency)
Slide34Slide35Slide36GSD 0(Glycogen
Synthase Deficiency):
*
Deficiency
of glycogen synthase
(GS), a key enzyme of glycogen synthesis. *Decreased liver glycogen*fasting hypoglycaemia
Slide37Inborn errors of
lipid
metabolism
Slide38Inborn errors of Fatty Acid Oxidation :
Mitochondrial
fatty acid β-oxidation
(FAO) is
essential
for maintaining energy homeostasis in the human body. Fatty acids are a crucial energy source in fasted state when glucose supply is limiting. FAO is a main energy source for the
heart and skeletal muscle even when glucose is abundantly available .Fatty acid oxidation defects demonstrate an abnormal response to
fasting adaptationAffect those tissues that utilize fatty acids as an energy
source (cardiac , skeletal muscle and liver)
Slide39Inborn errors of Fatty Acid Oxidation :
Fatty
acid oxidation disorders (FAODs) are inborn errors of
metabolism
due
to disruption of: Mitochondrial β-oxidation Fatty acid transport using the carnitine transport pathway.
FAODs are autosomal recessive disorders
Slide40Inborn errors of Fatty
Acids
Oxidation :
clinical presentation:
The
neonatal-onset type:newborns will develop cardiomyopathy, hypoketotic hypoglycemia, and liver dysfunction within the first few days or weeks of life, is often fatal.
The infantile-onset type:in infancy or childhood with intermittent episodes of lethargy and vomiting associated with hepatic dysfunction and hypoketotic hypoglycemia or sudden death
The adolescent or adult onset:
myopathic type presents with episodes of muscle weakness and myalgia
Slide41Medium-chain acyl-CoA dehydrogenase deficiency (MCADD
):
The
most common
FAOD.
Sudden Infant Death Syndrome (SIDS)
Slide42Carnitine
transport
disorders:
Slide43Carnitine
palmitoyltransferase
type 1 deficiency (CPT1D
) or CAT1 D
CPT1A deficient in
liver.Childhood onset presentationhypoketotic hypoglycemia, liver dysfunction
elevated free plasma
carnitine level decreased level of long-chain acylcarnitine
Slide44Carnitine
palmitoyltransferase type 2 deficiency (CPT2D) :
adulthood
onset
exercise
intolerance, myopathy, Myoglobinuria.
Decreased free plasma carnitine
levels elevated levels of long-chain acylcarnitines
Slide45Carnitine-acylcarnitine
translocase deficiency (CACTD):
Neonatal
onset
Sever cardiomyopathy, sudden death
Decreased free plasma carnitine levels
elevated
levels of long-chain acylcarnitines
Slide46Carnitine
transporter deficiency (CTD
)
or primary
carnitine
deficiency: Carnitine is transported across the plasma membrane by the organic cation
transporter (OCTN2).
CTD results in loss of carnitine in urine and low levels of carnitine in serum.hypoketotic hypoglycemia, liver dysfunction, cardiomyopathy, and hypotonia.
Slide47Nutrition management of
FAOD:
Nutrition management of all FAODs includes avoidance of
fasting
and supplementation of
carnitine.For (MCADD):Infants require frequent feedings dependent on their age
children, and adults require regular meals and snacks during the day and before bed, eat a normal, healthy diet (30% of energy from fat)Patients are educated to
avoid excessive consumption of coconut oil
For (LCFAOD) :fat restricted dietsupplementation of medium chain FAs (as a substrate for β-oxidation)
Slide48Peroxisomal
disorders affecting Fatty Acids oxidation:
Peroxisomes
are multiple membrane-bound
intracellular organelles catalyzing various functions of cellular metabolism: beta-oxidation of
(VLCFA) alpha oxidation for catabolism of branched-chain FAs
Peroxisomal disorders affecting FAs oxidation:
Refsum disease Zellweger syndromeAdrenoleukodystrophy
Slide49Refsum
disease:
Deficiency
of
phytanoyl-CoA hydroxylase (PAHX) or
peroxisomal biogenesis factor 7 (PEX7) which import cytosolic proteins into peroxisomes including PAHX enzyme.
phytanic acid
is branched-chain fatty acid, present dairy products and meat
Slide50Phytanic
acid
accumulates
in blood and tissues including
myelin
sheaths damage to the structural integrity of cells and tissues
Slide51Defects in
Peroxisomal
β
–Oxidation of VLCFAs:
X-linked
adrenoleukodystrophy Zellweger Syndrome
Slide52X-linked
adrenoleukodystrophy
Transport
of
VLCFA for β-oxidation across the peroxisomal membrane is an essential step in this metabolismATP-binding cassette (ABC) proteins have been implicated in this transportthree ABC proteins, classified into “subfamily D,” have been identified in mammalian peroxisomes (ABCD1, ABCD2, ABCD3)
Dysfunction of (ALDP /ABCD1) causes the human genetic disorder X-linked adrenoleukodystrophyX-ALD is a genetic defect in the ability to transport VLCFA across the
peroxisomal membrane
characterized by an accumulation of VLCFA in blood and tissuesnervous system white matter and the adrenal cortex.
Slide53Zellweger
Syndrome
Peroxisomal
biogenesis disorder
Genetic defect in the ability to target matrix proteins to peroxisomsesDue to mutations in one of 13 PEX genes
Accumlation of VLCFA in blood and tissueSever neurological manifestations
Slide54Inborn errors of lipoprotein metabolism
:
a
group of genetic disorders
characterized by changes in
plasma lipids due to defects in: the protein lipid-carriers : apolipoproteins enzymes responsible for the hydrolysis and clearance of lipoprotein-lipid complexes: lipoprotein lipase (LPL)
lipoprotein receptors: (LDL-R)
Slide55Slide56Laboratory
findings
Cause
Type of
hyperlipoproteineia autosomal recessiveTAG accumulates in tissue : pancreatitis, eruptive
xanthomas elevated chylomicrons, TAG, VLDL
ten times higher than normal, even during fasting
lipoprotein lipase deficiencyOrAPOC IIType-I:
Familial Hyperlipidemia (familial
hyperchylomicronemia
)
Autosomaldominant
premature atherosclerotic and cardiovascular disease
Elevated
LDL
Genetic
defect in LDL receptors
Type-II: familial
hypercholesterolaemia
autosomal recessive
Palnar
xanthomas
at the palmar surface,
CHD
.
Elevated
chylomicrons
,
IDL
(TAG ,cholesterol )
dysfunctional genetic variant of
apo
E (E2) or absence of
apo
E.
Type-III: familial
dys
-beta
Lipoproteinaemia
Slide57Normal
LDL receptor is not synthesized
no LDL-LDLR
binding
(also
known as familial defective
apoB,at
binding site on LDL, )
impaired LDL-LDLR complex internalization
recycling defect
Slide58reverse cholesterol transport by HDL.
Familial
hypoalphalipoproteinaemia
(Tangier’s disease):
Deficiency of ABCA1
transporter protein
Degradation of lipid poor apoA1 Patients typically have decreased blood HDL and Apo A-I storage
of cholesteryl esters in tissues premature
atherosclerosis
Slide59Slide60Deficiency
of Microsomal Triglyceride Transfer Protein
(MTTP)
MTTP is essential for
assembly and secretion
of the apo B-containing lipoproteins: chylomicrons from the intestine and VLDL from the liver. MTTP deficiency results in inability of apoB-containing lipoprotein particles to be secreted
deficiency of fat-soluble vitaminsextremely low LDL-c, triglyceride, and apo B levels
Abetalipoproteinemia
:
Slide61References
:
Ferreira, C. R., & van Karnebeek, C. D. (2019). Inborn errors of metabolism. In Handbook of clinical neurology
(Vol. 162, pp. 449-481). Elsevier.
McCorvie, T. J., & Timson
, D. J. (2011). The structural and molecular biology of type I galactosemia: enzymology of galactose 1‐phosphate uridylyltransferase. IUBMB life, 63(9), 694-700.Pasquali, M., Yu, C., & Coffee, B. (2018). Laboratory diagnosis of galactosemia: a technical standard and guideline of the American College of Medical Genetics and Genomics (ACMG). Genetics in Medicine, 20(1), 3-11.Kotb, M. A., Mansour, L., & Shamma
, R. A. (2019). Screening for galactosemia: is there a place for it?. International Journal of General Medicine, 12, 193.Timson, D. J. (2006). The structural and molecular biology of type III galactosemia. IUBMB life, 58(2), 83-89.Tran, C. (2017). Inborn errors of fructose metabolism. What can we learn from them?. Nutrients, 9(4), 356.
Slide62References :
Cappellini
, M. D., & Fiorelli, G. E. M. I. N. O. (2008). Glucose-6-phosphate dehydrogenase deficiency. The lancet, 371(9606), 64-74.
Luzzatto
, L., Nannelli, C., &
Notaro, R. (2016). Glucose-6-phosphate dehydrogenase deficiency. Hematology/Oncology Clinics, 30(2), 373-393.Jameson, E., & Walter, J. H. (2019). Medium-chain acyl-CoA dehydrogenase deficiency. Paediatrics and Child Health, 29(3), 123-126.Longo, N. (2016). Primary carnitine deficiency and newborn screening for disorders of the carnitine cycle. Annals of Nutrition and Metabolism, 68(Suppl. 3), 5-9.Merritt, J. L., II, M. N., & Kanungo, S. (2018). Fatty acid oxidation disorders. Annals of translational medicine, 6(24).Houten
, S. M., Violante, S., Ventura, F. V., & Wanders, R. J. (2016). The biochemistry and physiology of mitochondrial fatty acid β-oxidation and its genetic disorders. Annual review of physiology, 78, 23-44.Kumar, R., & De Jesus, O. (2020). Refsum Disease. StatPearlsMorita, M., Shinbo, S., Asahi, A., & Imanaka, T. (2012). Very long chain fatty acid β-oxidation in astrocytes: Contribution of the ABCD1-dependent and-independent pathways.
Biological and Pharmaceutical Bulletin, 35(11), 1972-1979.Regmi
, M., & Rehman, A. (2019). Familial Hyperlipidemia Type 1. In StatPearls. StatPearls Publishing.
Slide63Bouhairie
, V. E., & Goldberg, A. C. (2015). Familial hypercholesterolemia.
Cardiology clinics, 33(2), 169-179.Benito-Vicente, A., Uribe, K. B., Jebari
, S., Galicia-Garcia, U.,
Ostolaza, H., & Martin, C. (2018). Familial hypercholesterolemia: The most frequent cholesterol metabolism disorder caused disease.
International journal of molecular sciences, 19(11), 3426.Kolovou G.D., Anagnostopoulou K.K., Cokkinos D.V. (2009) Tangier Disease. In: Lang F. (eds) Encyclopedia of Molecular Mechanisms of Disease. Springer.Burnett, J. R., Hooper, A. J., & Hegele, R. A. (2018). Abetalipoproteinemia. In GeneReviews