By Noha nageh Brihan - PowerPoint Presentation

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By

Noha

nageh

Brihan

zamil

INBORN ERRORS OF METABOLISM

23/12/2020

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Outlines :

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Definition:

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

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General pathophysiology in inborn errors of metabolism (IEMs) :

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Inborn Errors

of

Carbohydrates Metabolism

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Carbohydrates 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

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Galactosemia

:

*

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

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Type 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

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*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.

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Type 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

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hypergalactosemia

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

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Type 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

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GALE deficiency

galactose-1 phosphate

disturbance of amino-sugar metabolism

Cataract within

the first few months of

life

followed by

liver, kidney

and brain damage

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Newborn 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

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Early identification affords prompt treatment, which consists

of

eliminating dietary galactose

and

its precursor lactose

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Inborn Errors of

Fructose

Metabolism

(

1) Essential

or benign fructosuria (2) Hereditary fructose intolerance These disorders are

autosomal recessive disorders

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Essential 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.

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Hereditary 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

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Symptoms

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.

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GLUCOSE-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

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The 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

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G6PD 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.

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G6PD 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

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Clinical 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

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Diagnosis:

*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.

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According to residual enzyme activity :

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Other 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

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Pyruvate 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

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Glycogen 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

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Glycogen 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)

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Symptoms

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)

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Symptoms

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)

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GSD 0(Glycogen

Synthase Deficiency):

*

Deficiency

of glycogen synthase

(GS), a key enzyme of glycogen synthesis. *Decreased liver glycogen*fasting hypoglycaemia

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Inborn errors of

lipid

metabolism

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Inborn 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)

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Inborn 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

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Inborn 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

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Medium-chain acyl-CoA dehydrogenase deficiency (MCADD

):

The

most common

FAOD.

Sudden Infant Death Syndrome (SIDS)

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Carnitine

transport

disorders:

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Carnitine

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

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Carnitine

palmitoyltransferase type 2 deficiency (CPT2D) :

adulthood

onset

exercise

intolerance, myopathy, Myoglobinuria.

Decreased free plasma carnitine

levels elevated levels of long-chain acylcarnitines

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Carnitine-acylcarnitine

translocase deficiency (CACTD):

Neonatal

onset

Sever cardiomyopathy, sudden death

Decreased free plasma carnitine levels

elevated

levels of long-chain acylcarnitines

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Carnitine

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.

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Nutrition 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)

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Peroxisomal

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

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Refsum

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

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Phytanic

acid

accumulates

in blood and tissues including

myelin

sheaths damage to the structural integrity of cells and tissues

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Defects in

Peroxisomal

β

–Oxidation of VLCFAs:

X-linked

adrenoleukodystrophy Zellweger Syndrome

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X-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.

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Zellweger

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

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Inborn 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)

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Laboratory

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

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Normal

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

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reverse 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

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Deficiency

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

:

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References

:

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.‏

‏‏

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References :

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.

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Bouhairie

, 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