INBORN ERRORS OF LIPID METABOLISM

Tapeshwar Yadav (Lecturer) BMLT, DNHE, M.Sc. Medical Biochemistry

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’’

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.

2) Lipid Storage diseases:-A. Niemann-pick diseaseB. Farber’s diseaseC. Gaucher’s diseaseD. Krabbe’s diseaseE. Tay- sachs diseaseF. Fabry’s disease

3) Disorders associated with Lipoprotein MetabolismA. 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).

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.

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.

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.

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.

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.

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.

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.

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

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.

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.

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.

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).

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.

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.

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.

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.

Tay-Sachs Disease

Hexosaminidase-A Ganglioside GM2 Blindness, mental retardation, death

within2-3yrs.

Fabry’s Disease

α-galactosidase Ceramidase trihexoside

Renal failure, skin rash, pain in

lower extremities.

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.

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.

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.

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.

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.

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”

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.

2) Type-II: familial hypercholesterolaemia(FHC):- Common disorder. Characterized by:-o Increased Total Cholesterol & HDL.o May be high TG & VLDL.Inheritance:- Autosomal dominantFrequency:- 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.

3) Type-III: familial dys-beta Lipoproteinaemia:- Synonyms:- Broad beta disease & Remnant removal disease.Characterised by:- Increased LDL & VLDL. Rise in IDL Hypercholesterolemia & hypertriglyceridaemiaInheritance:- Autosomal dominantFrequency:- 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

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

4) Type-IV: familial hypertriglyceridaemia:-Characterised by:- Increased TG & VLDL. Chol. May be normal or increased. Decreased HDL & LDL.Inheritance:- Autosomal dominantMetabolic defects:-over production of VLDL & Apo-CIIClinical features:- Associated with diabetes mellitus, IHD &

Obesity.Management:- Reduction of weight. Restriction of Carbohydrate & chol. Hypolipidaemic drugs.

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

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.

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.

2) Familial Alpha-Lipoprotein deficiency:- Also called Tangier’s diseaseCharacterized by:-

Deficiency of HDL. In homozygous patients plasma HDL may be nearly

completed absent.Inheritance:- Autosomal recessiveMetabolic defect:-

Reduction in apo-AI & apo-AIILeading to accumulation of cholesteryl esters in diff.

tissues.Clinical features-Increased risk of CAD.Adenoids.

All these Disease can be diagnosed Prenatally by:-

Amniocentesis Chorionic Villi Sampling Ultrasonography Fetal blood Sampling Maternal blood Sampling

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