Lakhasly

Disorders of Lipid Metabolism Dr. Amar Babikir Elhussein Associate Professor of Biochemistry and Molecular Biology Disorders of Lipid Metabolism ?Importance in clinical medicine.ketones o Features: muscle weakness, cardiomyopathy o Hypoketotic hypoglycemia o Tx: carnitine, avoid fasting MCAD Deficiency o Defect: medium-chain acyl-CoA dehydrogenase o Biochemical: block in ?-oxidation o Features: hypoketotic hypoglycemia, seizures o Risk of sudden infant death o Tx: avoid fasting, IV glucose Other FA Oxidation Defects o VLCAD deficiency (long-chain) o CPT I/II deficiency (carnitine shuttle) o Features: impaired fasting tolerance o Myopathy, weakness Ketone Body Disorder: HMG-CoA Lyase Deficiency o Defect: HMG-CoA lyase o Biochemical: cannot make ketones o Features: fasting hypoglycemia, seizures o Labs: absent ketones o Tx: frequent feeding, glucose Ketone Body Utilization: SCOT Deficiency o Defect: SCOT enzyme o Biochemical: cannot utilize ketones o Features: ketoacidosis, neurologic crises o Tx: avoid fasting, supportive Succinyl-CoA:3-ketoacid CoA transferase Gaucher Disease o Defect: ?-glucocerebrosidase o Biochemical: glucocerebroside accumulation o Features: hepatosplenomegaly, bone crises o Crumpled paper macrophages o Tx: enzyme replacement Niemann-Pick Disease o Defect: sphingomyelinase o Biochemical: sphingomyelin accumulation o Features: cherry-red macula, hepatosplenomegaly o Neurodegeneration Tay-Sachs Disease o Defect: hexosaminidase A o Biochemical: GM2 ganglioside accumulation o Features: cherry-red macula, neurodegeneration o No hepatosplenomegaly Fabry Disease o Defect: ?-galactosidase A (X-linked) o Biochemical: Gb3 accumulation o Features: angiokeratomas, neuropathic pain o Renal failure o Tx: enzyme replacement Summary & Take-Home Messages o Disorders grouped by defect o Key = enzyme/protein deficiency o Labs + clinical signs -> diagnosis o Therapy: diet, drugs, enzyme replacement o Clinical importance: CAD, pancreatitis, organ failurecholesterol o Tx: diet, fibrates, omega-3 Abetalipoproteinemia o Defect: MTP mutation -> no ApoB lipoproteins o Biochemical: no chylomicrons, VLDL, LDL o Features: fat malabsorption, vitamin deficiency o Labs: absent ApoB lipoproteins o Tx: vitamins, diet *Gene encodes the microsomal triglyceride transfer protein (MTP) Tangier Disease (Hypoalphalipoproteinemia) o Defect: ABCA1 mutation o Biochemical: impaired cholesterol efflux -> low HDL o Features: orange tonsils, neuropathy o Labs: HDL <5 mg/dL o Tx: supportive Other Hypolipoproteinemias o Familial hypobetalipoproteinemia (ApoB defect) o LCAT deficiency (complete/partial) o Fish-eye disease (partial LCAT deficiency) o Features: corneal opacity, anemia o Low LDL/HDL Clinical Correlation: CAD Risk o Low HDL strongly predicts CAD o High LDL accelerates atherosclerosis o Genetic hypoalphalipoproteinemias -> severe risk o Therapeutic target = ?Key Clinical Consequences o Dyslipidemia -> atherosclerosis, CAD o TG excess -> pancreatitis o FA oxidation defects -> hypoglycemia o Lysosomal defects -> organomegaly, neurodegeneration Classification of Disorders o Hyperlipoproteinemias (I-V) o Hypolipoproteinemias o FA oxidation defects o Ketone body disorders o Lysosomal storage diseases Type I: Familial Chylomicronemia o Defect: LPL or ApoC-II deficiency o Biochemical: TG not hydrolyzed o Features: eruptive xanthomas, pancreatitis o Labs: ?TG, milky plasma o Tx: very-low-fat diet Type IIa: Familial Hypercholesterolemia o Defect: LDL receptor/ApoB mutation o Biochemical: impaired LDL clearance o Features: tendon xanthomas, arcus cornealis o Labs: ?LDL Visual Summary (Hypolipoproteinemias) o ApoB deficiency -> absent LDL/chylomicrons o ABCA1 defect -> absent HDL o LCAT defect -> abnormal HDL o Lab patterns & signs compared Carnitine Deficiency o Defect: impaired FA transport o Biochemical: ?Identify hyper/hypolipoproteinemias ?Recognize FA oxidation & ketone body disorders ?Correlate defect with clinical outcome Normal Lipid Transport (Overview) o Chylomicrons: dietary TG transport.LDL + VLDL o Tx: statins +- fibrates Type III: Familial Dysbetalipoproteinemia o Defect: ApoE2 homozygous o Biochemical: ??Focus: lipoproteins, FA oxidation, storage diseases.

Disorders of Lipid
Metabolism
Dr. Amar Babikir Elhussein
Associate Professor of Biochemistry and Molecular Biology
Disorders of Lipid Metabolism
❑Importance in clinical medicine.
❑Biochemistry + genetics basis.
❑Focus: lipoproteins, FA oxidation, storage diseases.
❑Lecture outline with objectives.
Learning Objectives
➢By the end of this lecture, you should be able to:
✓Recall lipid metabolism pathways
✓Describe biochemical defects
✓ Identify hyper/hypolipoproteinemias
✓Recognize FA oxidation & ketone body disorders
✓Correlate defect with clinical outcome
Normal Lipid Transport (Overview)
• Chylomicrons: dietary TG transport.
• VLDL → LDL: endogenous lipid
transport.
• HDL: reverse cholesterol transport.
• Key enzymes: LPL, HL, LCAT,
CETP.
Key Clinical Consequences
• Dyslipidemia → atherosclerosis, CAD
• TG excess → pancreatitis
• FA oxidation defects → hypoglycemia
• Lysosomal defects → organomegaly, neurodegeneration
Classification of Disorders
• Hyperlipoproteinemias (I–V)
• Hypolipoproteinemias
• FA oxidation defects
• Ketone body disorders
• Lysosomal storage diseases
Type I: Familial Chylomicronemia
• Defect: LPL or ApoC-II deficiency
• Biochemical: TG not hydrolyzed
• Features: eruptive xanthomas, pancreatitis
• Labs: ↑ TG, milky plasma
• Tx: very-low-fat diet
Type IIa: Familial
Hypercholesterolemia
• Defect: LDL receptor/ApoB mutation
• Biochemical: impaired LDL clearance
• Features: tendon xanthomas, arcus cornealis
• Labs: ↑ LDL cholesterol
• Tx: statins, PCSK9 inhibitors
Type IIb: Familial Combined Hyperlipidemia
• Defect: ↑ ApoB100 lipoprotein production
• Biochemical: excess VLDL + LDL
• Features: most common inherited type
• Labs: ↑ LDL + VLDL
• Tx: statins ± fibrates
Type III: Familial Dysbetalipoproteinemia
• Defect: ApoE2 homozygous
• Biochemical: ↑ remnants (IDL,
chylomicrons)
• Features: palmar xanthomas
• Labs: ↑ cholesterol + TG
• Tx: fibrates, statins
Type IV & V: Hypertriglyceridemia / Mixed
• Type IV: ↑ VLDL → hypertriglyceridemia
• Type V: ↑ chylomicrons + VLDL
• Features: pancreatitis risk, metabolic syndrome
• Labs: ↑ TG, ± ↑ cholesterol
• Tx: diet, fibrates, omega-3
Abetalipoproteinemia
• Defect: MTP mutation → no ApoB lipoproteins
• Biochemical: no chylomicrons, VLDL, LDL
• Features: fat malabsorption, vitamin deficiency
• Labs: absent ApoB lipoproteins
• Tx: vitamins, diet
*Gene encodes the microsomal triglyceride transfer
protein (MTP)
Tangier Disease (Hypoalphalipoproteinemia)
• Defect: ABCA1 mutation
• Biochemical: impaired cholesterol efflux → low HDL
• Features: orange tonsils, neuropathy
• Labs: HDL