Mendelian Disorders

LEARNING OBJECTIVES At The End Of Lecture The Student Should Be Able To Give:

• Discuss the postulates of Mendelian Disorders

• Explore the pattern of inheritance in Autosomal Dominant Disorders, Autosomal

Recessive Disorders, X-Linked Disorders

• List the examples of autosomal and X-linked disorders

CLASSIFICATION OF MECHANISM

• Enzyme defects and their consequences

• Defects in membrane receptors in transport system

• Alteration in the structure, function or quantity of non enzyme proteins

• Mutations resulting in unusual reaction to drugs

ENZYME DEFECTS

• Defective enzyme with reduced activity

• Reduced amount of normal enzyme

• The consequence is a metabolic block

DECREASED END PRODUCTS

• End product is a feedback inhibitor of the enzyme involved in the early reactions

• Deficiency of the end product → overproduction of the intermediates and their

catabolic products

• Some may be injurious at higher concentrations

ALBINISM

Deficiency of tyrosinase → deficiency of melanin from its precursor tyrosine

INACTIVATION OF TISSUE DAMAGING SUBSTRATE

• Failure in inactivation of a tissue damaging substrate

α1-ANTITRYPSIN DEFICIENCY → inability to inactivate neutrophil elastase in

the lung → destruction of elastin in the walls of alveoli → pulmonary emphysema

DEFECTS IN MEMBRANE RECEPTORS IN TRANSPORT SYSTEMS

• Receptor mediated endocytosis

• Transport protein

• FAMILIAL HYPERCHOLESTEROLEMIA

Reduced synthesis or function of low density lipoproteins (LDL) receptors →

defective transport of LDL into the cells → excessive cholesterol synthesis by

complex intermediary mechanisms

ALTERATION IN STRUCTURE, FUNCTION, OR QUANTITY OF NON

ENZYME PROTEINS

• Sickle cell disease

Defects in the structure of the globin molecule

• Thalassemia

Mutation in the globin gene → amount in the globin chain synthesized

• Osteogenesis imperfecta

Defects in collagen and spectrin

• Muscular dystrophies

Defect in dystrophin

MUTATIONS RESULTING IN UNUSUAL REACTION TO DRUGS

• Genetically determined enzyme deficiencies are unmasked on exposure to certain

drugs

• G6PD deficiency Antimalarial drug primaquine → severe hemolytic anemia

CYSTIC FIBROSIS

Defect in the transport system of chloride ions in

• Sweat ducts

• Lungs

• Pancreas → serious injury in the lungs and pancreas

DISORDERS ASSOCIATED WITH DEFECTS IN STRUCTURAL PROTEIN

• Fibrillin: Marfan Syndrome

• Collagen: Ehler-Danlos Syndrome

• Dystrophin: Duchene/ Becker

• Spectrin/ Ankyrin/ Protein4,1: Spherocytosis

MARFAN SYNDROME

• Autosomal dominant inheritance

• Inherited defect in fibrillin, an extra cellular glycoprotein

• 70-80% familial vs. 20-30% new mutations

• Variable expression: genetically heterogeneous

• Mutation

– Negative dominant

– Chromosome 15q21.1

– FNB1 gene

FBN-1 Gene

• Located on chromosome 15

• Codes for the creation of protein Fibrillin1

• Disease is caused by over 500 different mutations on FBN1

• 60% mutations are change in one protein building block.

• 40% mutations produce small protein that can’t function.

SYMPTOMS

Skeleton

• Disproportionately long appendages

• Indented or protruding sternum

• Overcrowded teeth

Eyes

• Dislocated lenses

• Nearsightedness

• Development of cataracts

at a younger age: 30s to 50s

• Retinal detachment

Heart

• Mitral regurgitation

• Aortic regurgitation

• Tears in inner and

middle aortic layers

EHLER DANLOS SYNDROME (EDS)

• Genetically heterogeneous

• At least 10 variant

• Clinical manifestations

– Skin

• Hyperextensible

• Extremely fragile

– Joints

• Prone to dislocation

• Hypermobile

FAMILIAL HYPERCHOLESTROLEMIA

• The most frequent mendelian disorder

• Mutation in the gene encoding LDL receptor

– Hypercholestrolemia

• Premature atherosclerosis: MI

• Xanthoma

• Heterozygotes

1/500

2-3 times higher plasma cholestrol

• Homozygotes

5-6 times higher plasma cholestrol

MI before 20 years of age

FAMILIAL HYPERCHOLESTROLEMIA

Pathogenesis

• Decreased LDL clearance

• Increased LDL production

– More IDL coverts to LDL

– In both heterozygotes and homozygotes

• Increased LDL uptake by macrophage/ monocyte

– Acetylated or oxidized LDL.

LYSOSOMAL STORAGE DISEASES

Lack of any protein essential for the normal function of lysosomes

TAY-SACHS DISEASE

• Most common form of GM2 gangliosidosis

• All tissues lack hexosaminidase A

– Including leukocytes and plasma

• GM2 accumulation in many organs

– Heart, liver, spleen, CNS, ANS, retina

Ganglion cells with large lipid vacuolation

NIEMANN-PICK DISEASE

• Rare lysosomal storage disease

• Lysosomal accumulation of sphingomyelin

– Sphingomyelinase deficiency

• Common in Ashkenazi jews

• Types A & B

• Previously type C

– Defect in intracellular cholesterol esterification & transport.

DIAGNOSIS

• Biochemical studies:

– Sphingomyelinase activity in leukocytes and cultured fibroblasts

• DNA probes:

– Both patients and carriers.

GAUCHER DISEASE

• Glucocerebrosidase gene mutation

• Accumulation of glucocerebroside in phagocytes and sometimes CNS.

• Most common lysosomal storage disease

• Diagnosis

– Homozygotes

• Enzyme activity

– Peripheral blood leukocytes

– Cultured skin fibroblasts

– Heterozygotes

• Enzymatic methods not reliable

• Detection of mutation

– More than 30 different mutations

GAUCHER DISEASE

• Types

– I (chronic non-neuropathic): 99%

• Decreased enzyme activity

• Without CNS involvement

• Predominantly spleen & skeleton

• Pancytopenia or thrombocytopenia

• Pathologic Fractures and bone pain

– II (acute neuropathic)

• No enzyme activity

• No predilection for jews

• Infantile

• Progressive involvement of CNS & early death

• Hepatosplenomegaly

GLYCOGEN STORAGE DISEASES

Genetic disease with metabolic defect in synthesis or catabolism of glycogen.

– Pompe (acid maltase, -glucosidase)

• Lysosomal accumulation of glycogen

• Predominantly heart involvement

• Early death.

GLYCOGEN STORAGE DISEASES

• Hepatic type

– Hepatomegaly

– Hypoglycemia

– Examples

• Von Gierke: Glucose-6-phosphatase (I)

• Liver phosphorylase (VI)

• Debranching enzyme(III)

• Myopathic type

– Muscle weakness

– Cramps following exercise

– Following exercise lactate does not increase

– Examples

• McArdle: muscle phosphorylase(V)

• Muscle phosphofructokinase (VII)

GLYCOGEN STORAGE DISEASES

REFERENCES

PATHOLOGIC BASIS OF DISEASES

ROBBINS & COTRAN

8TH

EDITION

CH. 5 GENETIC DISORDERS

Pgs # 140 -155