CONNECTIVE TISSUE DISORDERS

Dr. Vijay Marakala, MBBS, MD.

Senior LecturerBIOCHEMISTRY

IMS, MSU.

CONNECTIVE TISSUE DISORDERS

Introduction ClassificationCommon

connective tissue disorders

Biochemical abnormalities

Clinical presentation

CONNECTIVE TISSUE

• Many of the cells in tissues are embedded in an extracellular matrix that fills the spaces between cells and binds cells and tissue together.

COLLAGEN

ELASTIN

PROTEOGLYCANS

GLYCOPROTEINS

CONNECTIVE TISSUE DISORDERS

Connective tissue diseases cover a wide range of autoimmune

diseases.

Mainly due to mutations in the gene

that are responsible for production of

connective tissue

CONNECTIVE TISSUE DISORDERS

Involve the major connective tissues of the body such as bone, skin, cartilage, blood vessels, kidney and eye

CONNECTIVE TISSUE DISORDERS - CLASSIFICATION

Inherited Disorders

• Osteogenesis imperfecta.

• Ehlers-Danlos syndrome

• Marfan syndrome. • Alport syndrome• Epidermolysis

bullosa

Autoimmune Diseases

• Polymyositis and dermatomyositis.

• Rheumatoid arthritis

• Scleroderma• Sjogren's syndrome• Systemic lupus

erythematosus.

Nutritional

• Scurvy• Lathyrism

Connective tissue disorders that can have severemanifestations, are relatively common are

Osteogenesis imperfecta.

Ehlers-Danlos syndrome

Marfan syndrome.

Alport syndrome

Epidermolysis bullosa

OSTEOGENESIS IMPERFECTA

• OI causes a generalized decrease in bone mass and makes the bones brittle• Positive family history.• Most patients with OI have mutations in one of the two genes that

encode type I procollagen.• Many are single base substitutions that replace GLYCINE by other

amino acid(CYSTEINE)• DNA sequencing showed substitution of T for G changed residue 998

from GLYCINE to CYSTEINE

OSTEOGENESIS IMPERFECTA

Blue sclerae Dental abnormalities

and fragile bone

Progressive hearing loss

CLASSIFICATION OF OSTEOGENESIS IMPERFECTA

OSTEOGENESIS IMPERFECTA - DIAGNOSIS

Diagnosis is usually made on the basis of clinical criteria

The presence of fractures

together with blue sclerae,

Dentinogenesis imperfecta

Positive family history of the

disease

A molecular defect in type I procollagen can be demonstrated

OSTEOGENESIS IMPERFECTA - TREATMENT

Many patients with OI have successful careers despite severe deformities.

Those with mild disorder may need little treatment when fractures

Women require special attention during pregnancy and after menopause,

EHLERS-DANLOS SYNDROME

• Group of inherited disorders of conective tissue• Characterized by hyperelasticity of the skin and hypermobile joints.• Fragile skin• A curved spine• Weak blood vessels• Bleeding gums• Problems with the lungs, heart valves, or digestion• 11 types have been recognized

EHLERS-DANLOS SYNDROME

Hyperextensibility of the skin,

Abnormal tissue fragility

Increased joint mobility

EHLERS-DANLOS SYNDROME - TYPES

Mutations in genes for type V collagenTYPE-I &II

Mutations in genes for type III procollagenType IV

mutations in the gene that encodes lysyl hydroxylase.Type VI

EHLERS-DANLOS SYNDROME - DIAGNOSIS

Diagnosis

Based on clinical criteria

Biochemical assays

Gene analyses

EHLERS-DANLOS SYNDROME - TREATMENT

TREATMENT There is no specific therapy.

Surgical repair and tightening of jointligaments

ALPORT SYNDROME

• Affecting the structure of type IV collagen fibers• Major collagen found in the basement membranes of the renal

glomeruli• Mutations in several genes encoding type IV collagen fibers• The presenting sign is hematuria, and patients may eventually

develop end-stage renal disease.

ALPORT SYNDROME

EPIDERMOLYSIS BULLOSA

• Skin breaks and blisters as a result of minor trauma.• Due to mutations in COL7A1, affecting the structure of type VII

collagen• Clinical manifestations range from lethal to mild.

EPIDERMOLYSIS BULLOSA

EPIDERMOLYSIS BULLOSA

DYSTROPIC FORM

• Mutations in gene encoding type VII collagen

JUNCTIONAL FORM

• Defects in laminin

SIMPLEX FORM

• Mataions in keratin filaments

MARFAN SYNDROME

• IS DUE TO MUTATIONS IN THE GENE FOR FIBRILLIN• Incidence is 1 in 10,000• Autosomal dominant• Affects eyes, skeletal system and cardiovascular system

MARFAN SYNDROME

Dislocation of the lens, known as ectopia lentis

Most patients are tall and exhibit long

digits

Dilation of theascending aorta

MARFAN SYNDROME

• Long arms, legs and fingers• Tall and thin body type• Curved spine• Chest sinks in or sticks out• Flexible joints• Flat feet• Crowded teeth

MARFAN SYNDROME - DIAGNOSIS

Clinical assessment

Detection of fibrillin defects in cultured

skin fibroblasts

DNA analysis of the gene

SCURVY

• Nutritional • Due to deficiency of vitamin C• Vitamin C plays a crucial role in the formation of collagen, a major

component of connective tissue.• Ascorbic acid is necessary for the post-translational hydroxylation of

proline and lysine residues• Hydroxyproline and hydroxylysine are essential for the formation of

cross links in the collagen,

SCURVY

Periodontal disease Bleeding gum Scurvy