Genetic Disorders

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Genetic Disorders
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• Marfan syndrome
• 70 to 85 are familial (Autosomal dominant)
  rest are sporadic ( new mutations)
• Molecular abnormality
• Defect is in an extra cellular glycoprotein
  called Fibrillin. Fibrillin is the major
  component of microfibrils
• Microfibrils are in ECM
• Microfibrils form a scaffolding on which
  tropoelastin forms elastic fibers
• Elastic fibers abundant in the aorta, ligaments,
  and ciliary zonules of the lens
• Fibrillin has two forms
• Fibrillin-1 (Gene FBN1, Chromosome- 15q21,
  Missence (point )mutations ?Marfan)
• Fibrillin-2 ( Gene- FBN2, Chromosome 5q3,
  Mutations ? congenital contractural
  arachinodactyly)

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• Marfan syndrome
• Pathology
• Disorder manifested in the skeleton, eyes, and
  cardiovascular system
• Skeletal most striking feature -unusually tall
  (lower segment of the body) long, tapering
  fingers and toes
• Joints double-jointed (lax ligaments), thumb -
  hyper extended back to the wrist
• Head Dolichocephalic (long-headed) with frontal
  bossing prominent supraorbital ridges
• Chest pectus excavatum (deeply depressed
  sternum) or a pigeon-breast deformity
• Spinal kyphosis, scoliosis, or rotation or
  slipping of the dorsal or lumbar vertebrae
• Ocular bilateral subluxation or dislocation
  (usually outward and upward) of the lens ,
  Ectopia lentis ( most important sign)
• Cardiovascular most life-threatening
• Rupture of aortic dissection MCC of death in
  Marfan (30 to 45 of patients)
• Mirtal valve prolapse (MVP)- MC cardiac
  abnormality ?MR

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• Marfan syndrome
• Clinical
• Variable expressivity
• all patients with FBN1 mutations are not
  classic Marfans
• Clinical diagnosis
• major involvement of 2 of 4 organ systems
  (skeletal, cardiovascular, ocular, and skin)
  minor involvement of another organ

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• Ehlers- Danlos Syndromes
• Molecular abnormality
• Defect in the synthesis or structure of
  fibrillar collagen
• Mode of inheritance all three Mendelian patterns
• Pathogenesis of EDS Abnormalities of collagen
  are fundamental
• Clinically and genetically heterogeneous
• Disorders affecting collagen synthesis
• Ehlers- Danlos Syndromes
• Ontogenesis imperfecta
• Alport syndrome
• Epidermolysis bullosa

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• Ehlers- Danlos Syndromes
• Clinical
• Six variants of EDS
• skin, ligaments, and joints frequently involved
  (rich in collagen)
• Skin hyper extensible, extremely fragile,
  vulnerable to trauma
• gaping of surgical wounds Heal with great
  difficulty, diaphragmatic hernia
• Joints hyper mobile risk of joint dislocation
• Complications
• rupture of the colon and large arteries
• Ocular fragility with rupture of cornea and
  retinal detachment

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Ehlers-Danlos Syndromes
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• Familial Hypercholesterolemia Receptor disease"
  
• The MC Mendelian disorder (1 in 500 individuals)
• Molecular abnormality
• Mutation ? gene encoding for low density
  lipoprotein (LDL) receptor
• LDLR? role in the transport and metabolism of
  cholesterol
• Loss of feedback control ? ?cholesterol ?
  premature atherosclerosis (AS) ?? risk of MI
• Homozygote
• 5-6 fold ?plasma cholesterol levels.
• Myocardial infarction may develop before age 20.
• skin xanthomas
• AS of coronary, cerebral, and peripheral vessels
• Heterozygote
• 2-3 fold ?plasma cholesterol level
• tendinous xanthomas premature atherosclerosis
  in adult life

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LDL metabolism and the role of the liver
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Familial Hypercholesterolemia LDL metabolism and
the role of the liver
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• Familial Hypercholesterolemia
• LDL Metabolism Liver
• Liver ? release VLDL (?Triglycerides TG) ?
  circulation ( blood)
• Plasma VLDL ? Adipose tissue, muscle Lipoprotein
  Lipase (LPL)? IDL (? Triglycerides, ?Cholesterol
  esters)
• Fate of IDL
• 50 of IDL ? Liver ( with help of LDLR) ? VLDL
• Remaining 50 ? Metabolic processing ? LDL
  (?Cholesterol esters)
• Fate of Plasma LDL
• 70 of LDL ? Liver (LDLR)
• LDL in Liver ? binds with Lysosomes ? break into
  Amino acids( from Apoprotein), Free cholesterol (
  from its Esters)
• Free cholesterol in liver ? ? HMG CoA reductase ?
  ? hepatic cholesterol synthesis
• 30 - Scavenger Receptors (Fibroblasts,
  Lymphocytes, SMC, Adrenal etc.,)

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Classification of LDL receptor mutations
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• Neurofibromatoses Types 1 and 2
• Autosomal dominant
• Neurofibromatosis(NF1) type 1 (previously called
  Von Recklinghausen disease)
• Neurofibromatosis(NF2) type 2 (previously called
  Acoustic neurofibromatosis)
• Type- 1
• Relatively common (Incidence-1 in 3000)
• 50 of the patients have a definite family
  history (remainder - new mutations)
• Penetrance is 100.
• Expressivity is extremely variable
• Three major features
• 1) Multiple neural tumors (Neurofibromas)
• 2) Numerous pigmented skin lesions
• (Café au lait spots)
• 3) Pigmented iris hamartomas (Lisch nodules)

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• Neurofibromatoses Types 1 and 2
• Type 1
• 1. Neurofibromas
• arise within or are attached to nerve trunks
• Can be on Skin, Internal site (include cranial
  nerves)
• Types of neurofibromas
• Cutaneous, Subcutaneous, Plexiform
• Plexiform
• involves subcutaneous tissues
• numerous tortuous, thickened nerves
• overlying skin is frequently hyper pigmented
• grow to massive proportions (enlargement of a
  limb or body part)
• ?risk of malignant transformation
• 2. café au lait macules
• six or more spots greater than 1.5 cm in diameter
  
• present in more than 90 of patients
• light brown, smooth borders often located over
  nerve trunks
• round to ovoid, with their long axes parallel to
  cutaneous nerve

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• Neurofibromatoses Types 1 and 2
• Types 1 (chromosome 17q11.2)
• 3. Lisch nodules (pigmented hamartomas in the
  iris)
• gt 94 of patients- age 6 years or older
• Asymptomatic, very helpful in diagnosis
• Associated abnormalities
• Most common (30 to 50) - skeletal lesions
• Erosive defects on bone
• Scoliosis
• Intraosseous cystic lesions
• Subperiosteal bone cysts
• Pseudoarthrosis of the tibia
• Chronic myeloid leukemia (CML)

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Plexiform neurofibromas
?
?
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• Neurofibromatoses Types 1 and 2
• Types 1
• Clinically
• Reduced intelligence
• GIT neurofibromas ? intestinal obstruction or GI
  bleeding
• renal artery narrowing ? HTN
• Diagnosis
• Lisch nodules
• NF-1 gene (family of tumor-suppressor genes)
• ? Neurofibromin protein ? down-regulates the
  function of the p21Ras oncoprotein

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• Neurofibromatoses Types 1 and 2
• Type 2 (chromosome 22q12)
• Much less common than NF1 (AD)
• 1. Bilateral acoustic schwannomas
• 2. Multiple meningiomas
• 3. Other tumors
• Gliomas,
• Ependymomas
• Café au lait spots - present
• Lisch nodules- ABSENT
• NF-2 gene (merlin) ?tumor-suppressor gene ?
  regulates contact inhibition and proliferation of
  Schwann cells

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Schwannoma