Pathophysiology. Tutorial 1 Genetic Diseases

Transcription

1 Pathophysiology Tutorial 1 Genetic Diseases

2 ILOs Analyze genetic pedigrees and recognize the mode of inheritance of diseases. Differentiate between patterns of inheritance based on the type of the protein affected. Recall the clinical manifestations of EDS and Marfan syndrome. Understand the effects of LDL mutations in FHC. Correlate clinical features, laboratory and genetic testing to diagnose cystic fibrosis. Suspect the diagnosis of galactosemia based on clinical manifestations of the disease. Recall the pathogenesis and pattern of inheritance of PKU.

3 Case 1 Evaluation of a pedigree for a certain abnormality reveals the following information: there are skipped generations with male-tomale transmission: females are affected at the same rate as are males; and the disease is produced in the homozygous state, while heterozygous individuals are carriers. Which of the following is the most common inheritance pattern for this disorder? a) Autosomal recessive b) Autosomal dominant c) X-linked recessive d) Mitochondrial

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5 Mendelian Transmission Patterns?? Human Genetics 5

6 Case 2 A 33-year-old man presents with acute severe abdominal pain. Physical examination finds hyper-extensible skin, hyper-mobile joints. Work-up finds that his acute abdominal pain is due to spontaneous rupture of the colon. Based on these clinical findings and appropriate work-up the diagnosis of vascular Ehlers-Danlos syndrome is made. As a general rule, familial disorders such as vascular Ehlers-Danlos syndrome that result from abnormalities of structural proteins (rather than deficiencies of enzyme proteins) and present during adulthood rather than childhood) have what type of inheritance pattern? a) Autosomal recessive b) Autosomal dominant c) Mitochondrial d) X-linked recessive

7 Elastic Man: Garry Turner sets stretchiest skin record! sets_10.html 7

8 Firestein: Kelley's Textbook of Rheumatology, 8th ed. 8

9 Case 3 A 27-year-old woman presents because of trouble with her vision. Physical examination reveals a very tall, thin woman with long thin fine fingers. Examining her eyes reveals dislocation of the lens of the eye to be in the anterior chamber. She had a variety of spinal deformities, as severe Kyphoscoliosis. Which of the following is most likely cause of this patient s signs and symptoms? a) Decreased synthesis of fibrillin b) Abnormal copper metabolism c) Decreased levels of vitamin D d) Decreased Synthesis of type I collagen

10 Habitus & Ligaments President Lincoln is thought to have had features suggestive of Marfan syndrome 10

11 Case 4 A 22-year-old man had a sudden loss of vision. On physical examination, there is a bilateral subluxation of the crystalline lens. On auscultation of the chest, a midsystolic click is audible. An echocardiogram shows a floppy mitral valve and dilated aortic arch. The patient s uncle and his cousin are similarly affected. Which statement of the following is true about this condition? a) Patient suffers from a lack of tensile strength in his connective tissue b) The family history is in favor of an autosomal recessive disease c) The cardiac manifestations are usually benign d) This disease results from one type of mutation in the small FBN1 gene e) More than 600 distinct causative mutations can be found in FBN1 gene

12 Mitral valve prolapse Spider fingers Nucleus Medical Media, Inc. Aortic incompetence High-arched palate Skeleton & Cardiovascular 12

13 Case 5 A 22-year-old man who had myocardial infarction 1 year ago now has chest pain when exercising. His underlying disease is due to an absence of LDL receptors on liver cells. Which of the following laboratory findings is most likely to be present in this patient? a) Hypercholesterolemia b) Hypertriglceridemia c) Hypoglycemia d) Ketonuria What is the mode of inheritance of this condition? Autosomal dominant

14 HMG-CoA reductase: 3-hydroxy-3-methylglutaryl coenzyme A reductase ACAT: cholesterol acyltransferases Normal Cholesterol Metabolism 14

15 xanthelasmata.html Clinical manifestations of familial hypercholesterolemia (A)Corneal arcus and xanthelasma (B) extensor tendon xanthomas (C and D) Achilles tendon xanthomas 15 The Australian Association of Clinical Biochemists

16 Case 6 21-year old primigravida gives birth to a term infant following an uncomplicated pregnancy. The infant is of normal height and weight and no abnormalities are noted. However the infant fails to pass meconium. Laboratory studies show an elevated sweat chloride levels. Genetic testing indicates that a critical protein coded by the gene is missing one phenylalanine amino acid in the protein sequence. Which of the following types of gene mutations is most likely to produce these findings? Frame shift Nonsense Point mutation Three base pair deletion Trinucleotide repeat

17 Case 7 An infant born at term develops abdominal distension in the first week of life. The infant fails to develop normally with multiple vitamin deficiencies. Later in childhood, multiple respiratory tract infections lead to widespread respiratory bronchial diseases. Which of the following laboratory findings is most likely related to this child s underlying disease? a) Elevated sweat chloride level b) Decreased serum thyroxin level c) Positive HIV serology d) Increased blood sugar e) Hyperbilirubinemia

18 Mendelian Disorders Cystic Fibrosis A chloride channel defect in the sweat duct causes increased chloride and sodium concentration in sweat. Decreased chloride secretion and increased sodium and water reabsorption in the airways, lead to dehydration of the mucus layer, defective mucociliary action, and mucous plugging predisposing to recurrent pulmonary infections. The impact of CFTR defect on transport function is tissue-specific. 18

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20 Case 8 A 7-month-old infant has failure to thrive, with vomiting and diarrhea noted since 1 month of age. Developmental neurologic milestones are not being met. A physical examination reveals hepatomegaly. The eyes show cataract formation in the crystalline lenses. The baby dies of fulminant Escherichia coli septicemia at 8 months of age. Which of the following congenital abnormalities is most likely to produce these findings? a) Von Gierke's disease b) Marfan's syndrome c) Galactosemia d) Phenylketonuria

21 Galactosemia Primitive reflexes in newborns Cataract 21

22 Case 9 Mental retardation in babies born to mothers with PKU is likely caused by? A. an enzyme deficiency in the baby B. PKU in the baby C. high blood phenylalanine D. the father carrying the gene for PKU E. too little protein in the mother s diet during pregnancy

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24 Thank you 24