Genetic Disorders

Question 1

Marfan Syndrome

1. What is the mutation?
2. What is its inheritance pattern?
3. What structure does it affect?
4. What is its function?
5. What are the symptoms?

Answer 1

1. FBN1 gene on 15q
2. Autosomal dominant (80% genetic)
3. Fibrillin-1 (ECM protein)
   
   • prevents correct microfibril elastic fiber formation
4. Component of microfibril elastic fibers
   
   • aorta
   • ligaments
   • ciliary zonules (holds lens in place)
   • Excess TGFß b/c no microfibrils to sequester it
5. Symptoms:
   
   • Arachnodactyly (long extremeties and long fingers)
   • Deeply depressed sternum
   • Ectopia lentis (dislocation of the lens)
   • CV disease:
     
     • mitral valve prolapse (most common)
     • Dilation of aortic valve ring/root of aorta –> rupture

Question 2

Ehlers-Danlos Syndromes

1. What is its inheritance pattern?
2. What structure does it affect?
3. What is its function?
4. What are the symptoms?

Answer 2

1. Autosomal dominant (80%) genetic
2. fibrillar collagen (lack of tensile strength)
3. part of ECM: holds things together
4. Classic form syptoms: (w/Hypermobility variant)
   
   • hyperextensible/stretchable skin
   • vulnerable to damage
   • Joint hypermobility
   • atrophic scars
5. Other variants:
   
   • diaphragmatic herniation
   • Ocular fragility (retinal detatchment/rupture cornea)

Question 3

Classical form of Ehlers-Danlos syndrome

Answer 3

1. Hyperextensible/stretchable skin
2. Vulnerable to damage from minor trauma
3. Hypermobile joints (Hypermobility variant)
4. Atrophic scars (Hypermobility variant)

Question 4

Characteristics of Vascular Ehlers-Danlos syndrome

1. Type of abnormal collagen
2. Symptoms

Answer 4

1. Type III collagen
2. Symptoms:
   
   • Rupture of uterus, colon, large arteries

Question 5

Characteristics of Kyphoscoliosis Ehlers-Danlos syndrome

1. Inheritance pattern
2. Symptoms

Answer 5

1. Autosomal recessive
2. Symptoms:
   
   • Congenital Scoliosis
   • Joint laxity

Question 6

Characteristics of Arthrochalasia EDS

1. Inheritance pattern
2. Specific Defect
3. Symptoms

Answer 6

1. Autosomal dominant
2. Problems converting Type I procollagen to collagen
3. Symptoms: Joint hypermobility

Question 7

Characteristics of dermatosparaxis EDS

1. Inheritance pattern
2. Specific Defect
3. Symptoms

Answer 7

1. Autosomal dominant
2. defective conversion of type I procollagen to collagen
3. Symptom: severe skin fragility

Question 8

Hypermobility variant of EDS

1. Associated with what other form?
2. Symptoms

Answer 8

1. With classical form
2. Symptoms:
   
   • joint hypermobility
   • joints painful, predisposed to dislocation
   • Atrophic scar

Question 9

Familial Hypercholesterolemia

1. What is its inheritance pattern?
2. What structure does it affect?
3. What is its function?
4. What is the difference in expression between heterozygotes and homozygotes? symptoms?
5. What is the treatment?

Answer 9

1. Autosomal dominant
2. Mutation in gene for LDL receptor –>
3. Uptake of LDL (low LDL –> overproduction of cholesterol)
4. Difference:
   
   • Homozygotes: 5-6x normal Cholesterol levels
     
     • xanthomas
     • premature atherosclerosis
     • MI before age 20
   • Heterozygotes: 2-3x normal lvls
     
     • premature atherosclerosis
5. Treatment: Statins
   
   • Inhibit HMG CoA reductase
     
     • (-) cholesterol synthesis

Question 10

What are the 5 classes of LDL receptor mutations?

Answer 10

1. Type 1
   
   • no receptor synthesis
2. Type 2
   
   • Folding defect in LDL receptor
   • doesn’t leave ER
3. Type 3
   
   • no or poor LDL binding to receptor
4. Type 4
   
   • Receptor not in clathrin-coated pit, so bound LDL is not internalized
5. Type 5
   
   • LDL not released from receptor,so receptor is not recycled

Question 11

What is pleotrophism?

Answer 11

a single gene affects a number of phenotypic traits in the same organism.

Question 12

Tay-Sachs disease

• Symptoms:
• Defect:
• Protein accumulated in cells
• Cytology

Answer 12

• Symptoms:
  
  • rapidly deteriorating motor and mental functioning at about 6 months of age
  • Cherry red spot in the macula
• Defect:
  
  • deficiency in hexosaminidase-alpha subunit
  • gene on 15q
• Protein:
  
  • GM2 Ganglioside
• Cytology:
  
  • Neurons enlarged
  • whorls of membrane layers in lysosomes

Question 13

Diagnose:

Patient is 6 months old. Presents with rapidly deteriorating motor and mental functioning. Exam finds cherry red spot in the macula.

1. What is the disease?
2. What is the pathology?

Answer 13

Tay-Sachs disease

• Defect:
  
  • deficiency in hexosaminidase-alpha subunit
  • gene on 15q
• Protein:
  
  • GM2 Ganglioside

Question 14

Neimann-Pick Disease Type A

• Symptoms:
• Defect:
• Protein accumulated in cells
• Cytology

Answer 14

• Symptoms: Severe infantile form
  
  • CNS involvement
  • Hepatosplenomegaly
• Defect:
  
  • deficiency in sphingomyelinase
• Protein accumulated in cells
  
  • sphingomyelin
• Cytology
  
  • Foamy cells from accumulation of lipid

Question 15

Neimann-Pick disease type B

• Symptoms:
• Defect:
• Accumulation in cells
• Cytology

Answer 15

• Symptoms:
  
  • little or no CNS involvement
  • Respiratory insufficiency
  • Hepatoslenomegaly
• Defect:
  
  • Deficiency in sphingomyelinase
• Protein accumulated in cells
  
  • sphingomyelin
• Cytology
  
  • foamy cells due to accumulation of lipid

Question 16

Neimann-Pick Type C

• Symptoms:
• Defect:
• Accumulation in cells

Answer 16

• Symptoms:
  
  • Neuronal degeneration (CNS effects)
  • Hepatosplenomegaly
• Defect:
  
  • NPC1 gene mutation: impaired regulation of cholesterol
  • NPC2 gene mutation: impaired release of free cholesterol from lysosomes
• Protein accumulated in cells:
  
  • cholesterol and glycolipids in lysosomes

Question 17

Gaucher Disease

• Symptoms:
• Defect:
• Accumulation in cells
• Cytology

Answer 17

• Symptoms:
  
  • varies by type
  • Often CNS manifestations (type II and III)
  • hepatosplenomegaly (Type I)
  • Anemia (Type I)
  • Pathological fractures (Type I)
• Defect:
  
  • Deficiency of glucocerebrosidase
• Accumulation in cells
  
  • Glucocerebroside
  • Accumulates in phagocytes
• Cytology
  
  • Gaucher cells (phagocyte, accumulation makes them foamy)

Question 18

Diagnose:

Patient is a few months old. Presents with CNS dysfunction and seizures along with hepatosplenomegaly. Cytology shows foamy macrophages.

• What is the disease? Be specific.
• What is the defect?
• What is the treatment?

Answer 18

Gaucher Disease Type II

• Defect: deficiency of glucocerebrosidase (accumulation)
• Treatment:
  
  • Recombinant glucocerebrosidase
  • Bone marrow transplant

(Type III onset in mid-to late childhood)

Question 19

Diagnose:

Patient presents with hepatosplenomegaly, anemia, bone pain and pathological fractures. Cytology shows foamy macrophages.

What is the disease? Be specific.
What is the defect?
What is the treatment?

Answer 19

Gaucher Disease Type I

• Deficiency of glucocerebrosidase
• Treatment:
  • Recombinant glucocerebrosidase
  • Bone marrow transplant

Question 20

Hurler’s syndrome/Mucopolysaccharidosis I

• Symptoms:
• Defect:
• Accumulation in cells
• Cytology

Answer 20

• Symptoms:
  
  • organomegaly
  • Growth and mental retardation
  • Skeletal deformities
  • Corneal clouding (different from MPSII/Hunters)
• Defect:
  
  • deficiency in alpha-L-iduronidase
• Accumulation in cells
  
  • Dermatan sulfate
  • Heparan sulfate
  • (both are glycosaminoglycans)
• Cytology
  
  • Enlarged, vacuolated nurons

Question 21

Diagnose:

Patient presents with growth and mental retardation, skeletal deformities, and corneal clouding. Cytology shows enlarged/vacuolated neurons with dermatan and heparan sulfate accumulations

• What is the disease?
• What is the defect?

Answer 21

Hurler’s syndrome

• Defect:
  
  • deficiency in alpha-L-iduronidase
  • Accumulation of dermatan and heparan sulfate

Question 22

Hunter’s Syndrome/Mucopolysaccharidosis II

• Symptoms:
• Defect:
• Accumulation in cells
• Cytology

Answer 22

• Symptoms:
  
  • growth and mental retardation
  • Skeletal deformities
• Defect:
  
  • deficiency in iduronate=2=sulfatase
• Accumulation in cells
  
  • Dermatan and heparan sulfate

Question 23

Diagnose:

Patient presents with growth and mental retardation and skeletal deformities. Cytology shows an accumulation of dermatan and heparan sulfate.

• What is the disease?
• What is the defect?

Answer 23

Hunter syndrome (MPSII)

• Defect:
  
  • iduronate-2-sulfatase
• Corneal clouding does not occur as in MPSI

Question 24

Von Gierke Disease

• Symptoms:
• Defect:
• Accumulation in cells
• Cytology

Answer 24

Type I glycogenosis

• Symptoms:
  
  • hepatomegaly (glycogen storage)
  • hypoglycemia (no glycogenolysis)
• Defect:
  
  • deficiency in glucose-6-phosphatase
• Accumulation in cells
• Cytology

Question 25

Diagnose: Patient presents with hepatomegaly and hypoglycemia. There is an excess of glycogen stored in the liver. * What is the disease? * What is the defect?

Answer 25

Von Gierke disease * Defect: * deficiency in glucose-6-phosphatase, so no gluconeogenesis

Question 26

McArdle disease * Symptoms: * Defect: * Accumulation in cells

Answer 26

Type V glycogenosis * Symptoms: * painful muscle cramps and weakness following exercise * Defect: * deficiency in muscle phosphorylase * Accumulation in cells * glycogen in muscle

Question 27

Diagnose: Patient presents with painful muscle cramps and weakness following exercise. * What is the disease? * What is the defect?

Answer 27

McArdle disease * Defect: * deficiency in muscle phosphorylase * accumulation of glycogen

Question 28

Pompe disease * Symptoms: * Defect: * Accumulation in cells

Answer 28

* Symptoms: * Cardiomegaly * death by cardiorespiratory failure in first 2-3 years of life * Defect: * deficiency of alpha-glucosidase * Accumulation in cells * glycogen

Question 29

Phenylketonuria * Symptoms: * Defect: * Accumulation in cells * Management

Answer 29

* Symptoms: * mental retardation * progressive demyelination * decreased pigment (hair/skin) * **must body odor** * Defect: * phenylalanine hydroxylase mutant * can't convert phenylalanine to tyrosine * Accumulation in cells * phenylalanine * Management: * low phenylalanine diet

Question 30

Alkaptonuria * Symptoms: * Defect: * Accumulation in cells * Management

Answer 30

* Symptoms: * arthritis of large joints * ochronosis in joints (turns blue-black) * **Black urine** on standing * Defect: * deficiency of homogentistic oxidase * incomplete metabolism of phenylalanine and tyrosine * Accumulation in cells * homogentistic acid * Management * Control phenylalanine and tyrosine intake

Question 31

Maple syrup urine disease * Symptoms: * Defect: * Accumulation in cells * Management

Answer 31

* Symptoms: * mental and physical retardation * **maple syrup odor to urine** * Defect: * defective branched-chain alpha-keto acid dehydrogenase complex * Accumulation in cells * branched chain amino acids * Management * control intake

Question 32

Neurofibromatosis type I * Symptoms: * Defect:

Answer 32

* Symptoms: * Neurofibromas * Cafe au lait spots (cutaneous pigmentation) * **Lisch nodules** in iris * Defect: * **NF1** gene mutation * Mutant **neurofibromin** (normally downregulates RAS to inhibit cell growth) * abnormal growth

Question 33

Neurofibromatosis type II * Symptoms: * Defect:

Answer 33

* Symptoms: * **Meningiomas** * **Acoustic schwannomas** * Cafe au lait spots * Defect: * **NF2** gene mutation (tumor suppressor gene) * Product is **merlin** (normally regulates contact inhibition and proliferation of schwann cells)

Question 34

Trisomy 13/ Patau syndrome * Symptoms * Cause

Answer 34

* Symptoms: * Midline abnormalities * cleft lip/palate * ocular abnormalities (closeness, cyclopia) * polydactyly * Rocker bottom feet * Causes: Trisomy 13 * Meiotic nondisjunction * Unbalanced translocation * mosaic

Question 35

Where is the Down Syndrome critical region located?

Answer 35

21q22

Question 36

DiGeorge's Syndrome * Defect * Deficiency * Symptoms and Patholgy

Answer 36

aka: Congenital tymic aplasia/velocardiofacial syndrome * Defect: deletion of 22q11.2 * Deficiency: T cells * Symptoms and Pathology: **CATCH 22** * **C**ardiac = congenital defects * **A**bnormal facies * **T **cell deficiency (recurrent infections) * incomplete development of thymus * **C**left palate * **H**ypocalcemia * incomplete development of parathyroid * Hypoparathyroidism * **22** deletion of 22q11

Question 37

Diagnose: Patient presents with disproportionately long legs, gynacomastia, hypogonadism, and infertility. * What is the disease? * What is the defect? * genetic * endocrine

Answer 37

Klinefelter syndrome * Genetic Defect: * extra X chromosomes (XXY) * nondisjunction or mosaic * Endocrine Cause: * decreased T levels * Elevated estradiole and FSH

Question 38

Diagnose: Patient presents with short stature, webbed neck, low posterior hairline, infertility, and amenorrhea. History of lymphedema of hands and feet during infancy. * What is the disease? * What is the cause?

Answer 38

Turner Syndrome * Defect: 45 X female * nondisjunction, mostly paternal * structural abnormalities of X * mosaic

Question 39

What are the causes of male pseudohermaphroditism?

Answer 39

1. tissue resistance to androgens (most common) * mutation in androgen receptor 2. defects in testosterone synthesis

Question 40

What are the causes of female pseudohermaphraditism?

Answer 40

1. Congenital adrenal hyperplasia (most common) * increased androgen hormones * 21-hydroxylase deficiency 2. Androgen-secreting adrenal/ovarian tumor in mother 3. Hormones given to mother during pregnancy

Question 41

Fragile X Syndrome * Symptoms * Gene involved * Repeat pattern

Answer 41

* Symptoms: * Mental retardation * macro-orchidism (enlarged testes) * Gene: * FMR-1 * produces **FMRP**: RNA binding protein associated with synaptic transmission * Repeat: * CGG * \>200 repeats for disease

Question 42

Myotonic Musclular Dystrophy * Symptoms * Gene defect * Repeat pattern

Answer 42

* Symptoms * myotonia (inability to relax muscles after contraction) * weakness/wasting of muscles * cataracts * Gene defect * myotonin protein kinase gene * Repeat pattern * CTG * Repeats over 50

Question 43

Huntington's Disease * Symptoms * Gene and protein involved * Repeat pattern

Answer 43

* Symptoms * mental impairment * chorea * Dysphagia and dysarthria * Gene and protein involved * **IT15 gene** that codes **Huntingtin protein** * repeat also inhibits **brain-derived neurotrophic factor** (needed for survival of neurons in striatum) * Repeat pattern * CAG

Question 44

Leber's hereditary optic neuropathy * Symptoms * Inheritance pattern

Answer 44

* Symptoms: * bilateral progressive loss of vision * optic nerve atrophy * Inheritance pattern: mitochondrial

Question 45

Chronic Progressive External Ophthalmoplegia * Symptoms * Inheritance Pattern

Answer 45

* Symptoms: * Presentation: bilateral drooping of superior eyelid * Paralysis of ocular muscles * Mitochondrial inheritance

Question 46

Adult Polycystic Kidney Disease * Symptoms * Genetic defect

Answer 46

* Symptoms: * hematuria * palpable renal masses * 50% renal failure * defect in chromosome 16p * Autosomal dominant

Question 47

Tuberous sclerosis * Symptoms

Answer 47

* Facial angiofibromas * Hypopigmented macules * Mental retardation Autosomal Dominant

Question 48

Diagnose: Patient presents with Facial angiofibroma, Hypopigmented macules, and Mental retardation. * What is the disease?

Answer 48

Tuberous sclerosis

Question 49

von Hippel-Lindau Disease * Symptoms:

Answer 49

* Hemangioblastomas * cerebellum, brain stem, retina * Adenomas and cysts * other organs

Question 50

Galactosemia * Symptoms * Defect * Accumulation

Answer 50

* Symptoms: * infantile cataracts * Mental retardation * Cirrhosis * Defect: * deficiency in galactose-1-phosphate uridyl transferase * Accumulation: * galactose-1-phosphate

Question 51

Fabry disease * Symptoms * Defect * Accumulation

Answer 51

* Symptoms: * skin lesions (angiokeratomas) * renal failure * Defect: * Deficiency of alpha-galactosidase A * Accumulation * ceramide trihexoside

Question 52

Lesch-Nyhan Syndrome * Symptoms: * Defect * Accumulation

Answer 52

* Symptoms: * gout * mental retardation * Defect * impaired purine metabolism * Accumulation * uric acid