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Flashcards in Single Gene Disorders Deck (33)
1

Polygenic disorders include:

- multiple gene alterations establish susceptibility
- environmental triggers induce active disease
- common diseases have no simple pattern of inheritance and have multiple contributing factors
EX) diabetes
hypertension
cancer

2

What traits are involved in Single-Gene disorders?

- gene alteration results in disease
- NO environmental influences
- Rare events (although collectively common)
Ex) Huntington Chorea
Myotonic Dystrophy
Cystic Fibrosis
Neurofibromatosis (NF)
Marfan Syndrome (MFS)
Duchenne Muscular Dystrophy (DMD)

3

Genetic disorders impact what percent of overall admissions cases? and end-of-life care admission to LTC facility?

50%
60%

Genetic disorders have huge impact on our society.

4

What can be positive from a deleterious gene?

confer and advantage in a heterozygous state
ex) sickle cell

5

List the inheritance patterns for single gene disorders.

Autosomal Dominant
Autosomal Recessive (most cases)
X-linked dominant
X-linked recessive
Y-linked
Mitochondrial

6

What is a characteristic of autosomal dominant?

appears in every generation

7

What is an example of an autosomal dominant single-gene disorder?

Hereditary Motor & Sensory Neuropathy (HMSN)
Neurofibromatosis (NF)
Marfan Syndrome (MFS)

8

What gene is duplicated in Hereditary Motor & Sensory Neuropathy (HMSN) ? result?

Periperal myelin protein - PMP-22 (17p) is duplicated and leads to arrests of Schwann cell division

- interrupts myelin stability

9

How does Hereditary Motor & Sensory Neuropathy (HMSN) present?

slowly progressing distal muscle weakness and wasting

Onset 10-30 years

- spread to upper limbs and tremors evident
- foot has high arch and toes curled (hammer toe)

10

What gene is mutated (can be deletion, insertion, duplications, point mutations) in Neurofibromatosis (NF)? result?

neurofibromin (NF1) gene on 17q>>truncation to complete absence

-downregulated Ras acivity through GTPase action (tumor suppressor gene)
-café au lait macules

-50% of new cases due to new mutations

11

What are some of the clinical diagnostic criteria for NF1?

- 6 or more cage au lait macules over 5mm (15mm in postpubertal)

- 2 or more neurofibromas or 1 plexiform neurofibroma

- optic glioma
- 2 or more Lisch nodules (iris hamartomas)
-distinctive osseous lesions
-1st degree relative with NF

12

What are some problems related to NF1?

-nonverbal learning disorder (1/3 of cases)
- epilepsy
-CNS tumor
-scoliosis

**onset by 5 years

13

How is NF1 definitively diagnosed?

Gene testing
- only certain labs

**FYI University of Alabama (UAB) are leaders in NF1 testing

14

What percent of patients over age 8 who carry the NF1 gene have detectable Lisch Nodules on slit-lamp ophthalmologic examination?

95%

15

What gene is mutated (missense with dominant-negative effect) in Marfan Syndrome? result?

Type 1 fibrillin (FBN1) (15q21)

- results in weakened elasticity of ECM
-cannot retain TGF-b
-promotes inflammation at sites consistent with MFS symptoms

16

What symptoms are a result of MFS?

-tall, reduced supper and lower segment body ratio
-scoliosis
-long limbs
-cardiovascular abnormalities
-aortic aneurysm is life threatening

17

List the symptoms that are part of the Ghent criteria in MFS?

MINIMUM OF TWO MAJOR Criteria plus 3rd organ system**

Skeletal (upper lower ratio >1.05, hypermobility, pes planus)
Ocular (ectopia lentis)
Cardiovascular (dilation/disection of ascending aorta)
Pulmonary (no major, minor - spontaneous pneumothorax)
Skin/Connective tissue
Dura (lumbosacral dural extasia)
Family history (**if applicable, ONE MAJOR criteria plus involvement of second organ system)

18

How would you get a definitive diagnosis of MFS?

Mutational analysis will detect 70-93%.
- false positives and negatives
Hence clinical evaluation is important.

**Should also be screened for homocystinuria (treatable IEM of homocysteine metabolism with diet & 50% respond to B6)

19

What is a characteristic of x-linked single-gene disorders?

Mothers can only transmit disease to sons.
Daughters can be carriers.

20

What is the average age of onset for Duchenne Muscular Dystrophy (DMD)?

3-5 years old

21

What are the symptoms of DMD?

- progressively muscle weakness
- awkward and clumsy walking on tiptoes
- most unable to walk by 10
- mild to moderate intellectual disability; avg 83

22

What gene is deleted in DMD?

dystrophin Xp21.1

23

What is dystrophin responsible for? result?

-connection of muscle fibers to the ECM
- absence of dystrophin results in excess calcium penetrating the sarcolemma (cell membrane)
- complex cascade results in cell death
-muscle fibers undergo necrosis and replaced with adipose and connective tissue

24

What treatment is available for DMD and MFS? mechanism of action?

Losartan
-blocks TGF-beta which is too active in MFS patients
- allowed aorta to develop normally

25

List some X-linked single-gene disorders.

Duchenne Muscular Dystrophy (DMD)
Fragile X
Rett's Syndrome (X-linked dominant)

26

What is the most common cause of inherited learning disability?

Fragile X

27

What genetic mutation occurs as a result of Fragile X?

-site on telomeric end of X chromosome susceptible to breakage
- increase in size of 5' untranslated region of CGG repeats of FMR-1 gene

> 200 repeats = full mutation

28

What are some clinical features of Fragile X?

autistic phenotype
hyperactive
high forehead
large ears
prominent jaw
learning difficulties

29

What X-linked dominant single-gene disorder affects 1 in 10,000 females?

Rett's Syndrome

*does occur in males

30

How many mutations are de novo in Rett's?

99% - only mutated in that individual

31

When does Rett's syndrome appear?

around 6-18 months

- decelerated head growth and development

- loss of acquired skills (speech, motor)

32

Where is the gene mutation for Rett's syndrome? results?

MECP2 gene of X chromosome
- assumed to be responsible for global gene silencing
-maintains normal neuronal interactions
-mutation causes inappropriate gene activation

33

What are the clinical features of Rett's syndrome?

- microcephaly - will see cortical and cerebellar atrophy

-autistic phenotypes - hand movements, regression neurological and social skills

- disease is spectrum from mildly altered speech to severe (unable to walk or interact)

- Males have severe encephalopathy to adult mental retardation