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Flashcards in Single Gene Disorders Deck (33)

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


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)


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


Genetic disorders have huge impact on our society.


What can be positive from a deleterious gene?

confer and advantage in a heterozygous state
ex) sickle cell


List the inheritance patterns for single gene disorders.

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


What is a characteristic of autosomal dominant?

appears in every generation


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

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


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


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)


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


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


What are some problems related to NF1?

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

**onset by 5 years


How is NF1 definitively diagnosed?

Gene testing
- only certain labs

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


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



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


What symptoms are a result of MFS?

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


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)


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)


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

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


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

3-5 years old


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


What gene is deleted in DMD?

dystrophin Xp21.1


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


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

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


List some X-linked single-gene disorders.

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


What is the most common cause of inherited learning disability?

Fragile X


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


What are some clinical features of Fragile X?

autistic phenotype
high forehead
large ears
prominent jaw
learning difficulties


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

Rett's Syndrome

*does occur in males


How many mutations are de novo in Rett's?

99% - only mutated in that individual


When does Rett's syndrome appear?

around 6-18 months

- decelerated head growth and development

- loss of acquired skills (speech, motor)


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


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