Genetic Disorders

Question 1

Threshold effect in mitochondrial disease:

Answer 1

The vulnerability of each tissue to express disease based on the number of mutant mitochondrial DNA.
(The proportion of normal and abnormal mitchondria can change from tissue to tissue in the same body.)

Question 2

Heteroplasmy

Answer 2

Presence of mixture of mutant and normal mitochondrial DNA.

Question 3

Charcot-Marie-Tooth (CMT):

Answer 3

Slowly progressive peripheral neuropathy which can cause weakness and loss of sensation in the extremities.
Affect feet and hands more than proximal legs and arms.
Structural changes to feet, balance problems, pain and numbness in the hands and feet, decreased fine-motor skills in the hands, difficulty walking and increased fatigue.
>70 genetic causes of CMT: genetic heterogeneity

Question 4

Most common type of CMT:

Answer 4

CMT type 1 is more common than CMT2 or other forms of CMT. CMT1A is the most common sub-type of CMT: 70-80% of CMT1
CMT1 is demyelinating –> slow nerve conduction.

Question 5

CMT1A is caused by:

Answer 5

Duplication of Peripheral Myelin Protein 22 (PMP22) gene which is located on chromosome 17. This is a protein that is essential for the function of the myelin.

Question 6

CMT1A inheritance:

Answer 6

Autosomal dominant

Question 7

Myotonic Dystrophy (Type 1) (DM1)

Answer 7

The word “myotonic” refers to the inability to relax muscles.
The word “dystrophy” refers to progressive muscle weakness and wasting, which is also a symptom of DM1. The muscles of the arms, hands, legs and feet are often affected. Muscle weakness in the feet and legs may lead to difficulty walking. The muscles of the face and neck may also weaken.
DM1 can also cause heart problems, cataracts, sleep apnea, digestive problems, gallstones and diabetes.

Question 8

Genetic mutation in DM1:

Answer 8

DMPK gene mutation on chromosome 19. CTG triplet repeat. 50 will have DM1. 36-49 wont get DM1 but will pass and expansion occurs. Usually from mother not father: Maternal Anticipation Greater # –> earlier onset and more sever.

Question 9

Spinocerebellar Ataxias (SCAs).

Answer 9

> 35 SCA mutations on diff genes.

Question 10

Huntington’s genetics:

Answer 10

Trinucleotide repeat retion “CAG” can expand and contract. Paternal anticipation.

Question 11

Spinal Muscular Atrophy (SMA)

Answer 11

Inherited, causes progressive problems with motor neuron in anterior horn cells. Muscle weakness and muscle loss; worse in legs than arms.

Question 12

Types of SMA:

Answer 12

SMA Type 1: most severe, affects infants

SMA Type 2: children

Question 13

Genetics of SMA:

Answer 13

On chromosome 5; survival motor neuron 1 gene (SMN1). Deletion of part of SMN1 gene. Allelic heterogeneity due to SMN2.
Autosomal recessivve.

Question 14

ALS genetics

Answer 14

AD with incomplete penetrance.

Hexanucleotide repeat with expansion leads to disease: GGGGCC.

Question 15

Lysosomal Storage Diseases - 3 examples:

Answer 15

Pompe
Gaucher
Fabry Disease

Question 16

Lysosomal Storage Diseases genetics:

Answer 16

For X-linked forms symptoms in females range: skewed X-inactivation.

Question 17

Neurofibromatosis Type NF1:

Answer 17

Symptoms:

1. cafe-au-lait (CALS) at least 6.
2. freckling in armpit (axillary) and groin (inguinal) region.
3. Lisch nodules - spots in colored parts of the iris.
4. Neurofibromas - most common tumor in NF1; benign, on skin, or in body (plexiform neurofibroma)-Often during puberty.
5. If severe: scoliosis, long bone defects, HTN, cancer. Only 15% have serious medical problems.
6. 50% inherited, rest are de novo muts.