Biochem - Genetics (Autosomal & X-linked recessive disorders)

Question 1

Name 12 autosomal recessive diseases. Include any necessary clarifications/exceptions, where applicable.

Answer 1

(1) Albinism (2) ARPKD (formerly known as infantile polycystic kidney disease) (3) cystic fibrosis (4) glycogen storage diseases (5) hemochromatosis (6) Kartagener syndrome (7) mucopolysaccharidoses (except Hunter syndrome) (8) phenylketonuria (9) sickle cell anemia (10) sphingolipidoses (except Fabry disease) (11) thalassemias (12) Wilson disease

Question 2

What is the mode of inheritance for cystic fibrosis? What is its defect (gene & chromosome)? What deletion commonly applies?

Answer 2

Autosomal recessive; defect in CFTR gene on chromosome 7 ; commonly a deletion of Phe508

Question 3

What is significant in the epidemiology of cystic fibrosis?

Answer 3

Most common lethal genetic disease in Caucasian population

Question 4

What is the normally encoded function of CFTR?

Answer 4

CFTR encodes an ATP-gated Cl- channel that secretes Cl- in lungs and GI tract, and reabsorbs Cl- in sweat glands.

Question 5

Give the sequence of steps that occur in the pathophysiology of cystic fibrosis.

Answer 5

Mutations –> misfolded protein –> protein retained in RER and not transported to cell membrane, causing decreased Cl- (and H2O) secretion; High intracellular Cl- results in compensatory increased Na+ reabsorption via epithelial Na+ channels –> H2O reabsorption –> abnormally thick mucus secreted into lungs and GI tract. High Na+ reabsorption also causes more negative transepithelial potential difference.

Question 6

What is diagnostic of cystic fibrosis?

Answer 6

Increased Cl- concentration (> 60 mEq/L) in sweat is diagnostic

Question 7

With what 2 metabolic disturbances can cystic fibrosis present, and why?

Answer 7

Can present with contraction alkalosis and hypokalemia (ECF effects analogous to patient taking a loop diuretic) because of ECF H2O/Na+ losses and concomitant renal K+/H+ wasting

Question 8

What are 3 respiratory complications associated with cystic fibrosis?

Answer 8

(1) Recurrent pulmonary infections (e.g., Pseudomonas) (2) Chronic bronchitis (3) Bronchiectasis

Question 9

Again, what are 3 respiratory complications associated with cystic fibrosis? What are 6 clinical findings that stem from these complications or are otherwise related to cystic fibrosis?

Answer 9

(1) Recurrent pulmonary infections (e.g., Pseudomonas) (2) Chronic bronchitis (3) Bronchiectasis; Reticulonodular pattern on CXR, pancreatic insufficiency, malabsorption and steatorrhea, nasal polyps, and meconium ileus in newborns.

Question 10

How might cystic fibrosis affect males in particular, and why?

Answer 10

Infertility in males (absence of vas deferens, absent sperm)

Question 11

What deficiencies are complications of cystic fibrosis?

Answer 11

Fast-soluble vitamin deficiencies (A, D, E, K)

Question 12

What is the treatment for cystic fibrosis, and how does this work?

Answer 12

N-acetylcysteine to loosen mucus plugs (cleaves disulfide bonds within mucus glycoproteins), dornase alfa (DNAase) to clear leukocyte debris

Question 13

What are 10 examples of X-linked recessive disorders?

Answer 13

(1) Bruton agammaglobulinemia (2) Wiskott-Aldrich syndrome (3) Fabry disease (4) G6PD deficiency (5) Ocular albinism (6) Lesch-Nyhan syndrome (7) Duchenne (and Becker) muscular dystrophy (8) Hunter [Syndrome] (9) Hemophilia a and b (10) Ornithine transcarbamylase deficiency; Think: “Be Wise, Fool’s GOLD Heeds [Silly] HOpe”

Question 14

In what fashion are female carriers affected by x-linked recessive disorders, and on what does this depend?

Answer 14

Female carriers can be variably affected depending on the percentage inactivation of the X chromosome carrying the mutant vs. normal gene

Question 15

What is the mutation in Duchenne muscular dystrophy, and what effects does it have?

Answer 15

X-linked frameshift mutation –> truncated dystrophin protein –> accelerated muscle breakdown; Think: “Duchenne = Deleted Dystrophin”

Question 16

Describe the pattern of weakness characteristic of Duchenne muscular dystrophy.

Answer 16

Weakness begins in pelvic girdle muscles and progresses superiorly.

Question 17

What muscular change characterizes duchenne muscular dystrophy, and what causes it?

Answer 17

Pseudohypertrophy of calf muscles due to fibrofatty replacement of muscle

Question 18

What maneuver is seen in Duchenne muscular dystrophy patients? Name and define it.

Answer 18

Gower maneuver - patients use upper extremity to help them stand up

Question 19

When is the onset of Duchenne muscular dystrophy?

Answer 19

Onset before 5 years of age.

Question 20

What is a common cause of death in duchenne muscular dystrophy patients?

Answer 20

Dilated cardiomyopathy is common cause of death

Question 21

Which gene has the longest coding region of any human gene? What consequence does this have?

Answer 21

Dystrophin gene (DMD) has the longest coding region of any human gene –> increased chance of spontaneous mutation

Question 22

In general, what is the function of dystrophin? Where does it primarily function?

Answer 22

Dystrophin helps anchor muscle fibers, primarily in skeletal and cardiac muscle

Question 23

What substances/structures does dystrophin connect? To what else are these substances/structures connected?

Answer 23

It connects the intracellular cytoskeleton (actin) to the transmembrane proteins alpha- and beta-dystroglycan, which are connected to the extracellular matrix (ECM)

Question 24

What cellular finding results form loss of dystrophin?

Answer 24

Loss of dystrophin results in myonecrosis

Question 25

What 2 lab findings are seen in Duchenne muscular dystrophy?

Answer 25

Increased CPK and aldolase are seen

Question 26

What 2 lab procedures are used to confirm the diagnosis of Duchenne muscular dystrophy?

Answer 26

Western blot and muscle biopsy confirm diagnosis

Question 27

What is usually the mutation that causes Becker muscular dystrophy?

Answer 27

Usually, X-linked point mutation in dystrophin gene (no frameshift)

Question 28

How does the severity of Becker muscular dystrophy compare/contrast with Duchenne?

Answer 28

Less severe than Duchenne

Question 29

When is the onset of Becker muscular dystrophy?

Answer 29

Onset in aldolescence or early adulthood

Question 30

What is important to know about gene deletions associated with muscular dystrophy?

Answer 30

Deletions can cause both Duchenne and Becker

Question 31

What is the defect myotonic type 1 muscular dystrophy, and what direct effect does it have?

Answer 31

CTG trinucleotide repeat expansion in the DMPK gene –> abnormal expression of myotonin protein kinase

Question 32

Again, what is the defect myotonic type 1 muscular dystrophy, and what direct effect does it have? What 6 symptoms result?

Answer 32

CTG trinucleotide repeat expansion in the DMPK gene –> abnormal expression of myotonin protein kinase –> myotonia, muscle wasting, frontal balding, cataracts, testicular atrophy, and arrhythmia

Question 33

What kind of defect is Fragile X syndrome? What gene is affected, and how so?

Answer 33

X-linked defect affecting the methylation and expression of the FMR1 gene

Question 34

What is the 2nd most common cause of genetic intellectual disability? What is the 1st?

Answer 34

Fragile X syndrome = The 2nd most common cause of genetic intellectual disability (after Down syndrome)

Question 35

What are 5 physical/clinical findings of Fragile X syndrome?

Answer 35

Findings: (1) post-pubertal macroorchidism (enlarged testes) (2) long face with a large jaw (3) large everted ears (4) autism (5) mitral valve prolapse; Think: “Fragile X = Xtra large testes, jaw, ears”

Question 36

What kind of repeat disorder is Fragile X? What are the specific repeats?

Answer 36

Trinucleotide repeat disorder (CGG)n