Biochem - Genetics (Autosomal & X-linked recessive disorders) Flashcards
Pg. 88-89 in First Aid 2014 Sections include: -Autosomal recessive disorders -Cystic fibrosis -X-linked recessive disorders -Muscular dystrophies -Fragile X syndrome
Name 12 autosomal recessive diseases. Include any necessary clarifications/exceptions, where applicable.
(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
What is the mode of inheritance for cystic fibrosis? What is its defect (gene & chromosome)? What deletion commonly applies?
Autosomal recessive; defect in CFTR gene on chromosome 7 ; commonly a deletion of Phe508
What is significant in the epidemiology of cystic fibrosis?
Most common lethal genetic disease in Caucasian population
What is the normally encoded function of CFTR?
CFTR encodes an ATP-gated Cl- channel that secretes Cl- in lungs and GI tract, and reabsorbs Cl- in sweat glands.
Give the sequence of steps that occur in the pathophysiology of cystic fibrosis.
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.
What is diagnostic of cystic fibrosis?
Increased Cl- concentration (> 60 mEq/L) in sweat is diagnostic
With what 2 metabolic disturbances can cystic fibrosis present, and why?
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
What are 3 respiratory complications associated with cystic fibrosis?
(1) Recurrent pulmonary infections (e.g., Pseudomonas) (2) Chronic bronchitis (3) Bronchiectasis
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?
(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.
How might cystic fibrosis affect males in particular, and why?
Infertility in males (absence of vas deferens, absent sperm)
What deficiencies are complications of cystic fibrosis?
Fast-soluble vitamin deficiencies (A, D, E, K)
What is the treatment for cystic fibrosis, and how does this work?
N-acetylcysteine to loosen mucus plugs (cleaves disulfide bonds within mucus glycoproteins), dornase alfa (DNAase) to clear leukocyte debris
What are 10 examples of X-linked recessive disorders?
(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”
In what fashion are female carriers affected by x-linked recessive disorders, and on what does this depend?
Female carriers can be variably affected depending on the percentage inactivation of the X chromosome carrying the mutant vs. normal gene
What is the mutation in Duchenne muscular dystrophy, and what effects does it have?
X-linked frameshift mutation –> truncated dystrophin protein –> accelerated muscle breakdown; Think: “Duchenne = Deleted Dystrophin”
Describe the pattern of weakness characteristic of Duchenne muscular dystrophy.
Weakness begins in pelvic girdle muscles and progresses superiorly.
What muscular change characterizes duchenne muscular dystrophy, and what causes it?
Pseudohypertrophy of calf muscles due to fibrofatty replacement of muscle
What maneuver is seen in Duchenne muscular dystrophy patients? Name and define it.
Gower maneuver - patients use upper extremity to help them stand up
When is the onset of Duchenne muscular dystrophy?
Onset before 5 years of age.
What is a common cause of death in duchenne muscular dystrophy patients?
Dilated cardiomyopathy is common cause of death
Which gene has the longest coding region of any human gene? What consequence does this have?
Dystrophin gene (DMD) has the longest coding region of any human gene –> increased chance of spontaneous mutation
In general, what is the function of dystrophin? Where does it primarily function?
Dystrophin helps anchor muscle fibers, primarily in skeletal and cardiac muscle
What substances/structures does dystrophin connect? To what else are these substances/structures connected?
It connects the intracellular cytoskeleton (actin) to the transmembrane proteins alpha- and beta-dystroglycan, which are connected to the extracellular matrix (ECM)
What cellular finding results form loss of dystrophin?
Loss of dystrophin results in myonecrosis
What 2 lab findings are seen in Duchenne muscular dystrophy?
Increased CPK and aldolase are seen
What 2 lab procedures are used to confirm the diagnosis of Duchenne muscular dystrophy?
Western blot and muscle biopsy confirm diagnosis
What is usually the mutation that causes Becker muscular dystrophy?
Usually, X-linked point mutation in dystrophin gene (no frameshift)
How does the severity of Becker muscular dystrophy compare/contrast with Duchenne?
Less severe than Duchenne
When is the onset of Becker muscular dystrophy?
Onset in aldolescence or early adulthood
What is important to know about gene deletions associated with muscular dystrophy?
Deletions can cause both Duchenne and Becker
What is the defect myotonic type 1 muscular dystrophy, and what direct effect does it have?
CTG trinucleotide repeat expansion in the DMPK gene –> abnormal expression of myotonin protein kinase
Again, what is the defect myotonic type 1 muscular dystrophy, and what direct effect does it have? What 6 symptoms result?
CTG trinucleotide repeat expansion in the DMPK gene –> abnormal expression of myotonin protein kinase –> myotonia, muscle wasting, frontal balding, cataracts, testicular atrophy, and arrhythmia
What kind of defect is Fragile X syndrome? What gene is affected, and how so?
X-linked defect affecting the methylation and expression of the FMR1 gene
What is the 2nd most common cause of genetic intellectual disability? What is the 1st?
Fragile X syndrome = The 2nd most common cause of genetic intellectual disability (after Down syndrome)
What are 5 physical/clinical findings of Fragile X syndrome?
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”
What kind of repeat disorder is Fragile X? What are the specific repeats?
Trinucleotide repeat disorder (CGG)n
