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Flashcards in Cystic Fibrosis Deck (26)
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1

describe cystic fibrosis

• Autosomal recessive defect in cystic fibrosis transmembrane conductance regulator (CFTR) gene which regulates chloride ion movements in pancreas, biliary tree, intestines, airway epithelium, sweat ducts, and vas deferens

2

typical presentation with CF

• Numerous mutations at this locus on chromosome 7 produce varying clinical manifestations
• 15% of homozygotes have ileal obstruction at birth (meconium ileus)
• Infants present with diarrhea and failure to thrive due to pancreatic insufficiency or lung infections due to S aureus or Pseudomonas lung infections
• Other presentations—liver disease, male infertility, spontaneous pneumothorax, hypochloremic dehydration, nasal polyps, sinusitis, rectal prolapse. Heterozygotes are unaffected
• Serum immunoreactive trypsinogen elevated in most neonates (except in meconium ileus)
• Sweat chloride >60 mmol/L in most cases. Genotyping identifies specific CFTR mutations

3

genetics and epidemiology of CF

This is one of the commonest autosomal recessive diseases (~1:2000; ~1:22 of Caucasians are carriers); it reflects mutations in the cystic fibrosis transmembrane conductance regulator gene (cftr) on chromosome 7, which codes for a cyclicamp-regulated sodium/chloride channel. There is a broad range of severity of exocrine gland function, leading to meconium ileus in neonates (and its equivalent in children), lung disease akin to bronchiectasis, pancreatic exocrine insufficiency and a raised Na+ sweat level—depending in part on the type of mutation (often ∆F508; but other mutations, eg in intron 19 of cftr, cause lung disease but no increased sweat Na+).

CF is the most common recessive lethal gene of Caucasians. Disease frequency is about 1:3000. The most common severe mutation is DF508. Median life expectancy is now in the mid-thirties because of early detection and aggressive pulmonary therapy

4

Diagnosis of CF

Antenatal ([link]) carrier-status testing is possible, as is preimplantation analysis after in vitro fertilization: at the 8 cell stage, 1 cell is removed from the embryo, and its dna analysed; only embryos without the cystic fibrosis gene are reimplanted. This may be more acceptable than fetal terminations.
Diagnosis
10% present with meconium ileus as neonates. Most present later with recurrent pneumonia (±clubbing), steatorrhoea (if 〉7g/day/100g of undigested fat), or slow growth.
Sweat test1:
Sweat Cl− 〈40mmol/L is normal (cf probability is low); 〉60mmol/L supports the diagnosis. Intermediate results are suggestive but not diagnostic of cystic fibrosis.447 The test is capricious, so find an experienced worker (there are false positives and false negatives; see opposite). Sweat is collected onto filter paper fixed to the forearm.448
Other tests:
irt/dna (below)2; cxr: shadowing suggestive of bronchiectasis (esp. upper lobes); malabsorption screen; glucose tolerance test; spirometry; sputum culture. Mycobacterial colonization affects up to 20%; consider if rapid deterioration.

5

DDx for cystic fibrosis

• Asthma and bronchiectasis mimic CF
• Primary ciliary dyskinesia (Kartagener syndrome) causes chronic bronchitis, sinusitis, and otitis starting at birth. Often associated with situs inversus. Males are infertile. Sweat test normal
• Immunodeficiency syndromes including AIDS
• Other causes of pancreatic exocrine insufficiency—Shwachman syndrome

6

Treatment of CF

• Progressive lung disease is the most important cause of morbidity and mortality. Prevention/treatment of lung infections is key to survival
• High-calorie, high-protein diet with exocrine pancreatic enzyme supplements and fat-soluble vitamins
• Inhaled mucolytics, inhaled recombinant human DNAase, inhaled tobramycin and oral azithromycin (for Pseudomonas infection), bronchodilators, anti-inflammatory medications, all preserve pulmonary function

7

complications of CF

• • Haemoptysis
• • Pneumonia
• • Pneumothorax
• • Pulmonary osteoarthropathy
• • Diabetes mellitus
• • Cirrhosis
• • Cholesterol gallstones
• • Fibrosing colonopathy
• • Male infertility

8

Pitfalls of sweat test: false positives and negatives

False-positive sweat test:
May be seen in atopic eczema, adrenal insufficiency, ectodermal dysplasia, some types of glycogen storage diseases, hypothyroidism, dehydration, malnutrition. On the first day of life, up to 25% of normal newborns show a sweat sodium concentration 〉65mmol/L, but this rapidly declines on the second day after birth.
False-negative sweat test:

Oedema is the most important cause. Poor technique can also give false negative results.

9

Describe Phenylketonuria (PKU)

• Deficiency of phenylalanine hydroxylase occurs in 1:10,000
Caucasian births. Autosomal recessive
• Symptoms—mental retardation, hyperactivity, seizures, light complexion,
eczematoid skin rash
• Severe deficiency associated with serum phenylalanine >20 mg/dL
on regular diet. Low or normal serum tyrosine and normal pterins
• Newborn screening is highly reliable

10

DDx of PKU

• Normal offspring of mothers with PKU may have transient hyperphenylalaninemia at birth
• Dihydropteridine reductase deficiency produces elevated pterin metabolites, seizures, and psychomotor regression secondary to neuronal serotonin and dopamine deficiency in affected infants
• Defects in biopterin synthesis produce low serum pterins and variable phenylalanine. Symptoms include myoclonus, tetraplegia, dystonia, oculogyric crises
• Benign tyrosinemia with moderate hyperphenylalaninemia occurs in premature infants due to transient 4-hydroxyphenylpyruvic acid oxidase deficiency

11

Treatment of PKU

• Lifelong limitation of dietary phenylalanine to maintain serum level

12

PKU and pregnancy

Control of PKU during pregnancy is important as elevated phenylalanine is teratogenic. Female patients should be encouraged to use contraceptives to prevent accidental conception and accidental injury to the fetus.

13

Describe Glycogen Storage Diseases and essentials of diagnosis

• Caused by enzyme defects in the synthesis and degradation of glycogen
• Hepatic forms (I, III, IV, VI, IX) usually produce hepatomegaly, growth failure, fasting hypoglycemia, and acidosis
• Myopathic forms produce weakness, rhabdomyolysis
• Screening tests—low serum glucose with fasting. Elevated serum lactate, triglycerides, cholesterol, uric acid, and creatine kinase (in myopathic forms). Generally normal transaminases (except in type IV)
• Confirmation by specific enzyme assay on leukocytes, liver, or muscle

14

types of GSDs

• Type Ia (von Gierke disease) glucose-6-phosphatase deficiency produces typical hepatomegaly, hypoglycemia, acidosis
• Type Ib glucose-6-phosphatase transporter deficiency also produces neutropenia with recurrent infection
• Type II acid maltase deficiency (Pompe disease). Infantile form produces hypertrophic cardiomyopathy and macroglossia
• Type III—debrancher enzyme deficiency, less severe symptoms
• Type IV—brancher enzyme deficiency causes progressive cirrhosis
• Type V and VII—muscle phosphorylase deficiency and phosphofructokinase deficiency
• Type VI—hepatic phosphorylase deficiency—similar to Ia but milder
• Type IX—phosphorylase kinase deficiency

15

Tx of GSDs

• In hepatic forms, prevent fasting hypoglycemia and lactic acidosis.
Frequent meals by day; support blood glucose during sleep with cornstarch feeding or enteral/parenteral carbohydrate administration
• In hepatic forms—monitor for late development of hepatic adenoma, gout, focal segmental glomerulosclerosis
• Enzyme replacement therapy may be effective in infantile Pompe disease, but cardiomyopathy usually requires cardiac transplant

16

Hypoglycemia and massive hepatomegaly with normal spleen and normal serum transaminases should prompt evaluation for what?

Hypoglycemia and massive hepatomegaly with normal spleen and normal serum transaminases should prompt evaluation for glycogen storage disease in infants, especially in the presence of acidosis, “unexplained” seizures, or failure to thrive.

17

Describe Homocystinuria

Autosomal recessive deficiency of cystathionine β-synthase
• Patients have mental retardation, arachnodactyly, osteoporosis, and dislocated ocular lens
• Thromboembolism is a major cause of morbidity and mortality
• Diagnosis confirmed by finding homocystinuria, elevated blood homocysteine and methionine in the setting of vitamin B12 sufficiency
• Newborn screening available

18

DDx of homocystinuria

• Vitamin B12 deficiency
• Marfan syndrome patients have similar arachnodactyly and lens dislocation
• Defects in methionine synthase or methylene tetrahydrofolate reductase deficiency (remethylation defects) cause elevated homocysteine with low methionine

19

Tx of homocystinuria

• 50% of patients with cystathionine β-synthase deficiency respond to high-dose pyridoxine
• Neurologic prognosis better in pyridoxine responders
• Treat pyridoxine nonresponders with dietary restriction of methionine
• Surgical correction of dislocated lens is often required
• Betaine and vitamin B12 supplementation

20

why is it important to detect homocystinuria early?

Early dietary restriction of methionine in pyridoxine nonresponders may improve or prevent mental retardation, thromboembolic events, and lens dislocations.

21

Autosomal dominant conditions:

Achondroplasia
Huntington's chorea
Polyposis coli
Marfan syndrome
Tuberous sclerosis
Myotonic dystrophy
Von Willebrand disease

22

Trinucleotide repeat disorders:

Triplet repeats are normal up to a certain number in some genes. The area is unstable, may expand on transmission to the next generation and cause disease
Acnitcipation is seen - earlier presentation and greater severity with successive generations
Most are autosomal dominant, eg myotonic dystrophy

Fragile-X is X-linked recessive

23

Autosomal recessive conditions:

Cystic fibrosis
Phenylkketonuria
Sickle cell disease
Thalassaemia
Variousinborn errors of metabolism (eg congenital adrenal hyperplasia)

24

X-linked recessive conditions

Fragile X
Duchenne muscular dystrophy
Haemophilia A and B
G6PD deficiency
Redgreen colour blindness

25

gene imprinting

Certain genes express differently depending on wheter they are inherited from the mother or the father. Affected individuals have the unopposed effect of maternally or paternally inherited gened. This occurs because of a mutation in the gene on one chromosome or because of inheritance of two copie of the gene from the same parent (uniparental disomy)

26

POLYGENIC OR MULTIFACTORIAL CONDITIONS

Atopy (asthma,eczema)
Spina bifida
Cleft lip and palate
Congenital heart disease
Adult coronary heart disease
Adult hypertension
Diabetes
Epilepsy