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Case Study Erstaunliche Autosomal Dominant

1. Verghese P, Langman CB. Pediatric polycystic kidney disease. Medscape (2014). Available from:

2. Harris PC, Torres VE. Polycystic kidney disease, autosomal dominant. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH, et al., editors. , editors. GeneReviews® [Internet]. Seattle, WA: University of Washington; (2002). Available from:

3. Daoust MC, Reynolds DM, Bichet DG, Somlo S. Evidence for a third genetic locus for autosomal dominant polycystic kidney disease. Genomics (1995) 25(3):733–6.10.1016/0888-7543(95)80020-M [PubMed][Cross Ref]

4. de Almeida E, Martins Prata M, de Almeida S, Lavinha J. Long-term follow-up of a family with autosomal dominant polycystic kidney disease type 3. Nephrol Dial Transplant (1999) 14(3):631–4.10.1093/ndt/14.3.631 [PubMed][Cross Ref]

5. Paterson AD, Pei Y. Is there a third gene for autosomal dominant polycystic kidney disease?Kidney Int (1998) 54(5):1759–61.10.1046/j.1523-1755.1998.00166.x [PubMed][Cross Ref]

6. Ward CJ, Peral B, Hughes J, Thomas S, Gamble V, Maccarthy AB, et al. The polycystic kidney-disease-1 gene encodes a 14-Kb transcript and lies within a duplicated region on chromosome-16. Cell (1994) 77(6):881–94.10.1016/0092-8674(94)90137-6 [PubMed][Cross Ref]

7. Glucksmannkuis MA, Tayber O, Woolf EA, Bougueleret L, Deng NH, Alperin GD, et al. Polycystic kidney-disease – the complete structure of the Pkd1 gene and its protein. Cell (1995) 81(2):289–98.10.1016/0092-8674(95)90339-9 [PubMed][Cross Ref]

8. Geng L, Segal Y, Peissel B, Deng NH, Pei Y, Carone F, et al. Identification and localization of polycystin, the PKD1 gene product. J Clin Invest (1996) 98(12):2674–82.10.1172/JCI119090 [PMC free article][PubMed][Cross Ref]

9. Gallagher AR, Germino GG, Somlo S. Molecular advances in autosomal dominant polycystic kidney disease. Adv Chronic Kidney Dis (2010) 17(2):118–30.10.1053/j.ackd.2010.01.002 [PMC free article][PubMed][Cross Ref]

10. Mochizuki T, Wu GQ, Hayashi T, Xenophontos SL, Veldhuisen B, Saris JJ, et al. PKD2, a gene for polycystic kidney disease that encodes an integral membrane protein. Science (1996) 272(5266):1339–42.10.1126/science.272.5266.1339 [PubMed][Cross Ref]

11. Ong ACM, Harris PC. Molecular pathogenesis of ADPKD: the polycystin complex gets complex. Kidney Int (2005) 67(4):1234–47.10.1111/j.1523-1755.2005.00201.x [PubMed][Cross Ref]

12. Hanaoka K, Qian F, Boletta A, Bhumia AK, Piontek K, Tsiokas L, et al. Co-assembly of polycystin-1 and-2 produces unique cation-permeable currents. Nature (2000) 408(6815):990–4.10.1038/35050128 [PubMed][Cross Ref]

13. Ward CJ. The polycystic kidney-disease-1 gene encodes a 14 Kb transcript and lies within a duplicated region on chromosome-16 (Vol 77, Pg 881, 1994). Cell (1994) 78(4):725. [PubMed]

14. Ibraghimov-Beskrovnaya O, Dackowski WR, Foggensteiner L, Coleman N, Thiru S, Petry LR, et al. Polycystin: in vitro synthesis, in vivo tissue expression, and subcellular localization identifies a large membrane-associated protein. Proc Natl Acad Sci U S A (1997) 94(12):6397–402.10.1073/pnas.94.12.6397 [PMC free article][PubMed][Cross Ref]

15. Bhunia AK, Piontek K, Boletta A, Liu L, Qian F, Xu PN, et al. PKD1 induces p21(waf1) and regulation of the cell cycle via direct activation of the JAK-STAT signaling pathway in a process requiring PKD2. Cell (2002) 109(2):157–68.10.1016/S0092-8674(02)00716-X [PubMed][Cross Ref]

16. Wilson PD. Polycystic kidney disease. N Engl J Med (2004) 350(2):151–64.10.1056/NEJMra022161 [PubMed][Cross Ref]

17. Demetriou K, Tziakouri C, Anninou K, Eleftheriou A, Koptides M, Nicolaou A, et al. Autosomal dominant polycystic kidney disease-type 2. Ultrasound, genetic and clinical correlations. Nephrol Dial Transplant (2000) 15(2):205–11.10.1093/ndt/15.2.205 [PubMed][Cross Ref]

Learning Objectives

  1. Explain the epidemiology of Alpha-1 Antitrypsin deficiency
  2. Explain the pathophysiology of Alpha-1 Antitrypsin deficiency
  3. Describe the typical presentation and disease progression of Alpha-1 Antitrypsin deficiency
  4.  Review the diagnosis of Alpha-1 Antitrypsin deficiency
  5. Review the mode of inheritance and the most common genes involved with Alpha-1 Antitrypsin deficiency
  6. Create a plan for genetic screening and counseling of family members for patients with Alpha-1 Antitrypsin deficiency
  7. Review the current and potential treatments for Alpha-1 Antitrypsin deficiency

Pretest Questions

  1. What is the characteristic phenotype of the most common genetic mutation found in Alpha-1 Antitrypsin deficiency patients with chronic liver disease?
    a. PI*Null
    b. PI*MM
    c. PI*FZ
    d. PI*ZZ
    e. PI*MZ
  2. What is the estimated prevalence of severe Alpha-1 Antitrypsin deficiency in the United States?
    a. 1,000-3,000
    b. 10,000-20,000
    c. 80,000-100,000
    d. 500,000-600,000
    e. 2,000,000-3,000,000
  3. What is the most common mode of inheritance seen in Alpha-1 Antitrypsin deficiency?
    a. autosomal dominant
    b. autosomal co-dominant
    c. autosomal recessive
    d. X-linked dominant
    e. X-linked recessive
  4. How are hepatocytes typically damaged in Alpha-1 Antitrypsin deficiency
    a. lack of a transport protein leading to buildup of waste products
    b. immune mediated damage to cell membrane
    c. cell membrane instability due to mutated protein
    d. destruction by trypsin
    e. build up of mutant cytotoxic protein
  5. At what age do patients with Alpha-1 Antitrypsin deficiency tend to have liver disease?
    a. neonate
    b. 20-30 years
    c. over 40 years
    d. both a and b
    e. both a and c
    f. a, b, and c

Answers:  1) d, 2) c, 3) b, 4) e, 5) e

Case Study

A 45 year old male presents to your office for a complaints of increased dyspnea on exertion for the last several months.  He reports he has always believed he has had some form of asthma or chronic lung infection, but lately he has had a great deal of difficulty performing any activity without shortness of breath.  He denies cough, hemoptysis, chest pain, dysphasia, weight loss, night sweats, or fevers.  He states he has no significant past medical or surgical history.  He knows no family members who have died prematurely or who have had asthma.  The patient states he use to smoke a few cigarettes a day while he was young but quit a few years ago.  He does not drink alcohol and takes no medication.  On physical exam you note mild expiratory wheezes and clubbing but note no other abnormal findings.  Chest X-ray is significant for flattened diaphragm and large lung fields with basal hyperlucency.  Pulmonary function tests are significant for a lower than expected FEV1/FEV ratio.  All other blood work is within normal limits except for mild to moderate elevation of liver transaminases.

Explain the epidemiology and prevalence of Alpha-1 Antitrypsin deficiency:

          Although Alpha-1 Antitrypsin deficiency (AAT) is traditionally believed to be a disease found in northern European populations, the disease has been described throughout the world in all racial subgroups.  Worldwide it is believed there are 116 million carriers and 3.4 million cases of deficiency (1).  It is estimated there are 70,000-100,000 affected individuals in the United States with a similar number of affected individuals in Europe.  There is a strong belief many cases of AAT have gone undiagnosed or misdiagnosed as emphysema, bronchiectasis, or cirrhosis.  AAT is typically diagnosed when neonates present with liver disease of unknown etiology or when adults develop early emphysema.   

Describe the pathophysiology associated with Alpha-1 Antitrypsin deficiency:

          Alpha-1 Antitrypsin is a serine protease inhibitor synthesized in the liver.  The protein reaches the lungs by diffusion from the circulation and by local production in macrophages and bronchial epithelial cells (2).   Its role is to inhibit several enzymes including elastase, collagenase, and trypsin.  These enzymes are located in neutrophils and are especially active in the lower respiratory tract. 
In the liver the cause of disease only tends to occur in individuals with Z phenotypes.  A substitution of a lysine for a glutamic acid in the Z protein widens the protein β-sheet and allows polymerisation, linking of one α1-antitrypsin molecule to the β-sheet of another molecule in an irreversible process.  This polymerisation within the hepatocyte prevents its secretion.  Only about 15% of Z-mutated antitrypsin is secreted into the plasma leading to a buildup of this protein in the endoplastic reticulum (2).  The buildup of this mutated protein is cytotoxic to hepatocytes and leads to cirrhosis.  It is unknown why some patients with this phenotype develop lung or liver disease and other do not.   Although there are very few studies available, there are no known risk factors, including the consumption of alcohol, other than male sex that have been identified as risk factors for development of chronic liver disease in adults or children with homozygous AAT.  There is some data suggesting cofactors such as HCV and alcohol are necessary to promote chronic liver disease in heterozygous AAT (3).
Emphysema in Alpha-1 Antitrypsin deficiency is thought to result from an imbalance between neutrophil elastase in the lung, and the elastase inhibitor AAT.  There are two proposed mechanisms leading to lung damage.  The AAT protein is much less effective than the wild type protein at inactivating elastin, and there is a decreased amount of the protein in the lung due to the buildup of the protein in the hepatocytes.  Smoking is thought to accelerate lung injury by increasing the amount of elastase (2).  

What is the typical presentation and disease progression of a patient with Alpha-1 Antitrypsin deficiency?

          AAT deficiency can present in a number of different organ systems.  Classic findings include lung disease, liver disease, and skin lesions, which is typically panniculitis, an inflammation of fat which can present as a necrotizing lesion or as subcutaneous nodules.  Other manifestations of AAT include vasculitis, glomerulonephritis, fibromuscular dysplasia, and lung, colorectal, and bladder cancers.  Many patients with severe AAT will only have one manifestation of the disease.  Most patients who have lung disease do not develop liver disease, and most patients with liver disease do not develop lung disease.   
The typical presentation of AAT is an adult patient with early onset panacinar emphysema.  As described above, several studies have found smokers tend to have a higher probability of developing emphysema (2).  It is estimated 1-2% of all COPD patients have inherited severe AAT (4).  The typical finding on plain films is large lung fields with bilateral basal hyperlucency.  
In adults, liver disease may not present clinically until the signs and symptoms of chronic liver disease manifest.  In contrast, liver disease is the highest cause or morbidity and mortaility in AAT patietns under 20.  Liver disease can present in the neonatal period as cholestasis with or without jaundice and hepatomeagly leading to cirrhosis.  However, one study found although 83% of AAT patients had abnormal liver enzymes during childhood, only 17% had serious liver disease (3).  AAT may also predispose to hepatocellular carcinoma by accumulation of protein within the cells and favoring a cancer prone state by surviving with intrinsic damage (5).
The prognosis of AAT depends on the severity of the disease, response to treatments including the availability of lung or liver transplantation, and ability to avoid exposure to cigarette smoke and other lung irritants.  Mortality rates for patients with a severe deficiency of AAT vary among different studies, presumably due to differences in study populations. Relatively normal survival appears possible for nonsmoking asymptomatic individuals.  A fall in FEV1 appears to correlate with overall mortality.

How do you diagnose Alpha-1 Antitrypsin deficiency?

          The key to a diagnosis is a strong clinical suspension in any child who has liver disease or any adult who presents with early onset emphysema, usually before the age of 45.  Due to the vague symptoms, it is common to miss or delay the diagnosis.  In a recent survery of AAT patients, one study found an average delay of 5.6 years between the first onset of symptoms and diagnosis (6). 

There are several tests used to confirm the diagnosis of ATA.

  1. Blood test- the first line screening test.  Subnormal concentrations in serum of α1 antitrypsin can be found in patients with deficiencies.  Normal amounts in blood are about 150–350 mg/dl.  Patients whose serum concentrations fall below 80 mg/dl are at increased risk of lung disease.  The blood levels of AAT are not a highly sensitive test.  Plasma levels are often normal in heterozygotes and may transiently increase to normal even in homozygous patients during periods of systemic inflammation (3).
  2. Histology- The Periodic acid-Schiff stain (PAS) stains both glycogen and AAT globules.  When the glycogen is dissolved with a diastase, liver biopsies with an abnormal amount of AAT protein within the hepatocytes will satin a dark, red/purple.  Immunohistochemical and electron microscopy can also be used to detect abnormal amounts of AAT protein trapped in the cell on the golgi apparatus.
  3. Genotype testing- the gold standard.  All patients who meet the recommendations listed below should have genetic screening.   Isoelectric focusing on gel electrophoresis can be used to isolate the AAT genotype and corresponding phenotype.  Commercial kits are now available to detect the Z and S alleles. 

What is the mode of inheritance and the common phenotypes in Alpha-1 Antitrypsin deficiency?

          AAT is inherited in a co-dominant manner.  The gene is located on chromosome 14 and results in a substitution of amino acids resulting is a misfolded protein that tends to polymerized as described above.  The gene has been designated by the name Pi.  The different mutations result in phenotypes which been assigned a letter based on the allele’s ability to migrate in a gel electrophoresis.  Normal alleles are assigned a letter M giving the normal phenotype the designation PiMM.  Patients who have a deficiency have several possible allele formations.  The most common allele deficiency associated with emphysema and liver disease is the Z allele.  In this allele, a glutamic acid has been replaced by a lysine.  Patients with this mutation are given the designation Pi*Z if heterozygous or PiZZ if homozygous.  Other common alleles leading to disease are PiF, PiS, and PiNull.  The Null allele is used when a patient has no detectable AAT in the serum.  This finding is very rare and patients with this phenotype have the most severe form of lung disease, but since there is no protein to accumulate in the hepatocytes, they do not have liver disease. 

Which patients and family members of patients with Alpha-1 Antitrypsin deficiency should be screened for AAT?

          As always with testing for genetic disease, all of the implications need to be discussed with the patient and family before they consent to testing.  There are well known psychological and financial risks to any type of genetic testing.
The following are the recommendation for testing and screening by the American Thoracic Society and European Respiratory Society (ATS-ERS) (3):

Type A recommendations: genetic testing should be performed

  1. symptomatic adults with emphysema, COPD, or asthma that does not respond to treatment with bronchodilators
  2. Individuals with unexplained liver disease including children
  3. Asymptomatic individuals with persistent obstruction on pulmonary function tests with identifiable risk factors such as smoking or toxin exposure
  4. Adults with necrotizing panniculitis
  5. Siblings of patients with AAT deficiency

Type B recommendation: genetic testing should be discussed and could be reasonable accepted or declined

  1. Adults with bronchiectasis without evident etiology
  2. Adolescents with persistent airflow obstruction
  3. Asymptomatic individuals with persistent airflow obstruction and no risk factors
  4. Adults with C-ANCA positive vasculitis
  5. Individuals with a family history of COPD or liver disease not known to be attributed to AAT deficiency
  6. Distant relatives of an individual who is homozygous for AAT deficiency
  7. Offspring or parents of an individual with homozygous AAT deficiency
  8. Siblings, offspring, parents, or distant relatives of an individual who is heterozygous for AAT deficiency
  9. Individuals at high risk of having AAT deficiency-related diseases
  10. Individuals who are not at risk themselves of having AAT deficiency but who are partners of individuals who are homozygous or heterozygous for AAT deficiency

Type C recommendation: genetic testing is not recommended

  1. Adults with asthma in whom airflow obstruction is completely reversible
  2. Population screening of smokers with normal spirometry

Type D recommendation: genetic testing should not be performed

  1. Predispositional fetal testing
  2. Population screening of either neonates, adolescents, or adults

What are the available treatments for patients with Alpha-1 Antitrypsin deficiency?

          At this time, there appear to be two aspects of management, treatment of symptoms and treatment of disease by attempting to raise AAT to a protective level.  
Treatment of pulmonary symptoms in individuals with AAT deficiency should include many of the interventions and medications recommended for patients with emphysema (3):
• Inhaled bronchodilators
• Preventive vaccinations against influenza and pneumococcus
• Supplemental oxygen when indicated by conventional criteria, including during commercial air travel
• Pulmonary rehabilitation for individuals with functional impairment
• Consideration of lung transplantation for selected individuals with severe functional impairment and airflow obstruction
• During acute exacerbations of COPD, management should again include usual therapies for COPD patients including systemic corticosteroids and ventilatory support when indicated.
The only treatment at this time for liver disease is liver transplantation.

At this time, there is only one approved treatment aimed at increasing AAT serum concentration, intravenous or aerosolized augmentation therapy which is the infusion of purified pooled human plasma alpha-1 antitrypsin.  Based on current evidence, it would appear augmentation therapy is beneficial only in patients with moderate pulmonary disease and offers little benefit to those with severe disease.  Augmentation therapy is not recommended for asymptomatic patients (3).  Future areas of study include gene therapy and promotion of hepatic secretion of AAT. 

Patient Resources

Alpha-1 Antitrypsin Deficiency Association

MedlinePlus: Alpha-1 Antitrypsin Deficiency

Genetics Home Reference: Alpha-1 Antitrypsin Deficiency


  1.  de Serres FJ.Worldwide racial and ethnic distribution of alpha1-antitrypsin deficiency: summary of an analysis of published genetic epidemiologic surveys. Chest. 122(5):1818-29, 2002 Nov
  1. Stoller JK, Aboussouan LS. Alpha1-antitrypsin deficiency.  Lancet. 365(9478):2225-36, 2005 Jun 25-Jul 1
  1. ATS/ERS statement: Standards for the Diagnosis and Management of Individuals with AAT Deficiency. 820-896, 2003 Feb
  1. Kasper D, Braunwald E, Fauci A, et al. Harrison’s Principles of Internal Medicine. 16thed, McGraw Hill, 2005, 1548.
  1. Rudnick D, Perlmutter D. Alpha-1 Antitrypsin Deficiency: A new papdigm for hepatocellular carcinoma in genetic liver disease. Hepatology. 42(3): 514-521, 2005 Sep
  1. Stoller JK, Sandhaus RA, Turino G, et al. Delay in diagnosis of alpha1-antitrypsin deficiency: a continuing problem. Chest. 128(4):1989-94, 2005 Oct.