medical genetics

1. CHRONIC
GRANULOMATOUS DISEASE
(CGD)
Duncan Mapeto Banda
Physiotherapy student
Malawi college of medicine
Physiotherapy department

2. Lecture objectives
• CGD definition
• Epidemiology & Causes
• Mode of inheritance & Genes involved
• Pathophysiology
• Signs & Symptoms
• Diagnosis and Treatment

3. CGD
• An inherited disease whereby phagocytes
ingest microbes but cannot kill them.
• Leads to formation of granulomas and
recurrent infections.

4. Epidemiology
• The hallmark of (CGD) is early onset of
severe recurrent bacterial and fungal
infections.
• The most commonly involved organs are
those that serve as barriers against the entry
of microorganisms from the environment,
e.g. the skin, lungs, GI tract, lymph nodes,
liver, and spleen.

5. Chronic presentation of CGD
• Granuloma formation in the GI
 E.g. dysphagia, nausea, vomiting and abdominal
pain
 Granulomas, nodular masses of inflammatory tissue,
form in response to persistent antigenic stimulus
(chronic infections) or because of lack of negative
feedback by oxygen radicals on proinflammatory
cytokines.
 In every 140 patients with chronic granulomatous
disease, 33% had GI involvement

6. Continued...
• Granuloma of genitourinary (GU)
Symptoms of GU obstruction include
dysuria, incontinence, abdominal
discomfort, and urinary retention.
NB: Skin infections or granulomatous
dermatitis occurs in almost two thirds of
patients.

7. Pathogenesis of CGD
• Fungal causation occur in up to 20% of
patients with CGD
• Pneumonia is the most common presentation
NB: Infections are caused mostly by catalase
positive organisms, such as Aspergillus spp. or
Staphylococcus spp., and are often life-
threatening.
• Aspergillus species infection in CGD is often
indolent, with mild or absent symptoms at the
outset.

8. Causes
• Mutation of CYBA, CYBB, NCF1,NCF2
and NCF4 genes which code for subunits of
NADPH oxidase
NADPH oxidase plays a role in immune
system
NADPH oxidase Hydrogen
peroxide (kills engulfed microbes)

9. Mode of inheritance
• X-linked reccessive pattern
CYBB is located on X-chromosome
More males affected than females
Heterozygous carriers
Homozygous recessive
(suffers)
Homozygous dominant
(normal)

10. Continued.....
• Autosomal recessive pattern
Involved CYBA, NCF1, NCF2 & NCF4
Equal chance of occurrence in males and
females
 No signs & symptoms
in carriers

11. Continued....
• Among those with GI involvement, 89%
had X91 versus 11% with autosomal
recessive chronic granulomatous disease.
• However, carriers of X-CGD have a notable
incidence of discoid lupus erythematosus,
photosensitivity, Raynaud phenomenon, and
aphthous ulcers.

12. Pathophysiology
• Phagocytes ingest microbes but fail to kill
them
• Killing of microbes is mediated by NADPH
oxidase also called phagocyte oxidase
(phox).
• When this is non functioning there is a
defect in the killing mechanism.

13. Phagocyte Defect
• The NADPH oxidase is a key component of
human innate host defences.
• In phagocytes, this enzyme complex is
activated to produce superoxide anion and
other secondarily derived ROS (reactive
oxygen species)
• NADPH − 2 e− + 2O2 −> NADP+ + H+ + 2 .O2
−

14. Continued…..
• All animals release superoxide (O2
−) during
respiration
• Superoxide dismutase (SOD) converts O2
−
into hydrogen peroxide (H2O2)
• H2O2 is used to kill pathogens
• Some pathogens e.g staphlococus aureaus
are catalase positive
• They release catalase and O2
−

15. Continued....
• Therefore patients with CGD experience
severe recurrent bacterial and fungal
infections due to accumulation of
phagocytes containing ingested bacteria.
• Apoptosis/turnover is abnormal.

17. Signs & Symptoms
• Pneumonia
• Prolonged infections
– skin, liver, bone & joints, etc.
• Hepatomegaly & splenomegaly
• May develop WBC clusters
Note: Most people diagnosed during early life

18. Diagnosis
• Chest therapy
• Nitroblue tetrazolium test
• Hydrogen peroxide amount test

19. Treatment
• Antibiotic therapy
– Antifungal; itraconazole & Amphotericin B
– Antibacterial; Trimethoprim
• Granulocyte transfusions from GCSF
• Hematopoietic stem cell transfusions
– From a matched donor
• Surgery to treat abscesses
• Gene therapy ? ? ?

20. Infection reduction measures
• Garden exposure limits
• No swimming other than in Chlorinated
water
• No Marijuana smoking
– Has Aspergillus spp

21. 21

22. References
• www.myoclinic.com
• http://www.patient.co.uk/doctor/chronic-granulomatous-
disease
• https://rarediseasesnetwork.epi.usf.edu/PIDTC/CGD
• http://www.nlm.nih.gov/medlineplus/ency/article/001239.h
tm
• http://ghr.nlm.nih.gov/condition/chronic-granulomatous-
disease
• http://www.cgdsociety.org/