Glucose-6-phosphate dehydrogenase deficiency - Wikipedia, the free encyclopedia

30/03/15 08:28

Glucose-6-phosphate dehydrogenase deficiency

From Wikipedia, the free encyclopedia

Glucose-6-phosphate dehydrogenase deficiency (G6PD deficiency)

also known as favism (after the fava bean) is an X-linked recessive
genetic condition that predisposes to hemolysis (spontaneous
destruction of red blood cells) and resultant jaundice in response to a
number of triggers, such as certain foods, illness, or medication. It is
particularly common in people of Mediterranean and African origin.
The condition is characterized by abnormally low levels of glucose-6phosphate dehydrogenase, an enzyme involved in the pentose
phosphate pathway that is especially important in the red blood cell.

Glucose-6-phosphate dehydrogenase deficiency

G6PD deficiency is the most common human enzyme defect.[1] There

is no specific treatment, other than avoiding known triggers.
Carriers of the G6PD allele appear to be protected to some extent
against malaria, and in some cases dominant males have shown
complete immunity to the disease. This accounts for the persistence of
the allele in certain populations in that it confers a selective
advantage.[2] G6DP deficiency resulted in 4,100 deaths in 2013 and

Glucose-6-phosphate dehydrogenase

3,400 deaths in 1990.[3]

Classification and external resources

ICD-10

D55.0
(http://apps.who.int/classifications/icd10/browse/2015/en#/D55.0)

ICD-9

282.2 (http://www.icd9data.com/getICD9Code.ashx?icd9=282.2)

1 Classification

OMIM

305900 (http://omim.org/entry/305900)

2 Signs and symptoms

DiseasesDB 5037 (http://www.diseasesdatabase.com/ddb5037.htm)

3 Cause

MedlinePlus 000528
(http://www.nlm.nih.gov/medlineplus/ency/article/000528.htm)

Contents

3.1 Drugs
3.2 Genetics
4 Pathophysiology
5 Diagnosis
6 Treatment

eMedicine

med/900 (http://www.emedicine.com/med/topic900.htm)

Patient UK Glucose-6-phosphate dehydrogenase deficiency

(http://www.patient.co.uk/doctor/favism)
MeSH

7 Epidemiology

D005955 (https://www.nlm.nih.gov/cgi/mesh/2015/MB_cgi?
field=uid&term=D005955)

8 Prognosis
9 History
10 References
11 External links

Classification
The World Health Organization classifies G6PD genetic variants into five classes, the first three of which are deficiency states.[4]
Class I: Severe deficiency (<10% activity) with chronic (nonspherocytic) hemolytic anemia
Class II: Severe deficiency (<10% activity), with intermittent hemolysis
Class III: Mild deficiency (10-60% activity), hemolysis with stressors only
Class IV: Non-deficient variant, no clinical sequelae
Class V: Increased enzyme activity, no clinical sequelae

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Signs and symptoms

Most individuals with G6PD deficiency are asymptomatic.
Symptomatic patients are almost exclusively male, due to the X-linked pattern of inheritance, but female carriers can be clinically affected due to
unfavorable lyonization, where random inactivation of an X-chromosome in certain cells creates a population of G6PD-deficient red blood cells
coexisting with normal red cells. A typical female with one affected X chromosome will show the deficiency in approximately half of her red
blood cells. However, in rare cases, including double X deficiency, the ratio can be much more than half, making the individual almost as
sensitive as a male.
Abnormal red blood cell breakdown (hemolysis) in G6PD deficiency can manifest in a number of ways, including the following:
Prolonged neonatal jaundice, possibly leading to kernicterus (arguably the most serious complication of G6PD deficiency)
Hemolytic crises in response to:
Illness (especially infections)
Certain drugs (see below)
Certain foods, most notably broad beans
Certain chemicals
Diabetic ketoacidosis
Very severe crises can cause acute renal failure
Favism may be formally defined as a haemolytic response to the consumption of broad beans. All individuals with favism show G6PD
deficiency. However, not all individuals with G6PD deficiency show favism. For example, in a small study of 757 Saudi men, more than 42%
showed a variant of G6PD deficiency, but none displayed symptoms of favism.[5] Favism is known to be more prevalent in infants and children,
and G6PD genetic variant can influence chemical sensitivity.[6] Other than this, the specifics of the chemical relationship between favism and
G6PD are not well understood.
6-phosphogluconate dehydrogenase (6PGD) deficiency has similar symptoms and is often mistaken for G6PD deficiency, as the affected enzyme
is within the same pathway, however these diseases are not linked and can be found within the same patient.

Cause
Drugs
Many substances are potentially harmful to people with G6PD deficiency. Variation in response to these substances makes individual predictions
difficult. Antimalarial drugs that can cause acute hemolysis in people with G6PD deficiency include primaquine, pamaquine, and chloroquine.
There is evidence that other antimalarials may also exacerbate G6PD deficiency, but only at higher doses. Sulfonamides (such as sulfanilamide,
sulfamethoxazole, and mafenide), thiazolesulfone, methylene blue, and naphthalene should also be avoided by people with G6PD deficiency as
they antagonize folate synthesis, as should certain analgesics (such as aspirin, phenazopyridine, and acetanilide) and a few non-sulfa antibiotics
(nalidixic acid, nitrofurantoin, isoniazid, dapsone, and furazolidone).[1][7][8] Henna has been known to cause haemolytic crisis in G6PD-deficient
infants.[9]

Genetics
Two variants (G6PD A and G6PD Mediterranean) are the most common in human populations. G6PD A has an occurrence of 10% of
American blacks while G6PD Mediterranean is prevalent in the Middle East. The known distribution of the disease is largely limited to people of
Mediterranean origins (Spaniards, Italians, Greeks, Armenians, and Jews).[10] These variants are believed to stem from a protective effect against
Plasmodium falciparum and Plasmodium vivax malaria.[11]
All mutations that cause G6PD deficiency are found on the long arm of the X chromosome, on band Xq28. The G6PD gene spans some 18.5
kilobases.[7] The following variants and mutations are well-known and described:
Table 1. Descriptive mutations and variants
Variants or mutations

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Gene

Protein

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Designation

Short

Isoform

name

G6PD-

OMIM-Code

Type

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Subtype Position Position

Structure change

Function
change

Protein
G6PD-A(+)

Gd-A(+) G6PD
A

+305900.0001 Polymorphism AG
nucleotide

376

126

(Exon

AsparagineAspartic

No

acid (ASN126ASP)

enzyme

5)

defect
(variant)

G6PD-A(-)

Gd-A(-)

G6PD
A

+305900.0002 Substitution

GA

nucleotide

376

68

ValineMethionine

(Exon

and

(VAL68MET)

5)

126

AsparagineAspartic

and

acid (ASN126ASP)

202
G6PD-

Gd-Med

G6PD B +305900.0006 Substitution

Mediterran

CT

nucleotide

563

188

(Exon

SerinePhenylalanine Class II
(SER188PHE)

6)
G6PD-

Gd-

Canton

Canton

G6PD-

Gd-

Chatham

Chatham

G6PD-

Gd-

Cosenza

Cosenza

G6PD B +305900.0021 Substitution

GT

1376

459

nucleotide
G6PD

+305900.0003 Substitution

Class II

(ARG459LEU)
GA

1003

335

nucleotide
G6PD B +305900.0059 Substitution

ArginineLeucine

AlanineThreonine

Class II

(ALA335THR)
GC

1376

459

nucleotide

ArginineProline

G6PD-

(ARG459PRO)

activity
<10%,
thus high
portion
of
patients.

G6PD-

Gd-

Mahidol

Mahidol

G6PD

+305900.0005 Substitution

GA

nucleotide

487

163

(Exon

GlycineSerine

Class III

(GLY163SER)

6)
G6PD-

Gd-

Orissa

Orissa

G6PD

+305900.0047 Substitution

CG

131

44

nucleotide

AlanineGlycine

NADP-

(ALA44GLY)

binding
place
affected.
Higher
stability
than
other
variants.

G6PD-

Gd-

G6PD

Asahi

Asahi

A-

+305900.0054 Substitution

AG

376

126

AsparagineAspartic

nucleotide

(Exon

68

acid (ASN126ASP)

(several)

GA

5)

ValineMethionine

202

(VAL68MET)

http://en.wikipedia.org/wiki/Glucose-6-phosphate_dehydrogenase_deficiency

Class III.

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Pathophysiology
Glucose-6-phosphate dehydrogenase (G6PD) is an enzyme in
the pentose phosphate pathway (see image, also known as the
HMP shunt pathway). G6PD converts glucose-6-phosphate into
6-phosphoglucono--lactone and is the rate-limiting enzyme of
this metabolic pathway that supplies reducing energy to cells by
maintaining the level of the reduced form of the co-enzyme
nicotinamide adenine dinucleotide phosphate (NADPH). The
NADPH in turn maintains the supply of reduced glutathione in
the cells that is used to mop up free radicals that cause
oxidative damage.
The G6PD / NADPH pathway is the only source of reduced
glutathione in red blood cells (erythrocytes). The role of red
cells as oxygen carriers puts them at substantial risk of damage
from oxidizing free radicals except for the protective effect of
G6PD/NADPH/glutathione.
People with G6PD deficiency are therefore at risk of hemolytic
anemia in states of oxidative stress. Oxidative stress can result
from infection and from chemical exposure to medication and
certain foods. Broad beans, e.g., fava beans, contain high levels
of vicine, divicine, convicine and isouramil, all of which are
oxidants.
When all remaining reduced glutathione is consumed, enzymes
and other proteins (including hemoglobin) are subsequently
damaged by the oxidants, leading to electrolyte imbalance,
cross-bonding and protein deposition in the red cell
membranes. Damaged red cells are phagocytosed and
sequestered (taken out of circulation) in the spleen. The
hemoglobin is metabolized to bilirubin (causing jaundice at
high concentrations). The red cells rarely disintegrate in the
circulation, so hemoglobin is rarely excreted directly by the
kidney, but this can occur in severe cases, causing acute renal
failure .
Deficiency of G6PD in the alternative pathway causes the
buildup of glucose and thus there is an increase of advanced
glycation endproducts (AGE). The deficiency also reduces the
amount of NADPH, which is required for the formation of
nitric oxide (NO). The high prevalence of diabetes mellitus type
2 and hypertension in Afro-Caribbeans in the West could be
directly related to the incidence of G6PD deficiency in those
populations.[12]
Although female carriers can have a mild form of G6PD deficiency (dependent on the degree of inactivation of the unaffected X chromosome
see lyonization), homozygous females have been described; in these females there is co-incidence of a rare immune disorder termed chronic
granulomatous disease (CGD).

Diagnosis
The diagnosis is generally suspected when patients from certain ethnic groups (see epidemiology) develop anemia, jaundice and symptoms of
hemolysis after challenges from any of the above causes, especially when there is a positive family history.
Generally, tests will include:
Complete blood count and reticulocyte count; in active G6PD deficiency, Heinz bodies can be seen in red blood cells on a blood film;
Liver enzymes (to exclude other causes of jaundice);
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Lactate dehydrogenase (elevated in hemolysis and a marker of hemolytic severity)

Haptoglobin (decreased in hemolysis);
A "direct antiglobulin test" (Coombs' test) this should be negative, as hemolysis in G6PD is not immune-mediated;
When there are sufficient grounds to suspect G6PD, a direct test for G6PD is the "Beutler fluorescent spot test", which has largely replaced an
older test (the Motulsky dye-decolouration test). Other possibilities are direct DNA testing and/or sequencing of the G6PD gene.
The Beutler fluorescent spot test is a rapid and inexpensive test that visually identifies NADPH produced by G6PD under ultraviolet light. When
the blood spot does not fluoresce, the test is positive; it can be falsely negative in patients who are actively hemolysing. It can therefore only be
done 23 weeks after a hemolytic episode.
When a macrophage in the spleen identifies a RBC with a Heinz body, it removes the precipitate and a small piece of the membrane, leading to
characteristic "bite cells". However, if a large number of Heinz bodies are produced, as in the case of G6PD deficiency, some Heinz bodies will
nonetheless be visible when viewing RBCs that have been stained with crystal violet. This easy and inexpensive test can lead to an initial
presumption of G6PD deficiency, which can be confirmed with the other tests.

Treatment
The most important measure is prevention avoidance of the drugs and foods that cause hemolysis. Vaccination against some common
pathogens (e.g. hepatitis A and hepatitis B) may prevent infection-induced attacks.[13]
In the acute phase of hemolysis, blood transfusions might be necessary, or even dialysis in acute renal failure. Blood transfusion is an important
symptomatic measure, as the transfused red cells are generally not G6PD deficient and will live a normal lifespan in the recipient's circulation.
Those affected should avoid drugs such as aspirin.
Some patients may benefit from removal of the spleen (splenectomy),[14] as this is an important site of red cell destruction. Folic acid should be
used in any disorder featuring a high red cell turnover. Although vitamin E and selenium have antioxidant properties, their use does not decrease
the severity of G6PD deficiency.

Epidemiology
G6PD deficiency is the most common human enzyme defect, being present in more than 400 million people worldwide.[15] G6DP deficiency
resulted in 4,100 deaths in 2013 and 3,400 deaths in 1990.[3] African, Middle Eastern and South Asian people are affected the most, including
those who have these ancestries.[16] A side effect of this disease is that it confers protection against malaria,[17] in particular the form of malaria
caused by Plasmodium falciparum, the most deadly form of malaria. A similar relationship exists between malaria and sickle-cell disease. One
theory to explain this is that cells infected with the Plasmodium parasite are cleared more rapidly by the spleen. This phenomenon might give
G6PD deficiency carriers an evolutionary advantage by increasing their fitness in malarial endemic environments.

Prognosis
G6PD-deficient individuals do not appear to acquire any illnesses more frequently than other people, and may have less risk than other people for
acquiring ischemic heart disease and cerebrovascular disease.[18]

History
In both legend and mythology, Favism has been known since antiquity. The priests of various Greek-Roman era cults were forbade to eat or even
mention beans, and Pythagoras had a strict rule that to join the society of the Pythagoreans' they must swear off beans.[19] This ban was
supposedly because beans somehow resembled the genitalia, but it is possible that this was a philosophical or scientific matter, being that the
belief was that beans and humans were created from the same material.[20]
The modern understanding of the condition began with the analysis of patients who exhibited sensitivity to primaquine.[21] The discovery of
G6PD deficiency relied heavily upon the testing of prisoner volunteers at Illinois State Penitentiary, although today such studies cannot be
performed. When some prisoners were given the drug primaquine, some developed hemolytic anemia but others did not. After studying the
mechanism through Cr51 testing, it was conclusively shown that the hemolytic effect of primaquine was due to an intrinsic defect of
erythrocytes.[22]
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References
1. Frank JE (October 2005). "Diagnosis and management of G6PD deficiency" (http://www.aafp.org/afp/20051001/1277.html). Am Fam Physician 72 (7): 1277
82. PMID 16225031 (https://www.ncbi.nlm.nih.gov/pubmed/16225031).
2. Lewis, Ricki (1997). Human Genetics. Chicago, IL: Wm. C. Brown. pp. 247248. ISBN 0-697-24030-4.
3. GBD 2013 Mortality and Causes of Death, Collaborators (17 December 2014). "Global, regional, and national age-sex specific all-cause and cause-specific
mortality for 240 causes of death, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013.". Lancet. doi:10.1016/S01406736(14)61682-2 (https://dx.doi.org/10.1016%2FS0140-6736%2814%2961682-2). PMID 25530442 (https://www.ncbi.nlm.nih.gov/pubmed/25530442).
4. WHO Working Group (1989). "Glucose-6-phosphate dehydrogenase deficiency.". Bulletin of the World Health Organization 67 (6): 60111. PMID 2633878
(https://www.ncbi.nlm.nih.gov/pubmed/2633878).
5. Al-Ali, AK (1996). "Common G6PD variant from Saudi population and its prevalence" (http://www.kfshrc.edu.sa/annals/Old/166/95-371.pdf) (PDF). Annals
of Saudi Medicine 16 (6): 6546. ISSN 0256-4947 (https://www.worldcat.org/issn/0256-4947). PMID 17429252
(https://www.ncbi.nlm.nih.gov/pubmed/17429252). Retrieved May 17, 2009. "This has led to the identification of one genetically determined common variant,
'G6PD Mediterranean.' The overall prevalence rate of this deficiency in these areas was determined to be in excess of 42%. None of the subjects studied
displayed any sign of favism"
6. Luzzatto, L. "GLUCOSE-6-PHOSPHATE DEHYDROGENASE DEFICIENCY." Advanced Medicine-Twelve: Proceedings of a Conference Held at the Royal
College of Physicians of London, 1114 February 1985. Vol. 21. Churchill Livingstone, 1986.
7. Warrell, David A.; Timothy M. Cox; John D. Firth; Edward J. Benz (2005). Oxford Textbook of Medicine, Volume Three. Oxford University Press. pp. 720
725. ISBN 0-19-857013-9.
8. A comprehensive list of drugs and chemicals that are potentially harmful in G6PD deficiency can be found in Beutler E (December 1994). "G6PD deficiency"
(http://www.bloodjournal.org/cgi/pmidlookup?view=long&pmid=7949118). Blood 84 (11): 361336. PMID 7949118
(https://www.ncbi.nlm.nih.gov/pubmed/7949118)..
9. Raupp P, Hassan JA, Varughese M, Kristiansson B (2001). "Henna causes life threatening haemolysis in glucose-6-phosphate dehydrogenase deficiency"
(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1718961). Arch. Dis. Child. 85 (5): 4112. doi:10.1136/adc.85.5.411
(https://dx.doi.org/10.1136%2Fadc.85.5.411). PMC 1718961 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1718961). PMID 11668106
(https://www.ncbi.nlm.nih.gov/pubmed/11668106).
10. http://www.britannica.com/EBchecked/topic/202897/favism
11. Kumar, Vinay; Abbas, Abul K.; Fausto, Nelson; Aster, Jon (2009-05-28). Robbins and Cotran Pathologic Basis of Disease, Professional Edition: Expert
Consult - Online (Robbins Pathology) (Kindle Locations 33351-33354). Elsevier Health. Kindle Edition.
12. Gaskin RS, Estwick D, Peddi R (2001). "G6PD deficiency: its role in the high prevalence of hypertension and diabetes mellitus". Ethnicity & disease 11 (4):
74954. PMID 11763298 (https://www.ncbi.nlm.nih.gov/pubmed/11763298).
13. Monga A, Makkar RP, Arora A, Mukhopadhyay S, Gupta AK (July 2003). "Case report: Acute hepatitis E infection with coexistent glucose-6-phosphate
dehydrogenase deficiency" (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2094938). Can J Infect Dis 14 (4): 2301. PMC 2094938
(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2094938). PMID 18159462 (https://www.ncbi.nlm.nih.gov/pubmed/18159462).
14. Hamilton JW, Jones FG, McMullin MF (August 2004). "Glucose-6-phosphate dehydrogenase Guadalajara a case of chronic non-spherocytic haemolytic
anaemia responding to splenectomy and the role of splenectomy in this disorder" (http://www.informaworld.com/openurl?
genre=article&doi=10.1080/10245330410001714211&magic=pubmed). Hematology 9 (4): 3079. doi:10.1080/10245330410001714211
(https://dx.doi.org/10.1080%2F10245330410001714211). PMID 15621740 (https://www.ncbi.nlm.nih.gov/pubmed/15621740).
15. Cappellini MD, Fiorelli G (January 2008). "Glucose-6-phosphate dehydrogenase deficiency". Lancet 371 (9606): 6474. doi:10.1016/S0140-6736(08)60073-2
(https://dx.doi.org/10.1016%2FS0140-6736%2808%2960073-2). PMID 18177777 (https://www.ncbi.nlm.nih.gov/pubmed/18177777).
16. G-6-PD FAQ section (http://www.rddiagnostics.com/g6pd_faq.htm)
17. Mehta A, Mason PJ, Vulliamy TJ (2000). "Glucose-6-phosphate dehydrogenase deficiency". Baillieres Best Pract. Res. Clin. Haematol. 13 (1): 2138.
PMID 10916676 (https://www.ncbi.nlm.nih.gov/pubmed/10916676).
18. thefreedictionary.com > glucose-6-phosphate dehydrogenase deficiency (http://medical-dictionary.thefreedictionary.com/G6PD+deficiency+anaemia) citing:
Gale Encyclopedia of Medicine. Copyright 2008
19. Simoons, F.J. (1996-08-30). "8:". Plants of Life, Plants of Death. University of Wisconsin Press. p. 216. ISBN 0299159043.
20. Rendall, Steven; Riedweg, Christoph (2005). Pythagoras: his life, teaching, and influence. Ithaca, N.Y: Cornell University Press. ISBN 0-8014-4240-0.
21. Alving AS, Carson PE, Flanagan CL, Ickes CE (September 1956). "Enzymatic deficiency in primaquine-sensitive erythrocytes"
(http://www.sciencemag.org/cgi/reprint/124/3220/484-a) (PDF). Science 124 (3220): 4845. Bibcode:1956Sci...124..484C
(http://adsabs.harvard.edu/abs/1956Sci...124..484C). doi:10.1126/science.124.3220.484-a (https://dx.doi.org/10.1126%2Fscience.124.3220.484-a).
PMID 13360274 (https://www.ncbi.nlm.nih.gov/pubmed/13360274).

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22. Beutler E (January 2008). "Glucose-6-phosphate dehydrogenase deficiency: a historical perspective"

(http://bloodjournal.hematologylibrary.org/cgi/content/full/111/1/16). Blood 111 (1): 1624. doi:10.1182/blood-2007-04-077412
(https://dx.doi.org/10.1182%2Fblood-2007-04-077412). PMID 18156501 (https://www.ncbi.nlm.nih.gov/pubmed/18156501).

External links
G6PD Deficiency Association (http://www.g6pd.org/)
G6PD Deficiency & Favism Website (http://www.g6pddeficiency.org/)
The G6PD homepage (http://www.rialto.com/g6pd/)
The G6PDdb (http://www.bioinf.org.uk/g6pd/) genetic and structural information database about glucose-6-phosphate dehydrogenase
deficiency
A FAQ page on G6PD Deficiency by R&D Diagnostics (http://www.rddiagnostics.com/g6pd_faq.htm)
Family Practice Notebook/G6PD Deficiency (Favism) (http://www.fpnotebook.com/Hemeonc/Hemolysis/G6pdDfcncy.htm)
The Most Common Disease You've Never Heard Of (http://www.huffingtonpost.com/randall-amster/the-most-common-diseasey_b_241635.html), by Randall Amster, The Huffington Post, July 22, 2009.
Rare Anemias Foundation (http://www.rareanemias.webs.com)
Retrieved from "http://en.wikipedia.org/w/index.php?title=Glucose-6-phosphate_dehydrogenase_deficiency&oldid=651735444"
Categories: Hereditary hemolytic anemias
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