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G6PD deficiency in Malaysia – the current situation
Prof Dr Narazah Mohd Yusoff, MBBS, PhDnarazah@usm.my; narazah@yahoo.com.
Universiti Sains Malaysia, MALAYSIAAreas of interest: G6PD deficiency and Southeast Asia ovalocytosis
(SAO)
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Key features of G6PD deficiency…..
Malaysia – prevalence of red blood cell disorders; Thalassemia, Haemoglobinopathy E, G6PD deficiency, SAO.
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Glucose-6-phosphate dehydrogenase (G6PD) deficiency
G6PD deficiency is an X-linked hereditary genetic defect; females may be affected
Caused by mutations in the G6PD gene
Protein variants with different levels of enzymatic activity
Associated with a wide range of biochemical and clinical phenotypes
Heterozygosity and hemizygosity - associated with approximately 50% protection against severe Plasmodium falciparum malaria
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Role of G6PD enzyme in protection against oxidative damage
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1 Background & EpidemiologyIncidence/prevalence of G6PD deficiency & What is known about the disease burden in Malaysia?
Molecular studies in Kelantan, Penang and Selangor
• Frequency distribution • General population 3.4%
• Male 5.3% • Female 1.05%
• Malays• Male 4.6% • Female 1.3%
• Chinese• Male 7.2% • Female 0.7%
• Indians• Male 2.7% • Female 0.7%
• Negrito (Orang Asli)• Male 11%• Female 7%
(Ainoon, Yu et al. 2003)
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National Screening
Is there any central reporting of cases?Ministry of Health facilities and university hospitalsIs there any national coordination? YesIs there a national screening service for G6PD screening? All general government and private hospitals in the country provide screening servicesPrimary health care delivery – is G6PD screening included?Screening pre-natal: None. Abortion of affected babies are not practised due to religious issuesPremarital: No.New born: since 1980s
G6PD – commonest cause of neonatal jaundice (NNJ) in Malaysia (33%)
Nation wide neonatal screening began in 19801
All infants must have a G6PD screening done on cord blood2 (Ministry of Health Malaysia, 1999)
The results of G6PD screening must be known before discharge and special management is indicated for those infants found deficient3
Molecular screening is advised if found deficient
1Amini, Ismail et al. 2011; 2Ministry of Health Malaysia, 1999, 20003
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DiagnosisBased on generation of NADPH from NADP
Fluorescent spot test
*Quantitative spectrophotometric assay
*DNA analysis for mutation
Females heterozygotes
Family studies
*not in all localities
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2 Current progress in the country[If presenting third-party data, please add this sentence: Data kindly provided by XXX][Please, indicate the status quo in your country; choose one of the levels in the table below]
A Countries where services are well established with a national system for prevention and control
B Countries where some elements of a national control program exist but it is not available to all; more effort is needed in areas like:i. Improving access to servicesii. Raising awareness among families and patients, health professionals and community in generaliii. Establishing national centres of excellence/expertise to provide advice, measure progressiv. Ensuring that savings from disease prevention are returned back to expand and improve services
C Countries where expertise in diagnosis, treatment, management and prevention exist but is not part of a sustainable national control program
D Countries where services are limited or not available
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3 National Registry For G6PD deficiency
Is there a national registry for G6PD deficiency? • Yes• Ministry of Health (MOH) for clinical data, USM and UKM for
mutation databaseWho is responsible for it?• Director General for MOH• UKM and USM – researchers involved
Who pays for it? • Government and research funds• Ministry of Higher Education
Who has access to the registry and how is access regulated?• Clinicians (permission required for access)
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Molecular basis of G6PD in Malays
There were 9 mutations were G-to-A nucleotide changes at nucleotide 871 of the G6PD gene (G871A), corresponding to G6PD Viangchan, G6PD Mediterranean (C563T), G6PD Vanua Lava (T383C), G6PD Coimbra (C592T), G6PD Kaiping (G1388A), G6PD Orissa (C131G), G6PD Mahidol (G487A), G6PD Canton (G1376T), and G6PD Chatham (G1003A)
Results: Our results document heterogeneous mutations of the G6PD gene in the Malays in Malaysia.
Narazah Mohd Yusoff , Taku Shirakawa , Kaoru Nishiyama, Selamah Ghazali et. al; 2002
G6PD in Malaysia
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Molecular characterisation reveals 86% of mutations
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To determine the prevalence of glucose-6-phosphate dehydrogenase (G6PD) deficiency among staff and students of a university community in USM as well as to identify molecular genetics by determination of G6PD mutations.
Results: Out of the 87 subjects (80 were Malay, 2 were Chinese, 1 was Indian and 4 were others). The total prevalence of G6PD deficiency among the subjects was 4.59 % (4/87), all of whom were Malay males. One of the deficient subjects had G6PD Viangchan, while the other three were G6PD Mahidol (487 G>A).
Conclusion: The finding of this study demonstrate that the most common mutation among AMDI staff and students is Mahidol (487G>A), followed by mutation Viangchan (871G>A).
G6PD among AMDI staffs
Ahmed M Sulaiman, Sultan AM Saghir2, Faisal M Al-Hassan, Narazah M Yusoff, Abdel-Hamid A Zaki. 2013
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Molecular basis of G6PD among staffs and students in USM
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G6PD mutations in Malaysia G6PD variant Nucleotide change Malay (%)1,4 Chinese (%)2,4,5 Indian (%)3 Orang Asli (%)5
Viangchan 871 G>A 37.2 0.8 12
Mediterranean 563 C>T 26.7 40
Mahidol 487 G>A 15.1 1.6
Canton 1376 G>T 4.7 42.3-50.0
Coimbra 592 C>T 3.5 4
Vanua Lava 383 T>C 3.5
Kaiping 1388 G>A 2.3 34.2-39.4 20
Union 1360 C>T 2.3 0.8
Orissa 131 C>G 1.2
Chatham 1003 G>A 2.3 0.8
Andalus 1361 G>A 1.2
Gaohe 95A>G - 5.2- 7.0
Mahidol-like 1024C>T - 1.5-2.2
Quing Yuang 392G>T 0.8
Namoru 208T>C 20
Combine 1401T>C with IVS 11 nt93T>C
1311T>C with 1455-13T>C
1 64-83.3
Uncharacterised 7 20
1Ainoon, Yu et al. 2003, 2Ainoon, Joyce et al. 1999; 3Wang, Luo et al. 2008; 4Yusoff, Shirakawa et al. 2002; 5Amini, Ismail et al. 2011; 6Ainoon, Boo et al. 2004
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4 Databases – collecting and sharing variant information
Polymorphism Database
Genotype & Phenotype Database
Clinical Database
• Not available yet• Data collection is on
going
• Not available yet• Data collection is on
going
Not available yetData collection is on going
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•Sources of funding available in Malaysia
- From academic institutions and national government funding.-1)Research University grant, 2)Ministry of Science, Technology and Innovation 3) Ministry of Education Malaysia
Technical assistance –training and equipment available in Malaysia
-Each institution conduct their own training and have their own equipments for haematological diagnosis and molecular diagnosis (e.g,DNA analysis)
Research:- any national research projects exist that are directed to G6PD deficiency?
-Yes, at least two of the academic institutions (UKM, USM) are involved. The key areas of research are clinical, public health and molecular
Any international research project / collaboration exist?
- Yes, 1) Department of Biohealth Science, Kobe Univ. Graduate School of Medicine, Japan 2) Dept. of Health, Cambodia, etc.
5 National resources - availability
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In relation to treatment and prevention:-
Treatment:
Counselling/prevention
services
Other issues
-All treatments are now available (Blood transfusion – voluntary and not directed, no replacement, -etc.)
- Genetic counselling to patients & families ?- available but still inadequate - Prenatal diagnosis?- None - Carrier detection ? – Available but there still a challenge with screening in Malaysia (female heterozygotes) - Premarital counselling? - not routinely available
Inadequacy of genetic counseling skills among Malaysian health care workers
6 6. Problems/Constraints/Challenges
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Challenges
Determination of mechanism of
pathogenesis of NNJ in G6PD deficiency
Development of yet simpler and more accurate kits for
determination of G6PD levels that can be used in
developing countries
Rapid methods for sequencing genes,
including G6PD, at low cost
*Philip J Mason, Jose M Batista, Florida Gilsanz 2007
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7 Recommendations/Plans
What our country wants to get out of GG2020 by 2020
Mutation analysis to be available in all facilities
Genotype & Phenotype Database
Personalised treatment
Do you have any suggestions for funding/support?
??
Any recommendation for joint research?
G6PD deficiency and SAO
Association with diseases e.g. cardiovascular, dengue fever (modifiers)
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9 Affiliated Society/Association
• Is there a national society / association for G6PD deficiency/ No
• Relationship to the national society of Human Genetics and Genomics – are they interested in G6PD deficiency?
- Yes, they are interested.
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In the interest of global health - G6PD deficiency
We now have the means to protect
G6PD deficient individuals from exposure to fava
beans and to iatrogenic risks
How G6PD protects against malaria –
not fully understood
If known, we might be able to mimic
the mechanism to protect others
Lucio Luzzatto, Caterina Nannelli, Rosario Naotaro, 2016
The road is still long…………………………
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Acknowledgements - staffs of Haematology Lab
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Thank you