G6PD Deficiency in Malaysia: the current situation - Narazah Mohd Yusoff

www.humanvariomeproject.org/GG2020

G6PD deficiency in Malaysia – the current situation

Prof Dr Narazah Mohd Yusoff, MBBS, [email protected]; [email protected].

Universiti Sains Malaysia, MALAYSIAAreas of interest: G6PD deficiency and Southeast Asia ovalocytosis

(SAO)

mailto:[email protected]


Key features of G6PD deficiency…..

Malaysia – prevalence of red blood cell disorders; Thalassemia, Haemoglobinopathy E, G6PD deficiency, SAO.


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


Role of G6PD enzyme in protection against oxidative damage


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)


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


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


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


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)


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

10

Molecular characterisation reveals 86% of mutations


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

11

Molecular basis of G6PD among staffs and students in USM


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


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


•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


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


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


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)


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.


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…………………………


Acknowledgements - staffs of Haematology Lab


Thank you

Date post:	12-Apr-2017
Category:	Science
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