Different Gene Preferences of Maple Syrup Urine Disease in the Aboriginal Tribes of Taiwan


Pediatrics and Neonatology (2014) 55, 213e217
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ORIGINAL ARTICLE
Different Gene Preferences of Maple Syrup
Urine Disease in the Aboriginal Tribes
of Taiwan
Jia-Woei Hou a,b,*, Tsann-Long Hwang c
a Department of Pediatrics, Cathay General Hospital, Taipei, Taiwan
b Department of Pediatrics, Fu-Jen Catholic University School of Medicine, New Taipei City, Taiwan
c Department of Surgery, Chang Gung University School of Medicine, Taoyuan, Taiwan
Received May 20, 2013; received in revised form Aug 27, 2013; accepted Sep 23, 2013
Available online 20 November 2013
Key Words
carrier frequency;
dihydrolipoyl
transacetylase
gene;

gene preference;
maple syrup urine
disease;

Taiwanese Aboriginal
Austronesian tribe
* Corresponding author. Department
E-mail address: hou76@cgh.org.tw

1875-9572/$36 Copyright ª 2013, Taiw
http://dx.doi.org/10.1016/j.pedneo.2
Background: Maple syrup urine disease (MSUD) is a rare inborn error of metabolism caused by a
deficiency of the branched-chain a-ketoacid dehydrogenase (BCKD) complex. Mutations in any
one of the three different genes encoding for the BCKD components, namely, BCKDHA,
BCKDHB, and DBT, may be responsible for this disease. In Taiwan, few MSUD cases were diag-
nosed clinically, and most of these patients are from Aboriginal tribes.
Materials and methods: To identify and detect the carrier frequency of MSUD in Taiwanese
Aboriginal tribes, we performed biochemical and molecular studies from peripheral blood in
MSUD patients and dried blood on filter paper in the enrolled screened populations.
Results: Homozygous A208T and I281T of BCKDHA were found in two patients from Hans (non-
Aboriginal Taiwanese), respectively; compound heterozygous mutations of the DBT gene
[4.7 kb deletion/c.650-651insT (L217F or L217fsX223) and c.650-651insT/c.88-89delAT] were
found in two patients from Amis, respectively, after direct DNA sequencing and polymerase
chain reaction-restriction fragment length polymorphism studies. There were no cases of
deleted 4.7-kb heterozygote out of 302 normal people (Hans, n Z 125; Atayal, n Z 156;
and Saisiyat, n Z 21); by contrast, the DBT mutations c.650-651insT and deleted 4.7-kb het-
erozygote were noted in 2/121 and 1/121, respectively, from the general population of the
Amis, a southeastern Taiwanese tribe.
Conclusion: Although the Taiwanese Austronesian Aboriginal tribes are considered to share a
common origin, different gene preferences of MSUD were noted. The novel DBT mutation
c.650-651insT was more prevalent than the deleted 4.7-kb heterozygote in the Amis
of Pediatrics, Cathay General Hospital, 280 Section 4, Jen-Ai Road, Taipei 10630, Taiwan.
(J.-W. Hou).

an Pediatric Association. Published by Elsevier Taiwan LLC. All rights reserved.
013.09.009

mailto:hou76@cgh.org.tw
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214 J.-W. Hou, T.-L. Hwang
population. The reported 4.7-kb deletion indicating a possible founder mutation may be pre-
served in the southern and eastern, but not in northern Aboriginal tribes of Taiwan.
Copyright ª 2013, Taiwan Pediatric Association. Published by Elsevier Taiwan LLC. All rights
reserved.
Aboriginals in Taiwan from the Lohkata Medical Service
1. Introduction

Maple syrup urine disease (MSUD) is an autosomal recessive
metabolic disorder, which is caused by mutations in any one of
the three different genes (BCKDHA, BCKDHB, and DBT ) that
encode components of the branched-chain a-ketoacid dehy-
drogenase (BCKD) complex (E1a, E1b, and E2 subunits).1 The
MSUD derives its name from the sweet, burnt sugar, or maple
syrup smell of the urine. If not detected and treated early in
life, the accumulation of branched-chain amino acids
(leucine, isoleucine, and valine) and their metabolites may
resultinacuteandchronicbraindysfunction.1e3 TheMSUD has
been described in all ethnic groups and occurs in approxi-
mately 1/185,000 and 1/101,624 newborns in the United
States and Taiwan, respectively.1,4,5 As an autosomal reces-
sive disorder, MSUD is more prevalent in selected inbred
populations with a high frequency of consanguinity, such as
the Mennonites in Pennsylvania, USA (whose incidence may be
as frequent as 1/176 newborns).1,6,7 Founder mutations
including Y393N/Y438Nofthe BCKDHAgeneintheMennonite/
non-Mennonite communities, R183P of the BCKDHB in Ashke-
nazi Jews, a 239-bp insertion after exon 10 of the DBT gene in
Filipino population, and a c.117delC-alpha (p.R40GfsX23)
deletion inthe BCKDHA gene ina PortugueseGypsy population
have been reported.8e11 Since the incorporation of tandem
mass spectrometry into the existing newborn screening pro-
gram, more patients with MSUD were detected earlier, and
thus an in-time therapy became possible.3,12,13 Recently,
MSUD has been found to have the tendency to occur in the
Austronesian Aboriginal tribes of southern Taiwan.5,13,14

Aboriginal Austronesian tribal populations in Taiwan are
considered as highly homogeneous within each tribe due to
geographic isolation over a long period.15 Therefore,
screening for some specific genetic mutations underlying
MSUD in certain populations may potentially facilitate the
prenatal diagnosis and carrier detection of MSUD. A previous
report indicated a founder effect after characterizing a DBT
gene 4.7-kb deletion of intron 10 found in the general popu-
lation from the Paiwan Austronesian Aboriginal tribe in
southern Taiwan.14 Because members of the Aboriginal tribe
in Taiwan may be at a higher risk of classic form of MSUD,5,14

we enrolled the Aboriginal patients and collected the ge-
netic epidemiological data in the general population to iden-
tify carriers of MSUD among northern and eastern Taiwanese
Aborigines, including the Atayal, Amis, and Saisiyat tribes.
This studywas donetogetherwiththe LohkataMedical Service
Team for Aborigines of Chang Gung Medical School.

2. Materials and methods

2.1. Patients

This study enrolled patients with MSUD from a hospital as
well as the general population of Aboriginals/non-
Team for Aborigines in Chang Gung Medical School over 4
years. Four affected individuals and their family members
were included in the first step of the study. The patients
exhibited the classical (n Z 3, including 2 Amis boys of 4
months and 1.5 years at molecular diagnosis, and 1 Han girl
of 6 months) or intermediate (n Z 1, Han boy of 8 months)
clinical phenotype of MSUD. Only one of them was diag-
nosed as having MSUD by newborn screening. The study was
approved by the Ethics Committee of Chang Gung Memorial
Hospital (IRB Number 94-779B) and informed consent was
obtained from all families.

2.2. Methods

Genomic DNA for further sequencing and polymerase chain
reaction-restriction fragment length polymorphism (PCR-
RFLP) analysis was extracted from peripheral blood in MSUD
patients or dried blood on filter paper in the enrolled
general population according the standard procedure. An
efficient and simple method for extracting and purifying
genomic DNA from dried blood spots stored on filter paper
for further DNA analysis was performed.12,16 For each
sample, six drops of approximately 100 mL of blood were
spotted on filter paper by direct application from a finger
stick. They were dried at room temperature, stored in
separated plastic bags, and shipped to the laboratory
within 2 days of processing. Samples were immediately
used for PCR analysis or stored at �20 �C. Direct sequencing
of the BCKDHA (9 exons), BCKDHB (11 exons), and DBT (9
exons) genes over the patients and their parents were
performed.9e11,17e19 The detection of heterozygote of DBT
4.7-kb deletion and carrier-frequency determination in the
enrolled populations were done on the genomic DNA by
duplex PCR.14 The detection of c.650-651insT mutation
(L217F or L217fsX223) was done with the PCR-RFLP method
by the MwoI (New England Biolabs, Ipswich, MA, US)
restriction analysis.

3. Results

The extraction and purification of genomic DNA from dried
blood specimens are efficient and appropriate for genetic
studies. A total of 435 blood samples were collected,
including 423 from normal controls (220 males and 203 fe-
males) and 12 from MSUD patients and their parents. After
PCR-RFLP and direct DNA sequencing studies, two homo-
zygous mutations A208T and I281T of BCKDHA were found in
two Han patients (non-Aboriginal Taiwanese), along with
two compound heterozygous mutations of the DBT gene:
4.7-kb deletion flanking parts of intron 10 and the 30-un-
translated region of exon 11 (Figure 1)/c.650-651insT
(L217F or L217fsX223) of exon 6 (Figure 2) and c.650-
651insT/c.88-89delAT of exon 2, in two patients from the
eastern Amis tribe, respectively. Their parents were all



Figure 2 Polymerase chain reactionerestriction fragment
length polymorphism analysis with restriction enzyme MwoI
revealing two additional bands of 194 bp and 181 bp in the
c.650-651insT (L217F) heterozygous mutation or maple syrup
urine disease carrier.

Gene preferences of maple syrup urine disease 215
heterozygous carriers. Possible maternal Paiwan lineage of
the second patient was mentioned.

Large-scale screening of the mutated sites was carried
out on 423 normal patients, including Hans (n Z 125, 20e65
years of age), and non-Hans including Atayal (n Z 156,
25e50 years of age), Saisiyat (n Z 21, 30e45 years of age),
and Amis (n Z 121, 21e66 years of age). The first two
Aboriginal tribes occupy highland areas, whereas the third
one occupies lowland areas. The deleted E2 gene (4.7 kb)
or L217F heterozygote was not found in Han, Atayal, or
Saisiyat patients, whereas 4.7-kb and L217F heterozygotes
were found in Amis (1/121 and 2/121, respectively;
Figure 3).

4. Discussion

The determination of prevalence of MSUD in a certain
population plays a very important role in genetic coun-
seling. The incidence of heterozygous carriers (i.e., carrier
frequency) and the pattern are the results of consanguinity
and founder effect. Certain ethnicities demonstrate higher
incidence with common mutations due to endogamous
practices, such as Ashkenazi Jews and Mennonites possibly
attributable to a founder effect.8,9 Taiwan’s indigenous
tribes are highly homogeneous within each tribe, but
diversified among the different tribes due to geographic
isolation over a long period. Results of immunohematologic
studies support the aforementioned theory.15,20 Recently,
MSUD was found to occur in the Austronesian Aboriginal
tribes of Taiwan. Meanwhile, a common 4.7-kb deletion on
the DBT gene indicating a founder mutation in the Paiwan
tribe in southern Taiwan was reported.14 This specific
change was also noted in the Philippines,10 which is
consistent with the previous description of proto-
Austronesian genetic affinities with Southeast Asian
populations.21
Figure 1 Identification of the heterozygous 4.7-kb deletion
by duplex PCR: the 388-bp duplex PCR product representing a
heterozygous deletion in the MSUD patient or carriers, whereas
only two bands of 244 bp and 750 bp are present in normal
controls. MSUD Z maple syrup urine disease;
PCR Z polymerase chain reaction.
This is the first comprehensive genetic study of MSUD in
the Austronesian tribal groups in northern and eastern
Taiwan. Mutations in Han patients occurred in the BCKDHA
gene; and no common genetic changes were found in the
Aboriginal population (Figure 3). The phylogenic tree made
from the distribution pattern of the human leukocyte an-
tigen gene and the haplotype frequencies/immunoglobulin
allotypes distinguishes Aborigines from Han populations in
Taiwan or China.22e25 This study suggests that although the
Taiwanese Aboriginal tribes are considered to share a
common origin, the DBT gene 4.7-kb founder deletion may
be preserved only in the southern14 and eastern tribes, but
not in northern Aboriginal tribes of Taiwan. The novel DBT
gene L217F mutation has more carrier frequency (2/121)
than that of 4.7 deletion (1/121) in the Amis population.
Moreover, we also identified a common c.88-89delAT of
exon 2 found in one MSUD patient of possible maternal
Paiwan lineage. Amis was delineated in a different fashion
from Paiwan in terms of immunohematology and mito-
chondrial polymorphisms.20,23,26 Further dilution, distance,
and selection factors, or intermixture by marriage in the
past century on the founder effect may explain this
condition.22e24

In conclusion, our findings suggest that a limited number of
mutations may exist in MSUD in certain Aboriginal Austrone-
sian tribal populations, and this finding may potentially facil-
itate prenatal diagnosis and carrier detection of MSUD. A close
genetic relationship between Taiwan’s southern and eastern
indigenous tribes and Southern Asians, such as Filipinos, ex-
ists. The identification could be performed by a simple,



Figure 3 Map of Taiwan showing the studied populations and carrier frequency. F1 Z frequency of E2 4.7-kb deletions, number
of heterozygotes/numbers being tested; F2 Z frequency of L217F, number of heterozygotes/numbers being tested.

216 J.-W. Hou, T.-L. Hwang
reliable, sensitive, and cost-effective DNA extraction method
from dried blood spots stored on filter paper along with a
newborn screening program.

Conflict of interest

The authors state that there is no conflict of interest
regarding the publication of this article.
Acknowledgments

We are very grateful to the families for participating
in this study, and family interview by medical students
of Lohkata Aboriginal Health and Medical service of Chang
Gung University. This work was supported by the grant
(Grant No. CMRP440011) from Chang Gung Memorial
Hospital.



Gene preferences of maple syrup urine disease 217
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	Different Gene Preferences of Maple Syrup Urine Disease in the Aboriginal Tribes of Taiwan
	1 Introduction
	2 Materials and methods
	2.1 Patients
	2.2 Methods

	3 Results
	4 Discussion
	Conflict of interest
	Acknowledgments
	References