Sudden Unexplained Nocturnal Death Syndrome SUNDS - Mahidol ...

SUNDS: Molecular Biology of
Sudden Unexplained Nocturnal Death
Syndrome
Naiphinich Kotchabhakdi
Vice President, Asian Sleep Research Society, and
Director, Neuro-Behavioural Biology Center, Institute of Science and
Technology for Research and Development, Mahidol University, Salaya,
aya,
Nakornpathom 73170 Thailand
Email: scnkc@mahidol.ac.th
Web: http://neuroscience.mahidol.ac.th
Sudden Unexplained Nocturnal
Death Syndrome
SUNDS
“Lai tai” or “Sleepy Death”
1

SUDDEN DEATH
1. Sudden Unexplained Death Syndrome (SUDS)
2. Sudden Unexplained Nocturnal Death
Syndrome (SUNDS)
3. Sudden Infant Death Syndrome (SIDS)
(or
“Crib
Death”)
SUDDEN UNEXPLAINED
DEATH SYNDROME (SUDS)
DEFINITION:
Sudden death in previously (within past 24 hrs) healthy
individuals, without known predisposing illness;
occurring in persons of both sexes, from age 20-44 yrs;
with no definitive pathological findings; no homicidal
or suicidal indications.
4

Sudden Unexplained Nocturnal Death
Syndrome
(SUNDS)
According to the 1990 ICSD- International
Classification of Sleep Disorders: Diagnostic and
Coding Manual, Sudden unexplained nocturnal
death syndrome (SUNDS) is characterized by
sudden death during sleep in healthy young adults,
particularly of Southeast Asian descent.
Neither clinical history nor autopsy provides
an explanation for the cause of death. According to
witnesses of SUNDS, the first signs are choking,
gasping, and labored respiration (without wheezing
or stridor). Attempts to awaken the person are
unsuccessful. In several successfully resuscitated
patients, ventricular fibrillation was subsequently
detected.
5

SUNDS are most often found among
Laotian, Kampuchean, and Vietnamese male
refugees, and Thai males from the Northeastern
part of Thailand between the ages of 25 and 44
years. There are descriptive terms in the Asian
languages which suggest that SUNDS has long
been recognized. Synonyms (translations) include
“Lai-Tai” and “Non-Lai-Tai” (Sleep death) in
Thai and Laotian respectively, “Bangungut or
Gangungut” (To arise and moan) in Tagalog of
the Philippines, and “Pokkuri” (Sudden death) in
Japanese.
Studies have failed to identify any social,
religious, or work-related activity, rituals, or
specific daytime events that could be associated
with SUNDS. Acutely stressful events were found
in few cases (4 of 51 cases in one study). Neither
exposure to chemical and biological toxins nor
use of drugs or alcohol has been implicated in the
death. Sleep terrors have been reported to occur
frequently in patients who subsequently have
been SUNDS victims.
6

Centers for Disease Control :(CDC), Atlanta, USA
7

N. Kotchabhakdi et al 98
แผนที่แสดงการกระจายของภูมิลําเนาของผูตายดวยโรคใหลตายในภาคอีสาน
9

Kotchabhakdi et al 1992
N. KOTCHABHAKDI et al 1992
11

In interviews with very old living Northeastern
Thais, it appears that ‘Lai Tai’ has probably
been present in the region for quite a long time,
as it is very well-known in the local folklore, in
traditional ‘folk medicine’ and among ‘healers’.
Mythical beliefs relate ‘Lai Tai’ to the spirits
of dead widows who try to harm or reclaim the
lives of males who had deceived them, in either
the present or some previous life.
12

The majority of SUDS victims died during
night-time sleep ( >90% ) or collapsed while
resting, rather than during active exertion;
hence,
SUDS
(Sudden Unexplained Death Syndrome)
is now referred to more frequently as:
SUNDS
(Sudden Unexplained Nocturnal Death Syndrome)
Definition:
‘Lai Tai’ or SUNDS
Sudden death during sleep (mainly nocturnal sleep,
but may also occur during daytime resting or
napping) in previously healthy individuals, without
known predisposing illness, predominantly in
males with ethnic origins in the Northeastern
region of Thailand, ages from 21-45 yrs, and with no
definitive pathological findings.
13

SUNDS has been reported from:
• southern parts of China
• Indochina (Laos, Cambodia, Vietnam,
and among certain small tribes, e.g.,
the Hmong)
• Northeastern region of Thailand
(E’sarn)
• Philippines
• Japan
• Mongolia
14

แผนที่แสดงประเทศในทวีปเอเชียที่มีรายงานของผูตายดวยอาการโรคใหลตาย
15

?
N. Kotchabhakdi et al 98
16

N. Kotchabhakdi et al 1998
RELATED SYNDROMES
1. Sleep Apnea:
-- Upper Airway Obstructive
-- Central
-- Mixed type
-- Sleep Breathing Disorders
2. Autonomic Dystonia
3. Prolonged QT Interval Syndrome
4. Brugada Syndrome (?)
17

Risk Factors and Hypotheses
on the Etiology of SUDS
1. Cardiac
-- Prolonged QT Interval Syndrome
-- Brugada Syndrome
-- Sudden Heart Block
2. Renal tubular acidosis (RTA)
3ใ Neurogenic
--
-- Dysautonomia
-- Abnormal reflex bradycardia
4. Sleepleep Apnea
5. Respiratory
Arrest
Risk Factors and Hypotheses
on the Etiology of SUDS
(continued)
6. Ionic Imbalance (e.g., Hypokalemia)
7. Nutritional Deficiencies (e.g., B-Vitamins)
8. Toxic Substances (e.g., PVC)
9. Infectious Processes (e.g., Influenza Virus A)
10. Genetic Abnormalities
18

Kirschner, R.H.; Eckner, F.A.; Baron, R.C. : The
cardiac pathology of sudden unexplained
nocturnal death in Southeast Asian refugees.
JAMA (KFR) 1986 Nov 21, 256(19), p.2700-5.
Of 18 hearts examined, 14 showed cardiomegaly,
characteristic of increased cardiac work load, 17 had
conduction system anomalies, including persistent fetal
dispersion of the A-V node and/or Bundle of His (14),
accessory conduction fiber connections (13), and
congenital heart block (1). Together with associated
variations in cardiac base structure, these abnormalities
suggest a common aberrant developmental process.
19

Okoye, M.I.; Congdon, D.E.; Mueller, W.F. Jr.:
Asymmetric septal hypertrophy of the heart: New
findings concerning the possible etiology of sudden
deaths in five males.
Am J Forensic Med Pathol (3HC) 1985 Jun: 6(2),
p.105-24.
In 5 male SUDS cases, autopsy revealed only
asymmetric septal hypertrophy (ASH). These
abnormalities in the conducting system and ventricular
myocardium are excellent anatomical substrates for
hemodynamic impairment and lethal arrhythmias,
triggered by hypoxia, increased oxygen demand or
abnormal sympathetic stimulus.
Drescher, J.; Zink, P.; Verhagen, W.; Flik, J.;
Milbradt, H. : Recent influenza virus A
infections in forensic cases of sudden
unexplained death.
Arch Virol (8L7) 1987: 92(1-2), p. 63-76.
84 forensic necropsy cases of SUDS were found to have
a significantly higher rate of influenza virus A (H3N2)
infection than either matched controls of the general
population or a group of forensic necropsy cases with
known cause of death (non-SUD).
20

Munger RG, Prineas RJ, Crow
RS, Changbumrung S, Keane V,
Wangsuphachart V, Jones MP.
Prolonged QT interval and risk
of sudden death in South-East
Asian men. Lancet 1991, 338,
280-281.
According to a group of cardiologists, the clinical features of SUNDS may include
ST-segment elevation in the right precordial leads (V1–V3), inconsistently
associated with right bundle branch block (RBBB) (Fig. 1) (2,3) and ventricular
tachycardia and fibrillation (VF) on surface electrocardiogram (ECG). These
clinical characteristics are similar to those of the Brugada syndrome, a disorder
diagnosed in individuals of European descent.
21

1 Baron,R.C., Thacker,S.B., Gorelkin,L., Vernon,A.A., Taylor,W.R. and Choi,K. (1983) Sudden death among
Southeast Asian refugees. An unexplained nocturnal phenomenon. J. Am. Med. Assoc., 250, 2947–2951
2 Nademanee,K., Veerakul,G., Nimmannit,S., Chaowakul,V., Bhuripanyo,K., Likittanasombat,K.,
Tunsanga,K., Kuasirikul,S., Malasit,P., Tansupasawadikul,S. et al. (1997) Arrhythmogenic marker for the
sudden unexplained death syndrome in Thai men. Circulation, 96, 2595–2600
3 Gilbert,J., Gold,R.L., Haffajee,C.I. and Alpert,J.S. (1986) Sudden cardiac death in a southeast Asian
immigrant: clinical, electrophysiologic and biopsy characteristics. Pacing Clin. Electrophysiol., 9, 912–
914.
22

The genetic cause of the Brugada syndrome was initially
described by our group and shown to be due to mutations
in the cardiac sodium channel gene, SCN5A. This has now
been confirmed by others (7,8). In previous publications, we
and others demonstrated that mutant sodium channels
have a reduced sodium channel current (INa) due to rapid
inactivation of the current or failure of the channel to
express currents (9,10). Due to the apparent clinical
similarities between Brugada syndrome and SUNDS, we
speculated that these could be allelic disorders (or even the
same disease). In this report, we describe the molecular
analysis of patients with SUNDS and identify mutations in
SCN5A, confirming this disorder to be genotypically,
phenotypically and functionally identical to Brugada
syndrome.
7 Bezzina,C., Veldkamp,M.W., van Den Berg,M.P., Postma,A.V., Rook,M.B., Viersma,J.W., van Langen,I.M., Tan-Sindhunata,G., Bink Boelkens,M.T.,
van Der Hout,A.H. et al. (1999) A single Na(+) channel mutation causing both long-QT and Brugada syndromes. Circ. Res., 85, 1206–1213
8 Rook,M.B., Alshinawi,C.B., Groenewegen,W.A., van Gelder,I.C., van Ginneken,A.C., Jongsma,H.J., Mannens,M.M. and Wilde,A.A. (1999) Human
SCN5A gene mutations alter cardiac sodium channel kinetics and are associated with the Brugada syndrome. Cardiovasc. Res., 44, 507–517
9 Chen,Q., Kirsch,G.E., Zhang,D., Brugada,R., Brugada,J., Brugada,P., Potenza,D., Moya,A., Borggrefe,M., Breithardt,G. et al. (1998) Genetic basis
and molecular mechanism for idiopathic ventricular fibrillation. Nature, 392, 293–296
10 Dumaine,R., Towbin,J.A., Brugada,P., Vatta,M., Nesterenko,D.V., Nesterenko,V.V., Brugada,J., Brugada,R. and Antzelevitch,C. (1999) Ionic
mechanisms responsible for the electrocardiographic phenotype of the Brugada syndrome are temperature dependent. Circ. Res.,85, 803–809.
Mutation analysis
Ten probands with clinical evidence of SUNDS were screened for
mutations in KVLQT1 (11), HERG (11), SCN5A (9,11), minK (12)
and MiRP1 (13) using single-strand DNA conformation
polymorphism (SSCP) analysis, denaturing high-performance liquid
chromatography (DHPLC) and DNA sequencing. In three patients
(M030, M032, M033), SCN5A mutations were identified. No mutations
were identified in any of the other genes screened. Patient M030 is a
sporadic case, whereas the other two cases were probands of
families. One of these was a family with multiple affected individuals
(family M032), and apparent autosomal dominant inheritance. The
second family (M033) included a pair of affected Japanese dizygotic
twins. One twin died unexpectedly during sleep at 4 months of age.
The other twin had frequent VF episodes at 6 months of age and has
been discussed previously (14). This living child and other family
members were studied.
11 Splawski,I., Shen,J., Timothy,K.W., Vincent,G.M., Lehmann,M.H. and Keating,M.T. (1998) Genomic structure of three
long QT syndrome genes: KVLQT1, HERG and KCNE1. Genomics, 51, 86–97
12 Schulze-Bahr,E., Wang,Q., Wedekind,H., Haverkamp,W., Chen,Q., Sun,Y., Rubie,C., Hordt,M., Towbin,J.A.,
Borggrefe,M. et al. (1997) KCNE1 mutations cause Jervell and Lange-Nielsen syndrome. Nat. Genet., 17, 267–268
13 Abbott,G.W., Sesti,F., Splawski,I., Buck,M.E., Lehmann,M.H., Timothy,K.W., Keating,M.T. and Goldstein,S.A. (1999)
MiRP1 forms IKr potassium channels with HERG and is associated with cardiac arrhythmia. Cell, 97, 175–187
14 Suzuki, H., Torigoe, K, Numata, O. and Yazaki, S. (2000) Infant case with a malignant form of Brugada syndrome. J.
Cardiovasc. Electrophysiol., 11, 1277–1280.
23

However, Brugada syndrome,
predominantly found among western
population, and other cardiac pathology
are related to autosomal genes,
therefore, they are inconsistent with
South-east Asian SUNDS
epidemiological data which are
predominantly males.
Also, they should have had some previous
history of illness, symptoms or abnormalities.
26

Munger, R.G. : Sudden death in sleep of Laotian-
Hmong refugees in Thailand: a case-control
study.
AM J Public Health (3XW) 1987 Sep: 77(9), p. 1187-
90.
16 SUNDS cases were studied in Northeastern Thailand,
similar to those among SEA refugees in the USA.
Associations were found between Green-Hmong
subgroup membership, a family history of sudden death
and previous non-fatal sleep disturbances, suggesting that
this is a regional phenomenon in culturally and
genetically distinct populations.
Munger RG, Booton EA. Thiamine and sudden
death in sleep of South-East Asian refugee.
Lancet. 1990 May 12; 335(8698): 1154-1155.
27

Munger RG, Booton EA.
Thiamine and sudden death
in sleep of South-East Asian
refugee. Lancet. 1990 May 12;
335(8698): 1154-1155.
28

Between 1990 – 1992,
intensive health promotions,
including vitamin and mineral
supplements,
did not alter the incidence rates of
SUDS or SUNDS among the
intervention groups of the target
population, especially young Thai
laborers working abroad, in Singapore,
Malaysia, Brunei, etc.
In Singapore and Thailand,
prolonged EKG monitoring and
echocardiographic studies did not
reveal any significantly higher
incidence of cardiac abnormalities
among the target group than in the
general population.
29

Melles, R.B. : Night terrors and Sudden
Unexplained Nocturnal Death.
Med. Hypotheses (MOM) 1988 Jun: 26(2), p. 149-154.
Post mortem analysis of SUNDS victims has disclosed a
high incidence of cardiac conduction defects in many
cases. Also, a careful review of terminal events suggests
the additional presence of night terrors, a sleep disorder
characterized by vocalization, motor activity, a nonarousable
state and severe autonomic discharge.
N. Kotchabhakdi et al 98
30

In interviews with very old living Northeastern
Thais, it appears that ‘Lai Tai’ has probably
been present in the region for quite a long time,
as it is very well-known in the local folklore, in
traditional ‘folk medicine’ and among ‘healers’.
Mythical beliefs relate ‘Lai Tai’ to the spirits
of dead widows who try to harm or reclaim the
lives of males who had deceived them, in either
the present or some previous life.
32

Several families in Northeastern Thailand have
been identified as having
(N = 24 have been studied so far, as of 2003)
2 - 3 generations of SUNDS victims.
Probands from these 24 families have significantly
higher incidences of sleep disturbances,
especially sleep apnea
--- resulting in O2 desaturation
and episodic bradycardia
--- than control families.
38

Is SUNDS
an X-linked recessive
inheritance
?
What are the possible gene – protein markers on
the X chromosome??
• pyruvate dehydrogenase
• ornithine carbamyl transferase
• glyceraldehyde-3 phosphate dehydrogenase
• a-phosphorylase kinase
• monoamine oxidase A and B
• glycine receptor
• GABA receptor
39

MAO Substrate sensitivity
MAO-A
MAO-B
Serotonin
Norepinephrine
Epinephrine
Phenylethylamine
Benzylamine
Alternative pathways and enzymes:
MAO Monoamine oxidae
COMT Catecholamine O-methy transferase
40

Midline Dorsal Raphe Nucleus (Controls vs SUNDS)
300.00
250.00
Number of cells counted
200.00
150.00
100.00
Control
SUNDS
50.00
0.00
DRN-A DRN-B DRN-AB
49

Medulla
30.00
25.00
Number of cells counted
20.00
15.00
10.00
Control
SUNDS
5.00
0.00
DRN-A DRN-B DRN-AB
Locus Ceruleus (Controls vs SUNDS)
600.00
500.00
Number of cells counted
400.00
300.00
200.00
Control
SUNDS
100.00
0.00
LC-A LC-B LC-AB
50

The “Serotonin excess” hypothesis.
The last genomic
aspects of SUNDS ? NO
What are the
environmental or
behavioral trigger
factors?
51

Have a good night sleep
and sweet dream
and
REM beahvioral disorde
no REM
SUNDS
Thank you
52