natural history of als among different populations in...

Natural History of ALS among Different Populations

in PACTALS

Dongsheng Fan Peking University Third Hospital

Beijing, China

REVIEW

Amyotrophic lateral sclerosis and motor neuronsyndromes in AsiaN Shahrizaila,1,2 G Sobue,3 S Kuwabara,4 S H Kim,5 Carol Birks,6 D S Fan,7 J S Bae,8

C J Hu,9 M Gourie-Devi,10 Y Noto,2,11 K Shibuya,2,4 K J Goh,1 R Kaji,12 CP Tsai,13

L Cui,14 P Talman,15 R D Henderson,16 S Vucic,17 M C Kiernan2

For numbered affiliations seeend of article.

Correspondence toDr N Shahrizaila, NeurologyUnit, Department of Medicine,Faculty of Medicine, Universityof Malaya, Lembah Pantai,Kuala Lumpur 50603,Malaysia; [email protected]

Received 7 February 2016Revised 9 March 2016Accepted 23 March 2016

To cite: Shahrizaila N,Sobue G, Kuwabara S, et al.J Neurol NeurosurgPsychiatry Published OnlineFirst: [please include DayMonth Year] doi:10.1136/jnnp-2015-312751

ABSTRACTWhile the past 2 decades have witnessed an increasingunderstanding of amyotrophic lateral sclerosis (ALS)arising from East Asia, particularly Japan, South Korea,Taiwan and China, knowledge of ALS throughout thewhole of Asia remains limited. Asia represents >50% ofthe world population, making it host to the largestpatient cohort of ALS. Furthermore, Asia represents adiverse population in terms of ethnic, social and culturalbackgrounds. In this review, an overview is presentedthat covers what is currently known of ALS in Asia frombasic epidemiology and genetic influences, through todisease characteristics including atypical phenotypeswhich manifest a predilection for Asians. With the recentestablishment of the Pan-Asian Consortium forTreatment and Research in ALS to facilitatecollaborations between clinicians and researchers acrossthe region, it is anticipated that Asia and the Pacific willcontribute to unravelling the uncertainties in ALS.

INTRODUCTIONAmyotrophic lateral sclerosis (ALS) is characterisedby degeneration of the upper and lower motorneuronal systems, heralded by progressive muscleweakness, paralysis and death.1 Although thereexists a growing body of ALS research that haslargely originated from developed Western coun-tries, the Asian region represents the majority ofthe world population. While recent years have seena rise in ALS research from Asia, knowledge of thedisease in Asia, especially from less developedcountries, remains limited. Asians represent awidely diverse population in ethnic, social and cul-tural background as well as in the provision ofhealthcare.Studies from mixed populations suggest pheno-

typic variability between patients from differentethnic backgrounds, although true differencesremain a source of ongoing debate.2 Recent discov-eries of new genes in ALS have led to greaterinsight into the underlying pathophysiology ofmotor degeneration. The C9orf72 repeat expansionaccounts for a significant percentage of familial andsporadic ALS in Caucasian populations but is rarein Asian cohorts.3 Speculative observation suggeststhat the origin of this mutation dates back1500 years to the Vikings, relating its spread toother populations through their European inva-sion.4 5 It remains to be determined whether a

similar founder effect exists in Asia and withinother ethnic groups.In this review, current knowledge of ALS in Asia

will be presented, highlighting similarities and dif-ferences with other disease populations. Central toaddressing the current shortcomings, there is aclear need to establish an active collaborativenetwork of clinicians and researchers within theregion and its surrounding partners that can workin synergy to achieve greater insight into this devas-tating disease.

EPIDEMIOLOGYWestern population-based studies have suggested auniform incidence rate of ALS at 2.16 per 100 000person-years.1 There is evidence to suggest that inpopulations where there is genetic admixture, theincidence of ALS is lower.6 This suggests that het-erogeneous populations are less likely to share‘at-risk’ genes that may result in increased suscepti-bility of developing ALS. Asia represents a largegeographical area with populations from diverseancestral backgrounds and within these popula-tions, there are likely to be inter-racial unionsresulting in a large genetic and racial admixedpopulation. For this reason, population studies inAsian cohorts are of interest. Although the reportedprevalence and incidence of ALS from differentAsian countries exists, most have been extrapolatedfrom single centred or multicentred cohort studies,rather than true population-based studies, therebyintroducing significant bias (table 1 and figure 1).In Japan, the crude incidence7 is similar to that inwestern cohorts, while a lower incidence isobserved in Chinese patients.8 9 A house-to-housepopulation survey in India showed a prevalence of4/100 000, inferring a low incidence.10 Thereasons underlying the low incidence in manyAsian cohorts are less certain. Possibilities includethe low incidence of genetic mutations in ALS suchas the C9orf72 repeat expansion and the lower lifeexpectancies in less-developed Asian countries.In Japan and South Korea, the mean age of

disease onset is 61 and 58 years, respectively,11 12

but other Asian cohorts have suggested a youngerage of disease onset compared with Caucasians. InChina, the mean age is approximately 52 years,13–15

whereas in a single study from India, the age ofonset was 46 years.16 The overall gender ratio ofAsian patients with ALS is comparable to that ofCaucasian patients where there is a higher

Shahrizaila N, et al. J Neurol Neurosurg Psychiatry 2016;0:1–10. doi:10.1136/jnnp-2015-312751 1

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a likely key positive regulator of TGF-β signalling that is criticalfor survival of motor neurons. Decreased expression ofZNF512B would thus lead to decreased TGF-β signalling result-ing in increased disease susceptibility. To date, this SNP has alsobeen significantly associated with Han Chinese patients withALS.37 In a separate study of 465 Japanese patients, linkage dis-equilibrium block was associated with decreased expression ofTTN and rapid functional decline of patients with sporadicALS.38

In a recent Korean study, multigene panel testing of 18ALS-related genes followed by exome sequencing was performedin 4 patients with familial ALS and 148 patients with sporadicALS. Four known mutations in four genes (SOD1, ALS2, MAPTand SQSTM1) and 28 non-synonymous heterozygous variants innine genes were found in patients with ALS. The findings sug-gested targeted multigene panel testing as an efficient method ofscreening for ALS-related genetic mutations.39

In India, an L84F mutation in exon 4 of SOD1 with a novelnucleotide variation, c.255G>Twas identified in four membersof a family with autosomal-dominant inherited ALS. The muta-tion was not detected in 48 patients with sporadic ALS or 35age-matched healthy controls. Of interest, patients with ALSwith the mutation demonstrated phenotypic variability in termsof age of onset, site of disease onset and duration of survival.40

ATYPICAL ASIAN PHENOTYPESAside from the conventional presentations of ALS, there areseveral atypical presentations of motor neuron disorders or

motor neuronopathies that appear to have a predilection forAsian patients. It is less clear if these conditions form part ofthe ALS spectrum, representing a less aggressive form of diseasein some, or if they are completely different diseases with differ-ent risk factors.

Juvenile muscular atrophy of the distal upper extremityThe initial descriptions of monomelic atrophy date back to1959 by Hirayama et al41 who described juvenile muscularatrophy of the unilateral upper extremity in Japanese patients.The condition continues to be referred to by its eponymousname, Hirayama disease, although Hirayama has since advo-cated use of the more descriptive term, juvenile muscularatrophy of the distal upper extremity.42 In 1984, Gourie-Deviet al43 described similar patterns of weakness in patients fromIndia, referring to the disease as monomelic amyotrophy toreflect the involvement of the lower as well as upper limbs.Although there have been descriptions of such cases in thewestern population, there is a disproportionately greaternumber of patients of Asian descent who are afflicted.

In juvenile muscular atrophy of the distal upper extremity, thediagnosis is made on the basis of distally dominant muscleweakness with age of onset from the teenage years up untilearly adulthood. There appears to be a preponderance of malesaccounting for almost 90% in one large series from Japan.44 Aninitial period of progression over a few years is typically fol-lowed by a plateau. The pattern of muscle atrophy affects thehand muscles and the ulnar aspect of the distal forearm or

Figure 1 Representative demographic data concerning amyotrophic lateral sclerosis of some Q10of the countries in the Asia-Pacific region (refer totable 1 for source data). F, female; M, male.

Shahrizaila N, et al. J Neurol Neurosurg Psychiatry 2016;0:1–10. doi:10.1136/jnnp-2015-312751 3

Neurodegeneration

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Background

•  ALS research largely originate from North America and Europe

•  However, •  Pan-Asia represents >50% of the world population •  Pan-Asia represents a diverse population in terms of

ethnic, social and cultural backgrounds

Comparisons between Pan-Asia and other regions

57

54.1

58.2

58.2

49.8

46.2

66.84

62.8

66

65.4

58.7

50

0 10 20 30 40 50 60 70

Europe

North America

Australia

Japan

China

India

Mean/median age at onset (years)

Youngest Eldest

0.71

0.98

3

1.6

1.37

1.2

2.1

2.3

1.9

2.9

1.5

0 0.5 1 1.5 2 2.5 3

Europe

North America

India

China

Japan

Australia

M:F ratio

Lowest Highest


19

16.5

36.8

25.3

14

6.5

39.3

33

30.3

34.5

27.1

0 5 10 15 20 25 30 35 40

Europe

North America

Australia

Japan

China

India

Percentage of bulbar-onset ALS

Lowest Highest


27.5

25.2

114.8

66.6

48

24

57.48

41.4

71

73

0 20 40 60 80 100 120

Europe

North America

India

China

Japan

Auatralia*

Mean/median survival (months)

Shortest Longest

*:The difference of survival in Australia was because of different phenotypes


*Developed Asia-Pacific areas include Japan, China Hong Kong, China Taiwan and Australia; Developing Asia-Pacific areas include Mainland China and India

57

54.1

55.5

46.2

66.84

62.8

66

52.6

0 10 20 30 40 50 60 70

Europe

North America

Developed Asia-Pacific areas

Developing Asia-Pacific areas

Age at onset (years)

Lowest Highest

Comparisons between developing and developed Pan-Asia areas

Mainland China Incidence: NA Prevalence: NA M:F 1.6-1.83:1 Age at onset: 49.8-52.6 Survival: 71 months

Taiwan, China Incidence: 0.51 Prevalence: 1.97 M:F 1.65:1 Age at onset: 56.3-56.6 Survival: 66.6 months

India Incidence: 112.6 (based on OPD attendance) Prevalence: NA M:F 3:1 Age at onset: 46.2 Survival: 114.8 months

Canada Incidence: 0.91-2.4 Prevalence: NA M:F 0.98:1 Age at onset: 62.8 Survival: 25.2 months

USA Incidence: 1.4-4.2 Prevalence: 3.84-5.0 M:F 1.24-2.3:1 Age at onset: 49.7-60.6 Survival: 25-41.4 months

Brazil Incidence: 0.4 Prevalence: 0.9 M:F 1.4-1.7:1 Age at onset: 52-57.2 Survival: 42-49 months

Japan Incidence: 0.69-2.50 Prevalence: 2.25-9.9 M:F 1.37-2.9:1 Age at onset: 58.2-65.4 Survival: 48 months

Hong Kong , China Incidence: 0.3-0.6 Prevalence: 0.95-3 M:F 1.72-1.95:1 Age at onset: 55-58.76 Survival: NA

Uruguay Incidence: 1.37-1.42 Prevalence: 1.9 M:F 2:1 Age at onset: 58.7 Survival: NA

Argentina Incidence: 6 (based on OPD attendance) Prevalence: NA M:F 1.59:1 Age at diagnosis: 55 Survival: NA

Africa Incidence: NA Prevalence: NA M:F 1.4-4:1 Age at onset: 50 Survival: 35.2 months

Europe North Incidence: 1.06-2.98 Prevalence: 3.1-8.2 M:F 0.71-2.1:1 Age at onset: 57-66.3 Survival: 28.7-33.6 months

Europe West Incidence: 1.8-2.77 Prevalence: 10.32 M:F 1.1-1.46:1 Age at onset: 63.5-67.8 Survival: 34.8 months

Europe South Incidence: 1.4-2.64 Prevalence: 6.0-10.8 M:F 0.88-1.65:1 Age at onset: 57-66.84 Survival: 27.5-57.48 months

Australia Incidence: NA Prevalence: NA M:F 1.2-1.5:1 Age at onset: 58.2-66 Survival: 24-73 months (different phenotypes)

0.71

0.98

1.2

1.6

2.1

2.3

2.9

3

0 0.5 1 1.5 2 2.5 3

Europe

North America



M:F ratio

Lowest Highest



19

16.5

25.3

14

39.3

33

36.8

27.1

0 5 10 15 20 25 30 35 40

Europe

North America



Percentage of bulbar-onset ALS

Lowest Highest



8

6.97

10

13.8

15.2

17

12

17.7

0 2 4 6 8 10 12 14 16 18 20

Europe

North America



Mean/median Diagnostic delay (months)

Shortest Longest



27.5

25.2

24

66.6

57.48

41.4

73

114.8

0 20 40 60 80 100 120

Europe

North America



Mean/median survival (months)

Shortest Longest



Mainland China Incidence: NA Prevalence: NA M:F 1.6-1.83:1 Age at onset: 49.8-52.6 Survival: 71 months

Taiwan, China Incidence: 0.51 Prevalence: 1.97 M:F 1.65:1 Age at onset: 56.3-56.6 Survival: 66.6 months

India Incidence: 112.6 (based on OPD attendance) Prevalence: NA M:F 3:1 Age at onset: 46.2 Survival: 114.8 months

Canada Incidence: 0.91-2.4 Prevalence: NA M:F 0.98:1 Age at onset: 62.8 Survival: 25.2 months

USA Incidence: 1.4-4.2 Prevalence: 3.84-5.0 M:F 1.24-2.3:1 Age at onset: 49.7-60.6 Survival: 25-41.4 months

Brazil Incidence: 0.4 Prevalence: 0.9 M:F 1.4-1.7:1 Age at onset: 52-57.2 Survival: 42-49 months

Japan Incidence: 0.69-2.50 Prevalence: 2.25-9.9 M:F 1.37-2.9:1 Age at onset: 58.2-65.4 Survival: 48 months

Hong Kong , China Incidence: 0.3-0.6 Prevalence: 0.95-3 M:F 1.72-1.95:1 Age at onset: 55-58.76 Survival: NA

Uruguay Incidence: 1.37-1.42 Prevalence: 1.9 M:F 2:1 Age at onset: 58.7 Survival: NA

Argentina Incidence: 6 (based on OPD attendance) Prevalence: NA M:F 1.59:1 Age at diagnosis: 55 Survival: NA

Africa Incidence: NA Prevalence: NA M:F 1.4-4:1 Age at onset: 50 Survival: 35.2 months

Europe North Incidence: 1.06-2.98 Prevalence: 3.1-8.2 M:F 0.71-2.1:1 Age at onset: 57-66.3 Survival: 28.7-33.6 months

Europe West Incidence: 1.8-2.77 Prevalence: 10.32 M:F 1.1-1.46:1 Age at onset: 63.5-67.8 Survival: 34.8 months

Europe South Incidence: 1.4-2.64 Prevalence: 6.0-10.8 M:F 0.88-1.65:1 Age at onset: 57-66.84 Survival: 27.5-57.48 months

Australia Incidence: NA Prevalence: NA M:F 1.2-1.5:1 Age at onset: 58.2-66 Survival: 24-73 months (different phenotypes)

Advantages for the natural history study of ALS in Pan-Asia

1.  A large and growing number of patients 2.  Multiple ethnic populations 3.  Both developed and developing countries 4.  Diverse habits and customs 5.  Diverse climate

Aims and Objectives 1.  To describe the natural history of ALS in Pan-Asian countries

2.  To identify prognostic factors for survival in Pan-Asian countries

3.  To compare the natural history, clinical features and prognostic factors both among different Pan-Asian countries and between the Pan-Asian region and other regions

4.  To uncover environmental, ethnic, social and cultural factors underlying certain features specific to Pan-Asian ALS patients

5.  To accelerate to establish the multicenter database for PACTALS

Brief methodology •  ALS patients in Pan-Asian countries will be collected

with uniform criteria and CRF.

ü  Make the diagnosis clean (excluded SBMA, other LMNS, ALS-mimic, etc.)

ü  Various phenotypes of ALS (such as FAS, UNM-D ALS, IBALS, but not Hirayama disease, Madras MND, and ALS-PD-dementia complex)

ü  Non-motor impairment (including to cognitive, behavioral, even sleeping)

Vacuolation

40d

Loss of MN

90d

Paresis

125d

Death

136d

orexins

Expected outcomes

1.  Pan-Asian ALS patients have different natural history, clinical features and prognostic factors compared to European and North American patients.

2.  Multiple environmental, ethnic, social and cultural factors account for the heterogeneity within Pan-Asia countries, and these factors may not have been identified in previous studies

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