ORIGINAL COMMUNICATION

Mapping the differences in care for 5,000 Spinal MuscularAtrophy patients, a survey of 24 national registries in NorthAmerica, Australasia and Europe

Catherine L. Bladen • Rachel Thompson • Jacqueline M. Jackson • Connie Garland • Claire Wegel •

Anna Ambrosini • Paolo Pisano • Maggie C. Walter • Olivia Schreiber • Anna Lusakowska • Maria Jedrzejowska •

Anna Kostera-Pruszczyk • Ludo van der Pol • Renske I. Wadman • Ole Gredal • Ayse Karaduman •

Haluk Topaloglu • Oznur Yilmaz • Vitaliy Matyushenko • Vedrana Milic Rasic • Ana Kosac • Veronika Karcagi •

Marta Garami • Agnes Herczegfalvi • Soledad Monges • Angelica Moresco • Lilien Chertkoff • Teodora Chamova •

Velina Guergueltcheva • Niculina Butoianu • Dana Craiu • Lawrence Korngut • Craig Campbell •

Jana Haberlova • Jana Strenkova • Moises Alejandro • Alatorre Jimenez • Genaro Gabriel Ortiz •

Gracia Viviana Gonzalez Enriquez • Miriam Rodrigues • Richard Roxburgh • Hugh Dawkins •

Leanne Youngs • Jaana Lahdetie • Natalija Angelkova • Pascal Saugier-Veber • Jean-Marie Cuisset •

Clemens Bloetzer • Pierre-Yves Jeannet • Andrea Klein • Andres Nascimento • Eduardo Tizzano •

David Salgado • Eugenio Mercuri • Thomas Sejersen • Jan Kirschner • Karen Rafferty • Volker Straub •

Kate Bushby • Jan Verschuuren • Christophe Beroud • Hanns Lochmuller

Received: 20 August 2013 / Revised: 8 October 2013 / Accepted: 9 October 2013

� Springer-Verlag Berlin Heidelberg 2013

Abstract Spinal muscular atrophy (SMA) is an autosomal

recessive genetic disorder characterised by the degeneration of

motor neurons and progressive muscle weakness. It is caused

by homozygous deletions in the survival motor neuron gene on

chromosome 5. SMA shows a wide range of clinical severity,

with SMA type I patients often dying before 2 years of age,

whereas type III patients experience less severe clinical man-

ifestations and can have a normal life span. Here, we describe

the design, setup and utilisation of the TREAT-NMD national

SMA patient registries characterised by a small, but fully

standardised set of registry items and by genetic confirmation

in all patients. We analyse a selection of clinical items from the

SMA registries in order to provide a snapshot of the clinical

Electronic supplementary material The online version of thisarticle (doi:10.1007/s00415-013-7154-1) contains supplementarymaterial, which is available to authorised users.

C. L. Bladen � R. Thompson � K. Rafferty � V. Straub �K. Bushby � H. Lochmuller (&)

MRC Centre for Neuromuscular Diseases at Newcastle,

Institute of Genetic Medicine, Central Parkway,

Newcastle upon Tyne NE1 3BZ, UK

e-mail: hanns.lochmuller@ncl.ac.uk

C. L. Bladen

e-mail: catherine.bladen@ncl.ac.uk

J. M. Jackson � C. Garland � C. Wegel

Indiana University School of Medicine,

410 West 10th Street, HS4000, Indianapolis,

IN 46202-3002, USA

A. Ambrosini � P. Pisano

Associazione Italiana dei pazienti con malattie neuromuscolari/

Fondazione Telethon-Piazza Cavour 1, 20121 Milan, Italy

M. C. Walter � O. Schreiber

Department of Neurology, Friedrich-Baur-Institute,

Ludwig-Maximilians-University of Munich,

Ziemssenstr. 1a, 80336 Munich, Germany

A. Lusakowska � M. Jedrzejowska � A. Kostera-Pruszczyk

Department of Neurology, Medical University of Warsaw,

Banacha 1a, 02-970 Warsaw, Poland

L. van der Pol � R. I. Wadman

Department of Neurology and Neurosurgery, Rudolf Magnus

Institute of Neuroscience, Brain Center Rudolf Magnus,

University Medical Center Utrecht, Heidelberglaan 100, 3584

CX Utrecht, The Netherlands

O. Gredal

The Rehabilitation Centre for Neuromuscular Diseases,

Kongsvang Alle 23, Arhus C 8000, Denmark

A. Karaduman � H. Topaloglu � O. Yilmaz

Department of Physiotherapy and Rehabilitation Hacettepe,

University Faculty of Health Sciences, 06100Altındag, Ankara,

Turkey

V. Matyushenko

Foundation for Children with Spinal Muscular Atrophy,

Gogolya Street 7, Kharkiv, Ukraine

123

J Neurol

DOI 10.1007/s00415-013-7154-1

data stratified by SMA subtype, and compare these results with

published recommendations on standards of care. Our study

included 5,068 SMA patients in 25 countries. A total of 615

patients were ventilated, either invasively (178) or non-inva-

sively (437), 439 received tube feeding and 455 had had sco-

liosis surgery. Some of these interventions were not available

to patients in all countries, but differences were also noted

among high-income countries with comparable wealth and

health care systems. This study provides the basis for further

research, such as quality of life in ventilated SMA patients, and

will inform clinical trial planning.

Keywords Spinal muscular atrophy � Rare disease �Disease registries � TREAT-NMD

Introduction

Spinal muscular atrophy (SMA) is an autosomal recessive

neurodegenerative disorder of the lower motor neurons.

SMA is caused by homozygous deletions or point mutations

in exon 7 of the telomeric copy of the survival motor neuron

gene (SMN1) at locus 5q13 [1–3]. The SMN gene is present

in two copies on each copy of chromosome 5 (SMN1 and

SMN2). SMA patients generally retain at least one copy of

the centromeric form of the SMN2 gene [4]. SMN2 produces

reduced but varying amounts (10–20 %) of full-length SMN

mRNA, explaining in part the differences in phenotypic

severity (designated types I–III) [5–8]. According to a clin-

ical classification, type I SMA patients never achieve the

ability to sit, type II patients will sit but never walk, and type

III patients will at some time have walking ability [9]. Within

individual SMA subtypes, there is significant phenotypic

variation, such that a mild type II SMA patient and a severe

type III SMA patient might present clinically with a similar

phenotype. Moreover, SMA type III patients may lose

ambulation with disease progression, and then fall into the

same functional group as SMA II patients, ‘‘sitters’’, for

stratification in clinical trials.

Type I SMA (Werdnig–Hoffman disease) presents early,

between birth and 6 months of age. These infants have

profound progressive proximal weakness, usually affecting

the legs more than the arms. They commonly present as

‘floppy’ babies, with poor head control and significant

hypotonia, and are never able to sit independently. Infants

with type I SMA usually develop respiratory failure, with

death occurring by the age of 2. A clinically relevant

increase in survival has been shown with the use of non-

invasive, assisted ventilation [10].

Presentation of type II SMA normally occurs at

6–18 months of age and presents with progressive proximal

weakness and hypotonia. Patients often develop scoliosis,

which, along with increased risk for respiratory disease, leads

to a shortened life expectancy (around 25 years of age) [11].

V. M. Rasic � A. Kosac

Clinic for Neurology and Psychiatry for Children and Youth,

Dr Subotica 6A, 11000 Belgrade, Serbia

V. M. Rasic

Faculty of Medicine, University of Belgrade, Belgrade, Serbia

V. Karcagi � M. Garami � A. Herczegfalvi

Molecular Genetic Department, NIEH, Gyali Str 2-6, Budapest

1097, Hungary

S. Monges � A. Moresco � L. Chertkoff

Pichincha 1881, Hospital Pediatrıa J. P. Garrahan, Buenos Aires,

Argentina

T. Chamova � V. Guergueltcheva

Department of Neurology, Medical University-Sofia, 1 Georgi

Sofiiski Str, Sofia, Bulgaria

N. Butoianu � D. Craiu

Pediatric Neurology Department, Hospital Al. Obregia, Sos.

Berceni No 10-14 Sect 1, Bucharest, Romania

L. Korngut

University of Calgary, Rm 2019, Health Sciences Centre, 3330,

Hospital Drive, NW, Calgary, AB T2N 4N1, Canada

C. Campbell

Shulich School of Medicine and London Health Sciences Centre,

Western University, London, ON, Canada

J. Haberlova

University Hospital in Motol, V Uvalu 84, 150 06 Prague 5,

Czech Republic

J. Strenkova

Institute of Biostatistics and Analysis, Masaryk University,

Kamenice 3, 625 00 Brno, Czech Republic

M. Alejandro � G. G. Ortiz � G. V. G. Enriquez

Asociacion Mexicana de Atrofia Muscular Espinal Guadalajara,

Jalisco Mexico and CUCS, Universidad de Guadalajara,

Guadalajara, Jalisco, Mexico

A. Jimenez � M. Rodrigues � R. Roxburgh

Department of Neurology, Auckland City Hospital, Private Bag

92024, Auckland 1142, New Zealand

H. Dawkins � L. Youngs

Department of Health, Office of Population Health Genomics,

Stirling Street, PO Box 8172, Perth, WA 6849, Australia

J. Lahdetie

Turku University Central Hospital, P.B. 52, 20521 Turku,

Finland

N. Angelkova

Department of Child Neurology, University Hospital for

Children Disease, Skopje, Macedonia

J Neurol

123

Type III SMA (Kugelberg–Welander disease) in most

cases presents much later ([18 months of age). These

patients are able to walk at some point in their lives. They are

affected by progressive proximal weakness but develop little

respiratory muscle weakness or scoliosis. Their life expec-

tancy is generally in line with the general population [11].

SMA is a rare disease (incidence of 1 in every

6,000–10,000 live births) [12, 13] with a heterozygosity

frequency of about 1 in 35 people [14]. Individual countries

have small cohorts of affected patients. Often the patient

cohort is too small for the initiation of clinical trials or for

meaningful statistical analysis of clinical data [15]. As with

other rare diseases, individual groups have therefore opted

to share patient information in the form of patient registries

to increase the overall patient cohorts on which clinical

outcomes and new technologies can be assessed.

TREAT-NMD was initially established as an EU funded

‘network of excellence’ with the remit of ‘reshaping the

research environment’ in the neuromuscular field [15]. Initial

TREAT-NMD milestones for disease specific registries

included: defining the data content for each disease/gene,

defining the regulatory and ethical framework, identifying and

analysing existing national registries, and training curators for

quality control of new and existing registries. The primary

objective for a harmonised set of registries was to allow fea-

sibility assessment, planning, and recruitment for clinical trials.

Secondary objectives included collecting epidemiological

data, establishing genotype-phenotype correlations, defining

the natural history, and assessing treatment outcomes and

standards of care. Information collected followed a mandatory

and highly encouraged set of questions agreed on by the

TREAT-NMD global database oversight committee (TGDOC)

[http://www.treat-nmd.eu/about/governance/tgdoc/].

Similar to the case of other rare diseases, individual

clinicians or centres see only a limited number of SMA

patients. A specific experience with one or a few patients

will not be representative of all patients, meaning that a

lack of experience and exposure may exist before a clini-

cian needs to make an important decision for the well-

being or survival of an SMA patient. Therefore, ‘‘best

practice guidelines’’ or ‘‘standards of care’’ were developed

through an international expert consensus procedure facil-

itated by the International Standards of Care Committee

(SCC) for SMA with the participation and support of

TREAT-NMD. Following a scientific publication (9), they

were translated into 13 languages in addition to English

and converted in lay-friendly language (family guides) for

distribution to families and general practitioners (http://

www.treat-nmd.eu/resources/care-overview/sma/care-

standards-for-sma/). In this study, we utilised the patient

registries to map current care practice in SMA in 25

countries in comparison with the accepted standards of

care, and highlight differences and developments that may

require further research or remedial action.

Methods

National registries for SMA were developed following the

TREAT-NMD registry model of ‘‘minimal’’ datasets for

‘‘maximal’’ uptake to allow for clinical trial ‘‘readiness’’.

We present here a systematic review of the content and

activities of the SMA registry members in August 2012

collected via a comprehensive questionnaire. Twenty-three

of a possible 26 countries with active patient registries

replied to the questionnaire, along with two countries

P. Saugier-Veber � J.-M. Cuisset

Laboratoire de genetique moleculaire, Service de genetique,

Faculte de medecine et de pharmacie de Rouen, 22 Boulevard

Gambetta, 76183 Rouen, France

C. Bloetzer � P.-Y. Jeannet

Paediatric Neurology and Neurorehabilitation Unit, Departement

medicochirurgical de pediatrie - DMCP, University Hospital of

Lausanne, Lausanne, Switzerland

A. Klein

Department of Paediatric Neurology, University Children’s

Hospital, Zurich, Switzerland

A. Nascimento

Hospital Sant Joan de Deu, Barcelona, Spain

E. Tizzano

Hospital de Sant Pau and CIBERER, U-705, Barcelona, Spain

D. Salgado � C. Beroud

INSERM UMR_S910, Aix-Marseille Universite Faculte de

Medecine La Timone, 4eme etage, 27 boulevard Jean Moulin,

41AP-HM, 13385 Marseille Cedex 05, France

D. Salgado

Australian Regenerative Medicine Institute, EMBL-Australia,

Monash University, Clayton Campus, Melbourne, Australia

E. Mercuri

Pediatric Neurology Unit, Catholic University, Rome, Italy

T. Sejersen

Karolinska Institutet, Stockholm, Sweden

J. Kirschner

Department of Paediatric Neurology and Muscle Disorders,

University Medical Centre, Freiburg, Germany

J. Verschuuren

Department of Neurology, Leiden University Medical Centre,

Albinusdreef 2, 2333 ZA Leiden, The Netherlands

C. Beroud

AP-HM, Departement de Genetique Medicale, Hopital

d1enfants, Timone, Marseille, France

J Neurol

123

whose registries are still under construction (Greece and

the Former Yugoslav Republic of Macedonia), for a total of

25 countries representing 24 registries. We go on to

describe a detailed analysis of clinical items from the SMA

registries in order to provide a snapshot of the clinical data

stratified by SMA subtype, i.e. current ambulation status,

age, scoliosis surgery, feeding tube requirement and ven-

tilation status. All data collected meets ethical approval

requirements for each local country, and only non-identi-

fiable, aggregated data was used in our analysis.

Results

Geographical patient demographics

The registries contained 5,068 patients from 25 different

countries. The smallest registry consisted of three patients

(Macedonia) and the largest contained 2,834 patients

(USA) (Fig. 1a). Eighty percent of the registries reported

geographical coverage at the national level, 10 % at the

regional level (a specific region within a country) and 10 %

either at the international or EU level (e.g.). Germany and

Austria have a joint registry.

Functions of the registries

Respondents to the questionnaire (national SMA registry

curators) reported multiple functions of the individual

registries ranging from natural history and epidemiological

research to healthcare services and social planning. The

most frequent use of registries was for clinical research and

recruitment of patients into clinical trials (95 %), epide-

miological research (80 %), natural history surveys and

disease surveillance (80 %), genotype/phenotype analysis

(60 %), and mutation data collection (60 %). Forty percent

Fig. 1 Demographic information from the SMA registries. a Number

of patients in national SMA registries by country. Numbers of patients

in each national registry by country. Data is shown on a log10 scale

and arranged in order of number of patients (highest to lowest).

b Purpose of the registry. The most prevalent use of registries was

clinical research and recruitment of patients to clinical trials (95 %),

epidemiological research (80 %), natural history surveys and disease

surveillance (80 %), genotype/phenotype analysis (60 %), and muta-

tion data collection (60 %). Forty percent of the registries reported

use for social planning and healthcare services planning. c. Age

ranges of SMA patients within the registries. Patients in the SMA

registries were stratified by age range (i.e.) 0–11 months, 1–2, 3–5,

6–9, 10–19, 20–29, 30–39, 40–49, 50–59, 60–69, 70? years. d. SMA

subtype. Patients in the SMA registries were stratified by SMA

subtype, i.e. SMA type I, SMA type II, and SMA type III. ’Highest

motor function unknown’ was also captured in instances where the

registry had been unable to obtain current information regarding a

patient

J Neurol

123

of the registries reported use for social planning and

healthcare services planning (Fig. 1b).

With the exception of the USA (whose registry existed

prior to TREAT-NMD), the respondents reported that their

registry had been established following TREAT-NMD

guidelines, either as part of a research project or following

autonomous initiatives (clinician- or patient-driven).

Funding sources for setting up registries

Responses to the comprehensive questionnaire indicated

that initial funding provided to set up the registries came

from a variety of sources ranging from personal donations

to designated national and regional funding. TREAT-NMD

funded or partially funded a number of national SMA

registries, e.g. Hungary, Italy, the UK, Germany, and

Finland. Thirty-five percent of the registries were funded

by patient organisations, 25 % were funded with national

authority funds, 15 % were set up with money from

foundations, and 25 % were set up with funding from more

than two sources; for example, Mexico received funds from

national authority funding, Mexican Social Security Insti-

tute (IMSS), a university/research institute (Universidad de

Guadalajara), a hospital (Hospital San Javier), and industry

(The Rotary International). The amount of money used for

initial funding of the registries was variable, with some

registries being set up with B3,000€, while others had

funds in excess of 250,000€. The median amount of money

invested to set up a registry was 20,000€. Australia was a

slightly different case, with its initial funding coming from

the Department of Health at the Government of Western

Australia, with guaranteed funding until 2014.

Annual funding of the registries was highly variable,

with 30 % of registries reporting no current annual funding

at all. Fifty percent were funded with 50,000€ or less, 5 %

with 51,000–100,000€, and 15 % with 101,000–200,000€.

The total amount of annual funding for the 24 registries for

1 year (2012) was in excess of 600,000€.

Governance

Our study found that 2/3 of the registries had a governing

board, with the majority of the board being made up of

internal registry staff, e.g. curators (45 %). External

experts and patient organisation representatives were also

represented on the governing boards (40 and 25 %,

respectively).

For the majority of registries, the primary function of the

governing board was to oversee ethical and legal issues,

and to facilitate data access and use by internal and

external researchers (45 and 40 %). Dealing with financial/

administrative issues and the coordination of all parties

involved in the registries was also listed as an important

function of the governing body (15 %). Most governing

bodies reported having all three functions (96 %).

Provision and entry of data

The construction of the TREAT-NMD registry structure

allows individual registries to collect data entered either by

patients, patient organisations, or by clinicians.

Most of the registries obtained data directly from the

patients and their families (35 %) or clinicians (35 %).

Clinical genetics units provided 20 % of the data reported.

Patient organisations provided 10 % of the data collected.

Data entry methods were also variable, with the some

registries capturing data on paper for later entry by registry

staff (55 %), whereas 25 % of data providers directly

uploaded their data online. Data is updated annually in

71 % of registries (17 of 24 that replied).

Utilization of the registries

Third party access to the data in the registries is governed

by a charter, and for international studies, by the TREAT-

NMD oversight committee (TGDOC) [http://www.treat-

nmd.eu/about/governance/tgdoc/]. To obtain access to data,

a third party approaches the TREAT-NMD SMA global

registry with a request for information contained within the

registry. The oversight committee reviews the request and

votes whether or not the request is in line with the charter

and SMA patient interests. A vote of 2/3 is required to

achieve approval. If approval occurs, then the global reg-

istry approaches the national registries and obtains the data

requested. The information is then put into a report, which

is given to the third party company.

In order to further facilitate clinical trial development,

the TREAT-NMD Network established a Care and Trial

Site Registry (CTSR) in December 2007. The TREAT-

NMD CTSR is the largest and most comprehensive data-

base of neuromuscular centres in the world (http://www.

treat-nmd.eu/resources/neuromuscular-centres/ctsr/).

At the national level, the registries had been used for a

total of 15 studies, some registries having only been

involved in one or two studies while others were involved

in[5. Overall, 40 % of registries were used for feasibility

studies, while 60 % of registries were used for recruitment.

International industrial liaison

The registries have been used for clinical trial activities

including one feasibility study and one recruitment study

for a trial in SMA type II/III in Europe.

In 2010, a feasibility study was undertaken to identify

patients and trial sites (through the CTSR) able to recruit

J Neurol

123

non-ambulant SMA type II and III patients aged

3–25 years. A total of 38 trial sites were identified in 19

European countries, and 641 genetically-confirmed SMA

patients were identified as potentially eligible for the study

according to the clinical profiles held by their registries.

In 2011, a recruitment study was undertaken by the

same pharmaceutical company involved in the 2010 fea-

sibility study. Trial sites in Belgium, Germany, Italy, the

Netherlands, Poland and the UK were identified and sup-

ported by the national SMA registries. Registered SMA

patients fulfilling the inclusion criteria of the trial received

targeted information about the study. The company

acknowledged that it met its recruitment target of 150

patients within less than 9 months, which was largely

facilitated through the TREAT-NMD SMA patient regis-

tries, both at the planning stage (feasibility) as well as

during the active trial (recruitment).

Data collected by the SMA registries

Information collected by the registries follows a mandatory

and highly encouraged set of questions agreed on by the

TREAT-NMD global database oversight committee

(Table 1). As a result, information can be shared and

compared between the different national registries, with the

ultimate goal of all national registries eventually linking

into a centralised global SMA registry. It is important to

note that SMA genetic confirmation is obtained for all

SMA patients entering the registries.

‘‘Snap-shot’’ of clinical data held within the SMA

registries

Age

The data in the registries allowed us to analyse the age

ranges of the SMA registry population (Fig. 1c). We found

that a large number of registered patients were children

between the ages of 0 to 19 years [0–1 (284), 1–2 (421),

3–5 (424), 6–9 (523), 10–19 (654)]. After the age of 20,

patient numbers in the registries steadily decreased [20–29

(443), 30–39 (400), 40–49 (397), 50–59 (167), 60–69

(105), 70 ? (32)]. The population represented by the

largest number of patients was ages 10–19 (626).

SMA subtype

The subtype with the smallest number of patients across all

countries represented by the registries was SMA type I

(Fig. 1d). However, since this is the most severe and often

fatal subtype, we have to assume that many of the patients

that would make up this subtype have already died or are

not accounted for in the registry. In terms of incidence

SMA type I is considered to be the most frequently

occurring SMA subtype, reviewed in [16]. We found that

generally, the subtype with the largest numbers of patients

in the registries was SMA type II; examples include

Argentina, Czech Republic, Germany/Austria, Italy, Mex-

ico, New Zealand, Spain, Switzerland, Turkey and

Table 1 Mandatory and

highly-encouraged items

collected in TREAT-NMD

SMA registries

Data collected in all TREAT-NMD SMA registries

Mandatory items Highly encouraged items

Mutation name in SMN1 gene Non-invasive ventilation (yes-all day/

yes-part-time/no/unknown)

Diagnosis (SMA/other/unknown) Invasive ventilation (yes-all day/

yes-part-time/no/unknown)

Currently able to walk (yes/no) Last FVC [%, specify date or (age)

of examination]

Currently able to sit without support (yes/no) Signed up for other registries

[yes (specify)/no/unknown]

Best motor function achieved [Walking

(age at acquisition)/Sitting independently (age at

acquisition)/Never able to walk or sit independently]

Other affected family members

[Yes (specify)/No/Unknown]

Wheelchair use if aged over 3 years

(yes-permanent/yes-intermittent/never/unknown)

SMA classification (I/II or III)

Scoliosis surgery (yes/no/unknown) Number of SMN2 copies

Gastric/nasal tube (yes/no/unknown)

Currently included in clinical trial

Age

Last follow-up (date-day/month/year)

or age (years)

Personal data (pseudonymised before

upload to global system)

J Neurol

123

Ukraine. There were, however, a number of countries

where SMA type III had the largest patient numbers, and

these included Bulgaria, France, Hungary, Poland, Roma-

nia, the USA and the UK (Fig. 1d).

Ventilation in SMA

Ventilation in type I SMA is a controversial and highly

emotive subject among patients, parents and physicians

[17]. While non-invasive ventilation in type I SMA is

generally accepted, either as a treatment option or as a

palliative care option, invasive ventilation remains a dis-

puted subject in type I SMA, since such children are

entirely dependent on a ventilator and significantly dis-

abled [9]. Quality of life issues for these children also arise

[18].

The data in the registries reveal a number of interesting

findings regarding ventilation. Overall, the total number of

patients represented by the registries who received venti-

lator assistance was 615/5,068 (12 %). Of the ventilated

patients, 29 % (178/615) were ventilated using invasive

methods and 71 % (437/615) were ventilated using non-

invasive methods. Of the invasively ventilated patients,

85 % (153/178) were type I SMA patients, 7 % (12/178)

were type II SMA patients and 7 % (13/178) were non-

ambulant type III SMA patients. Of the non-invasively

ventilated patients, 57 % (250/437) were type I SMA

patients, 29 % (127/437) type II and 14 % (60/437) non-

ambulant type III. We observed country specific variations

in the use of invasive ventilation in type I SMA, (Fig. 2a),

with some countries not having any registered patients

using invasive ventilation in their SMA type I patients (e.g.

Bulgaria, Macedonia, Romania, Serbia) while others

reported having patients in their registry using invasive

ventilation. In the countries that did use invasive ventila-

tion in their type I SMA population, we saw considerable

variability (Fig. 2a). For example, in Germany/Austria

3/46 type I SMA patients received invasive ventilation,

compared with 13/44 type 1 patients in Italy. The reason

for this variability is unknown but might reflect differences

in health care systems, availability of specialist care cen-

tres, physician personal preference or social and cultural

considerations. In the UK, 3/83 SMA type I patients were

invasively ventilated, 3/10 SMA type I patients were

invasively ventilated in France, and 88/526 SMA type I

patients in the USA. In Mexico, the entire SMA type I

population on the registry (nine patients) was invasively

ventilated. Argentina and Poland both utilise invasive

ventilation in their SMA I patients (7/14) and (17/46)

respectively. For patients with type I SMA, the largest

number of invasively ventilated patients on the registries is

currently 3-9 years old. This represents 61/917 (7 %) of all

patients currently aged 3-9 years old.

Non-invasive ventilation in type I SMA showed less

variability (Fig. 2a). For example, in Germany/Austria,

18/46 SMA type I patients received non-invasive ventila-

tion, while in Italy, the number was 18/44, in the UK, 16/83

SMA type I patients, in France, 5/10 SMA type I patients,

and in the USA, 167/526 SMA type I patients. Some

Fig. 2 Ventilation in SMA: a Ventilation in type I SMA. Invasive

and non-invasive ventilation described by the registries is shown in

the graph. Countries with no patients reported in the registry using

ventilation in type I SMA include: Bulgaria, Macedonia, Romania

and Serbia. b Ventilation in type II SMA. Invasive and non-invasive

ventilation described by the registries is shown in the graph. Countries

with no patients reported in registry using ventilation in type II SMA

include: Bulgaria, Czech Republic, Hungary, Macedonia, Romania,

Serbia, Switzerland, Turkey, and Ukraine. c Ventilation in non-

ambulant type III SMA. Invasive and non-invasive ventilation

described by the registries is shown in the graph. Countries with no

patients reported in registry using ventilation in type II SMA include:

Bulgaria, Czech Republic, Hungary, Macedonia, Mexico,the Nether-

lands, Romania, Serbia, Switzerland, and Ukraine

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countries were unable to offer non-invasive ventilation to

their type I patients due to absence of equipment (Ukraine).

For patients with type I SMA, the largest number of non-

invasively ventilated patients across all of the registries is

currently 10-19 years old. The USA differs from the other

registries in that it reported large numbers of young chil-

dren that were receiving non-invasive ventilation,

0-11 months (66 patients), and 1–2 years (50 patients).

Ventilation in type II SMA was more uniform and

generally followed the recommended standards of care

guidelines [9] (Fig. 2b). Many registries reported having a

cohort of their type II SMA patients using non-invasive

ventilation (Fig. 2b). Some minor differences were

observed between countries in the use of non-invasive

ventilation for type II SMA patients, e.g. in Germany/

Austria, 6/218 type II SMA patients received non-invasive

ventilation compared with 18/117 for Italy, 20/100 in the

UK, 8/81 in Spain, 14/70 in France, and 60/762 in the

USA. For patients with type II SMA, the largest number of

non-invasively ventilated patients on the registries is cur-

rently 6–19 years old. This represents 95/1,101 (9 %) of

SMA patients currently aged 6–19 years old. Poland,

Argentina, Italy, the Netherlands, France, Spain and the

USA all reported small numbers of type II SMA patients

receiving invasive ventilation (1/66, 1/31, 3/117, 4/80, 2/70

and 2/762).

Our survey only identified a small minority of non-

ambulant type III SMA patients receiving invasive venti-

lation (Fig. 2c): Argentina with 1/27, Poland with 2/47, and

the USA with 8/297. We observed a number of countries

utilising non-invasive ventilation in their non-ambulant

type III SMA populations (Fig. 2c). Finland had 1/2 of

their non-ambulant SMA type III patients using non-inva-

sive ventilation, Germany/Austria reported 4/67, Italy

reported 6/63, the USA reported 40/297, France reported

6/41 and the UK had 2/37.

For patients with non-ambulant type III SMA, the

largest number of non-invasively ventilated patients on the

registries is currently 50–59 years old. This represents

12/163(7 %) of non-ambulant SMA type III patients cur-

rently aged 50–59 years old.

Gastric/nasogastric tubes in SMA (PEG or naso-gastric)

Adequate nutrition is an important consideration in chil-

dren with SMA. Poorly nourished children are more sus-

ceptible to infection and become fatigued easily. Nutrition

is also important for a good quality of life. Therefore, it is

generally recommended that patients with SMA receive

feeding assistance via gastro/nasogastric tube feeding once

decreased feeding and poor nutrition becomes an issue [9].

The registry item on ‘‘tube feeding’’ does not distinguish

between the two different types (nasogastric tube or PEG).

Overall, the total number of patients represented by the

registries who received nutritional assistance through a

feeding tube was 439/5,068 (9 %). Of the patients receiv-

ing feeding tubes, 83 % (366/439) were type I SMA

patients, 13 % (57/439) were type II SMA patients and 4 %

(18/439) were non-ambulant type III SMA patients. We

found that the most prevalent use of gastro/nasogastric tube

feeding was in patients with SMA type I, with much lower

incidence of gastro/nasogastric tube feeding being used in

SMA type II, or in non-ambulant patients with SMA type

III (Fig. 3a–c). We did, however, see country specific

variability in the use of gastro/nasogastric tube feeding in

SMA type I. For example, in Mexico, all nine SMA type I

patients on the registry utilised gastro/nasogastric tube

feeding. In Spain, only 2/81 type I SMA patients received

gastro/nasogastric tube feeding, while in Argentina, Ger-

many/Austria, Italy, Poland, the USA, France and the UK,

9/14, 17/46, 21/44, 17/46, 233/526, 4/10 and 29/83 type I

SMA patients received gastro/nasogastric tube feeding,

respectively. The largest number of SMA I patients on the

registries receiving tube-feeding is currently 3-9 years old,

117/359 (33 %). This represents 117/917(13 %) of SMA

patients currently aged 3-9 years old within the registries.

Countries where gastro/nasogastric tube feeding was not

or only rarely reported for registered patients included

Bulgaria, Czech Republic, Hungary, Turkey, Romania and

Serbia.

Significantly fewer incidences of feeding tube usage

were observed in SMA type II and non-ambulant SMA

type III (Fig. 3), with the largest cohorts being 14/100 for

SMA II in the UK and 50/297 for SMA II in the USA.

Scoliosis surgery in SMA

Scoliosis occurs in many non-ambulant SMA patients. The

consensus statement for standards of care in SMA [9]

recommends the use of scoliosis surgery in patients whose

scoliosis is contributing to respiratory difficulties or pre-

vents comfortable sitting.

Overall, the total number of patients represented by the

registries who received scoliosis surgery was 455/5,068

(9 %). Of the patients receiving scoliosis surgery, 6 % (27/

455) were type I SMA patients, 55 % (254/455) were type

II SMA patients and 38 % (174/455) were non-ambulant

type III SMA patients. We found that scoliosis surgery was

rare in SMA type I patients with only 26 cases being

reported (average age 10-19 years) (Fig. 4a). Scoliosis

surgery was most commonly utilised in patients with type

II or non-ambulant type III SMA (Fig. 4b, c). For example,

in type II SMA the numbers were as follows: Germany/

Austria 20/218, Italy 15/117, Poland 3/47, Turkey 3/31,

France 7/70 and the USA 70/762. A higher rate was

reported for registered patients in Spain, the UK and the

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Fig. 3 Gastro/nasogastric tube feeding: a gastro/nasogastric tube

feeding in type I SMA. Tube feeding described by the registries is

shown in the graph. Countries with no patients reported in registry

using tube feeding in type I SMA include: Bulgaria, Macedonia, New

Zealand, Romania, Serbia and Turkey. b Gastro/nasogastric tube

feeding in type II SMA. Tube feeding described by the registries is

shown in the graph. Countries with no patients reported in registry

using tube feeding in type II SMA include: Bulgaria, Macedonia,

New Zealand, Poland, Romania, Serbia and Switzerland. c Gastro/

nasogastric tube feeding in non-ambulant type III SMA. Tube feeding

described by the registries is shown in the graph. Countries with no

patients reported in registry using feeding in type III SMA include:

Bulgaria, Czech Republic, Hungary, Macedonia, Mexico, the Neth-

erlands, New Zealand, Romania, Serbia, Switzerland, Ukraine and the

UK

Fig. 4 Scoliosis surgery: a Scoliosis surgery in type I SMA. Scoliosis

surgery described by the registries is shown in the graph. Countries

with no patients reported in registry using scoliosis surgery in type I

SMA include: Argentina, Bulgaria, Germany/Austria, Hungary, Italy,

Macedonia, Mexico, the Netherlands, New Zealand, Poland, Roma-

nia, Serbia, Switzerland, Turkey and Ukraine. b Scoliosis surgery in

type II SMA. Scoliosis surgery described by the registries is shown in

the graph. Countries with no patients reported in the registry using

scoliosis surgery in type II SMA include: Argentina, Bulgaria, Czech

Republic, Hungary, Macedonia, Mexico, Romania, Serbia, and

Ukraine. c Scoliosis surgery in non-ambulant type III SMA. Scoliosis

surgery described by the registries is shown in the graph. Countries

with no patients reported in registry using scoliosis surgery in non-

ambulant type III SMA include: Bulgaria, Czech Republic, Hungary,

Macedonia, Mexico, Switzerland and Ukraine

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Netherlands, where 26/81, 43/100 and 49/80 type II SMA

patients received scoliosis surgery, respectively. In non-

ambulant type III SMA, the numbers were as follows:

(Fig. 4), Argentina 2/4, Germany/Austria 20/67, Italy

15/63, Poland 15/49, Serbia 2/8, Turkey 1/6, the Nether-

lands 6/61, France 5/31, the USA, 84/297 and the UK

12/37. The largest number of patients receiving scoliosis

surgery in both type II and type III SMA was 10–19 years

at the time of data capture. This represents 134/597(22 %)

of type/II/III patients currently aged 10–19 within the

registries. A number of countries reported that they didn’t

have any patients who had undergone scoliosis surgery

including: Bulgaria, Hungary, Mexico and Ukraine. Rep-

resentatives from Ukraine, however, expressed that they

had patients in their registry that would benefit from sco-

liosis surgery but that it wasn’t available through local

healthcare provision.

Loss of ambulation in Type III SMA patients

Additional data was requested from the registries (in June

2013) regarding the loss of ambulation in previously

ambulant type III SMA patients (Fig. 5). We analysed the

time interval between initial diagnosis of SMA (confirmed

through genetic testing) and eventual loss of ambulation.

For some older patients within the registries, diagnosis

(genetic testing) was not carried out until many years after

loss of ambulation. Other registries did not collect the date

of diagnosis of SMA or initial onset of symptoms as

requested data fields, and therefore were unable to provide

us with this information. This significantly reduced the

number of cases we were able to analyse. Sample sizes in

the registries that did provide us with loss of ambulation

data were variable, with the smallest cohort being n = 4

and the largest n = 52.

Generally, we observed that loss of ambulation followed a

similar progression for most countries that replied [Argen-

tina (n = 4), Germany/Austria (n = 18), Hungary (n = 5),

Ukraine (n = 16), Switzerland (n = 8), Serbia (n = 10) and

the UK (n = 52)]. We did, however, observe some country-

specific differences, e.g. Argentina, Hungary, Ukraine and

Serbia showed a statistically significant earlier loss of

ambulation than Germany/Austria, Switzerland and the UK

(p = 0.0141). Median time to loss of ambulation (months)

was Argentina (48), Germany/Austria (86), Hungary (48),

Ukraine (40), Switzerland (138), Serbia (54) and the UK

(111). Mean age at loss of ambulation for Ukraine was

9-years-old but for the UK was 19-years-old.

Discussion

To our knowledge, this study reports the largest SMA

patient population to date. The total number of patients

represented by the TREAT-NMD SMA registries was

5,068. The aggregated data from 24 national registries

allowed us to analyse demographics and standardised

medical information (age, SMA subtype, care options) for

a large number of genetically confirmed patients that

wouldn’t have been available using patient data from a

single centre, or indeed multiple centres in a single country.

We have utilised the patient registries to map current care

practices in SMA in the 24 registries in comparison with

each other and with reference to the accepted standards of

care, and highlight differences and developments that may

require further research or remedial action.

The study also highlighted how the registries have been

utilised for research and clinical trial activities.

There are a number of limitations of our study. SMA

type I is the most severe and often fatal subtype [16]. SMA

I patients made up 20 % of the registry population, which

is less than half of the predicted total SMA I population

(thought to represent up to 50 % of the SMA patient

population) [16] and therefore should be considered

underrepresented in the registries. However, it is important

to point out that the 964 type I SMA patients that we have

analysed within this data set still represents the largest

SMA type I cohort to be analysed to date.

The published ‘‘standards of care’’ document for SMA is

likely to undergo change as more is learnt about novel

treatment options, alternative care protocols, natural his-

tory and clinical studies, an example being invasive vs.

non-invasive ventilation in SMA type I. Generally, it is

accepted that non-invasive ventilation should be offered to

Fig. 5 Loss of ambulation in previously ambulant type III SMA: We

analysed the time interval between initial diagnosis of SMA

(confirmed through genetic testing) and eventual loss of ambulation.

Argentina, Hungary, Ukraine and Serbia showed a statistically

significant earlier loss of ambulation than Germany/Austria, Switzer-

land and the UK (p = 0.0141). Median time to loss of ambulation

(months) was Argentina (48), Germany/Austria (86), Hungary (48),

Ukraine (40), Switzerland (138), Serbia (54) and the UK (111)

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SMA type 1 patients in an effort to maintain a reasonable

quality of life (palliative care). However, our analysis has

shown that several countries utilise invasive ventilation in

their SMA type I patient populations (notably the USA).

Understanding both clinical outcome and quality of life

outcomes for these patients may directly affect future

iterations of the standards of care recommendations.

Feeding assistance via gastro/nasogastric tube feeding is

recommended once poor nutrition becomes an issue [9].

Our data have shown that the use of feeding tubes is more

prevalent in Western Europe and the USA than in countries

in Eastern Europe, due primarily to lack of funding in some

countries. This potentially has an impact on both quality of

life and survival outcomes in Eastern European countries.

Scoliosis surgery is recommended in patients whose

scoliosis is contributing to respiratory difficulties or pre-

venting comfortable sitting. Several Eastern European

countries reported that they didn’t offer scoliosis surgery to

their SMA patient population in contrast to Western

European countries and the USA.

Variation from the standards of care guidelines occurs

via many different mechanisms (nationalised/private

healthcare systems, financial constraints, availability of

specialist care, social/cultural attitudes toward life-limiting

diseases, etc.). This study has highlighted a need for a

critical evaluation of the current care practices for SMA

patients globally. Perhaps a research project like the

TREAT-NMD-led CARE-DMD (http://www.treat-nmd.eu/

care/dmd/care-nmd/) should be undertaken for SMA. Fur-

ther research might link standards of care with natural

history and health economic studies in order to provide a

more comprehensive view of the issues surrounding suc-

cessful management of SMA.

Our data highlighted further differences between East-

ern and Western Europe with respect to loss of ambulation

in previously ambulant SMA type III patients. We analysed

the time interval between the initial diagnosis of SMA and

eventual loss of ambulation. Results highlighted country-

specific differences, with patients in Argentina, Hungary,

Ukraine and Serbia showing a statistically significant ear-

lier loss of ambulation than Germany/Austria, Switzerland

and the UK.

Currently, there are a number of countries who have

SMA patient registries either planned or under develop-

ment. Increasing the number of SMA registries will

increase the potential data set upon which further clinical

trials, natural history studies and healthcare planning can

be based. It is clear that the current SMA patient registries

provide an unparalleled resource for patient information,

clinical and academic research, and best standards of care

assurance. The data held within the registries will also be

useful for the development of national plans for rare dis-

ease and associated care and social planning.

Acknowledgments The authors would like to acknowledge the

families of those living with Spinal Muscular Atrophy who have been

instrumental in the formation of the SMA national registries. We also

acknowledge former and current members of the TREAT-NMD office

at the Institute of Genetic Medicine in Newcastle, including Agata

Mertyn, Stephen Lynn and Emma Heslop. We also acknowledge the

members of the current TGDOC: Jan Verschuuren (Chair), Hugh

Dawkins (Chair elect), Anna Ambrosini, Svetlana Artemieva, Alex-

ander N. Baranov, Farhad Bayat, Christophe Beroud, Ria Broekga-

arden, Filippo Buccella, Craig Campbell, Nick Catlin, Monica Ensini,

Pat Furlong, Kevin Flanigan, Ole Gredal, Lauren Hache, Serap Inal,

Jacqueline Jackson, Pierre-Yves Jeannet, Anna Kaminska, A. Ayse

Karaduman, Veronika Karcagi, En Kimura, Janbernd Kirschner, Ja-

ana Lahdetie, Hanns Lochmuller, Vitaliy Matyushenko, Vedrana

Milic-Rasic, Violeta Mihaylova, Marie-Christine Ouillade, Ian Mur-

phy, Miriam Rodrigues, Rosario dos Santos, Pascale Saugier-Veber,

Inge Schwersenz, Thomas Sejersen, Rasha El Sherif, Eduardo Tizz-

ano, Isabela Tudorache, Sylvie Tuffery-Giraud, Jen Wang, Simon

Woods, W. Ludo van der Pol, Peter Van den Bergh, and Petr Vo-

ndracek. We acknowledge funding provided to the national SMA

registries, including: AFM Grant No. 16104, Jennifer Trust for Spinal

Muscular Atrophy (2012), TREAT-NMD: EU FP6 contract number

036825 (2007 to 2011), TREAT-NMD Operating Grant: (2012), VUL

317/2007 (Bulgaria), German Ministry of Education and Research,

MD-NET #01GM0302 (Germany), Italian Association of Patients

with Neuromuscular Diseases (Italy), Neuromuscular Research

Foundation Trust (New Zealand), Ministry of Science and Higher

Education (641/N-TREAT/09/2010/0 and Ministry statutory grant to

the Department of Neurology, Warsaw (Poland), KUKAS (Registry

of Neuromuscular Disorders at Hacettepe) and Association Francais

contre les Myopathies (AFM), Princes Beatrix Spierfonds and the

Spieren voor Spieren Foundation (the Netherlands), Association de la

Suisse Romande et Italienne contre les Myopathies (ASRIM), Fon-

dation Suisse de Recherche sur les Maladies Musculaires (FSRMM)

and Schweizerische Muskelgesellschaft (Switzerland), International

Spinal Muscular Atrophy Patient Registry (Indiana University), which

is supported by Families of SMA (USA), Mexican Social Security

Institute (IMSS) and Instituto Jalisciense de Asistencia Social, Uni-

versidad de Guadalajara, Fundacion Hospitales San Javier, The

Rotary International, Fundacion Atrofia Muscular Espinal (FUN-

DAME Spain), GENAME Project (Hospital Sant Pau, Hospital

Ramon y Cajal, Hospital La Fe, Hospital Virgen del Rocio, Hospital

Sant Joan de Deu and Hospital Valle Hebron), Spain.

Conflicts of interest Professor Hanns Lochmuller was elected chair

of the TREAT-NMD Alliance in April 2012 and is the previous chair

of the oversight committee. Professor Lochmuller has a financial

interest/arrangement with Pfizer, Ultragenyx and GlaxoSmithKline

(Research grant investigator).

Ethical standard Ethical approval was in place for each of the

national registries.

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