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*For all graphs: age is shown on the X-axis and total number of responses on the Y-axis
0
2
4
6
8
10
12
14
Speak in full sentences
12%
88%
Current
Yes No
30%
70%
Ever
Yes No
MPS IIIA93 (59%)
MPS IIIB43 (27%)
MPS IIIC18 (12%)
MPS IIID3 (2%)
0102030405060
0-5 6-10 11-15 15-20 20-25 25-30 30-40 55+ MoreAge
0 10 20 30 40 50 60 70 80
Failure to achieve development milestones
Speech/language problem
MPS IIID
0 10 20 30 40 50 60 70 80
Speech/language problem
Failure to achieve development milestones
Behavior problem
Sleep problem
Loss of developmental milestones
Other
None of the above
Unsure
Percentage
Chavez E1, Yu C1, Humphrey P1, Wood J2, Clarke S3, Rangel Miller V3, Maricich SM1
1BioMarin Pharmaceutical Inc., Novato, CA, USA; 2Jonah’s Just Begun, Levittown, NY, USA; 3Invitae Corporation, San Francisco, CA, USA
Insights into Sanfilippo syndrome provided by the ConnectMPS Worldwide Online Registry in collaboration with BioMarin and Invitae
Background
Presented at the 15th International Symposium on MPS and Related Diseases: August 2-4, 2018, San Diego, CA ©2018 BioMarin Pharmaceutical Inc. All rights reserved.
Sanfilippo syndrome (Mucopolysaccharidosis type III) is a group of four lysosomal storage diseases (types A, B, C and D) caused by different enzyme deficiencies that lead to accumulation of heparansulfate in the central nervous system and visceral body tissues
Unlike other MPS disorders, Sanfilippo syndrome is characterized chiefly by neurological symptoms starting with developmental delay, behavioral problems and progressive neurodegeneration
The rarity of Sanfilippo syndrome (~1 in every 70,000 births) presents a major impediment to collecting comprehensive information about how it presents and affects patient health
To better understand how Sanfilippo syndrome affects patients and their families we extended ConnectMPS, an online patient registry represented by 27 advocacy organizations, to collect additional data regarding Sanfilippo syndrome
Three survey sections: Demographic, disease history and treatment data: 17
questions about disease presentation and progression (presented here)
Sanfilippo Behavioral Rating Scale (SBRS): an inventory of questions designed to query specific characteristics of the disorder
Lab and other diagnostic data: upload de-identified lab results or enter them into a form
Surveys translated into English, German, Mandarin, Portuguese and Spanish
Survey went live in January 2017 Respondents are from 27 countries Site URL: connectmps.org
Invitae CONNECT Registry PlatformMethods
Demographic data (160 patients)
Results
Significant delays (1-3 years average) exist between symptom onset and Sanfilippo diagnosis
Sanfilippo C and D patients become symptomatic and are diagnosed later than those with A or B
Data agree with previous reports1- 7
Initial symptom
Milestone acquisition and loss
0 10 20 30 40 50 60 70 80 90
Walk independently
Feed self independently
Speak a few words
Dress self with assistance
Feed self with assistance
Speak in full sentences
Walk with assistance
Potty trained
Dress self independently
None of the above
Unsure
Percent Response
Has the participant achieved the following developmental milestones?
N = 160
N = 160Mean = 14 yrsRange = 0-53 yrs
0 10 20 30 40 50 60 70 80
Speech/language problem
Failure to achieve development milestones
Behavior problem
Sleep problem
Loss of developmental milestones
Other
MPS IIIA0 10 20 30 40 50 60 70 80
Speech/language problem
Failure to achieve development milestones
Behavior problem
Sleep problem
Loss of developmental milestones
Other
MPS IIIB
0
5
10
15
20
25
30
Feed self with assistance
0
2
4
6
8
10
12
Potty trained
0
10
20
30
40
50
Speak a few words
0
2
4
6
8
10
12
Dress self independently
0
2
4
6
8
10
12
14
Dress self with assistance
0
10
20
30
40
Feed self independently
Patient age
0 10 20 30 40 50 60 70 80
Speech/language i.e. expressive (talking)
Intellectual disability
Speech/language i.e receptive (hearing/understanding)
Fine motor skills (ability to manipulate small objects)
Gross motor skills (ability to sit, crawl, walk, run, ride abike, etc.)
Behavior
Sleep
Coordination
Difficulty feeding
None of the above
MPS IIIA0 5 10 15 20 25 30 35
Speech/language i.e. expressive (talking)
Intellectual disability
Speech/language i.e receptive (hearing/understanding)
Fine motor skills (ability to manipulate small objects)
Gross motor skills (ability to sit, crawl, walk, run, ride abike, etc.)
Behavior
Sleep
Coordination
Difficulty feeding
None of the above
MPS IIIB
0 2 4 6 8 10 12 14 16
Behavior
Speech/language i.e. expressive (talking)
Intellectual disability
Speech/language i.e receptive (hearing/understanding)
Fine motor skills (ability to manipulate small objects)
Gross motor skills (ability to sit, crawl, walk, run, ride abike, etc.)
Sleep
Coordination
Difficulty feeding
MPS IIIC0 1 2 3 4
Intellectual disability
Behavior
Difficulty feeding
Speech/language i.e. expressive (talking)
Speech/language i.e receptive(hearing/understanding)
Coordination
MPS IIID
0
5
10
15
20
25
Tota
l Num
ber
MPS IIID
MPS IIIC
MPS IIIB
MPS IIIA
Age at symptom onset
0 10 20 30 40 50 60 70 80
Behavior problem
Speech/language problem
Other
Failure to achieve development milestones
Sleep problem
Loss of developmental milestones
MPS IIIC
Sanfilippo subtype representation
Clinical trial participation
The authors thank the patients and caregivers who participated in this study. BioMarin Pharmaceutical Inc. provided funding for the study, data analysis, writing, editing, and poster production.
Acknowledgments The ConnectMPS registry is a rich source of data regarding multiple aspects of Sanfilippo
disease Sanfilippo A and B present and progress in similar fashion, while Sanfilippo C and D show
some key differences (age of onset, age of diagnosis, initial and most prevalent neurological symptoms)
Significant delays in diagnosis continue to exist across subtypes Registry data agree with published reports, supporting the validity of the reporting method
and generalizable nature of the data
Conclusions
Disease presentation with speech/language problems is pervasive across Sanfilippo subtypes
Behavior problems appear earlier in Sanfilippo C than in other subtypes
Presenting symptoms are similar to those described previously1,2,4,6-9
www.bmrn.com/pdf/ISMPS2018p7.pdf
Speech/language problems and intellectual disability are the most common neurological manifestations
Behavior problems are more common in Sanfilippo C and D patients
Neurological symptoms are similar to those described previously1,2,4,6-9
Sanfilippo patients achieve these developmental milestones on time or with a slight delay
Loss of speech milestones occurs first, followed by complex behaviors (dressing, feeding, potty training)
Ambulation is maintained in most patients in this age range
Data agree with previous reports1,6-9
ConnectMPS registry translation to additional languages for increased global participation
Public availability of registry data
Next steps
0 10 20 30 40 50 60 70 80 90
Speech/language (Expressive)Intellectual Disability
Speech/language (Receptive)Fine Motor Skills
Gross Motor SkillsBehavior
SleepCoordination
Difficulty feedingNone of the above
UnsureOther
Percentage
N = 93Mean Age = 19-24 monthsRange= 0-9 yrs
N = 43Mean Age = 12-18 monthsRange = 0-5 yrs
N = 18Mean Age = 5 yrsRange= 1-10+ yrs
N = 3Mean Age = 7 yrsRange= 2-9 yrs
N = 160Mean Age= 19-24 monthsRange = 0 – 9 yrs
N = 160Mean Age= 19-24 monthsRange = 0 – 10+ yrs
N = 93Mean Age = 12-18 months
Range= 0-9 yrs
N = 43Mean Age = 12-18 months
Range= 0-6 yrs
N = 18Mean Age = 4 yrsRange= 1-10+ yrs
N = 3Mean Age = 5 yrs
Range= 1-9 yrs
1. Wjburg FA et al. Acta Paediatr 2013; 102: 462-70. 2. Truxal KV et al. Mol Genet Metab 2016; 119: 239-48. 3. Shapiro EG et al. J Pediatr 2016; 170: 278-87. 4. Buhrman D et al. J Inherit Metab Dis 2014; 37: 431-7. 5. Kuiper GA et al. Orphanet J Rare Dis 2018; 13: 2-14. 6. Héron B et al. Am J Med Gen A 2010; 155A: 58-68. 7. Malm G & Mansson JE. Acta Paediatr 2010; 99: 1253-7. 8. Nidiffer FD & Kelly TE. J Ment Defic Res 1983; 27: 185-203. 9. Delgadillo V et al. Orphanet J Rare Dis 2013; 8: 189-99.
Subtype Mean age at symptom onset (range) Mean age at diagnosis (range)A 25-30 mo (0-9 yrs) 4 yrs (0-10+ yrs)B 25-30 mo (0-6 yrs) 42-47 mo (1-10+ yrs)C 31-35 mo (1-10+ yrs) 6 yrs (1-10+ yrs)D 25-30 mo, 9 and 9 yrs 10, 10+ and 10+ yrs
Age at diagnosis
0
5
10
15
20
Tota
l Num
ber
MPS IIID
MPS IIIC
MPS IIIB
MPS IIIA
Results (continued)
0
10
20
30
40
50
60
70
80
90
Walk independently
0
5
10
15
20
25
30
35
Walk with assistance
Neurological symptoms
References