BioMarin Pharmaceutical Inc., Novato, CA, USA;...

*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