Newborn Screening for Pompe Disease in New York State ...
Transcript of Newborn Screening for Pompe Disease in New York State ...
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September 10, 2016
Newborn Screening for Pompe Disease in New York State: Outcomes and the Role of Long-term Follow-upBeth Vogel, MS, CGC
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Pilot Main Objectives
1. Validate and implement screening for Pompe disease 2. Determine confirmatory tests and procedures for out-of-range results3. Perform short-term follow-up and track positive cases 4. Begin a mechanism to ensure individuals who are confirmed with Pompe
disease are followed long-term to assess natural history and treatment outcomes
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NYS NBS Pompe Advisory Committee
Priya KishnaniUsha KrishnanDavid KronnMelissa WassersteinPatrick HopkinsDeeksha BaliSarah YoungChunli Yu
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Main Objectives
1. Validate and implement screening for Pompe disease October 1, 2014 to May 25, 2016
2. Determine confirmatory tests and procedures for out-of-range results3. Perform short-term follow-up and track positive cases 4. Begin a mechanism to ensure individuals who are confirmed with Pompe
disease are followed long-term to assess natural history and treatment outcomes
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Cutoffs and Testing Algorithm
All specimens tested for Enzyme activity
> 20% of daily mean< 20% of
daily mean
Retested in duplicate (or more)
Average of 3 samples > 15%
(GAA/IDUA)
Average of 3 samples≤ 15%(GAA/IDUA)
Screen negative
Screen PositiveReferral
DNA testing GAA
1 or more mutations No mutationsSlide from J. Orsini
364,555 Infants
67 infants
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Main Objectives
1. Validate and implement screening for Pompe disease 2. Determine confirmatory tests and procedures for out-of-range results3. Perform short-term follow-up and track positive cases 4. Begin a mechanism to ensure individuals who are confirmed with Pompe
disease are followed long-term to assess natural history and treatment outcomes
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Special considerations:
· If clinical symptoms are present, infant
should be evaluated for Pompe disease
regardless of mutation status
· Cardiac evaluation should include a
minimum of an echo and EKG
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Pompe Disease Management Recommendations
1. Recommendations for Determining Cross Reactive Immunologic Material
(CRIM) Status
2. Recommendations & Considerations for Initiating ERT
3. Table 1. Evaluations for Monitoring of Asymptomatic Patients with Pompe
Disease
4. Table 2. Evaluations for Monitoring of Symptomatic Individuals with Pompe
Disease
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Main Objectives
1. Validate and implement screening for Pompe disease 2. Determine confirmatory tests and procedures for out-of-range results3. Perform short-term follow-up and track positive cases 4. Begin a mechanism to ensure individuals who are confirmed with Pompe
disease are followed long-term to assess natural history and treatment outcomes
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Classification GAA Mutation Analysis Number of infants
Infantile-onset Pompe 2 variants + symptoms 2
Probable Late-onset Pompe 2 known pathogenic variants 12
Possible Late-onset Pompe 1 known pathogenic variant + 1 VOUS
12
Uncertain significance 2 VOUS 7
Carrier 1 known pathogenic mutation or 1 VOUS
13
1 known pathogenic mutation or 1 VOUS + pseudodeficiency allele(s)
21
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Main Objectives
1. Validate and implement screening for Pompe disease 2. Determine confirmatory tests and procedures for out-of-range results3. Perform short-term follow-up and track positive cases 4. Begin a mechanism to ensure individuals who are confirmed with Pompe
disease are followed long-term to assess natural history and treatment outcomes
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Classification GAA Mutation Analysis Number of infants
Infantile-onset Pompe 2 variants + symptoms 2
Probable Late-onset Pompe 2 known pathogenic variants 12
Possible Late-onset Pompe 1 known pathogenic variant + 1 VOUS
12
Uncertain significance 2 VOUS 7
Carrier 1 known pathogenic mutation or 1 VOUS
13
1 known pathogenic mutation or 1 VOUS + pseudodeficiencyallele(s)
21
Role of Long-term Follow-up
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Role of Long-term Follow-up
• Public health Implications
– Calculating positive predictive value
– Without LTFU - assume all potential LOPD
cases will develop symptoms
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Role of Long-term Follow-up
• Clinical Implications
– Variants of unknown significance
– Decisions on monitoring and treatment
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• p.V222M variant - 7 referrals
• 2 infants were homozygous
• diagnostic GAA enzyme analysis: low GAA enzyme activity, but
slightly above the late-onset disease range
• The Erasmus MC GAA mutation database: variant is non-
pathogenic
• based on in vitro studies of GAA enzyme activity using site-
directed mutagenesis and transient expression in cell lines
(Kroos et al., 2012).
• Long-term follow-up to determine whether this variant is pathogenic or a pseudodeficiency allele
Variants of Unknown Significance
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Case Study: Zoe• Abnormal screen reported at 7 DOL
• GAA activity – 6.2%
• Genotype: Late onset / Infantile
• Diagnostic GAA results: 15.0 (Range: 67.7-706.4)
• Pediatrician and metabolic specialist: No symptoms noticed; cardiac evaluation normal
• Physical therapist (specializing in neuromuscular disorders): Some subtle delay identified
• What’s next for Zoe?
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Case Study: Megumi• Abnormal screen reported at 10 DOL
• GAA activity – 9.2%
• Genotype: Late onset / Variant of unknown significance + pseudo deficiency allele
• Diagnostic GAA results:
• 3.8 (Range: 67.7-706.4)
• 1.7 (Range: > 3.88)
• No symptoms; cardiac evaluation normal at of 6 months of age
• What’s next for Megumi?
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Long-term Follow-up Process
Identify Data Elements
IRB approval and data collection
tool
Consent and data collection
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NBSTRN Resources
Identify data elements –List developed by panel
of experts led by NBSTRN
Data collection tool –Longitudinal Pediatric
Data Resource
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Status of LTFU for Pompe in NYS
• IRB approval from NYS DOH
• Working through IRB at each institution (9)
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Barriers to LTFU Implementation
• IRB approval – Multi-site study
• Consent
• Data collection
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Acknowledgements
NYS NBS Program
• Michele Caggana
• Joseph Orsini
• Erin Hughes
• Colleen Stevens
• Sarah Bradley
NYS NBS Pompe Advisory Committee
• Priya Kishnani
• Usha Krishnan
• David Kronn
• Melissa Wasserstein
• Patrick Hopkins
• Deeksha Bali
• Sarah Young
• Chunli Yu
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Thank you