Krabbe Disease Clinical Experience and Long-term Management.
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Transcript of Krabbe Disease Clinical Experience and Long-term Management.
Krabbe DiseaseClinical Experience and
Long-term Management
Sphingolipids
Glucocerebroside
Farber disease
Ceramidase
Sphingosine
Fatty acid
-Galctosidase
Ceramide
Galactosylcerebroside
Galactosylceramide -galactosidase
Krabbe disease
Arylsulfatase AMetachromatic leukodystrophy
Sulfatide
CeramideSO4
Krabbe Disease
Galacotoceramide β-galactosidase deficiency Also called Globoid Cell Leukodystrophy Infantile form (85 – 90%): onset at 6 months
and death by 2 yearsExtreme irritability
Spastic quadriparesis
Blindness with optic atrophy
CNS infiltration with globoid cells (inflammatory reaction)
Late onset form (10 – 15%): onset between 1 year and 5th decade
2006 New York State
Newborn Screening of Krabbe Disease Began
Referred infants: After NBS Screening
• Confirmatory Enzyme Analysis (Dr. David A. Wenger)Consult with Geneticist/ Child NeurologistDraw blood sample – e.g. HLA typing
• If enzyme test affirms Krabbe disease likely..ExamCSF proteinMRINerve conduction, BAER, VER, and other studies
recommend periodic evaluation, depending on dx lab enzyme activity level
• A point system is used, if 4 or more points:Consideration given to receive cord blood treatment
Referred infants - Risk categories
GALC ACTIVITY RISK CATEGORYnmol/hr/mg protein
0.0 0.15 High
0.16 0.29 Moderate
Eliminated low risk category Jan. 1, 2012
> 0.3 * No Risk
Courtesy of Dr. P. Duffner
• Note that infants found with 2 or more mutations and > 0.3 activity, will be categorized as at moderate risk.
CRITERIA FOR HCT REFERRAL
Consider Transplantation for scores > 4 PointsPoints
• Abnormal Neurologic Exam 2• Abnormal MRI 2• Abnormal LP (Increased Protein) 2• Abnormal NCV 1• Abnormal BAER 1• Abnormal VER 1• 30 KB Homozygous Deletion 4
8
New York State Newborn Screening for Krabbe Disease August 7, 2006 to May 31, 2012
1,556,172 Screened for low GALC ActivityThreshold activity ≤12% daily mean
High Throughput MS/MS
601 DNA sequencing started452 sequencing completed191 low activity polymorphisms
261→ Counseling and Venous Confirmation
25 mod. risk
12 high risk(4 KD*)
3H labeled - natural substrate0.3 - 0.5 ηmol/h/mg protein0.15 - 0.3 ηmol/h/mg protein
DriedBloodSpot
DriedBloodSpot
VenousBlood &Follow up
8 “healthy” up to 60 mos3 → HCT, 1 dead, 1 chronic hemolytic anemia 1 → refused HSCT
< 0.15 ηmol/h/mg protein
*4KD Predicted to have infantile formBased on genotype and neurodiagnostic testing
Annual Assessments
Center VisitsNeurologic Assessment
Neurologic Testing
(LP, MRI, BAER, VER, NCT)—high and moderate risk babies only
Cognitive Testing
Courtesy of Dr. P. Duffner
Outcomes Study
Phone call interviews: 4, 8, 12, 18, 24 months of age--Ages and Stages Questionnaire
--Wee FIM 0-3
--Warner IDEA FSEarly intervention referral as neededComparison with annual Bayley III
Courtesy of Dr. P. Duffner
Neurological Evaluation Neurodiagnostic
Year 1 Q Month Q 3 MonthsHigh Risk
Year 2 Q 3 Months Q 6 Months
Year 1 Q 3 Months AnnualMod Risk
Year 2 Q 3 Months Annual
Year 1 Q 6 Months Annual*Low Risk
Year 2 Q 6 Months Annual*
EVALUATION SCHEDULE
12
Referred Infants: Follow-up Schedule
• Low rate of compliance (unsure of percentage): • Neurodiagnostic testing is evasive• Cultural issues• Asking families to participate in long-term follow-up
activities when the child is considered healthy
• Compliance with phone call interviews is much better (unsure of percentage)
• Need some other less evasive tool to assess and monitor risk of biochemically enzyme deficient individuals.
From Screening: High-risk, infantile KD
1. g.30 Kb deletion // p.X670Qext42 [TP]9.9% 0.01 nmol/hr/mg protein
2. g.30Kb deletion // g.30 Kb deletion [TP]10.9% 0.05 nmol/hr/mg protein
3. g.30Kb deletion // g.30 Kb deletion [parents refused TP; symptomatic]7.6% 0.02 nmol/hr/mg protein
4. g.30Kb deletion // p.A5P/ G360DfsX2 [TP]5.6% 0.12 nmol/hr/mg protein
High Risk Children/Asymptomatic
p.A5P / p.D232N / p.Y303C // p.A5P / p.D232N / p.Y303C6.1% 0.06 nmol/hr/mg protein
p.A5P / p.D232N / p.Y303C / p.I546T // p.D556X8.3% 0.12 nmol/hr/mg protein
Genotype/phenotype correlations are very difficult;Examples of point mutations associated with infantile KD:
Y551S, T513M , Y287F, R380L
Major difficulty: If low GALC activity and DNA variants of unknown significance, how do we determine who is a candidate for cord blood transplant? Currently use exam, MRI, CSF Protein, and other neurodiagnostic tests to assess.
Moderate Risk Children: Genotype examples
p.A5P / p.D232N / p.Y303C // p.A5P / p.D232N / p.T96A9.7% 0.18 nmol/hr/mg protein
30Kb deletion / p.R168C // p.R168C / p.I546T7.1% 0.26 nmol/hr/mg protein
c.-335G>A / p.P73L / p.I546T // g.30Kb deletion / p.R168C 9.8% 0.29 nmol/hr/mg protein
p.L618S / p.D445A // p.L618S8.3% 0.24 nmol/hr/mg protein
p.A5P / p.D232N / p.Y303C // p.A5P / p.D232N / p.Y303C8.9% 0.28 nmol/hr/mg protein
What does our DNA data tell us?
1. All patients that were determined to have infantile Krabbe disease have two mutations, which would be considered to be pathogenic.- This doesn’t mean this will always be the case- Some pathogenic mutations that are not obvious examples: Y551S, T513M , Y287F, R380L
2. All high risk patients have two mutations (some are novel, some are known to be disease- causing)
3. Most moderate risk patients (12/18) have two mutations. Hard to predict if someone with two variants will be high or moderate risk
4. Most low risk patients only have one detected mutation
What constitutes a Diagnosis?
Diagnosis
Low Enzyme activity
Elevated substrate(currently unknown as not measured)
Two known disease causing mutations
Clinical symptoms (or abnormal neurodiagnostic test results)
In newborn screening, by definition, the child is asymptomatic, if low GALC activity, and one or two variants in DNA of unknown significance, need more information
• Involve treatment centers early – to get buy-in and determine steps to diagnose
- Determine best mechanism for communicating a screen positive result! Varied communications lead to varied compliance with follow-up.
- If possible, determine exactly how the patient will be evaluated, and steps to be taken to treatment.
• Involve neurologists-not always linked to TCs
• Involve transplant physicians
• Engage payers / Public and Private
Managing Screen Positive ReferralsCross discipline effort is required