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Krabbe Disease

Krabbe Disease. Clinical Experience and Long-term Management . Sphingolipids. Arylsulfatase A. Ceramide. Ceramide. Glucocerebroside. Galactosylcerebroside. Galactosylceramide  -galactosidase. Krabbe disease. Sulfatide.  -Galctosidase. SO 4. Ceramidase. Farber disease.

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Krabbe Disease

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  1. Krabbe Disease Clinical Experience and Long-term Management

  2. Sphingolipids

  3. Arylsulfatase A Ceramide Ceramide Glucocerebroside Galactosylcerebroside Galactosylceramide -galactosidase Krabbe disease Sulfatide -Galctosidase SO4 Ceramidase Farber disease Fatty acid Metachromatic leukodystrophy Sphingosine

  4. Krabbe Disease • Galacotoceramideβ-galactosidase deficiency • Also called Globoid Cell Leukodystrophy • Infantile form (85 – 90%): onset at 6 months and death by 2 years • Extreme 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

  5. 2006 New York State Newborn Screening of Krabbe Disease Began

  6. Referred infants: After NBS Screening • Confirmatory Enzyme Analysis (Dr. David A. Wenger) • Consult with Geneticist/ Child Neurologist • Draw blood sample – e.g. HLA typing • If enzyme test affirms Krabbe disease likely.. • Exam • CSF protein • MRI • Nerve 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

  7. Referred infants -Risk categories GALC ACTIVITY RISK CATEGORY nmol/hr/mg protein 0.0 0.15 High 0.16 0.29 Moderate Eliminated low risk category Jan. 1, 2012 > 0.3 * No Risk • Note that infants found with 2 or more mutations and > 0.3 activity, will be categorized as at moderate risk. Courtesy of Dr. P. Duffner

  8. CRITERIA FOR HCT REFERRAL Consider Transplantation for scores > 4 Points Points 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

  9. New York State Newborn Screening for Krabbe Disease August 7, 2006 to May 31, 2012 Dried Blood Spot 1,556,172 Screened for low GALC Activity Threshold activity ≤12% daily mean High Throughput MS/MS Dried Blood Spot 601 DNA sequencing started 452 sequencing completed 191 low activity polymorphisms Venous Blood & Follow up 261→ Counseling and Venous Confirmation 25 mod. risk 3H labeled - natural substrate 0.3 - 0.5 ηmol/h/mg protein 0.15 - 0.3 ηmol/h/mg protein 12 high risk (4 KD*) 8 “healthy” up to 60 mos 3 → HCT, 1 dead, 1 chronic hemolytic anemia 1 → refused HSCT < 0.15 ηmol/h/mg protein *4KD Predicted to have infantile form Based on genotype and neurodiagnostic testing

  10. Annual Assessments Center Visits • Neurologic Assessment • Neurologic Testing (LP, MRI, BAER, VER, NCT)—high and moderate risk babies only • Cognitive Testing Courtesy of Dr. P. Duffner

  11. Outcomes Study • Phone call interviews: 4, 8, 12, 18, 24 months of age --Ages and Stages Questionnaire --Wee FIM 0-3 --Warner IDEA FS • Early intervention referral as needed • Comparison with annual Bayley III Courtesy of Dr. P. Duffner

  12. Neurological EvaluationNeurodiagnosticYear 1 Q Month Q 3 MonthsHigh Risk Year 2 Q 3 Months Q 6 MonthsYear 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

  13. 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.

  14. 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

  15. High Risk Children/Asymptomatic • p.A5P / p.D232N / p.Y303C // p.A5P / p.D232N / p.Y303C • 6.1% 0.06 nmol/hr/mg protein • p.A5P / p.D232N / p.Y303C / p.I546T // p.D556X • 8.3% 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.

  16. Moderate Risk Children: Genotype examples • p.A5P / p.D232N / p.Y303C // p.A5P / p.D232N / p.T96A • 9.7% 0.18 nmol/hr/mg protein • 30Kb deletion / p.R168C // p.R168C / p.I546T • 7.1% 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.L618S • 8.3% 0.24 nmol/hr/mg protein • p.A5P / p.D232N / p.Y303C // p.A5P / p.D232N / p.Y303C • 8.9% 0.28 nmol/hr/mg protein

  17. What does our DNA data tell us? • 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 • All high risk patients have two mutations (some are novel, some are known to be disease- causing) • Most moderate risk patients (12/18)have two mutations. Hard to predict if someone with two variants will be high or moderate risk • Most low risk patients only have one detected mutation

  18. What constitutes a Diagnosis? Diagnosis Clinical symptoms (or abnormal neurodiagnostic test results) Low Enzyme activity Elevated substrate (currently unknown as not measured) Two known disease causing mutations 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 Dx Positive

  19. Managing Screen Positive Referrals Cross discipline effort is required • 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

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