Neuroimaging Characteristics in Fabry Disease: White Matter Hyperintensity Volume Assessment in...
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Neuroimaging Characteristics in Fabry Disease: White Matter Hyperintensity Volume Assessment in Patients with Fabry Disease Katherine Sims, Kaitlin Fitzpatrick, Danielle Metterville, Natalia Rost, Massachusetts General Hospital, Harvard Medical School, Boston, MA, US Background: Cerebrovascular disease is a significant source of morbidity in patients with Fabry disease (FD). Current markers of central nervous system (CNS) disease burden in FD patients are limited to histories of stroke and transient ischemic attacks (TIA). MRI- detectable white matter hyperintensity volume (WMHV) has been associated with stroke and poor outcome in the general population. We hypothesize that WMHV is a marker of increasing CNS disease burden in FD patients. Methods: We recruited FD patients with one or more MRI scans. Using semi-automated techniques (MRIcro), we calculated the WMHV for each scan. We collected subjects’ medical history through chart review. Results and Discussion: 73 MRIs from 42 subjects (21 females, 21 males) were analyzed. The mean age at MRI was 39.5 years (range 9.6 - 67.9). The mean scans per subject was 1.7 (range 1–5). The mean WMHV was 3.6±4.4 cc, compared to 0.96±1.7 cc in a previously reported control population and 11.15±13.4 cc in a stroke popula- tion. Of the 17 subjects with multiple scans,11 demonstrated stable WMHV, 4 patients had increased WMHV and 2 patients had decreased WMHV. Conclusion: We calculated WMHV in 42 FD patients. The mean WMHV in FD subjects was greater than that of the general population, but lower than a stroke population. We plan to next explore associations between WMHV, treatment status and clinical history. Identifying markers of CNS involvement in FD will be important in characterizing early signs of disease, progression and response to therapy. doi:10.1016/j.ymgme.2011.11.151 Genotype, Disease Onset, And Neurocognitive Phenotype Of Sanfilippo Syndrome Type A Chester B. Whitley a , Renee Cooksley a , Brenda Diethelm-Okita a , Kathleen Delaney a , Patrick Haslett b , Charles Richard b , Elsa Shapiro a , a University of Minnesota, Minneapolis, Minnesota, USA, b Shire Human Genetic Therapies (HGT), Inc., Lexington, Massachusetts, USA Background: Sanfilippo syndrome type A (MPS IIIA) is an autosomal recessive disorder resulting from deficiency of N-sulpho- glucosamine sulphohydrolase (SGSH) which degrades heparan sulfate. SGSH is localized to 17q25.3 and more than 68 mutations have been described. Hypothesis: Genotype is a major determinant of the rate of neurocognitive decline, and will be crucial in assessing future treatments. Materials and Methods: Toward understanding genotype-phenotype correspondence, SGSH mutations were determined in 25 affected children (including 6 sibling pairs) and compared to neurocognitive phenotype. “Age at diagnosis” was examined as a hypothetical proxy for disease severity. Patients underwent appropriate neurodevelopmental testing (Bayley Scales of Infant Development or Kaufman Assessment Battery for Children) yielding a cognitive age equivalent and develop- mental quotient. Results: Study of the 38 alleles revealed several novel mutations: P293S, L12P, L59F, N389S, M376R, A311D, c.220 C>T, and 1272del11. Among the nineteen patients who were diagnosed before age 6 years, most had alleles previously associated with severe disease (R245H, Q380R, S66W, R433Q, E447K, R74C, c.197 C>G, c.734 G>A, and c.1080delC) supporting the idea that age of diagnosis can be used as a proxy for disease severity. One set of siblings had an abnormality in the introns, int7 +1G>C. These patients had exhibited rapid progression, and all were below a developmental level of 28 months. Of the 6 patients diagnosed after the age of 6 years, 2 had one mutation (S298P) previously not associated with an attenuated phenotype and 3 had one mutation not previously described (P293S). Two siblings had an unknown allele (A311D) in combination with a severe mutation (1079delC). One had a severe allele (R245H) and an unknown allele (L59F). Conclusion: A growing catalog of genotype-phenotype correspon- dence will be useful in determining prognosis, and describing the effect of future treatments. (Supported by Shire HGT.) doi:10.1016/j.ymgme.2011.11.152 Identification of Immunodominant Epitopes in N-Acetylgalacto- samine 6-Sulfate Sulfatase (GALNS) for Designing an Effective Peptide-Based Immunotherapy Angela Sosa a , Barbara Kariuki b , Alan Knutsen b , Clifford Bellone c , Luis Barrera d , Shunji Tomatsu e , MontanoAdriana Montaño b , a Saint Louis University / Pontificia Universidad Javeriana, Saint Louis, Missouri, USA, b Saint Louis University, School of Medicine - Department of Pediatrics., St. Louis, MO, USA, c Saint Louis University, School of Medicine -Department of Molecular Microbiology and Immunology, St Louis, MO, USA, d Pontificia Universidad Javeriana, Instituto de Errores Innatos del Metabolismo, Bogotá, Colombia, e Nemours/ Alfred I. duPont Hospital for Children., Wilmington, DE, USA Mucopolysaccharidosis type IVA (MPS IVA) or Morquio syndrome type A is an autosomal recessive disorder caused by mutations in the N-acetyl-galactosamine-6-sulfate sulfatase (GALNS) gene that results in the intralysosomal accumulation of keratan sulfate and chondroitin 6-sulfate. Like other lysosomal storage disorders (LSD), MPS IVA is a good candidate for enzyme replacement therapy (ERT). Preclinical studies for ERT in a Morquio syndrome type A mouse model have been established, and a clinical trial in Morquio syndrome type A patients is being carried out, however, current treatment for MPS IVA patients is not available. The immune response against the infused protein in ERT has been reported as the main obstacle in the effectiveness of the treatment. In the present study, our main goal is to determine the immunodominant sequences in GALNS protein. Two different bioinformatic tools (RANKPEP and Immune Epitope Data Base) were used for the prediction of potential T and B epitopes. Ten predicted peptides were selected and evaluated. Splenocytes of C57BL/6 mice treated by ERT were stimulated with individual peptides to determine cellular proliferation and cytokine secretion (IL-4, IL-5, IL-13 and IFN-α ). Three of the ten peptides elucidated strong cellular responses in the in-vitro assays. The identification of immunodominant peptides will allow the establishment of a peptide- based immunotherapy for Morquio syndrome type A and could be extrapolated to other LSD in which the immune response hinders the development of ERT. doi:10.1016/j.ymgme.2011.11.153 Abstracts / Molecular Genetics and Metabolism 105 (2012) S15–S69 S58
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Transcript of Neuroimaging Characteristics in Fabry Disease: White Matter Hyperintensity Volume Assessment in...
Neuroimaging Characteristics in Fabry Disease: White MatterHyperintensity Volume Assessment in Patients with FabryDisease
Katherine Sims, Kaitlin Fitzpatrick, Danielle Metterville, NataliaRost, Massachusetts General Hospital, Harvard Medical School, Boston,MA, US
Background: Cerebrovascular disease is a significant source ofmorbidity in patients with Fabry disease (FD). Current markers ofcentral nervous system (CNS) disease burden in FD patients arelimited to histories of stroke and transient ischemic attacks (TIA).MRI- detectable white matter hyperintensity volume (WMHV) hasbeen associated with stroke and poor outcome in the generalpopulation. We hypothesize that WMHV is a marker of increasingCNS disease burden in FD patients.
Methods: We recruited FD patients with one or more MRI scans.Using semi-automated techniques (MRIcro), we calculated theWMHV for each scan. We collected subjects’ medical history throughchart review.
Results and Discussion: 73 MRIs from 42 subjects (21 females, 21males) were analyzed. The mean age at MRI was 39.5 years (range9.6 - 67.9). The mean scans per subject was 1.7 (range 1–5). The meanWMHV was 3.6±4.4 cc, compared to 0.96±1.7 cc in a previouslyreported control population and 11.15±13.4 cc in a stroke popula-tion. Of the 17 subjects with multiple scans, 11 demonstrated stableWMHV, 4 patients had increased WMHV and 2 patients haddecreased WMHV.
Conclusion: We calculated WMHV in 42 FD patients. The meanWMHV in FD subjects was greater than that of the generalpopulation, but lower than a stroke population. We plan to nextexplore associations between WMHV, treatment status and clinicalhistory. Identifying markers of CNS involvement in FD will beimportant in characterizing early signs of disease, progression andresponse to therapy.
doi:10.1016/j.ymgme.2011.11.151
Genotype, Disease Onset, And Neurocognitive Phenotype OfSanfilippo Syndrome Type A
Chester B. Whitley a, Renee Cooksley a, Brenda Diethelm-Okita a,Kathleen Delaney a, Patrick Haslett b, Charles Richard b, Elsa Shapiro a,aUniversity of Minnesota, Minneapolis, Minnesota, USA, bShire HumanGenetic Therapies (HGT), Inc., Lexington, Massachusetts, USA
Background: Sanfilippo syndrome type A (MPS IIIA) is anautosomal recessive disorder resulting from deficiency of N-sulpho-glucosamine sulphohydrolase (SGSH) which degrades heparansulfate. SGSH is localized to 17q25.3 and more than 68 mutationshave been described.
Hypothesis: Genotype is a major determinant of the rate ofneurocognitive decline, and will be crucial in assessing futuretreatments.
Materials and Methods: Towardunderstandinggenotype-phenotypecorrespondence, SGSH mutations were determined in 25 affectedchildren (including 6 sibling pairs) and compared to neurocognitivephenotype. “Age at diagnosis”was examined as a hypothetical proxy fordisease severity. Patients underwent appropriate neurodevelopmentaltesting (Bayley Scales of Infant Development or Kaufman AssessmentBattery for Children) yielding a cognitive age equivalent and develop-mental quotient.
Results: Study of the 38 alleles revealed several novel mutations:P293S, L12P, L59F, N389S, M376R, A311D, c.220 C>T, and 1272del11.Among the nineteen patients who were diagnosed before age 6 years,most had alleles previously associated with severe disease (R245H,Q380R, S66W, R433Q, E447K, R74C, c.197 C>G, c.734 G>A, andc.1080delC) supporting the idea that age of diagnosis can be used as aproxy for disease severity. One set of siblings had an abnormality inthe introns, int7 +1G>C. These patients had exhibited rapidprogression, and all were below a developmental level of 28 months.Of the 6 patients diagnosed after the age of 6 years, 2 had onemutation (S298P) previously not associated with an attenuatedphenotype and 3 had one mutation not previously described (P293S).Two siblings had an unknown allele (A311D) in combination with asevere mutation (1079delC). One had a severe allele (R245H) and anunknown allele (L59F).
Conclusion: A growing catalog of genotype-phenotype correspon-dence will be useful in determining prognosis, and describing theeffect of future treatments. (Supported by Shire HGT.)
doi:10.1016/j.ymgme.2011.11.152
Identification of Immunodominant Epitopes in N-Acetylgalacto-samine 6-Sulfate Sulfatase (GALNS) for Designing an EffectivePeptide-Based Immunotherapy
Angela Sosa a, Barbara Kariuki b, Alan Knutsen b, Clifford Bellone c, LuisBarrera d, Shunji Tomatsu e, MontanoAdriana Montaño b, aSaint LouisUniversity / Pontificia Universidad Javeriana, Saint Louis, Missouri, USA,bSaint Louis University, School of Medicine - Department of Pediatrics.,St. Louis, MO, USA, cSaint Louis University, School of Medicine-Department of Molecular Microbiology and Immunology, St Louis,MO, USA, dPontificia Universidad Javeriana, Instituto de Errores Innatosdel Metabolismo, Bogotá, Colombia, eNemours/ Alfred I. duPont Hospitalfor Children., Wilmington, DE, USA
Mucopolysaccharidosis type IVA (MPS IVA) or Morquio syndrometype A is an autosomal recessive disorder caused by mutations in theN-acetyl-galactosamine-6-sulfate sulfatase (GALNS) gene that resultsin the intralysosomal accumulation of keratan sulfate and chondroitin6-sulfate. Like other lysosomal storage disorders (LSD), MPS IVA is agood candidate for enzyme replacement therapy (ERT). Preclinicalstudies for ERT in a Morquio syndrome type A mouse model havebeen established, and a clinical trial in Morquio syndrome type Apatients is being carried out, however, current treatment for MPS IVApatients is not available. The immune response against the infusedprotein in ERT has been reported as the main obstacle in theeffectiveness of the treatment. In the present study, our main goal isto determine the immunodominant sequences in GALNS protein. Twodifferent bioinformatic tools (RANKPEP and Immune Epitope DataBase) were used for the prediction of potential T and B epitopes. Tenpredicted peptides were selected and evaluated. Splenocytes ofC57BL/6 mice treated by ERT were stimulated with individualpeptides to determine cellular proliferation and cytokine secretion(IL-4, IL-5, IL-13 and IFN-α ). Three of the ten peptides elucidatedstrong cellular responses in the in-vitro assays. The identification ofimmunodominant peptides will allow the establishment of a peptide-based immunotherapy for Morquio syndrome type A and could beextrapolated to other LSD in which the immune response hinders thedevelopment of ERT.
doi:10.1016/j.ymgme.2011.11.153
Abstracts / Molecular Genetics and Metabolism 105 (2012) S15–S69S58
![Natural history of Fabry disease in females in the Fabry ... · Fabry disease is 1 in 117 000 male live births,[2] though estimates vary from 1 in 40000 to over 1 in 400 000. Fabry](https://static.fdocuments.net/doc/165x107/5f410e03f751a3285a719c0d/natural-history-of-fabry-disease-in-females-in-the-fabry-fabry-disease-is-1.jpg)
