- Email: [email protected]
Enzyme Therapy
Abstracts / Molecular Genetics and Metabolism 105 (2012) S15–S69
Objective: There is currently no recognised method for the measurement of LAL in DBS. Our aim was to develop a method using DBS and validate the technique using samples from patients with CESD. Methods: LAL was extracted from DBS with distilled water and incubated with 4 mU-palmitate in acetate buffer pH 4.0 and cardiolipin as an activator of LAL. Lalistat 2 was used as a specific inhibitor of LAL and activity estimated by measuring total lipase activity and lipase activity in the presence of Lalistat 2. LAL activity was determined by subtracting activity measured in the inhibited reaction from that in the uninhibited reaction. The assay was performed using 96 well plates and read at 355 nm/460 nm. Results: LAL activity in normal controls was 1.70 – 3.40 umol/l/hr. Samples from patients with confirmed CESD had significantly reduced LAL activity - <0.05 umol/l/hr. Activity in carriers was in the range 0.73-1.02 umol/l/hr. Conclusions: Measurement of LAL using DBS is made difficult by the presence of other forms of lipase in whole blood. Lalistat 2 is a specific inhibitor of LAL which allows the reliable determination of LAL in DBS. Results show the method differentiates clearly between normal controls, carriers and affected cases. doi:10.1016/j.ymgme.2011.11.068
Multiparametric 3.0 Tesla MRI of the Brain in Fabry Disease Eric Hanson a, e, Jonathan Bernstein b, Cayce Roach c, Priya Simonelli d, Daniel Morris d, Kathyrn Lowery d, William Orrison a, f, g, aTier 7 Research and Development, Las Vegas, NV, USA, bChildren's Center for Cancer, Las Vegas, USA, cTemple University School of Medicine, Philadelphia, USA, dTouro University Nevada, Las Vegas, USA, eUniversity f of Nevada Las Vegas, Las Vegas, USA, Advanced Medical Imaging and Genetics, Inc. (Amigenics), Las Vegas, USA, gCHW Nevada Imaging Company, Las Vegas, USA Purpose: This study was performed to identify incremental diagnostic information that can be captured with multi-parametric MRI studies of the brain in patients with Fabry disease (FD). A secondary goal was the clinical utilization of a checklist of MRI brain findings in FD developed based on a literature review to assist readers in capturing the complex findings of this disease. Materials and Methods: Five cases (n = 3 male) with FD (age range19-48 years) were evaluated on a 3.0 T MRI system with the following protocols: structural MRI, diffusion tensor imaging (DTI) of the corpus callosum, multi-voxel brain MR spectroscopy (MRS), and noncontrast-enhanced MR angiography (NCE-MRA). Results: Novel findings of hippocampal atrophy (n = 2), fornix atrophy (n = 2), and abnormal quantitative corpus callosum DTI findings (n = 5) were identified. At least one white matter lesion was present in all patients. Basilar artery dolichoectasia (n = 1) and middle cerebral and basilar artery ectasia (n = 1) were identified in separate patients. NCE-MRA identified bilateral fetal origin posterior cerebral arteries in one male patient. Periventricular leukoencephalopathy in the parietal lobe was identified in one female patient. Abnormal choline MRS values were identified in all patients. Conclusions: Improved clinical assessment of patients with FD can be accomplished using a multiparametric imaging including structural 3 T MRI, DTI, NCE-MRA, and MRS. In addition, utilization of a FD Brain MRI checklist assisted researchers in the assessment of the heterogeneous and numerous abnormalities, and reading fo the images obtained in this pilot study. The novel findings of hippocampal atrophy, fornix atrophy, and abnormal corpus callosum DTI findings warrant further study. doi:10.1016/j.ymgme.2011.11.069
S33
Mucopolysaccharidosis VI (Maroteaux-Lamy Syndrome): Development of Clinical and Laboratory Guidelines for Diagnosis Paul Harmatz 1, Children's Hospital & Research Center Oakland, Oakland, California, USA Mucopolysaccharidosis (MPS) VI is a lysosomal storage disease in which deficient N- acetylgalactosamine 4-sulfatase (arylsulfatase B, or ASB) impairs degradation of dermatan sulfate. Accurate diagnosis is critical to ensure that patients receive appropriate enzyme replacement therapy. Review of laboratory tests for mucopolysaccharidoses and their use in diagnosis of MPS VI was the topic of a recent expert panel meeting, inclusive of clinicians and laboratory directors. Clinicians completed a survey on MPS VI diagnosis practices. There was consensus on the requirement to evaluate ASB enzyme activity to obtain a final diagnosis. While the reported use of additional tests was variable, such as urinary glycosaminoglycans (uGAG) analysis (qualitative and quantitative), molecular testing, and multiple lysosomal enzymes testing, it was recommended that these laboratory tests be included as part of diagnosis of MPS VI. All participants emphasized the importance of direct communication between the diagnostic laboratory and clinician. In addition to high clinical suspicion, diagnosis of MPS VI requires quality results from tests run at laboratories with expertise in MPS testing and result interpretation. The use of multiple specimens and tests, such as qualitative and quantitative uGAG, multiple lysosomal enzyme activities, and molecular testing, when possible, was the unanimous recommendation of the panel. *MPS VI Laboratory Diagnostic Scientific Summit participants: Bodamer O, Burin MG, D'Almeida V, Eng CM, Fietz M, Giugliani R, Harmatz P, Hendriksz CJ, Hwu WL, Ketteridge D, Lukacs Z, Mendelsohn NJ, Miller N, Pasquali M, Schenone A, Schoonderwoerd K, Winchester B, Wood T. 1
On behalf of the participants at the MPS VI Laboratory Diagnostics Scientific Summit.
doi:10.1016/j.ymgme.2011.11.070
Large Animal Models of Lysosomal Storage Diseases: Lessons on the Limits of Gene/Enzyme Therapy Mark Haskins a, Meg Sleeper a, Gus Aguirre a, Steven U. Walkley b, Van Knox a, Charles Vite a, Richard Steet c, Brittney Gurda a, Jim Wilson a, Alberto Auricchio d, Lachlan Smith a, Lilla Simonaro e, Katherine Ponder f, aUniversity of Pennsylvania, Philadelphia, Pennsylvania, USA, b Albert Einstein College of Medicine, Bronx, New York, USA, cUniversity of Georgia, Athens, Georgia, USA, dTelethon Institute Of Genetics And Medicine, Naples, Italy, eMount Sinai Medical Center, New York, NY, USA, f Washington University in St. Louis, St. Louis, Missouri, USA Dog and cat orthologs of human genetic disease provide the opportunity to investigate the pathogenesis of these disorders and test therapeutic efficacy and toxicity in large species with naturally occurring disease. The long-lived large species, for which there are board-certified clinical specialists and sophisticated techniques to evaluate disease including echocardiography and magnetic resonance imaging, provide an important intermediate step in translational medicine from the mouse to mankind. A group of investigators have collaborated to treat dogs and cats with various lysosomal storage diseases including mucopolysaccharidosis (MPS) I, VI, and VII, alphamannosidosis, and Niemann Pick disease type C. Many were treated using retroviral and adeno-associated viral vectors from 3 days to 60 days of age. Serum enzyme activities have ranged from 10% of normal to 60-fold normal, has been maintained for up to 11 years in some animals, and has produced some significant improvements in
S34
Abstracts / Molecular Genetics and Metabolism 105 (2012) S15–S69
clinical phenotype and quality of life. Yet, in spite of constant circulating mannose 6-phosphorylated enzyme, lesions persist, particularly in the cervical spine and cardiovascular system in MPS and in the CNS in alpha-mannosidosis. Having recognized limitations with enzyme therapy, we now need to understand why these limitations exist and develop methods to circumvent them. This will include understanding the pathogenicity of the stored substrates, including the production of an inflammatory response, and testing combination therapies to improve the clinical outcome of enzyme therapy alone. doi:10.1016/j.ymgme.2011.11.071
Intrathecal Hydroxy-Propyl-Beta-Cyclodextrin Reverses Hearing Loss in Identical Twin Girls with Niemann-Pick Type C Disease Caroline Hastings, Joseph Torkildson, Robert Raphael, Children's Hospital & Research Center Oakland, Oakland, CA, USA Niemann-Pick type C (NPC) disease is a rare, fatal, autosomal recessive neurodegenerative disorder characterized by widespread intracellular accumulation of unesterified cholesterol and glycosphingolipids. To date, no medical intervention has received regulatory approval in the USA to treat this disorder. Hydroxypropyl-beta-cyclodextrin (HPBCD) is a sugar compound shown to reverse cholesterol trafficking defects in murine and feline NPC models and significantly lengthen life expectancy. We began administration of intravenous (IV) infusions of HPBCD under the FDA's Individual IND exemptions. Our patients, aged 5 years 2 months, had loss of developmental milestones (speech and communication) and were ataxic. We observed no toxicities related to the therapy. HPBCD does not cross the blood–brain barrier in mice, and based on promising animal data with CNS directed delivery demonstrating complete reversal or prevention of neurodegeneration and prolongation of life, we amended our protocol to administer HPBCD directly into the CNS. Treatment with intrathecal (IT) HPBCD was initiated at a dose of 175 mg (later increased to 350 mg) administered every 2 weeks by lumbar puncture. Again, no toxicites have been observed. We have seen significant clinical improvement utilizing a previously validated NIH NPC Clinical Severity Score. The most draumatic improvement was in hearing, as assessed by brainstem auditory evoked response, which improved from moderate-severe loss at baseline to normal-very mild loss (normal range) following 6 months of directed CNS therapy. This combination of systemic and central nervous system HPBCD drug delivery provides a promising new therapeutic approach for children with NPC to target every organ affected. doi:10.1016/j.ymgme.2011.11.072
Serial ECG, Echocardiography and Holter Monitoring in Children with Anderson-Fabry Disease Stepan Havranek a, Ales Linhart a, Uma Ramaswami b, aFirst Faculty of Medicine, Charles University and General University Hospital Prague, Czech Republic, bPaediatric Metabolic Unit, Box 181, Addenbrooke's Hospital, Cambridge, UK E-mail address: [email protected] (U. Ramaswami). Objective: Cardiac manifestations are common in adults with Anderson Fabry disease (AFD). We evaluated early cardiac manifestations in children with a confirmed diagnosis of AFD. Methods: This was a retrospective review of data from 21 children (11 male; mean age 9.6 ±4.6y) from a single site in Cambridge, UK.
Echocardiography, ECG and ECG monitor data including heart rate variability (HRV) parameters taken during routine clinical reviews (maximum of four year follow up) were analysed and divided into groups 1 and 2, based on very low or normal/mildly reduced enzyme activity respectively. Results: Mean left ventricle (LV) mass in group 1 (N = 12) differed significantly from group 2 (N = 9) at baseline (75.4 ± 8.9 vs. 55.6 ± 6.6 g/m2, p = 0.02). Group 1 showed progressive increase in LV hypertrophy ECG parameters (Sokolow voltage 2.9 ± 1.03 vs. 1.74 ± 0.51 mV, p = 0.04) with significant shortening of PR interval over two years (137 ± 8.6 vs. 156 ± 22 ms; p = 0.033). No diferences between groups was detected in conduction intervals at follow up and there were no clinically significant arrhythmias. Baseline HRV parameters were reduced in group 2 (rMSSD: 62.6 ± 20.3 vs. 39.0 ± 25.8, p = 0.05; pNN50: 36.9 ± 13.9 vs. 24 ± 10.6, p = 0.05) and remained unchanged after two years of follow-up. Conclusions: Low residual enzyme activity may predict early progression of cardiac disease in AFD, with ECG evidence of progressive LV hypertrophy and LV mass, with significantly shorter PR interval, emphasising the importance of regular and early follow up of children with AFD.
doi:10.1016/j.ymgme.2011.11.073
Cardiac Ultrasound Findings in Sanfilippo Syndrome Type A Brandon Hays, Elizabeth Braunlin, James Berry, Brenda Diethelm-Okita, Chester Whitley, University of Minnesota, Minneapolis, MN, USA Background: Although the incidence of cardiac abnormalities in Sanfilippo syndrome type A (MPS IIIA) is thought to be low, case reports suggest that, if present, such abnormalities may be severe and clinically significant. Methods: As part of a natural history study (Clinicaltrials.gov NCT01047306), we performed and reviewed cardiac ultrasounds in 24 youngsters with MPS IIIA and compared the results to subjects’ genotypes. Left ventricular end-diastolic dimension (LVEDD), left ventricular posterior wall (LVPWD) and septal (IVSD) thicknesses in diastole were measured and normalized to body surface area by zscores, positive z-scores indicating standard deviation (SD) values greater than normal. The presence of aortic or mitral valve thickness, regurgitation or stenosis was noted. Results: There were 8 female and 16 male subjects, average age 6.7 ± 4.5 (range 1.8 -18) years. Cardiac abnormalities were identified in 22/24 (92%) subjects. Left ventricular hypertrophy (z-score 2SD > normal) occurred in 14/24 (58%). Valve thickening occurred in 8/24 (33%) subjects: mitral only (N = 8); aortic only (N = 4); mitral and aortic (N = 3). Mild mitral regurgitation occurred in 1 subject; moderate to severe aortic regurgitation occurred in 2/24 (8%) subjects. Mutation R245H was present in 4/7 subjects with valve thickening and in 5/17 without this mutation (p = 0.35). Moderate to severe aortic regurgitation was present in two 7-year olds: both were heterozygous for mutation R245H. Conclusions: Cardiac abnormalities are common in young children with MPS IIIA. Given the developmental delays in the children, symptoms may go under-reported. Therefore, routine echocardiography is indicated in these patients as part of a comprehensive program of care. The presence of mutation R245H in subjects with aortic regurgitation merits further study. (Supported by Shire HGT.) doi:10.1016/j.ymgme.2011.11.074
Objective: There is currently no recognised method for the measurement of LAL in DBS. Our aim was to develop a method using DBS and validate the technique using samples from patients with CESD. Methods: LAL was extracted from DBS with distilled water and incubated with 4 mU-palmitate in acetate buffer pH 4.0 and cardiolipin as an activator of LAL. Lalistat 2 was used as a specific inhibitor of LAL and activity estimated by measuring total lipase activity and lipase activity in the presence of Lalistat 2. LAL activity was determined by subtracting activity measured in the inhibited reaction from that in the uninhibited reaction. The assay was performed using 96 well plates and read at 355 nm/460 nm. Results: LAL activity in normal controls was 1.70 – 3.40 umol/l/hr. Samples from patients with confirmed CESD had significantly reduced LAL activity - <0.05 umol/l/hr. Activity in carriers was in the range 0.73-1.02 umol/l/hr. Conclusions: Measurement of LAL using DBS is made difficult by the presence of other forms of lipase in whole blood. Lalistat 2 is a specific inhibitor of LAL which allows the reliable determination of LAL in DBS. Results show the method differentiates clearly between normal controls, carriers and affected cases. doi:10.1016/j.ymgme.2011.11.068
Multiparametric 3.0 Tesla MRI of the Brain in Fabry Disease Eric Hanson a, e, Jonathan Bernstein b, Cayce Roach c, Priya Simonelli d, Daniel Morris d, Kathyrn Lowery d, William Orrison a, f, g, aTier 7 Research and Development, Las Vegas, NV, USA, bChildren's Center for Cancer, Las Vegas, USA, cTemple University School of Medicine, Philadelphia, USA, dTouro University Nevada, Las Vegas, USA, eUniversity f of Nevada Las Vegas, Las Vegas, USA, Advanced Medical Imaging and Genetics, Inc. (Amigenics), Las Vegas, USA, gCHW Nevada Imaging Company, Las Vegas, USA Purpose: This study was performed to identify incremental diagnostic information that can be captured with multi-parametric MRI studies of the brain in patients with Fabry disease (FD). A secondary goal was the clinical utilization of a checklist of MRI brain findings in FD developed based on a literature review to assist readers in capturing the complex findings of this disease. Materials and Methods: Five cases (n = 3 male) with FD (age range19-48 years) were evaluated on a 3.0 T MRI system with the following protocols: structural MRI, diffusion tensor imaging (DTI) of the corpus callosum, multi-voxel brain MR spectroscopy (MRS), and noncontrast-enhanced MR angiography (NCE-MRA). Results: Novel findings of hippocampal atrophy (n = 2), fornix atrophy (n = 2), and abnormal quantitative corpus callosum DTI findings (n = 5) were identified. At least one white matter lesion was present in all patients. Basilar artery dolichoectasia (n = 1) and middle cerebral and basilar artery ectasia (n = 1) were identified in separate patients. NCE-MRA identified bilateral fetal origin posterior cerebral arteries in one male patient. Periventricular leukoencephalopathy in the parietal lobe was identified in one female patient. Abnormal choline MRS values were identified in all patients. Conclusions: Improved clinical assessment of patients with FD can be accomplished using a multiparametric imaging including structural 3 T MRI, DTI, NCE-MRA, and MRS. In addition, utilization of a FD Brain MRI checklist assisted researchers in the assessment of the heterogeneous and numerous abnormalities, and reading fo the images obtained in this pilot study. The novel findings of hippocampal atrophy, fornix atrophy, and abnormal corpus callosum DTI findings warrant further study. doi:10.1016/j.ymgme.2011.11.069
S33
Mucopolysaccharidosis VI (Maroteaux-Lamy Syndrome): Development of Clinical and Laboratory Guidelines for Diagnosis Paul Harmatz 1, Children's Hospital & Research Center Oakland, Oakland, California, USA Mucopolysaccharidosis (MPS) VI is a lysosomal storage disease in which deficient N- acetylgalactosamine 4-sulfatase (arylsulfatase B, or ASB) impairs degradation of dermatan sulfate. Accurate diagnosis is critical to ensure that patients receive appropriate enzyme replacement therapy. Review of laboratory tests for mucopolysaccharidoses and their use in diagnosis of MPS VI was the topic of a recent expert panel meeting, inclusive of clinicians and laboratory directors. Clinicians completed a survey on MPS VI diagnosis practices. There was consensus on the requirement to evaluate ASB enzyme activity to obtain a final diagnosis. While the reported use of additional tests was variable, such as urinary glycosaminoglycans (uGAG) analysis (qualitative and quantitative), molecular testing, and multiple lysosomal enzymes testing, it was recommended that these laboratory tests be included as part of diagnosis of MPS VI. All participants emphasized the importance of direct communication between the diagnostic laboratory and clinician. In addition to high clinical suspicion, diagnosis of MPS VI requires quality results from tests run at laboratories with expertise in MPS testing and result interpretation. The use of multiple specimens and tests, such as qualitative and quantitative uGAG, multiple lysosomal enzyme activities, and molecular testing, when possible, was the unanimous recommendation of the panel. *MPS VI Laboratory Diagnostic Scientific Summit participants: Bodamer O, Burin MG, D'Almeida V, Eng CM, Fietz M, Giugliani R, Harmatz P, Hendriksz CJ, Hwu WL, Ketteridge D, Lukacs Z, Mendelsohn NJ, Miller N, Pasquali M, Schenone A, Schoonderwoerd K, Winchester B, Wood T. 1
On behalf of the participants at the MPS VI Laboratory Diagnostics Scientific Summit.
doi:10.1016/j.ymgme.2011.11.070
Large Animal Models of Lysosomal Storage Diseases: Lessons on the Limits of Gene/Enzyme Therapy Mark Haskins a, Meg Sleeper a, Gus Aguirre a, Steven U. Walkley b, Van Knox a, Charles Vite a, Richard Steet c, Brittney Gurda a, Jim Wilson a, Alberto Auricchio d, Lachlan Smith a, Lilla Simonaro e, Katherine Ponder f, aUniversity of Pennsylvania, Philadelphia, Pennsylvania, USA, b Albert Einstein College of Medicine, Bronx, New York, USA, cUniversity of Georgia, Athens, Georgia, USA, dTelethon Institute Of Genetics And Medicine, Naples, Italy, eMount Sinai Medical Center, New York, NY, USA, f Washington University in St. Louis, St. Louis, Missouri, USA Dog and cat orthologs of human genetic disease provide the opportunity to investigate the pathogenesis of these disorders and test therapeutic efficacy and toxicity in large species with naturally occurring disease. The long-lived large species, for which there are board-certified clinical specialists and sophisticated techniques to evaluate disease including echocardiography and magnetic resonance imaging, provide an important intermediate step in translational medicine from the mouse to mankind. A group of investigators have collaborated to treat dogs and cats with various lysosomal storage diseases including mucopolysaccharidosis (MPS) I, VI, and VII, alphamannosidosis, and Niemann Pick disease type C. Many were treated using retroviral and adeno-associated viral vectors from 3 days to 60 days of age. Serum enzyme activities have ranged from 10% of normal to 60-fold normal, has been maintained for up to 11 years in some animals, and has produced some significant improvements in
S34
Abstracts / Molecular Genetics and Metabolism 105 (2012) S15–S69
clinical phenotype and quality of life. Yet, in spite of constant circulating mannose 6-phosphorylated enzyme, lesions persist, particularly in the cervical spine and cardiovascular system in MPS and in the CNS in alpha-mannosidosis. Having recognized limitations with enzyme therapy, we now need to understand why these limitations exist and develop methods to circumvent them. This will include understanding the pathogenicity of the stored substrates, including the production of an inflammatory response, and testing combination therapies to improve the clinical outcome of enzyme therapy alone. doi:10.1016/j.ymgme.2011.11.071
Intrathecal Hydroxy-Propyl-Beta-Cyclodextrin Reverses Hearing Loss in Identical Twin Girls with Niemann-Pick Type C Disease Caroline Hastings, Joseph Torkildson, Robert Raphael, Children's Hospital & Research Center Oakland, Oakland, CA, USA Niemann-Pick type C (NPC) disease is a rare, fatal, autosomal recessive neurodegenerative disorder characterized by widespread intracellular accumulation of unesterified cholesterol and glycosphingolipids. To date, no medical intervention has received regulatory approval in the USA to treat this disorder. Hydroxypropyl-beta-cyclodextrin (HPBCD) is a sugar compound shown to reverse cholesterol trafficking defects in murine and feline NPC models and significantly lengthen life expectancy. We began administration of intravenous (IV) infusions of HPBCD under the FDA's Individual IND exemptions. Our patients, aged 5 years 2 months, had loss of developmental milestones (speech and communication) and were ataxic. We observed no toxicities related to the therapy. HPBCD does not cross the blood–brain barrier in mice, and based on promising animal data with CNS directed delivery demonstrating complete reversal or prevention of neurodegeneration and prolongation of life, we amended our protocol to administer HPBCD directly into the CNS. Treatment with intrathecal (IT) HPBCD was initiated at a dose of 175 mg (later increased to 350 mg) administered every 2 weeks by lumbar puncture. Again, no toxicites have been observed. We have seen significant clinical improvement utilizing a previously validated NIH NPC Clinical Severity Score. The most draumatic improvement was in hearing, as assessed by brainstem auditory evoked response, which improved from moderate-severe loss at baseline to normal-very mild loss (normal range) following 6 months of directed CNS therapy. This combination of systemic and central nervous system HPBCD drug delivery provides a promising new therapeutic approach for children with NPC to target every organ affected. doi:10.1016/j.ymgme.2011.11.072
Serial ECG, Echocardiography and Holter Monitoring in Children with Anderson-Fabry Disease Stepan Havranek a, Ales Linhart a, Uma Ramaswami b, aFirst Faculty of Medicine, Charles University and General University Hospital Prague, Czech Republic, bPaediatric Metabolic Unit, Box 181, Addenbrooke's Hospital, Cambridge, UK E-mail address: [email protected] (U. Ramaswami). Objective: Cardiac manifestations are common in adults with Anderson Fabry disease (AFD). We evaluated early cardiac manifestations in children with a confirmed diagnosis of AFD. Methods: This was a retrospective review of data from 21 children (11 male; mean age 9.6 ±4.6y) from a single site in Cambridge, UK.
Echocardiography, ECG and ECG monitor data including heart rate variability (HRV) parameters taken during routine clinical reviews (maximum of four year follow up) were analysed and divided into groups 1 and 2, based on very low or normal/mildly reduced enzyme activity respectively. Results: Mean left ventricle (LV) mass in group 1 (N = 12) differed significantly from group 2 (N = 9) at baseline (75.4 ± 8.9 vs. 55.6 ± 6.6 g/m2, p = 0.02). Group 1 showed progressive increase in LV hypertrophy ECG parameters (Sokolow voltage 2.9 ± 1.03 vs. 1.74 ± 0.51 mV, p = 0.04) with significant shortening of PR interval over two years (137 ± 8.6 vs. 156 ± 22 ms; p = 0.033). No diferences between groups was detected in conduction intervals at follow up and there were no clinically significant arrhythmias. Baseline HRV parameters were reduced in group 2 (rMSSD: 62.6 ± 20.3 vs. 39.0 ± 25.8, p = 0.05; pNN50: 36.9 ± 13.9 vs. 24 ± 10.6, p = 0.05) and remained unchanged after two years of follow-up. Conclusions: Low residual enzyme activity may predict early progression of cardiac disease in AFD, with ECG evidence of progressive LV hypertrophy and LV mass, with significantly shorter PR interval, emphasising the importance of regular and early follow up of children with AFD.
doi:10.1016/j.ymgme.2011.11.073
Cardiac Ultrasound Findings in Sanfilippo Syndrome Type A Brandon Hays, Elizabeth Braunlin, James Berry, Brenda Diethelm-Okita, Chester Whitley, University of Minnesota, Minneapolis, MN, USA Background: Although the incidence of cardiac abnormalities in Sanfilippo syndrome type A (MPS IIIA) is thought to be low, case reports suggest that, if present, such abnormalities may be severe and clinically significant. Methods: As part of a natural history study (Clinicaltrials.gov NCT01047306), we performed and reviewed cardiac ultrasounds in 24 youngsters with MPS IIIA and compared the results to subjects’ genotypes. Left ventricular end-diastolic dimension (LVEDD), left ventricular posterior wall (LVPWD) and septal (IVSD) thicknesses in diastole were measured and normalized to body surface area by zscores, positive z-scores indicating standard deviation (SD) values greater than normal. The presence of aortic or mitral valve thickness, regurgitation or stenosis was noted. Results: There were 8 female and 16 male subjects, average age 6.7 ± 4.5 (range 1.8 -18) years. Cardiac abnormalities were identified in 22/24 (92%) subjects. Left ventricular hypertrophy (z-score 2SD > normal) occurred in 14/24 (58%). Valve thickening occurred in 8/24 (33%) subjects: mitral only (N = 8); aortic only (N = 4); mitral and aortic (N = 3). Mild mitral regurgitation occurred in 1 subject; moderate to severe aortic regurgitation occurred in 2/24 (8%) subjects. Mutation R245H was present in 4/7 subjects with valve thickening and in 5/17 without this mutation (p = 0.35). Moderate to severe aortic regurgitation was present in two 7-year olds: both were heterozygous for mutation R245H. Conclusions: Cardiac abnormalities are common in young children with MPS IIIA. Given the developmental delays in the children, symptoms may go under-reported. Therefore, routine echocardiography is indicated in these patients as part of a comprehensive program of care. The presence of mutation R245H in subjects with aortic regurgitation merits further study. (Supported by Shire HGT.) doi:10.1016/j.ymgme.2011.11.074