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A quantitative comparison of brain morphology in MPS I, MPS II, and MPS VI
Abstracts
Pompe disease has resisted enzyme replacement therapy (ERT) with acid alpha-glucosidase (GAA). ERT can be enhanced by stimulating cation-independent mannose-6-phosphate receptor mediated uptake with a 2 agonist drug, clenbuterol. We evaluated the effect of adjunctive clenbuterol upon muscle-specific GAA expression with an adeno-associated virus (AAV) vector in GAA knockout (KO) mice. Clenbuterol in combination with the AAV vector increased latency in the Rotarod (p= 0.02) and wirehang (p= 0.006) functional tests at 12 weeks, and resulted in a significantly lower glycogen content in cardiac and skeletal muscle homogenates (pb 0.05 for heart, quadriceps, diaphragm, soleus; p = 0.06 for EDL) harvested from GAAKO mice at 12 weeks, in comparison with vector alone. The urinary glucose tetrasaccharide (Glc4) biomarker of glycogen storage and turnover was significantly lower (pb 0.05) in GAA-KO mice following combination therapy (mean± SD: 12± 1.7 mmol/mol CN, n = 8) compared with vector-only treated mice (18 ± 2.4, n = 5). Elevated GAA activity in heart correlated with reduced glycogen content, whereas GAA was nearly equivalent in skeletal muscle following either combination therapy or vector alone. The latter data suggested that the 2 agonist treatment enhanced trafficking of GAA to lysosomes within myofibers in the context of muscle-specific GAA expression. In summary, 2 agonist treatment enhanced the efficacy of muscle-specific GAA expression from AAV vector-mediated gene therapy in Pompe disease. A similar benefit might be expected in other lysosomal storage disorders that involve primarily the brain by enhancement of receptormediated uptake at the blood brain barrier. doi:10.1016/j.ymgme.2012.11.132
119 Comparing IC6 and thalamic AAV5 injections on MPS IIIB model Andrew Kolarich, Coy Heldermon, Janine Gilkes, University of Florida, Gainesville, FL, United States Sanfilippo syndrome type IIIB (MPS IIIB), a lysosomal storage disorder, results from the lack of alpha-N-acetylglucosaminidase (NAGLU). Affected children develop progressive mental deterioration, resulting in death during the mid to late teens. There is no curative therapy available. Despite the success of viral vectors from prior research within mouse models, significant gaps in understanding still remain in regards to the distribution and efficacy of AAV serotypes across injection types within the MPS IIIB model. We hypothesize that six-site intracranial and thalamic injections will differ in overall transduction within the brain. AAV serotypes with green fluorescent protein (GFP) gene driven by a CAG promoter were examined for distribution in the brain. A NAGLU-deficient mouse strain was utilized for six-site intracranial (IC6) and thalamic injections using AAV serotype 5 at three days of age, using both mutant (−/−) and wild type (+/+) or (+/−) individuals. At three months, animals were sacrificed and brains harvested. Each right hemisphere was cut sagitally, stained for GFP, and equidistant slices compared by GFP-positive cell count. Results suggest that AAV5 transduction is inhibited in mutant animals by a factor of 3.69 for IC6 and 14.8 for thalamic injection. Analysis of transduction efficiency suggests that for mutant individuals IC6 injection had an efficiency 2.5 times higher than thalamic injection. In wild type individuals thalamic injection had an efficiency 1.26 times higher than IC6. The large difference in overall transduction between wild type and mutant individuals is being evaluated and will be presented in a separate abstract. doi:10.1016/j.ymgme.2012.11.133
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120 Experience in the use of innovative non-Medication technologies in treatment of children with mucopolysacharidoses in the Federal Clinical Center Olga Konova, Elena Dmitrienko, Leyla Namazova-Baranova, Ludmila Kuzenkova, Anna Gevorkyan, Nato Vashakmadze, Scientific Center of Children's Health, Moscow, Moscow region, Russia The increase of survival rate of children suffering from mucopolysacharidoses defined an urgency of their complex rehabilitation treatment with physiotherapy inclusion. Our purpose was the evaluation of the effectiveness of innovative drug-free technology in the treatment of children with mucopolysacharidoses. In the physiotherapy department, 26 children with different types of mucopolysacharidoses have been observed. Their age range was 3–17 years. Complex nonpharmacological treatment was performed after a comprehensive indepth survey; the course of treatment required some pharmacotherapy. Enteral oxygen therapy was used in all the children, the other physical factors were selected individually according to the principle of synergy depending on the identified symptoms in each child, targeting different pathogenetic links. The average course of treatment lasted for 3 weeks and was based on 3 factors. The most frequently used were shock-wave therapy, electrostatic massage, “dry” immersion. Our results were: improvement in functions of the musculoskeletal in 69 (2% of cases) and respiratory in 80 (8%) systems, increased physical activity in 80, 8%), correction of coordination in 46 (2%), analgesia in 53 (8%), improved discharge of sputum in catamnesis-reduced frequency of episodes of acute respiratory infection. No adverse effects were observed in any patient. Conclusions: Individual selection of a complex of advanced medication-free technologies that affect different pathogenetic links of the disease, ensures progress in various clinical manifestations of mucopolysacharidoses diseases in children without causing any adverse reactions.
doi:10.1016/j.ymgme.2012.11.134
121 A quantitative comparison of brain morphology in MPS I, MPS II, and MPS VI Victor Kovaca, Igor Nestrasila, Kyle Rudsera, Michael De Bellisb, Elsa Shapiroa, aUniversity of Minnesota, Minneapolis, MN, USA, bDuke University, USA Background: Each type of mucopolysaccharidosis (MPS), a lysosomal storage disease, distinguishably affects the morphology and physiology of various organ systems, especially the central nervous system (CNS). Goal: To create a profile of brain morphology in MPS disorders, delineating the effect of different disease types. Methods: All T1-weighted magnetic resonance (MR) images were acquired with MPRAGE sequences on Siemens 3 T Trio scanners. Volumetric analysis was performed by automated segmentation using Freesurfer with cortical grey matter (CGM), white matter (WM), corpus callosum (CC), and ventricles chosen as regions of interest (ROI). Only children between 6 and 20 were included for analysis. Participants were divided into the following groups: MPS IH (Hurler syndrome, n =16; mean age=11.7), MPS I attenuated disease (n=12; mean age=14.2), MPS II (n=11; mean age=10.5), and MPS VI (n =8; mean age=15.9); and a normal control group, (n=63; mean age=10.9). Results: Comparison with controls: All MPS types showed larger ventricles and smaller CC. MPS II showed a significantly higher volume of
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Abstracts
CGM. MPS IH participants showed smaller volumes of WM. Comparison within MPS groups: MPS II has larger CC, CGM and WM than MPS IH. Discussion: Brain characteristics in MPS disorders are disease specific but also show some common elements. All groups showed large ventricular volume compared to controls. All groups of MPS showed decreased CC compared to controls but the effects were the greatest in the MPS IH. As both groups of MPS I showed decreased CC, the large effect size in MPS IH points to both treatment (transplant) and disease effects. Reduced CC volume in Hurler syndrome has also been observed in a canine model. The markedly larger volume of CGM in MPS II may result from build up of the glycosaminoglycans (GAG). doi:10.1016/j.ymgme.2012.11.135
122 Quality-of-life in children with Hurler syndrome who have not yet been transplanted and those who are one year post transplant Alicia Kunin-Batson, Brianna Yund, Kyle Rudser, Elsa Shapiro, University of Minnesota, Minneapolis, MN, USA Background: Hurler syndrome (MPS IH) is an inherited metabolic disorder that manifests in infancy and progressively affects most organ systems. Allogeneic hematopoietic stem cell transplantation (HSCT) can lead to long-term metabolic correction. An important measure of success of transplantation is not only longevity but also improvement in functional status and quality of life (QOL). Little is known about QOL and functional status of very young children following HSCT for MPS IH. We examined parent-report of children's QOL and adaptive functioning in a small cohort of children with MPS IH who were either pre- (n = 8) or post-HSCT (n = 7). Methods: Parents of young children with MPS IH who were between the ages of 3 months and 57 months at the time of evaluation completed the Infant Toddler Quality of Life Questionnaire (ITQOL) and the Vineland Adaptive Behavior Scales (VABS) as part of their child's participation in a longitudinal study. Results: Parent ratings of children's functional behavior (VABS) fell in the average range though lower than population norms on scales sampling functional communication, daily living skills, and global adaptive composite. Parent ratings of children who were pre-HSCT tended to be lower in these domains (reflecting more difficulty) than those post- HSCT. Socialization was an area of strength regardless of transplant status and not discrepant from population norms. ITQOL ratings were lower than averages from a healthy community-based reference group on scales of physical functioning, growth/development, bodily pain, and general health. Lower scores were noted on scales of the emotional and time impact on parents' functioning. Parent ratings of children with MPS IH were similar to the reference group on temperament/mood, general behavior, ability to get along with others, and family cohesion. Conclusions: The VABS and ITQOL sample distinct areas of strength and weakness in children with MPS IH and may be useful in measuring children's functioning pre- and post-HSCT. doi:10.1016/j.ymgme.2012.11.136
123 Mucopolysaccharidosis type II clinical case Ludmila Kuzenkova, Tatyana Podkletnova, Leyla Namazova-Baranova, Anna Gevorkyan, Nato Vashakmadze, Natalya Zhurkova, Nadezhda Nechaeva, Research Centre for Children's Health of RAMS, Moscow, Russian Federation
Patient A. Six years and 8 months. Anamnesis: During the first year of the patient's life, he grew and developed according to his age. Due to changes in facial features suggesting Hurler syndrome, and based on a family history (the mother's brother was affected) the diagnosis of mucopolysaccharidosis type II was confirmed at 2 years age when examined in MGSC Moscow. Based on phenotypic features and examination findings (i.e., increased dermatan sulfate and heparan sulfate in the urine, DNA diagnostics data with IDS mutation R233G) the diagnosis was made. Complaints: Noisy nasal breathing, frequent ear infections, adenoiditis, hearing loss, enlarged abdomen, stiffness of large and small joints, retarded mental development. Diagnosis mucopolysaccharidosis type II (Hunter disease). Retarded psycho-speech development. Secondary cardiomyopathy. Failure of the mitral, tricuspid valve and pulmonary valve. CF 1 degree. Bilateral acute otitis media. Hypertrophy of the adenoids of second degree. Dysontogenetic thoracolumbar scoliosis of first degree. Contractures of large and small joints of the extremities of second degree. Valgus deformity of the lower extremities. Treatment started at the age of 4 years 2 months was initiated: Idursulfase 0.5 mg/kg/ injection. Now, after receiving more than 90 infusions, no side effects of the infusion have been observed. Rehabilitation treatment: physical therapy, breathing exercises, development of large and fine motor skills. Results of of the LFT treatment: Facial changes decrease, accelerating growth, improvement of hearing, memory, attention, exercise capacity, reducing the frequency and severity of SARS, increase range of motion in joints, reducing the size of internal organs. doi:10.1016/j.ymgme.2012.11.137
124 Particular features of neurological symptoms with children suffering from MPS syndrome type II Ludmila Kuzenkova, Tatyana Podkletnova, Leyla Namazova-Baranova, Anna Gevorkyan, Nato Vashakmadze, Natalya Zhurkova, Nadezhda Nechaeva, Research Centre for Children's Health of RAMS, Moscow, Russian Federation Objective: To study the incidence and characteristics of neurological symptoms in children with mucopolysaccharidosis (MPS) type II. Patients and methods: 58 patients with MPS types, of which MPS II type — 31 children (53%), MPS type I — 6 (10%), MPS type III — 14 (24%), MPS type IV — 3 (5%), MPS type VI — 4 (8%). The average age of patients with MPS II was 9.5± 2.9 years. The examination of this group of patients aimed to find out the range and incidence of neurological symptoms. Results: The structure of the neurological symptoms in children: carpal tunnel syndrome — 90%; symptomatic epilepsy — 41%; pseudobulbar syndrome — 50%; central tetraparesis — 31%; central tetraparesis myelopathy — 25%; hydrocephalus — 37%; sleep disorders — 41%; behavioral disorders — 56%; regression of intellectual skills — 62%; delay of psycho-speech development — 81% Conclusions: 1. Neurological symptoms in children with MPS II and I have been observed in 100% of cases. 2. Basic neurological syndrome complexes with MPS type II include: delay in psychospeech development, regression of intellectual skills, behavioral disorders, sleep disorders, carpal tunnel syndrome, hydrocephalus, cervical myelopathy, central tetraparesis, pseudobulbar syndrome, symptomatic epilepsy. 3. Carpal tunnel syndrome and delayed psychospeech development have occurred in most patients (90% and 81%, respectively), and are most common in MPS type II sufferers. 4. Symptoms of cervical myelopathy (25%) occur most rarely in patients with MPS type II due to lower incidence of the spine in patients with MPS type II
Pompe disease has resisted enzyme replacement therapy (ERT) with acid alpha-glucosidase (GAA). ERT can be enhanced by stimulating cation-independent mannose-6-phosphate receptor mediated uptake with a 2 agonist drug, clenbuterol. We evaluated the effect of adjunctive clenbuterol upon muscle-specific GAA expression with an adeno-associated virus (AAV) vector in GAA knockout (KO) mice. Clenbuterol in combination with the AAV vector increased latency in the Rotarod (p= 0.02) and wirehang (p= 0.006) functional tests at 12 weeks, and resulted in a significantly lower glycogen content in cardiac and skeletal muscle homogenates (pb 0.05 for heart, quadriceps, diaphragm, soleus; p = 0.06 for EDL) harvested from GAAKO mice at 12 weeks, in comparison with vector alone. The urinary glucose tetrasaccharide (Glc4) biomarker of glycogen storage and turnover was significantly lower (pb 0.05) in GAA-KO mice following combination therapy (mean± SD: 12± 1.7 mmol/mol CN, n = 8) compared with vector-only treated mice (18 ± 2.4, n = 5). Elevated GAA activity in heart correlated with reduced glycogen content, whereas GAA was nearly equivalent in skeletal muscle following either combination therapy or vector alone. The latter data suggested that the 2 agonist treatment enhanced trafficking of GAA to lysosomes within myofibers in the context of muscle-specific GAA expression. In summary, 2 agonist treatment enhanced the efficacy of muscle-specific GAA expression from AAV vector-mediated gene therapy in Pompe disease. A similar benefit might be expected in other lysosomal storage disorders that involve primarily the brain by enhancement of receptormediated uptake at the blood brain barrier. doi:10.1016/j.ymgme.2012.11.132
119 Comparing IC6 and thalamic AAV5 injections on MPS IIIB model Andrew Kolarich, Coy Heldermon, Janine Gilkes, University of Florida, Gainesville, FL, United States Sanfilippo syndrome type IIIB (MPS IIIB), a lysosomal storage disorder, results from the lack of alpha-N-acetylglucosaminidase (NAGLU). Affected children develop progressive mental deterioration, resulting in death during the mid to late teens. There is no curative therapy available. Despite the success of viral vectors from prior research within mouse models, significant gaps in understanding still remain in regards to the distribution and efficacy of AAV serotypes across injection types within the MPS IIIB model. We hypothesize that six-site intracranial and thalamic injections will differ in overall transduction within the brain. AAV serotypes with green fluorescent protein (GFP) gene driven by a CAG promoter were examined for distribution in the brain. A NAGLU-deficient mouse strain was utilized for six-site intracranial (IC6) and thalamic injections using AAV serotype 5 at three days of age, using both mutant (−/−) and wild type (+/+) or (+/−) individuals. At three months, animals were sacrificed and brains harvested. Each right hemisphere was cut sagitally, stained for GFP, and equidistant slices compared by GFP-positive cell count. Results suggest that AAV5 transduction is inhibited in mutant animals by a factor of 3.69 for IC6 and 14.8 for thalamic injection. Analysis of transduction efficiency suggests that for mutant individuals IC6 injection had an efficiency 2.5 times higher than thalamic injection. In wild type individuals thalamic injection had an efficiency 1.26 times higher than IC6. The large difference in overall transduction between wild type and mutant individuals is being evaluated and will be presented in a separate abstract. doi:10.1016/j.ymgme.2012.11.133
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120 Experience in the use of innovative non-Medication technologies in treatment of children with mucopolysacharidoses in the Federal Clinical Center Olga Konova, Elena Dmitrienko, Leyla Namazova-Baranova, Ludmila Kuzenkova, Anna Gevorkyan, Nato Vashakmadze, Scientific Center of Children's Health, Moscow, Moscow region, Russia The increase of survival rate of children suffering from mucopolysacharidoses defined an urgency of their complex rehabilitation treatment with physiotherapy inclusion. Our purpose was the evaluation of the effectiveness of innovative drug-free technology in the treatment of children with mucopolysacharidoses. In the physiotherapy department, 26 children with different types of mucopolysacharidoses have been observed. Their age range was 3–17 years. Complex nonpharmacological treatment was performed after a comprehensive indepth survey; the course of treatment required some pharmacotherapy. Enteral oxygen therapy was used in all the children, the other physical factors were selected individually according to the principle of synergy depending on the identified symptoms in each child, targeting different pathogenetic links. The average course of treatment lasted for 3 weeks and was based on 3 factors. The most frequently used were shock-wave therapy, electrostatic massage, “dry” immersion. Our results were: improvement in functions of the musculoskeletal in 69 (2% of cases) and respiratory in 80 (8%) systems, increased physical activity in 80, 8%), correction of coordination in 46 (2%), analgesia in 53 (8%), improved discharge of sputum in catamnesis-reduced frequency of episodes of acute respiratory infection. No adverse effects were observed in any patient. Conclusions: Individual selection of a complex of advanced medication-free technologies that affect different pathogenetic links of the disease, ensures progress in various clinical manifestations of mucopolysacharidoses diseases in children without causing any adverse reactions.
doi:10.1016/j.ymgme.2012.11.134
121 A quantitative comparison of brain morphology in MPS I, MPS II, and MPS VI Victor Kovaca, Igor Nestrasila, Kyle Rudsera, Michael De Bellisb, Elsa Shapiroa, aUniversity of Minnesota, Minneapolis, MN, USA, bDuke University, USA Background: Each type of mucopolysaccharidosis (MPS), a lysosomal storage disease, distinguishably affects the morphology and physiology of various organ systems, especially the central nervous system (CNS). Goal: To create a profile of brain morphology in MPS disorders, delineating the effect of different disease types. Methods: All T1-weighted magnetic resonance (MR) images were acquired with MPRAGE sequences on Siemens 3 T Trio scanners. Volumetric analysis was performed by automated segmentation using Freesurfer with cortical grey matter (CGM), white matter (WM), corpus callosum (CC), and ventricles chosen as regions of interest (ROI). Only children between 6 and 20 were included for analysis. Participants were divided into the following groups: MPS IH (Hurler syndrome, n =16; mean age=11.7), MPS I attenuated disease (n=12; mean age=14.2), MPS II (n=11; mean age=10.5), and MPS VI (n =8; mean age=15.9); and a normal control group, (n=63; mean age=10.9). Results: Comparison with controls: All MPS types showed larger ventricles and smaller CC. MPS II showed a significantly higher volume of
S56
Abstracts
CGM. MPS IH participants showed smaller volumes of WM. Comparison within MPS groups: MPS II has larger CC, CGM and WM than MPS IH. Discussion: Brain characteristics in MPS disorders are disease specific but also show some common elements. All groups showed large ventricular volume compared to controls. All groups of MPS showed decreased CC compared to controls but the effects were the greatest in the MPS IH. As both groups of MPS I showed decreased CC, the large effect size in MPS IH points to both treatment (transplant) and disease effects. Reduced CC volume in Hurler syndrome has also been observed in a canine model. The markedly larger volume of CGM in MPS II may result from build up of the glycosaminoglycans (GAG). doi:10.1016/j.ymgme.2012.11.135
122 Quality-of-life in children with Hurler syndrome who have not yet been transplanted and those who are one year post transplant Alicia Kunin-Batson, Brianna Yund, Kyle Rudser, Elsa Shapiro, University of Minnesota, Minneapolis, MN, USA Background: Hurler syndrome (MPS IH) is an inherited metabolic disorder that manifests in infancy and progressively affects most organ systems. Allogeneic hematopoietic stem cell transplantation (HSCT) can lead to long-term metabolic correction. An important measure of success of transplantation is not only longevity but also improvement in functional status and quality of life (QOL). Little is known about QOL and functional status of very young children following HSCT for MPS IH. We examined parent-report of children's QOL and adaptive functioning in a small cohort of children with MPS IH who were either pre- (n = 8) or post-HSCT (n = 7). Methods: Parents of young children with MPS IH who were between the ages of 3 months and 57 months at the time of evaluation completed the Infant Toddler Quality of Life Questionnaire (ITQOL) and the Vineland Adaptive Behavior Scales (VABS) as part of their child's participation in a longitudinal study. Results: Parent ratings of children's functional behavior (VABS) fell in the average range though lower than population norms on scales sampling functional communication, daily living skills, and global adaptive composite. Parent ratings of children who were pre-HSCT tended to be lower in these domains (reflecting more difficulty) than those post- HSCT. Socialization was an area of strength regardless of transplant status and not discrepant from population norms. ITQOL ratings were lower than averages from a healthy community-based reference group on scales of physical functioning, growth/development, bodily pain, and general health. Lower scores were noted on scales of the emotional and time impact on parents' functioning. Parent ratings of children with MPS IH were similar to the reference group on temperament/mood, general behavior, ability to get along with others, and family cohesion. Conclusions: The VABS and ITQOL sample distinct areas of strength and weakness in children with MPS IH and may be useful in measuring children's functioning pre- and post-HSCT. doi:10.1016/j.ymgme.2012.11.136
123 Mucopolysaccharidosis type II clinical case Ludmila Kuzenkova, Tatyana Podkletnova, Leyla Namazova-Baranova, Anna Gevorkyan, Nato Vashakmadze, Natalya Zhurkova, Nadezhda Nechaeva, Research Centre for Children's Health of RAMS, Moscow, Russian Federation
Patient A. Six years and 8 months. Anamnesis: During the first year of the patient's life, he grew and developed according to his age. Due to changes in facial features suggesting Hurler syndrome, and based on a family history (the mother's brother was affected) the diagnosis of mucopolysaccharidosis type II was confirmed at 2 years age when examined in MGSC Moscow. Based on phenotypic features and examination findings (i.e., increased dermatan sulfate and heparan sulfate in the urine, DNA diagnostics data with IDS mutation R233G) the diagnosis was made. Complaints: Noisy nasal breathing, frequent ear infections, adenoiditis, hearing loss, enlarged abdomen, stiffness of large and small joints, retarded mental development. Diagnosis mucopolysaccharidosis type II (Hunter disease). Retarded psycho-speech development. Secondary cardiomyopathy. Failure of the mitral, tricuspid valve and pulmonary valve. CF 1 degree. Bilateral acute otitis media. Hypertrophy of the adenoids of second degree. Dysontogenetic thoracolumbar scoliosis of first degree. Contractures of large and small joints of the extremities of second degree. Valgus deformity of the lower extremities. Treatment started at the age of 4 years 2 months was initiated: Idursulfase 0.5 mg/kg/ injection. Now, after receiving more than 90 infusions, no side effects of the infusion have been observed. Rehabilitation treatment: physical therapy, breathing exercises, development of large and fine motor skills. Results of of the LFT treatment: Facial changes decrease, accelerating growth, improvement of hearing, memory, attention, exercise capacity, reducing the frequency and severity of SARS, increase range of motion in joints, reducing the size of internal organs. doi:10.1016/j.ymgme.2012.11.137
124 Particular features of neurological symptoms with children suffering from MPS syndrome type II Ludmila Kuzenkova, Tatyana Podkletnova, Leyla Namazova-Baranova, Anna Gevorkyan, Nato Vashakmadze, Natalya Zhurkova, Nadezhda Nechaeva, Research Centre for Children's Health of RAMS, Moscow, Russian Federation Objective: To study the incidence and characteristics of neurological symptoms in children with mucopolysaccharidosis (MPS) type II. Patients and methods: 58 patients with MPS types, of which MPS II type — 31 children (53%), MPS type I — 6 (10%), MPS type III — 14 (24%), MPS type IV — 3 (5%), MPS type VI — 4 (8%). The average age of patients with MPS II was 9.5± 2.9 years. The examination of this group of patients aimed to find out the range and incidence of neurological symptoms. Results: The structure of the neurological symptoms in children: carpal tunnel syndrome — 90%; symptomatic epilepsy — 41%; pseudobulbar syndrome — 50%; central tetraparesis — 31%; central tetraparesis myelopathy — 25%; hydrocephalus — 37%; sleep disorders — 41%; behavioral disorders — 56%; regression of intellectual skills — 62%; delay of psycho-speech development — 81% Conclusions: 1. Neurological symptoms in children with MPS II and I have been observed in 100% of cases. 2. Basic neurological syndrome complexes with MPS type II include: delay in psychospeech development, regression of intellectual skills, behavioral disorders, sleep disorders, carpal tunnel syndrome, hydrocephalus, cervical myelopathy, central tetraparesis, pseudobulbar syndrome, symptomatic epilepsy. 3. Carpal tunnel syndrome and delayed psychospeech development have occurred in most patients (90% and 81%, respectively), and are most common in MPS type II sufferers. 4. Symptoms of cervical myelopathy (25%) occur most rarely in patients with MPS type II due to lower incidence of the spine in patients with MPS type II