New entries will always be added to the top of this list. I added two entries on December 3, 2000 - see them below.

SUBJECT: BMT NEW

Title: Upper airway complications in children after bone marrow transplantation.

Author: Drew B; Peters C; Rimell F.

Address: Department of Otolaryngology, University of Minnesota Medical School, Minneapolis 55455, USA.

Source: Laryngoscope 2000 Sep;110(9):1446-51.

Abstract: OBJECTIVE: To describe the upper and lower airway complications in children during bone marrow transplantation (BMT). STUDY DESIGN: Review of medical records of patients requiring airway intervention during BMT over a 4-year period. RESULTS: During the 4-year period, 832 pediatric BMTs were performed. Of these, 87 patients (10.5%) required mechanical ventilation. Patients had intubation for a mean of 79 days (range, -7-638 d) after BMT. Patients received mechanical ventilation for a mean of 12 days (range, 1-85 d). Duration of ventilation was significantly longer in patients with difficult intubation; in these 54 patients there were 64 intubations. Of these intubations, 19 (30%) were difficult. These difficult intubations occurred in 16 (30%) patients. Patients with Hurler syndrome and congenital immunodeficiencies had significantly more difficult intubations than children with leukemia. The incidence of complications causing difficult intubation were difficulty visualizing cords, because of the presence of blood (63%); difficulty visualizing cords, because of edema (19%); anatomically narrowed airway (13%); limited neck extension (13%); and limited jaw opening (6%). The resulting mortality rate was 82% in children requiring intubation. Survivors were significantly younger than nonsurvivors. CONCLUSIONS: Pediatric BMT has become increasingly more common. Airway management is rarely required during the engraftment phase, but when intervention is required, it is often difficult, particularly in the nonleukemic child, and may require the skills of an otolaryngologist. Representative cases are presented, and management is discussed.

SUBJECT: BMT NEW

Title: Correction of odontoid dysplasia following bone-marrow transplantation and engraftment (in Hurler syndrome MPS 1H).

Author: Hite SH; Peters C; Krivit W.

Address: Department of Pediatrics, University of Minnesota, Minneapolis 55455, USA.

Source: Pediatr Radiol 2000 Jul;30(7):464-70.

Abstract: BACKGROUND: Odontoid dysplasia is recognized as a major component of the constellation of dysostosis multiplex lesions associated with Hurler's syndrome (MPS 1H). Because of this abnormality, there is an increased risk of atlantoaxial subluxation with potential cervical spinal cord injury. A significant alteration of the natural history of the disease with respect to the visceral, cardiac, and skeletal systems has resulted in an increased life span for MPS 1H patients associated with engraftment from normal donors. OBJECTIVE: The purpose of this study was to evaluate the longitudinal changes of odontoid dysplasia in MPS 1H following engraftment from bone-marrow transplantation (BMT). MATERIALS AND METHODS: A retrospective review of sequential plain film or cervical spine MR was performed in patients with MPS 1H. Odontoid morphology was graded as aplasia, severe dysplasia, moderate dysplasia, mild dysplasia, or normal. Odontoid morphology was plotted against the time interval. Fully engrafted, nontransplanted, and partially engrafted patients had careful imaging evaluation of the odontoid process. RESULTS: Ten patients were studied with a mean interval follow-up of 8.7 years post-BMT. Seven patients were totally engrafted. Two patients were nontransplanted, and one patient had only partial engraftment (20% enzyme activity). All totally engrafted patients had a progressive improvement in the grade of odontoid dysplasia following BMT. Patients with partial engraftment or without transplantation demonstrated static or increasing odontoid dysplasia. MR imaging showed abnormal dural soft-tissue masses at the level of C2 in all patients. Reduction in the grade of odontoid dysplasia was not associated with significant change in the appearance of the upper cervical soft-tissue masses. CONCLUSION: For the first time, this report documents that patients with MPS 1H show a decrease in the degree of odontoid dysplasia on imaging after successful engraftment following BMT.

SUBJECT: Anesthesia

Title: Failed epidural anaesthesia in a patient with Hurler's disease.

Author: Vas L; Naregal F.

Address: Bai Jerbai Wadia Hospital for Children, Acharya Donde Marg, Parel Bombay 40, India.

Source: Paediatr Anaesth 2000;10(1):95-8.

Abstract: Failure of epidural anaesthesia in a patient with Hurler's disease is presented. The possibility that epidural anaesthesia may fail due to deposition of mucopolysaccharide in the meninges, or in the epidural space is discussed. A granuloma in the upper trachea and severe choanal stenosis complicated the already difficult airway management.

SUBJECT: Anesthesia

Title: Anaesthesia for children with mucopolysaccharidoses.

Author: Moores C; Rogers JG; McKenzie IM; Brown TC.

Address:: Department of Anaesthesia, Royal Children's Hospital, Melbourne, Victoria.

Source: Anaesth Intensive Care, 1996 Aug, 24:4, 459-63.

Abstract: The mucopolysaccharidoses are a group of inherited disorders of metabolism, with varying clinical manifestations. A number of them present anaesthetic difficulties. This paper presents a summary table of the syndromes and reviews our experience over ten years with patients with these diagnoses. The clinical presentations, anaesthetic management, and complications are described. The effect of age and diagnosis on airway difficulties was studied. There were 31 patients, 28 of whom required anaesthesia, on a total of 99 occasions, for 115 procedures. The patients with Hunter, Hurler and Maroteaux-Lamy syndromes had significantly more airway difficulties as they grew older, and compared with patients in this group with other syndromes. Patients with Hurler's syndrome may have coronary artery involvement and one patient was given fentanyl and pancuronium for this reason. He proved impossible to intubate and an emergency tracheostomy was performed.

SUBJECT: BMT/Orthopedics

Title: Genu valgum deformity in Hurler syndrome after hematopoietic stem cell transplantation: correction by surgical intervention.

Author: Odunusi E; Peters C; Krivit W; Ogilvie J.

Address: Department of Pediatrics, University of Minnesota, Minneapolis 55455, USA.

Source: J Pediatr Orthop 1999 Mar-Apr;19(2):270-4.

Abstract: Hematopoietic stem cell transplantation has increased the survival of patients with Hurler syndrome. Genu valgum occurs frequently in untransplanted patients and has been noted in 52% of our patients after stable engraftment. No deformities spontaneously corrected. We describe the orthopaedic management of genu valgum in Hurler syndrome. Medial epiphyseal stapling predictably affects angular deformity in these patients. Recurrence of deformities either after staple dislodgement or surgical removal can occur, and repeated stapling may be required. Surgical epiphyseal stapling has a role in the management of genu valgum in successfully engrafted Hurler patients. We discuss the relationship of this skeletal deformity to other skeletal deformities and alternative therapies for genu valgum.

SUBJECT: BMT

Title: Outcome of unrelated donor bone marrow transplantation in 40 children with Hurler syndrome.

Author: Peters C; Balthazor M; Shapiro EG; King RJ; Kollman C; Hegland JD; Henslee Downey J; Trigg ME; Cowan MJ; Sanders J; Bunin N; Weinstein H; Lenarsky C; Falk P; Harris R; Bowen T; Williams TE; Grayson GH; Warkentin P; Sender L; Cool VA; Crittenden M; Packman S; Kaplan P; Lockman LA; et al.

Address:: Department of Pediatrics University of Iowa, Iowa City 52242, USA.

Source: Blood, 1996 Jun, 87:11, 4894-902.

Abstract: Long-term survival and improved neuropsychological function have occurred in selected children with Hurler syndrome (MPS I H) after successful engraftment with genotypically matched sibling bons marrow transplantation (BMT). However, because few children have HLA-identical siblings, the feasibility of unrelated donor (URD) BMT as a vehicle for adoptive enzyme therapy was evaluated in this retrospective study. Forty consecutive children (median, 1.7 years; range, 0.9 to 3.2 years) with MPS I H received high-dose chemotherapy with or without radiation followed by BMT between January 27, 1989 and May 13, 1994. Twenty-five of the 40 patients initially engrafted. An estimated 49% of patients are alive at 2 years, 63% alloengrafted and 37% autoengrafted. The probability of grade II to IV acute graft-versus-host disease (GVHD) was 30%, and the probability of extensive chronic GVHD was 18%. Eleven patients received a second URD BMT because of graft rejection or failure. Of the 20 survivors, 13 children have complete donor engraftment, two children have mixed chimeric grafts, and five children have autologous marrow recovery. The BM cell dose was correlated with both donor engraftment and survival. Thirteen of 27 evaluable patients were engrafted at 1 year following URD BMT. Neither T-lymphocyte depletion (TLD) of the bone marrow nor irradiation appeared to influence the likelihood of engraftment. Ten of 16 patients alive at 1 year who received a BM cell dose greater than or equal to 3.5 x 10(8) cells/kg engrafted, and 62% are estimated to be alive at 3 years. In contrast, only 3 of 11 patients receiving less than 3.5 x 10(8) cells/kg engrafted, and 24% are estimated to be alive at 3 years (P = .05). The mental developmental index (MDI) was assessed before BMT. Both baseline and post-BMT neuropsychological data were available for 11 engrafted survivors. Eight children with a baseline MDI greater than 70 have undergone URD BMT (median age, 1.5 years; range, 1.0 to 2.4 years). Of these, two children have had BMT too recently for developmental follow-up. Of the remaining six, none has shown any decline in age equivalent scores. Four children are acquiring skills at a pace equal to or slightly below their same age peers; two children have shown a plateau in learning or extreme slowing in their learning process. For children with a baseline MDI less than 70 (median age, 2.5 years; range, 0.9 to 2.9 years), post-BMT follow-up indicated that two children have shown deterioration in their developmental skills. The remaining three children are maintaining their skills and are adding to them at a highly variable rate. We conclude that MPS I H patients with a baseline MDI greater than 70 who are engrafted survivors following URD BMT can achieve a favorable long-term outcome and improved cognitive function. Future protocols must address the high risk of graft rejection or failure and the impact of GVHD in this patient population.

SUBJECT: BMT

Title: Hurler syndrome: II. Outcome of HLA-genotypically identical sibling and HLA-haploidentical related donor bone marrow transplantation in fifty-four children. The Storage Disease Collaborative Study Group.

Author: Peters C; Shapiro EG; Anderson J; Henslee Downey PJ; Klemperer MR; Cowan MJ; Saunders EF; deAlarcon PA; Twist C; Nachman JB; Hale GA; Harris RE; Rozans MK; Kurtzberg J; Grayson GH; Williams TE; Lenarsky C; Wagner JE; Krivit W.

Address:: Department of Pediatrics, Division of Bone Marrow Transplant, University of Minnesota, Minneapolis 55455, USA.

Source: Blood, 1998 Apr, 91:7, 2601-8.

Abstract: Untreated patients with Hurler syndrome (MPSIH) experience progressive neurologic deterioration and early death. Allogeneic bone marrow transplantation (BMT) ameliorates or halts this course. The Storage Disease Collaborative Study Group was formed to evaluate the effectiveness and toxicity of BMT. Effectiveness was defined as engrafted survival with continuing cognitive development. Fifty-four patients deficient in leukocyte alpha-L-iduronidase enzyme activity (median age, 1.8 years; range, 0.4 to 7.9) received high-dose chemotherapy with or without irradiation and BMT from HLA-genotypically identical sibling (GIS) or HLA-haploidentical related (HIR) donors between September 16, 1983 and July 14, 1995; all children were included in this report. Thirty-nine of 54 patients (72%) engrafted following the first BMT. The probability of grade II to IV acute graft-versus-host disease (GVHD) at 100 days was 32% for GIS and 55% for HIR patients. The probability of extensive chronic GVHD was 0% for GIS and 24% for HIR patients. The actuarial probability of survival at 5 years was 64% for all patients, 75% for GIS patients, 53% for HIR patients, and 53% for patients with donor marrow engraftment. The baseline Mental Developmental Index (MDI) was examined both for children less than and greater than 24 months of age at BMT. Children transplanted before 24 months had a mean baseline MDI of 78, while those transplanted after 24 months had a mean baseline MDI of 63 (P = . 0002). Both baseline and post-BMT neuropsychologic data were available for 26 of 30 engrafted survivors. Of 14 patients transplanted before 24 months of age, nine demonstrated developmental trajectories that were normal or somewhat slower than normal. In contrast, of 12 patients transplanted after 24 months of age, only three showed developmental trajectories that were normal or somewhat slower than normal (P = .01). For children with a baseline MDI greater than 70, there was a significant correlation between the MDI at follow-up study and leukocyte alpha-L-iduronidase enzyme activity (P = .02). Children were more likely to maintain normal cognitive development if they were fully engrafted following BMT from a donor with homozygous normal leukocyte alpha-L-iduronidase enzyme activity. Children who developed acute GVHD of grade II or worse had significantly poorer cognitive outcomes (P < .009). No difference in the post-BMT MDI was observed between patients whose preparative therapies did (n = 10; radiation dose, 300 to 1,400 cGy) or did not (n = 16) include radiation. We conclude that MPSIH patients, particularly those less than 24 months of age with a baseline MDI greater than 70, can achieve a favorable long-term outcome with continuing cognitive development and prolonged survival after successful BMT from a related donor with homozygous normal enzyme activity.

SUBJECT: BMT

Title: Follow-up of nine patients with Hurler syndrome after bone marrow transplantation.

Author: Guffon N; Souillet G; Maire I; Straczek J; Guibaud P.

Address:: Centre d'Etude des Maladies MÆetaboliques, HÈopital Central, Nancy, France.

Source: J Pediatr, 1998 Jul, 133:1, 119-25.

Abstract: We report our experience in nine patients with Hurler syndrome (six with a severe and three with an intermediate phenotype) who successfully engrafted after bone marrow transplantation. The donor was a human leukocyte antigen-identical sibling in six cases, the human leukocyte antigen-identical father in one case, and an unrelated donor in two cases. One patient with Hurler syndrome and an intermediate phenotype received two successive grafts from the same donor. There was a beneficial effect of bone marrow transplantation on visceral features (hepatosplenomegaly, obstruction of the upper airway, and coarse facies); however, dysostosis multiplex worsened. All patients but one required surgery for carpal tunnel syndrome. Visual acuity was low because of corneal clouding, and two patients had glaucoma several years after the graft. Five patients had normal hearing before the graft that remained normal, and four had hearing impairment that improved. All patients had learning difficulties, but none had severe mental retardation (IQ ranging from 75 to 103). The follow-up of patients with severe Hurler syndrome engrafted for more than 10 years emphasizes the limits and benefits of bone marrow transplantation.

SUBJECT: BMT

Title: Bone marrow transplant in a case of mucopolysaccharidosis I Scheie phenotype: skin ultrastructure before and after transplantation.

Author: Navarro C; Dominguez C; Costa M; Ortega JJ.

Address: Division of Neuropathology, Hospital Infantil, Ciudad Sanitaria Valle de Hebrón, Universidad Autónoma, Barcelona, Spain.

Source: Acta Neuropathol (Berl), 1991, 82:1, 33-8.

Abstract: An 11-year-old girl with mucopolysaccharidosis I Scheie phenotype (MPS I-S) received a bone marrow transplant (BMT) from her heterozygous HLA-identical LMC-non-reactive mother. Multidisciplinary studies were carried out and results evaluated 21 months after transplantation. Herein we report the ultrastructural findings pre- and post-BMT in skin. Multidisciplinary studies are commonly used to evaluate the benefits of metabolic correction following BMT in some MPS and other inherited metabolic disorders, and changes in morphology have been described in liver and few other tissues. In this case, we elected skin, since connective tissue is universally involved in MPS and is safely and easily obtainable. Comparison of skin biopsy specimens taken before and after BMT showed a considerable change in dermal fibroblast morphology, with marked reduction in cell size and the number and size of abnormal lysosomes, thus indicating the clearance of storage. Our results demonstrate that dermal cells respond to enzyme replacement therapy in MPS I-S, with the clearance of glycosaminoglycan lysosomal accumulation in connective tissue fibroblasts, which had near-normal morphology 21 months after BMT. Therefore, the practice of skin biopsy after BMT in MPS and other metabolic disorders in which dermal cells are involved should be encouraged.

SUBJECT: BMT

Title: Ocular abnormalities in the mucopolysaccharidoses after bone marrow transplantation. Longer follow-up.

Author: Gullingsrud EO; Krivit W; Summers CG.

Address: Department of Ophthalmology, University of Minnesota, Minneapolis, USA.

Source: Ophthalmology, 1998 Jun, 105:6, 1099-105.

Abstract: OBJECTIVE: The purpose of the study was to provide longer follow-up of ocular findings in patients with mucopolysaccharidoses (MPS) after bone marrow transplantation (BMT). DESIGN: The study design was a retrospective 6-year cohort evaluation. PARTICIPANTS: Twenty-three patients with MPS (19 with MPS type I-H, 3 with MPS type III, 1 with MPS type VI) were studied. INTERVENTION: Bone marrow transplantation was performed. MAIN OUTCOME MEASURES: The following outcome measures were considered: vision, slit-lamp biomicroscopic and funduscopic examinations, intraocular pressure, electroretinography (ERG), and retinoscopy. RESULTS: Thirteen (81%) of 16 patients showed ERG improvement in the first year. However, all patients showed slowly progressive decline of the ERG over longer follow-up. Other ocular findings included optic atrophy (n = 7 patients), disc edema (n = 6 patients), strabismus (n = 6 patients), nystagmus (n = 6 patients), cataract (n = 3 eyes), keratoconjunctivitis sicca (n = 4 eyes), ocular hypertension (n = 2 eyes), and glaucoma (n = 2 eyes). CONCLUSIONS: The MPS are rare and heterogeneous disorders characterized by progressive retinal degeneration and blindness. Ocular abnormalities can occur as a result of the disease or as a consequence of BMT. Successful BMT has been shown to improve systemic health, but this may not reflect continuing ocular status and retinal function. Despite early improvement in ERG function, longer follow-up suggests progressive retinal decline.

SUBJECT: BMT

Author: Vellodi A; Young EP; Cooper A; Wraith JE; Winchester B; Meaney C; Ramaswami U; Will A.

Address: Medical Unit, Institute of Child Health, London.

Source: Arch Dis Child, 1997 Feb, 76:2, 92-9.

Abstract: Bone marrow transplantation was carried out on 38 patients with mucopolysaccharidosis type I over a period of 15 years. The donor was an HLA identical relative in 10 cases, an HLA non-identical relative in 16 cases, and an HLA identical unrelated volunteer donor in 12 cases. Ten patients received a second transplant. One patient received three transplants. Thirteen engrafted patients have survived five years or more. Most patients have shown an arrest or slowing down of psychomotor regression. However, dysostosis multiplex has progressed. Careful selection of patients may be necessary to ensure optimum results.

SUBJECT: BMT

Title: Allogeneic bone marrow transplantation in the treatment of (lysosomal) storage diseases.

Author: Maaswinkel Mooij PD; Poorthuis BJ; Hoogerbrugge PM; Brouwer OF; Vossen JM.

Address: Afd. Kindergeneeskunde, Academisch Ziekenhuis, Leiden.

Source: Ned Tijdschr Geneeskd, 1998 Jan, 142:4, 169-74.

Abstract: The first report of a positive effect of allogeneic bone marrow transplantation (BMT) on the clinical course in a patient with a lysosomal storage disease was described in 1981. Since then, over 200 patients have been treated in this way but data are scarce and fragmentary. Allogeneic BMT involves replacement of the patient's haemopoietic system by that of a donor. The new cells that repopulate the body can correct the metabolic disturbance. Most experience with allogeneic BMT was gained in patients with mucopolysaccharidosis type I, metachromatic leukodystrophy and adrenoleukodystrophy. Allogeneic BMT reduces the amount of storage material in internal organs: skeletal abnormalities and neurological symptoms are at best stabilized. Transplantation-related mortality and morbidity are high. The applicability of allogeneic BMT is limited.

SUBJECT: BMT

Title: The use of partially HLA-mismatched donors for allogeneic transplantation in patients with mucopolysaccharidosis-I [see comments].

Author: Fleming DR; Henslee Downey PJ; Ciocci G; Romond EH; Marciniak E; Munn RK; Thompson JS.

Address: University of Louisville School of Medicine, James Graham Brown Cancer Center, Division of Hematology/Oncology, KY, USA.

Source: Pediatr Transplant, 1998 Nov, 2:4, 299-304.

Abstract: Allogeneic bone marrow transplantation (BMT) from an HLA-matched sibling appears to improve survival and diminish some of the physiologic derangements seen in children with mucopolysaccharidosis (MPS)-I (Hurler Syndrome), an inherited metabolic storage disease resulting from the lack of alpha-L-iduronidase enzyme activity. Death is usually expected in the first decade of life. Unfortunately, most patients lack an HLA-matched sibling donor and alternative donors have been identified for transplant. This study reports on a five-year median follow-up (range: 985-2,355 days) in 11 Hurler Syndrome patients who underwent allogeneic BMT from partially mismatched related donors (PMRDs). The median age was 20 months (range: 11-44 months). The overall survival rate was 64% (95% CI 34-94%). The overall graft failure rate (36%) was higher than reported with matched sibling BMT. All patients with sustained engraftment experienced improvement in physical manifestations, such as corneal opacity, gum and tongue hypertrophy, hepatosplenomegaly and joint mobility. Skeletal abnormalities, such as dysostosis-multiplex, were stabilized but not reversed. Some patients have continued to show decline in neuropsychometric testing, while others appear to stabilize and one has demonstrated improvement. Until better methods for replacing enzyme activity are developed, BMT from a matched sibling of alternative donors can be considered a viable intervention for Hurler Syndrome patients to achieve partial improvement or stabilization from the deterioration caused by substrate storage, particularly in minimally affected patients early in life.

SUBJECT: Cardiac

Title: Cardiovascular changes in children with mucopolysaccharide storage diseases and related disorders--clinical and echocardiographic findings in 64 patients.

Author: Dangel JH.

Address: The Children Memorial Health Institute, Department of Cardiology, Warsaw, Poland. joanna@czd.waw.pl.

Source: Eur J Pediatr, 1998 Jul, 157:7, 534-8.

Abstract: Cardiovascular abnormalities were evaluated in 64 children aged between 1 year 9 months and 25 years with mucopolysaccharidoses (MPS) and related disorders. A heart murmur was heard in 18 patients, but in only 6 was it characteristic for specific valvular lesions. Echocardiography was performed in 63 children. In one girl cardiac lesions were diagnosed on autopsy. In 46 patients (72%), valvular lesions and/or different types of cardiomyopathy were detected. There were no characteristic changes for different types of MPS. In the majority of children in whom dermatan sulphate accumulated, cardiac involvement was the most frequent (88%) and severe. The most common lesion, regardless of MPS type, was thickening of the mitral valve (66%), with regurgitation or stenosis in 28 (44%). Aortic valve thickening was detected in 17 patients (27%), asymmetric septal hypertrophy or hypertrophic cardiomyopathy in 18, congestive cardiomyopathy in 1 and endocardial thickening in 13 patients. Cardiac involvement was less frequent in children with Sanfilippo disease. Two or more echocardiographic examinations were performed in 23 patients. In 19 of them (83%) cardiac changes were more severe during the second examination. One 7-year-old boy with Hunter disease underwent successful mitral valve replacement. CONCLUSIONS; Cardiac involvement is present in most patients with MPS although there are few clinical signs and symptoms. The most common and severe changes are in Hurler, Hunter, Maroteaux-Lamy and I-cell disease, rarely in Sanfilippo disease. Mitral valve deformation is most frequent in all patients. The cardiac lesions are progressive.

SUBJECT: ERT

Title: Recombinant -L-iduronidase replacement therapy in mucopolysaccharidosis I: Results of a human clinical trial.

Author: E. Kakkis1; J. Muenzer2; G. Tiller3; L. Waber4; J. Belmont5; M. Passage1; B. Izykowski1; J. Phillips6; I. Walot6; R. Doroshow1; R. Hoft7; K. T. Yu1; S. Okazaki8; D. Lewis9; R. Lachman6; E. F. Neufeld10.

Address: 1) Pediatrics, Harbor-UCLA Medical Ctr, Torrance, CA; 2) Univ. of North Carolina, Chapel Hill, NC; 3) Vanderbilt Univ., Nashville, TN; 4) Univ. of Texas Southwestern Medical Center, Dallas, TX; 5) Baylor College of Medicine, Houston, TX; 6) Radiology, Harbor-UCLA Medical Ctr, Torrance, CA; 7) Ophthalmology, Harbor-UCLA Medical Ctr, Torrance, CA; 8) Physical Therapy, Harbor-UCLA Medical Ctr, Torrance, CA; 9) Respiratory Medicine, Harbor-UCLA Medical Ctr, Torrance, CA; 10) Biological Chemistry, UCLA School of Medicine, Los Angeles, CA.

Source:On-line reference

Abstract: The treatment of mucopolysaccharidosis I (MPS I) by enzyme replacement therapy was proposed many years ago based on the in vitro corrective effects of the enzyme -L-iduronidase but the ability to test this therapy in human patients became possible only recently. Following a successful trial in canine MPS I, we enrolled 10 MPS I patients (8 Hurler-Scheie, 1 Hurler, 1 Scheie) in a 26 week treatment protocol. The patients were examined at baseline and infused with 125,000 units (~0.5 mg) per kg intravenously over 3-4 hours once each week. Biochemical and clinical labs are monitored every other week and repeat exams performed at 6, 12, and 26 weeks. Clinical changes include decreased fatigue,improved endurance,improved appetite and improved range of motion. Quantitative MRI studies demonstrate a 20% or more reduction in liver size in nearly all patients by 6-12 weeks. Enzyme levels in leukocytes increase from <0.1% to an average of 18% of normal levels before the next dose. Urinary glycosaminoglycan analysis shows a sharp drop in excretion by the 3rd to 4th dose and all patients achieve 60% or better reduction by 6-12 weeks. Quantitative range of motion measurements demonstrate 10-30° improvements in range of motion of shoulders, elbows and knees in some patients. Antibodies are present in many patients but the titers stabilize. Urticaria occurred in 4 patients but did not recur in 3. Complement activation occurred in 4 patients (only one with hives) and is symptomatic in one patient. All patients continue to receive therapy. To date, recombinant -L-iduronidase appears to be a promising treatment for many somatic features of MPS I disease.

SUBJECT: ERT

Title: Long-term and high-dose trials of enzyme replacement therapy in the canine model of mucopolysaccharidosis I.

Author: Kakkis ED; McEntee MF; Schmidtchen A; Neufeld EF; Ward DA; Gompf RE; Kania S; Bedolla C; Chien SL; Shull RM.

Address: Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, California, 90502, USA.

Source: Biochem Mol Med, 1996 Aug, 58:2, 156-67.

Abstract: Enzyme replacement is a potential therapy for mucopolysaccharidosis I (MPS I), a lysosomal storage disorder caused by alpha-L-iduronidase deficiency. Previous work showed improvement in the tissues of MPS I dogs treated intravenously for 3 months with recombinant human alpha-L-iduronidase (25,000 units or approximately 0.1 mg/kg/week). We have now treated an MPS I-affected dog for 13 months to assess the clinical effects of enzyme replacement. The treated dog gained more weight, was more active, and had less joint stiffness than the untreated littermate. Biochemical and histologic studies demonstrated uptake of alpha-L-iduronidase and decreased lysosomal storage in the liver, kidney, spleen, lymph nodes, synovium, adrenals, and lungs. The brain had detectable enzyme activity and decreased glycosaminoglycan storage although histologic improvement was not evident. Cartilage and heart valve did not show any detectable improvement. A fivefold higher dose (approximately 0.5 mg/kg) administered five times over 10 days to two other dogs resulted in higher tissue enzyme activity and similarly decreased glycosaminoglycan storage and excretion. Antibodies to human alpha-L-iduronidase were induced in all treated dogs and may be associated with immune complex deposition and proteinuria. Recombinant canine alpha-L-iduronidase also induced antibody formation to a similar degree. The results support the conclusion that enzyme replacement is a promising therapy for MPS I though immunologic complications may occur.

SUBJECT: ERT

Title: Enzyme replacement in a canine model of Hurler syndrome.

Author: Shull RM; Kakkis ED; McEntee MF; Kania SA; Jonas AJ; Neufeld EF.

Address: Department of Pathology, College of Veterinary Medicine, University of Tennessee, Knoxville 37916.

Source: Proc Natl Acad Sci U S A, 1994 Dec, 91:26, 12937-41.

Abstract: The Hurler syndrome (alpha-L-iduronidase deficiency disease) is a severe lysosomal storage disorder that is potentially amenable to enzyme-replacement therapy. Availability of a canine model of the disease and a sufficient supply of corrective enzyme have permitted a therapeutic trial lasting 3 mo. Recombinant human alpha-L-iduronidase, purified to apparent homogeneity from secretions of a stably transfected Chinese hamster ovary cell line, was administered i.v. to homozygous affected animals in doses of approximately 1 mg. The enzyme rapidly disappeared from the circulation in a biphasic manner, with t1/2 of 0.9 and 19 min, respectively, and was taken up primarily by the liver. Biopsy of the liver before and after a very short trial (seven doses administered over 12 days) showed remarkable resolution of lysosomal storage in both hepatocytes and Kupffer cells. After weekly administration of enzyme to three affected animals over a period of 3 mo, the level of enzyme was about normal in liver and spleen, lower but significant in kidney and lung, and barely detectable (0-5% of normal) in brain, heart valves, myocardium, cartilage, and cornea. Light and electron microscopic examination of numerous tissues showed normalization of lysosomal storage in liver, spleen, and kidney glomeruli, but there was no improvement in brain, heart valves, or cornea. Even though the treated dogs developed complement-activating antibodies against alpha-L-iduronidase, clinical symptoms could be prevented by slow infusion of enzyme and premedication.

SUBJECT: ERT

Title: Enzymes as agents for the treatment of disease.

Author: Goldberg DM.

Address: Department of Clinical Biochemistry, University of Toronto, Ontario, Canada.

Source: Clin Chim Acta, 1992 Mar 13, 206:1-2, 45-76.

Abstract: The replacement of genetically deficient enzymes in patients with inherited metabolic disorders by infusion of purified enzymes or by organ transplantation has had very limited success, although good results with bone marrow transplantation have been obtained in some patients with mucopolysaccharidosis, Gaucher disease and inherited immunodeficiency diseases. Genetic engineering of the patient's lymphocytes may ultimately render these approaches redundant, at least for some of these diseases. Treatment of chronic pancreatic insufficiency and of disaccharidase deficiency with oral enzymes can be very effective; therapy can be monitored in the latter by measuring the breath hydrogen excretion and in the former by a range of tests of which stool chymotrypsin assay is the most convenient. Treatment of acute myocardial infarction by intracoronary perfusion of thrombolytic enzymes can improve both cardiac function and long-term survival if given early enough. Successful reperfusion can be identified by changes in the kinetics of serum enzyme release and clearance, especially for the isoenzymes and isoforms of creatine kinase. In cancer chemotherapy, L-asparaginase has long been a useful adjunct in the treatment of acute lymphoblastic leukemia, but recent experience suggests a role in acute nonlymphoblastic leukemia as well.

SUBJECT: ERT

Title: Enzyme replacement therapy for murine mucopolysaccharidosis type VII leads to improvements in behavior and auditory function.

Author: OConnor LH; Erway LC; Vogler CA; Sly WS; Nicholes A; Grubb J; Holmberg SW; Levy B; Sands MS.

Address: Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri 63110, USA.

Source: J Clin Invest, 1998 Apr, 101:7, 1394-400.

Abstract: Mucopolysaccharidosis type VII (MPS VII; Sly syndrome) is one of a group of lysosomal storage diseases that share many clinical features, including mental retardation and hearing loss. Lysosomal storage in neurons of the brain and the associated behavioral abnormalities characteristic of a murine model of MPS VII have not been shown to be corrected by either bone marrow transplantation or gene therapy. However, intravenous injections of recombinant beta-glucuronidase initiated at birth reduce the pathological evidence of disease in MPS VII mice. In this study we present evidence that enzyme replacement initiated at birth improved the behavioral performance and reduced hearing loss in MPS VII mice. Enzyme-treated MPS VII mice performed similarly to normal mice and significantly better than mock- treated MPS VII mice in every phase of the Morris Water Maze test. In addition, the auditory function of treated MPS VII mice was dramatically improved, and was indistinguishable from normal mice. These data indicate that some of the learning, memory, and hearing deficits can be prevented in MPS VII mice if enzyme replacement therapy is initiated early in life. These data also provide functional correlates to the biochemical and histopathological improvements observed after enzyme replacement therapy.

SUBJECT: ERT

Title: Effect of enzyme replacement therapy on bone formation in a feline model of mucopolysaccharidosis type VI.

Author: Byers S; Nuttall JD; Crawley AC; Hopwood JJ; Smith K; Fazzalari NL.

Address: Department of Chemical Pathology, Women's and Children's Hospital, North Adelaide, Australia. sbyers@medicine.adelaide.edu.au.

Source: Bone, 1997 Nov, 21:5, 425-31.

Abstract: A range of skeletal abnormalities are evident in mucopolysaccharidosis type VI (MPS VI, Maroteaux-Lamy syndrome) including short stature and dysostosis multiplex, resulting from a deficiency in the lysosomal hydrolase N-acetylgalactosamine-4-sulphatase (4S). In this article, bone pathology was assessed in a feline model of MPS VI to evaluate the efficacy of enzyme replacement therapy (ERT) as a treatment modality for this genetic disorder. Osteopenia is clearly evident in MPS VI animals, with bone mineral volume (BV/TV) falling well below that of normal animals (4.39% vs. 20.11%, respectively). Trabecular bone architecture was also affected in MPS VI with fewer, thinner, and more widely spaced trabeculae apparent. Bone formation rate (BFR/BS) was also lower in MPS VI animals than controls (0.0011 mm3/mm2 per day vs. 0.008 mm3/mm2 per day, respectively). Vertebral and tibial bone length in MPS VI animals progressively fell behind normal values with increasing age, as did cortical bone thickness. Vertebral body shape was also altered. ERT with recombinant human 4S (rh4S) resulted in a vertebral BV/TV of 8.23% in animals treated with an intravenous enzyme dose of 1 mg/kg and a BV/TV of 14.33% in animals treated with a dose of 5 mg/kg. BFR/BS also increased to 0.0034 mm3/mm2 per day in animals treated with enzyme doses of either 1.0 or 5.0 mg/kg rh4S. All other affected histomorphometric parameters also improved with ERT to a level intermediate between MPS VI untreated animals and normals. However, individual animals treated with 0.2 mg/kg rh4S intravenously or 1.0 mg/kg rh4S administered subcutaneously did not exhibit an improvement over untreated MPS VI animals. Vertebral and tibial bone lengths, tibial cortical bone thickness, and vertebral body shape also responded to ERT, with a trend away from the untreated group. Thus, ERT had a positive effect on bone development in MPS VI animals that was dependent upon the dose of enzyme administered and the route of administration.

SUBJECT: ERT

Title: Immune response to enzyme replacement therapy: clinical signs of hypersensitivity reactions and altered enzyme distribution in a high titre rat model.

Author: Brooks DA; Hopwood JJ; King BM.

Address: Lysosomal Diseases Research Unit, Department of Chemical Pathology, Women's and Children's Hospital, North Adelaide, SA 5006, Australia. dbrooks@medicine.adelaide.edu.ac.

Source: Biochim Biophys Acta, 1998 Aug 14, 1407:2, 163-72.

Abstract: Immune responses to enzyme replacement therapy (ERT) have been reported and can result in a hypersensitivity/anaphylacti c reaction during or immediately after enzyme infusion. We have investigated the infusion of the lysosomal enzyme N-acetylgalactosamine 4-sulphatase (4-sulphatase) into immunized, high titre rats as a model of immune response to ERT. To simulate ERT, high and low titre rats were infused with different doses of radiolabelled recombinant human 4-sulphatase (3H-rh4S). There was evidence of altered targeting, inactivation and degradation of 4-sulphatase in high titre (titre 1024000) compared to low titre (titre 64) rats. There was more 4-sulphatase enzyme activity detected in 5 mg/kg high titre rats when compared to 1 mg/kg high titre rats, suggesting that the antibodies could be saturable in vivo. However, the rats treated with 5 mg/kg 3H-rh4S all had clinical signs of hypersensitivity reactions to 4-sulphatase infusion. There were no apparent signs of adverse reactions in either the high titre 1 mg/kg rats or the low titre rats (1, 5 mg/kg). The high titre 5 mg/kg rats also had changes in 3H-rh4S distribution, with lower levels delivered to the liver and a marked increase in the level remaining in plasma, when compared to either 1 mg/kg high titre rats or low titre rats (1, 5 mg/kg).

SUBJECT: Gene Therapy

Title: Gene therapy in lysosomal diseases.

Author: Moullier P; Salvetti A; Bohl D; Danos O; Heard JM.

Address: Laboratoire RÆetrovirus et Transfert gÆenÆetique, Institut Pasteur, Paris, France.

Source: C R Seances Soc Biol Fil, 1996, 190:1, 45-51.

Abstract: The study of the mechanisms of secretion and recapture of lysosomal enzymes has lead to the proposal of a treatment of lysosomal diseases by enzyme replacement. Autologous implants of genetically modified cells which secrete enzymes ensure systemic distribution of the lacking enzyme. A procedure which permits reimplantation of genetically modified fibroblasts is described. The stable secretion of human glucuronidase by autologous fibroblasts was thus obtained in animal species. This approach should by applicable to the treatment of Hurler's syndrome by obtaining the production and distribution of alpha-L-iduronidase in patients lacking this enzyme by retroviral transfer of the human alpha-L-iduronidase gene to cultured fibroblasts and by preparation of implants.

SUBJECT: Gene Therapy

Title: Towards gene therapy of Hurler syndrome.

Author: Fairbairn LJ; Lashford LS; Spooncer E; McDermott RH; Lebens G; Arrand JE; Arrand JR; Bellantuono I; Holt R; Hatton CE; Cooper A; Besley GT; Wraith JE; Anson DS; Hopwood JJ; Dexter TM.

Address: Department of Experimental Haematology, Paterson Institute for Cancer Research, Christie Hospital NHS Trust.

Source: Cas Lek Cesk, 1997 Jan, 136:1, 27-31.

Abstract: Allogeneic bone marrow transplantation is the most effective treatment for Hurler's syndrome. However, due to a lack of matched related donors and unacceptable morbidity of matched unrelated transplants, this therapy is not available to all patients. Therefore we have been developing an alternative approach based on transfer and expression of the normal gene in autologous bone marrow. A retroviral vector carrying the full length cDNA for alpha-L-iduronidase has been constructed and used to transduce bone marrow from patients with this disorder. A number of different gene transfer protocols have been assessed including the effect of intensive schedules of exposure of bone marrow to viral supernatant and the influence of growth factors. With these protocols we have demonstrated successful gene transfer into primitive CD34+ cells and subsequent enzyme expression in their maturing progeny. Also, using long-term bone marrow cultures, we have demonstrated high levels of enzyme expression sustained for several months. The efficiency of gene transfer has been assessed by PCR analysis of haemopoietic colonies as around 50%. No advantage has been demonstrated for the addition of growth factors or intensive viral exposure schedules. Indeed a possible disadvantage has been identified for the use of intensive transduction procedures. The enzyme is secreted into the medium and functional localisation has been demonstrated by reversal of the phenotypic effects of lysosomal storage in macrophages. This pre-clinical work forms the basis for a clinical trial of gene therapy for Hurler syndrome.

SUBJECT: Gene Therapy

Title: Myoblast gene therapy in canine mucopolysaccharidosis. I: Abrogation by an immune response to alpha-L-iduronidase.

Author: Shull RM; Lu X; McEntee MF; Bright RM; Pepper KA; Kohn DB.

Address University of Tennessee College of Veterinary Medicine, Department of Pathology, Knoxville 37996, USA.

Source: Hum Gene Ther, 1996 Aug, 7:13, 1595-603.

Abstract: Three dogs with deficiency of the lysosomal enzyme alpha-L-iduronidase were treated by gene replacement therapy targeted at muscle. Direct intramuscular injections of plasmid encoding the alpha-L-iduronidase gene cDNA resulted in no detectable enzyme production, but may have resulted in immunologic sensitization to iduronidase protein, which the dogs lack totally. Myoblasts were grown from skeletal muscle biopsies and transduced with a retroviral vector containing the canine gene under control of the muscle creatine kinase enhancer. Several hundred-fold overexpression of enzyme production occurred in cultured cells; however, following reintroduction of the cultured cells into dogs, enzyme production declined rapidly. Concurrent with the falling enzyme levels, there was production of specific immunoglobulin G (IgG) antibody against iduronidase that was further associated with cellular infiltration of the myoblast injection sites. Most inflammatory cells were lymphocytes and plasma cells, suggesting local humoral and cellular immune responses to the enzyme-producing muscle cells. PCR analysis of tissues collected 2-22 weeks after the final treatment showed the persistence of Neo and canine alpha-L-iduronidase sequences in a progressively decreasing percentage of myoblasts. Results from this study in a canine model of mucopolysaccharidosis I underscore the fact that immunologic reactions to cells producing desirable, normal, but foreign, proteins may be as much an impediment to gene therapy as reactions to the viral vectors used to introduce the foreign gene.

SUBJECT: General Research

Title: Mucopolysaccharidoses--current aspects of diagnosis and therapy.

Author: Fang Kircher S.

Address: Institut fÂur Medizinische Chemie, UniversitÂat Wien.

Source: Wien Klin Wochenschr, 1995, 107:22, 698-701.

Abstract: The mucopolysaccharidoses, first described at the beginning of this century, are still subject of research. The accumulation of pathological metabolites and the underlying enzyme defects are now correlated to specific gene mutations. A comparison of genotype and phenotype of the individual forms of the mucopolysaccharidoses is the subject of ongoing studies. In many cases, symptomatic treatment was not able to increase the quality of life of patients suffering from mucopolysaccharidosis to a satisfactory degree. International working groups are, thus, currently trying to improve and standardize symptomatic therapies. A causal therapeutic approach was attempted by implanting different cells and tissues that are able to produce the missing enzymes. Bone-marrow transplantations were also performed, but both treatment approaches were not very effective and in some cases even proved fatal for the patients. An intensive international research effort focuses on enzyme-replacement therapy and gene therapy. Mucopolysaccharidoses are rare diseases, affecting only about one hundred patients in Austria. Nevertheless, Austria plays an active role in researching these metabolic disorders.

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