Natural history of craniovertebral abnormalities in a single-center study in 54 patients with Hurler syndrome.

OBJECTIVE: Craniovertebral junction (CVJ) abnormalities are common and well documented in mucopolysaccharidosis type I-Hurler syndrome (MPS IH), often causing severe spinal canal narrowing. However, the requirement for surgical decompression and/or fusion is uncommon. Although hematopoietic cell transplant (HCT) has been shown to prolong the lives of patients with MPS IH, its effect in halting or reversing musculoskeletal abnormalities is less clear. Unfortunately, there are currently no universal guidelines for imaging or indication for surgical interventions in these patients. The goal of this study was to track the progression of the CVJ anatomy in patients with MPS IH following HCT, and to examine radiographic features in patients who needed surgical intervention. METHODS: Patients with MPS IH treated at the University of Minnesota with allogeneic HCT between 2008 and 2020 were retrospectively reviewed. Patients who underwent CVJ surgery were identified with chart review. All MPS IH cervical scans were examined, and the odontoid retroflexion angle, clivoaxial angle (CXA), canal width, and Grabb-Oakes distance (pB-C2) were measured yearly for up to 7 years after HCT. Longitudinal models based on the measurements were made. An intraclass correlation coefficient was used to measure interrater reliability. Nine children without MPS IH were examined for control CVJ measurements. RESULTS: A total of 253 cervical spine MRI scans were reviewed in 54 patients with MPS IH. Only 4 (7.4%) patients in the study cohort required surgery. Three of them had posterior fossa and C1 decompression, and 1 had a C1-2 fusion. There was no statistically significant difference in the spinal parameters that were examined between surgery and nonsurgery groups. Among the measurements, canal width and CXA varied drastically in patients with different neck positions. Odontoid retroflexion angle and CXA tended to decrease with age. Canal width and pB-C2 tended to increase with age. CONCLUSIONS: Based on the data, the authors observed an increase in canal width and pB-C2, whereas the CXA and odontoid retroflexion angle became more acute as the patients aged after HCT. The longitudinal models derived from these data mirrored the development in children without MPS IH. Spinal measurements obtained on MR images alone are not sufficient in identifying patients who require surgical intervention. Symptom monitoring and clinical examination, as well as pathological spinal cord changes on MRI, are more crucial in assessing the need for surgery than is obtaining serial imaging.

Long-Term Outcomes of Big Bubble Deep Anterior Lamellar Keratoplasty in Mucopolysaccharidoses: A Retrospective Case Series and Review of the Literature.

PURPOSE: The purpose of this study was to report the long-term surgical and visual outcomes of patients with mucopolysaccharidoses (MPS) after big bubble deep anterior lamellar keratoplasty (BB-DALK). METHODS: This was a retrospective case series of patients with MPS who underwent BB-DALK at a single academic institution. All patients had corneal clouding secondary to MPS limiting visual acuity for which keratoplasty was indicated. Each patient was evaluated and underwent surgery by a single surgeon. Reported data included age at keratoplasty, sex, MPS type, best spectacle-corrected visual acuity, change in pachymetry, ocular comorbidities, surgical complications, and MPS-related medication use. RESULTS: Outcomes of 12 eyes from 7 patients with MPS type I (Hurler, Scheie, and Hurler-Scheie) are reported using the newest nomenclature. The mean follow-up was 5.58 years (range: 1-10 years). All cases underwent BB-DALK with a type 1 big bubble during the surgery. Two cases (16.6%) required rebubbling because of partial Descemet membrane detachment. One case was complicated by a suture abscess and required a penetrating keratoplasty. No episodes of rejection occurred. Statistically significant improvement in the best spectacle-corrected visual acuity (from a mean 0.85-0.33 logarithm of the minimum angle of resolution, P = logarithm of the minimum angle of resolution 0.0054) and pachymetry (mean reduction of -145.4 µm, P = 0.0018) was observed. CONCLUSIONS: BB-DALK seems to be an acceptable long-term surgical option in patients with MPS. Our findings suggest that this technique is reproducible and can achieve clear corneal grafts with good visual results on a long-term follow-up.

Evidence of Treatment Benefits in Patients with Mucopolysaccharidosis Type I-Hurler in Long-term Follow-up Using a New Magnetic Resonance Imaging Scoring System.

We developed a brain and spine magnetic resonance scoring system based on a magnetic resonance assessment of 9 patients with mucopolysaccharidosis type I-Hurler who underwent hematopoietic stem-cell transplantation. The score is reliable and correlates with long-term clinical and cognitive outcome in patients with mucopolysaccharidosis type I-Hurler.

Mucopolysaccharidosis Type I-Associated Corneal Disease: A Clinicopathologic Study.

PURPOSE: To report the anterior segment clinical features and histopathologic and histochemical characteristics of explanted corneas from the largest reported cohort of patients with Hurler syndrome and other variants of mucopolysaccharidosis (MPS) I undergoing corneal transplantation. DESIGN: Retrospective observational case series. METHODS: This institutional study reviewed 15 corneas from 9 patients with MPS I spectrum disease who underwent corneal transplant to treat corneal clouding between May 2011 and October 2020. We reviewed the clinical data, hematoxylin-eosin-stained sections, and histochemical stains, including those for mucopolysaccharides (Alcian blue and/or colloidal iron). The main outcome measures were pathology observed under light microscopy and postsurgical clinical outcomes. RESULTS: Nine patients underwent 15 corneal transplants for corneal clouding (14/15 procedures were deep anterior lamellar keratoplasty). All corneas had mucopolysaccharide deposition visible on hematoxylin-eosin-stained sections, which was highlighted in blue with histochemical stains. All corneas also showed alterations in Bowman's layer and the majority also showed epithelial abnormalities. CONCLUSION: MPS I shows significant corneal clouding that is successfully treated with deep anterior lamellar keratoplasty. The excised corneas show characteristic epithelial changes, disruption or breaks in Bowman's membrane, and amphophilic collections of stromal granular mucopolysaccharides which are visible on hematoxylin-eosin-stained sections and highlighted by special histochemical stains (Alcian blue and collodial iron). These changes, although subtle, should alert the pathologist to the possibility of an underlying lysosomal storage disorder.

Quantifying the Effects of Hip Surgery on the Sphericity of the Femoral Head in Patients with Mucopolysaccharidosis Type I.

BACKGROUND: The introduction of stem cell transplantation has improved life expectancy and cognitive outcome in patients with mucopolysaccharidosis I, but this condition remains associated with substantial residual disease in several parts of the body. Many patients have hip dysplasia with progressive medial flattening of the femoral head. Quantitative evidence on the effect of surgery on remodeling to sphericity of flattened femoral heads is lacking. In the present study, we used statistical shape modeling to quantify the effect of hip surgery on the sphericity of the femoral head in patients with mucopolysaccharidosis I. METHODS: We performed a retrospective case control study involving a series of 23 patients with hip dysplasia due to mucopolysaccharidosis I. Surgery was not offered to the first 11 children (control group). Following a change in treatment protocol, the next 12 children underwent bilateral proximal femoral varus derotation osteotomy and Pemberton osteotomy for the treatment of acetabular dysplasia with progressive femoral head flattening (surgery group). The surgery and control groups were compared with a reference group of patients with normal hips. Statistical shape modeling was used to quantify the shape of the femoral head (i.e., flattening and/or roundness of the epiphysis). RESULTS: The mean age at the time of stem cell transplantation in the surgery and control groups was comparable (1.2 years). The mean age at the time of surgical intervention was 5.5 years, and mean duration of postoperative follow-up was 3.3 years. Statistical shape modeling showed variations within the total group in terms of medial indentation, width, height, and sphericity of the femoral heads. In contrast to the progressive femoral head flattening in the control group, the surgery group showed improvement of the sphericity of the femoral head after surgery. The overall shape characteristics of the femoral head in the surgery group were similar to those of the reference group of patients with normal hips. CONCLUSIONS: To our knowledge, this is the first study in patients with mucopolysaccharidosis I that has shown quantitative remodeling of the dysplastic, flattened femoral head to normal sphericity after increasing containment of the femoral head. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Multimodal imaging of Hurler syndrome-related keratopathy treated with deep anterior lamellar keratoplasty.

BACKGROUND: Hurler syndrome-associated keratopathy is an exceedingly rare corneal disorder that requires corneal transplantation in advanced stages. Precise assessment of the corneal condition is necessary for deciding which type of keratoplasty (i.e., deep anterior lamellar or penetrating) should be proposed. We aimed to confront the results of multimodal imaging with those of histology in a case of Hurler syndrome-associated keratopathy. CASE PRESENTATION: A 16-year-old patient with Hurler's syndrome treated with hematopoietic stem cell transplantation was referred for decreased vision related to advanced keratopathy. The patient was treated with deep anterior lamellar keratoplasty (DALK) in both eyes with uncomplicated outcome. Visual acuity improved from 0.1 (20/200) preoperatively to 0.32 (20/63) and 0.63 (20/32) after transplantation. The corneal endothelial cell density was 2400 cells/mm2 in both eyes 3 years after transplantation. In vivo confocal microscopy (IVCM) and spectral domain optical coherence tomography (SD-OCT) were performed preoperatively. The corneal buttons retrieved during keratoplasty were processed for histology. In SD-OCT scans, corneal opacities appeared as diffuse stromal hyperreflectivity associated with increased corneal thickness. IVCM showed diffuse cytoplasmic granular hyperreflectivity and rounded/ellipsoid aspects of keratocytes, presence of small intracellular vacuoles, and hyperreflective epithelial intercellular spaces. Bowman's layer was thin and irregular. The corneal endothelium was poorly visualized but no endothelial damage was observed. Histology showed irregular orientation and organization of stromal lamellae, with the presence of macrophages whose cytoplasm appeared clear and granular. A perinuclear clear halo was visible within the epithelial basal cells. Bowman's layer featured breaks and irregularities. CONCLUSIONS: The observed corneal multimodal imaging features in mucopolysaccharidosis-related keratopathy were concordant with histology. Compared with standard histology, multimodal imaging allowed additional keratocyte features to be observed. It revealed both morphological and structural changes of all corneal layers but the endothelium. This information is essential for therapeutic management which should include DALK as the first-choice treatment in case of impaired visual acuity.

Improvement in functional gait parameters following corrective thoracolumbar surgery in children affected by Mucopolysaccharidosis 1 (Hurler syndrome).

OBJECTIVE: Thoracolumbar kyphosis is a common indication for spinal surgery in children with Mucopolysaccharidosis. Functional outcome of spinal surgical intervention has never been published in patients with this rare disease. We present a cohort of patients with Mucopolysaccharidosis 1(Hurler syndrome) who underwent thoraco-lumbar spinal deformity correction and functional outcome assessed by pre-operative and post-operative gait analysis. This study represents the first attempt at presenting a functional assessment of surgical outcome in any Mucopolysaccharidosis subtype. METHODS: A retrospective analysis of prospectively collected data was carried out from 11 children diagnosed with this subtype of Mucopolysaccharidosis. All patients underwent thoracolumbar kyphosis correction between the years 2013 to 2016. Gait assessment was performed using GAITRite™ electronic walkway pre-operatively and post-operatively within 9 to 24 months from the index surgery. Walking distance, cadence and gait velocity were the three spatio-temporal parameters analysed. Wilcoxon signed rank test was used to analyse the data and P-Value ≤0.05 was deemed significant. RESULTS: There was a statistically significant improvement in walking distance in 9 out of 11 patient post-operatively with a mean increase of 232.06 cms (P = 0.05). There was marginal improvement in cadence by 6.33 steps/min post-operatively (P-value 0.79). Gait velocity also showed a marginal increase by 8.73 cms/sec post-operatively (P-value 0.32). CONCLUSION: The results of our study suggest that correction of thoracolumbar kyphosis in children with Mucopolysaccharidosis 1 resulted in a significant improvement of walking distance with a trend towards improved gait in the other parameters. Post-operative change in cadence was not statistically significant suggesting that physiological maturation of gait had minimal effect in the specified post-operative assessment timeframe. This study emphasizes that outcomes of spinal surgery in children with Mucopolysaccharidosis 1 should be determined by functional measures aiming to maintain or improve quality of life.

Post-transplant laronidase augmentation for children with Hurler syndrome: biochemical outcomes.

Allogeneic hematopoietic cell transplantation (HCT) benefits children with Hurler syndrome (MPS-IH). However, survivors remain burdened by substantial MPS-IH related residual disease. We studied the feasibility, safety and biochemical impact of augmentative recombinant intravenous enzyme replacement therapy (IV-ERT) post transplantation. Ten children with MPS-IH and ≥2 years from successful HCT underwent IV-ERT for 2 years' duration. Patients were monitored for anti-drug antibody (ADA) development, including inhibitory capacity and changes in urinary excretion of glycosaminoglycans (uGAG). Three patients demonstrated low-level ADA at baseline, though all children tolerated IV-ERT well. Eight patients developed ADA over the 2-year study, with 3 (38%) meeting criteria for an inhibitory ADA response. The aggregate cohort experienced a reduction in uGAG from baseline to study end, which was enhanced in children with low or no ADA response. Conversely, children with inhibitory ADA showed increase in uGAG over time. IV-ERT in previously transplanted children with MPS-IH appears safe and can reduce uGAG, although this is reversed by the presence of inhibitory ADA. These data show a biochemical change after initiation of post-HCT IV-ERT, but the occurrence of ADA and inhibitory antibodies are a concern and should be monitored in future efficacy trials. This trial was registered at www.clinicaltrials.gov , NCT01173016, 07/30/2010.

Ampliação do transplante de células-tronco hematopoiéticas para mucopolissacaridose tipo I / Extension of hematopoietic stem cell transplantation for mucopolysaccharidosis type I

INTRODUÇÃO: A mucopolissacaridose do tipo I (MPS I) é uma doença lisossômica progressiva, de herança autossômica recessiva, causada pela atividade deficiente da alfa-L-iduronidase (IDUA), enzima codificada pelo gene IDUA. A IDUA é responsável pela clivagem dos resíduos de ácido idurônico dos glicosaminoglicanos (GAGs) heparan e dermatan sulfato. Na MPS I ocorre o acúmulo desses GAG parcialmente degradados no interior dos lisossomos e o aumento da sua excreção na urina [1]. Em consequência, os pacientes apresentam comprometimento dos sistemas respiratório, nervoso, musculoesquelético, gastrointestinal (fígado e baço) e cardiovascular, entre outros. A MPS I está associada a três formas clássicas, que diferem entre si com base na presença de comprometimento neurológico, na velocidade de progressão da doença e na gravidade do acometimento dos órgãos-alvo [1]: -Forma grave (síndrome de Hurler): os pacientes costumam ser diagnosticados até os 2 anos de idade, apresentar atraso de desenvolvimento cognitivo aparente entre os 14 e 24 meses e estatura geralmente inferior a 110 cm. A história clínica é dominada por problemas respiratórios: a maioria das crianças apresenta história de infecção de vias aéreas, otite média recorrente e rinorreia. É o fenótipo mais grave da MPS I [2], envolvendo ainda características faciais grosseiras, hepatoesplenomegalia, valvulopatia cardíaca, opacificação de córnea, hidrocefalia e manifestações musculoesqueléticas, como rigidez, contraturas e disostose múltipla. O óbito ocorre geralmente durante a primeira década de vida por insuficiência cardíaca ou respiratória [3]; -Forma intermediária ou moderada (síndrome de Hurler-Scheie): esses pacientes costumam apresentar evidência clínica da doença entre os 3 e 8 anos de idade. A baixa estatura final é relevante, a inteligência pode ser normal, e a sobrevivência até a idade adulta é comum [3]; -Forma atenuada (síndrome de Scheie): a sintomatologia desses pacientes costuma iniciar-se entre os 5 e 15 anos de idade e progride de forma lenta. O curso clínico é dominado por problemas ortopédicos, e a altura final é normal ou quase normal, assim como o tempo de vida, o qual, entretanto, pode se mostrar reduzido pela doença cardíaca [3]. METODOLOGIA E ESTUDOS SELECIONADOS: A busca de evidências foi realizada no Pubmed utilizando a seguinte estratégia: "Bone Marrow Transplantation"[Mesh] AND "Mucopolysaccharidosis I"[Mesh] OR ("Stem Cell Transplantation"[Mesh]) AND "Mucopolysaccharidosis I"[Mesh], limitado para estudos em humanos. O resultado foram 191 artigos, destes nenhum ensaio clínico, mas para a melhor tomada de decisão foram selecionados os estudos com maior número de pacientes e desfechos relevantes [22­33]. Além disso, foram avaliados dois relatos de casos brasileiros encontrados [34,35] e um estudo recente avaliando a implementação de um protocolo internacional para TCTH alogênico em pacientes com mucopolissacaridose [36]. RESULTADOS: O TCTH (alogênico mieloablativo) foi eficaz em reduzir a progressão de alguns desfechos em crianças com MPS I grave [22,27,28,37­39]. Entre os efeitos positivos dessa terapia encontram-se a diminuição da hepatoesplenomegalia, da opacificação de córnea e das complicações cardiopulmonares. Segundo Wraith et al. (2007), o TCTH parece não ter efeito sobre as anormalidades esqueléticas, sobre a valvulopatia cardíaca e no comprometimento ocular [20]. Segundo estudo de Fahnehjelm et al., entretanto, o TCTH alogênico parece reduzir, porém, não eliminar a opacificação de córnea [40]. O TCTH (alogênico mieloablativo) foi eficaz em reduzir a progressão de alguns desfechos em crianças com MPS I grave [22,27,28,37­39]. Entre os efeitos positivos dessa terapia encontram-se a diminuição da hepatoesplenomegalia, da opacificação de córnea e das complicações cardiopulmonares. Segundo Wraith et al. (2007), o TCTH parece não ter efeito sobre as anormalidades esqueléticas, sobre a valvulopatia cardíaca e no comprometimento ocular [20]. Segundo estudo de Fahnehjelm et al., entretanto, o TCTH alogênico parece reduzir, porém, não eliminar a opacificação de córnea [40]. Os pacientes avaliados foram transplantados com idades variando entre 0,2 e 7,9 anos e foram seguidos por períodos igualmente variáveis, mas em geral superior a 5 anos [22­33]. Nos estudos brasileiros, os pacientes foram transplantados com idades de 2-4 anos em um estudo (n=3) [34] e 1,9 e 2,2 anos em outro (n=2) [35]. Apesar da heterogeneidade da doença tornar mais difícil a interpretação dos resultados, dados disponíveis demonstram os seguintes resultados: A taxa de mortalidade relatada foi se reduzindo ao longo do tempo, de 49% de sobrevida em 2 anos num estudo de 1996 [25], a 77% em 3 anos [47] a 86% de sobrevida em 5 anos [31]. Vale relatar outro estudo publicado em 2017 e avaliando o TCTH alogênico nas MPSs (n=62 pacientes, MPS I n=56), cuja sobrevida global foi excelente (95,2%) e a vida livre de eventos (90,3%) com baixa toxicidade: 13,3% e 14,8% de doença do enxerto contra o hospedeiro aguda e crônica, respectivamente [36]. Quanto à funcionalidade e qualidade de vida: a pontuação de uma escala que avalia comportamento adaptativo foi melhor em pacientes transplantados antes dos 2 anos de idade, quando comparados transversalmente a um grupo não transplantado [32]. A capacidade cognitiva, e não a idade, no transplante correlacionou-se significativamente com o nível adaptativo final. Outro estudo com 47 pacientes transplantados entre 6 e 44 meses não apresentou impacto significativo do tipo de transplante, número de transplantes, idade no transplante, tempo desde o transplante no funcionamento adaptativo; no entanto, indivíduos submetidos a TCTH em uma idade mais avançada relataram qualidade de vida física mais pobre. [49] DISCUSSÃO E CONCLUSÃO: A morbi-mortalidade relacionada ao TCTH alogênico vem reduzindo-se progressivamente com o advento de novos protocolos, imunossupressores, melhor seleção dos pacientes candidatos e doadores [36]. Além disso é válido salientar que a TRE intravenosa não atravessa a barreira hematoencefálica e deve ser realizada semanalmente por toda a vida, fatos que podem contribuir para considerar a TCTH como alternativa terapêutica. Deste modo, o TCTH alogênico mieloablativo aparentado (preferencialmente com doadores homozigotos normais, ou seja, não portadores de mutações patogênicas no gene IDUA) e não aparentado parece ter um risco de morbi-mortalidade progressivamente menor ao passar dos anos e alguns efeitos positivos na MPS I, especialmente nos pacientes com idade de 2,5 anos ou menos. Uma vez que a média de idade ao diagnóstico para MPS I na população brasileira é de aproximadamente 6 anos [55] e que há consenso sobre benefícios do TCTH se realizado até 3 anos de idade, o TCTH alogênico está indicado até 3 anos de idade.

A Case of a Bilateral Cicatricial Upper Eyelid Entropion After Hematopoietic Stem Cell Transplantation in Mucopolysaccharidosis Type I.

Minor eyelid abnormalities are commonly encountered in mucopolysaccharidosis, but only rarely leading to a clinically relevant situation. The authors report a clinical case of severe bilateral cicatricial entropion of the upper eyelids, leading to recurrent conjunctival infections, corneal erosion, persistent epiphora, and a major decline in life quality in a 7-year-old boy with mucopolysaccharidosis type I who underwent hematopoietic stem cell transplantation at 1.6 years old. A bilateral anterior lamellar repositioning including eyelid split and cryoepilation was performed to correct bilateral upper eyelid entropium and trichiasis. Three months after the surgical intervention, the patient showed a persistent regular eyelid position with only mild recurrent right-sided lateral upper eyelid entropion. A significant reduction in conjunctival infections and epiphora with complete discontinuation of topical therapy was achieved. Although mucopolysaccaridosis is associated with eyelid abnormalities, the authors conclude that the described case is most likely due to chronic graft versus host disease.

Neurological outcomes after hematopoietic stem cell transplantation for cerebral X-linked adrenoleukodystrophy, late onset metachromatic leukodystrophy and Hurler syndrome.

OBJECTIVE: To describe survival and neurological outcomes after HSCT for these disorders. METHODS: Seven CALD, 2 MLD and 2 MPS-IH patients underwent HSCT between 2007 and 2014. Neurological examinations, magnetic resonance imaging, molecular and biochemical studies were obtained at baseline and repeated when appropriated. RESULTS: Favorable outcomes were obtained with 4/5 related and 3/6 unrelated donors. Two patients died from procedure-related complications. Nine transplanted patients were alive after a median of 3.7 years: neurological stabilization was obtained in 5/6 CALD, 1/2 MLD, and one MPS-IH patient. Brain lesions of the MPS-IH patient were reduced four years after HSCT. CONCLUSION: Good outcomes were obtained when HSCT was performed before adulthood, early in the clinical course, and/or from a related donor.

Neurological outcomes after hematopoietic stem cell transplantation for cerebral X-linked adrenoleukodystrophy, late onset metachromatic leukodystrophy and Hurler syndrome / Desfechos neurológicos após transplante de células tronco hematopoiéticas na adrenoleucodistrofia ligada ao X, forma cerebral, na leucodistrofia metacromática de início tardio e na síndrome de Hurler

ABSTRACT Hematopoietic stem cell transplantation (HSCT) is the only available treatment for the neurological involvement of disorders such as late-onset metachromatic leukodystrophy (MLD), mucopolysaccharidosis type I-Hurler (MPS-IH), and X-linked cerebral adrenoleukodystrophy (CALD). Objective To describe survival and neurological outcomes after HSCT for these disorders. Methods Seven CALD, 2 MLD and 2 MPS-IH patients underwent HSCT between 2007 and 2014. Neurological examinations, magnetic resonance imaging, molecular and biochemical studies were obtained at baseline and repeated when appropriated. Results Favorable outcomes were obtained with 4/5 related and 3/6 unrelated donors. Two patients died from procedure-related complications. Nine transplanted patients were alive after a median of 3.7 years: neurological stabilization was obtained in 5/6 CALD, 1/2 MLD, and one MPS-IH patient. Brain lesions of the MPS-IH patient were reduced four years after HSCT. Conclusion Good outcomes were obtained when HSCT was performed before adulthood, early in the clinical course, and/or from a related donor.

RESUMO O transplante de células tronco hematopoiéticas (TCTH) é o único tratamento disponível para o envolvimento neurológico de doenças como a leucodistrofia metacromática (MLD), a mucopolissacaridose tipo I-Hurler (MPS-IH) e a adrenoleucodistrofia (CALD). Objetivos Descrever a sobrevida e os desfechos neurológicos após o TCTH nessas doenças. Métodos Sete pacientes CALD, 2 MLD e 2 MPS-IH realizaram TCTH entre 2007 e 2014. Avaliações neurológicas, ressonância nuclear magnética e estudos bioquímicos e moleculares foram feitos no baseline e repetidos quando apropriado. Resultados Desfechos favoráveis foram obtidos em 4/5 TCTH de doadores relacionados e em 3/6 não relacionados. Dois pacientes faleceram de complicações do procedimento. Nove transplantados sobreviveram após uma mediana de 3,7 anos: estabilização neurológica foi obtida em 5/6 CALD, ½ MLD e em um caso MPS-IH. As lesões encefálicas de um caso MPS-IH reduziram-se quatro anos após o TCTH. Conclusão Bons desfechos foram obtidos quando o TCTH foi feito antes da vida adulta, cedo no curso clínico e/ou a partir de um doador relacionado.

Urgent resection of a giant left atrial appendage aneurysm and mitral valve replacement in a complex case of Hurler-Scheie syndrome.

Hurler-Scheie syndrome is a rare lysosomal storage disease affecting the cardiovascular system. Besides the cardiac manifestations, it presents with complications from abnormal proteoglycan deposition in soft tissues in many locations, resulting in joint contractures, paraplegia, impaired vision, airway narrowing and restrictive lung function, to name a few. There are very few reports of surgical management of valvular heart disease due to mucopolysaccharidosis (MPS). We describe the successful management of a patient with an extremely challenging case of mitral valve stenosis and a giant left atrial appendage aneurysm due to MPS type 1 (Hurler-Scheie syndrome). The patient underwent mitral valve replacement and excision of the giant left atrial appendage aneurysm; a similar case has not been previously reported.

Total hip arthroplasty in very young bone marrow transplant patients.

Concerns remain about total hip arthroplasty (THA) performed in very young patients, especially those with complex medical history such as allogeneic bone marrow transplantation (ABMT). This study retrospectively reviews the perioperative courses and functional outcomes of ABMT patients <21 years old undergoing primary uncemented THA. Nine THAs were performed in five ABMT patients at an average age of 19.7 years. The interval between ABMT and THA was 73.0 months with clinical follow-up of 25.8 months. Harris Hip Scores (HHS) increased dramatically from preoperatively 44.5 (range, 31.1-53.4) to postoperatively 85.2 (range, 72.0-96.0) and all patients subjectively reported a good (four hips) to excellent (five hips) overall outcome. There was one reoperation for periprosthetic fracture fixation but there were no infections or revisions performed. Despite the history of severe hematopoietic conditions requiring ABMT, these very young patients do appear to have improved pain and function following primary THA with short-term follow-up.

Airway-related symptoms and surgeries in patients with mucopolysaccharidosis I.

OBJECTIVE: Mucopolysaccharidosis I (MPS I) is a progressive, debilitating, and life-threatening genetic disease, which, owing to the nonspecific nature of the early symptoms, is often unrecognized and associated with significant diagnostic delays. To improve early recognition leading to early diagnosis and initiation of treatment, we characterized the extent of airway-related symptoms and surgeries among patients with MPS I. METHODS: Analysis of the frequency of airway-related symptoms and surgeries from 1041 patients enrolled in the MPS I Registry and correlation with other systemic manifestations of MPS I. RESULTS: Airway-related symptoms (macroglossia, enlarged tonsils, reactive airway disease/asthma, or sleep disturbances) were reported for as many as 85% of Hurler, 83% of Hurler-Scheie, and 65% of Scheie patients-very often before the diagnosis of MPS I was established. Surgeries for an airway indication were reported in 39% of patients and many had at least 1 airway-related surgery before the diagnosis of MPS I was confirmed. The mean percentage of patients with airway-related symptoms for whom hernias and/or dysostosis multiplex were also reported was 84% and 54%, respectively. CONCLUSION: Airway-related symptoms and surgeries are common and often the earliest presenting feature in MPS I. Improved recognition of early MPS I disease manifestations may lead to earlier diagnosis and treatment.

Mucopolysaccharidosis type I.

Mucopolysaccharidosis type I (MPS I) is caused by a deficiency of the lysosomal hydrolase a-L-Iduronidase leading to accumulation of the GAGs, dermatan sulfate, and heparan sulphate, The disease spectrum includes a disorder with severe involvement and CNS disease Hurler disease (HPS I H) a chronic disease without CNS disease Scheie disease (HPS I S5) and the intermediate Hurler/Scheie disease(HPS I HIS).The urine GAGs pattern. confirmed by Iduronidase enzyme assay is diagnostic. Over 200 mutations exist. Genotype / phenotype correlation is poor but two nonsense mutations results in Hurler disease.The skeletal disease dysostosis multiplex (DM) is seen in severe variants of MPS I. The hypoplastic odontoid putting these patients at high risk of cervical cord damage. MPS IH (Hurler Disease) affected infants develop a spinal 'gibbus' deformity, persistent nasal discharge, middle ear effusions and frequent upper respiratory infection. They have "coarse", facial features, and an enlarged tongue. . Progressive upper airway disease leads to obstructive sleep apnoea. Corneal clouding and cognitive impairment appears, growth ceases. Joint stiffness and contractures limit mobility. Cardiac disease is universal. Death occurs before 10 years. SCHEIE patients are diagnosed as teenagers with hepatomegaly, joint contractures, cardiac valve abnormalities and corneal clouding . Prolonged survival with considerable disability without cognitive impairment is usual. MPS IH/S Hurler/Scheie. is diagnosed by 6.5 years, with variable skeletal and visceral manifestations without cognitive involvement. Joint stiffness, corneal clouding, , umbilical hernia, abnormal facies, hepatomegaly, joint contractures, and cervical myelopathy occur. Patients die in their 20s .Haematopoietic stem cell transplantation (HSCT) the standard treatment of MPS IH for 30 years is unpredictable .When performed before 2 years it can stabilize cognitive impairment. Hepatosplenomegaly, urine GAGs excretion, upper airways obstruction and cardiomyopathy improve . The coarse hair and facial features soften and corneas partly clear,but dysostosis multiplex and cervical instability are not improved. Enzyme replacement therapy (ERT) in patients with MPS IH is associated with improved GAG excretion, left ventricular hypertrophy,sleep studies and liver size. The standard treatment of MPS IHIS and MIPS IS is ERT a-L-Iduronidase, laronidase, a life-long therapy. GAG excretion is reduced, respiratory function and physical endurance improve. Joint mobility improves but not dural thickening, cardiac valve lesions or eye changes. MPS I mice have been successfully treated with IDUA-expressing mesenchymaf stem cells . Gene therapy may be developed for MPS I, via an ex vivo approach demonstrated to improve even skeletal outcomes in animal models.

Deep anterior lamellar keratoplasty in case of Hurler-Scheie syndrome.

A 12-year-old boy with Hurler-Scheie syndrome (H/S syndrome) reported with reduced vision in both the eyes for past few years. Deep anterior lamellar keratoplasty (DALK) was performed for visual rehabilitation in his left eye. During surgery, the predescemet's plane was reached by meticulously dissecting the lamellar fibres using a manual technique. Histopathology of the dissected cornea showed the presence of numerous alcian blue positive deposits corroborating with the diagnosis of mucopolysaccharidosis (MPS). Postoperative course was uneventful. One year following surgery, the graft was clear and had a visual acuity of 20/50 with +1.00 170° - 0.75 refractive correction. Endothelial cell count, as measured by non-contact specular microscopy, was 2473.4 cells/mm(2). This case report highlights the application of DALK in a case of MPS-related corneal stromal opacification.

Unexpected coronary artery findings in mucopolysaccharidosis. Report of four cases and literature review.

INTRODUCTION: The mucopolysaccharidosis syndromes are a group of lethal inherited disorders affecting multiple organ systems by the progressive deposition of glycosaminoglycan. Advances in treatment such as enzyme replacement and hematopoietic stem cell transplantation have significantly improved the outcome of these disorders. An in-depth understanding of the pathophysiology of heart disease in these disorders is essential since death from cardiac causes continues to be common. Epicardial coronary artery luminal narrowing from myointimal proliferation and glycosaminoglycan deposition is well described in severe mucopolysaccharidosis type I [Hurler syndrome, mucopolysaccharide IH] but poorly understood in other "non-Hurler" phenotypes of these disorders. Given the rarity of these conditions, autopsy specimens are uncommon. METHODS: Tissue from epicardial coronary arteries from autopsies of four patients with non-Hurler mucopolysaccharidosis (attenuated type I, type IIIA, type IIIC, and type VI) who had died after hematopoietic cell transplantation (within 1 month in three cases; after 5 years in the fourth) was examined by light microscopy. RESULTS: Unexpectedly, near-normal coronary arteries were observed in the patient with attenuated mucopolysaccharidosis type I, while the coronaries from patients with type IIIA, IIIC, and VI demonstrated classic histologic features of glycosaminoglycan deposition. The most severe findings were found in the MPS IIIC patient who had 5 years of full donor engraftment after transplantation. CONCLUSIONS: Our current understanding of the cardiac manifestations of the mucopolysaccharidoses fails to explain why near-normal coronary arteries may be observed when abnormalities would be most likely to be expected and, conversely, why significant histopathology is present when it would be least expected. Identification of downstream effects of glycosaminoglycan deposition may identify other metabolites or metabolic pathways that are important in the clinicopathologic manifestations of these diseases. SUMMARY: The mucopolysaccharidosis diseases are a group of inherited disorders affecting multiple organ systems by the progressive deposition of glycosaminoglycan. Severe coronary artery disease is well recognized in severe type I mucopolysaccharidosis (Hurler syndrome), but unexpected coronary artery disease occurs in other, "non-Hurler" mucopolysaccharidoses. Factors responsible for the development of coronary pathology in the mucopolysaccharidoses remain elusive.

Mucopolysaccharidosis type I and craniosynostosis.

Mucopolysaccharidosis type-I is caused by a deficiency of the lysosomal enzyme α-L-iduronidase, resulting in gradual deposition of glycosaminoglycans in multiple body organs, affecting physical appearance and system functioning. We present the first reported case associating MPS-I (Hurler-Scheie subtype) with craniosynostosis. A 2.5-year-old girl presented initially with macrocrania. On clinical and radiological examinations we noted a scaphocephaly with dysmorphic facial features of MPS confirmed later on. Intracranial hypertension was documented at fundoscopy (papilloedema) and ICP monitoring, and then surgically treated. This association of scaphocephaly and MPS-I highlights the importance of a meticulous physical examination performed by craniofacial, metabolic and ophthalmologic teams.