The surgical management of spinal disorders in lysosomal storage diseases: a systematic review.

BACKGROUND: The skeletal manifestations of lysosomal storage diseases (LSDs) are largely refractory to available therapeutic modalities. Consequently, there is an increasing need to manage their spinal deformities. The aim was to perform a systematic review to answer the questions, "What are the reported indications for surgery for spinal deformity in patients with LSDs?" and "what are the published surgical management strategies?". METHODS: Articles that made reference to at least one LSD, a spinal abnormality and surgical management were included. Extracted study data included: study type, sample size, methodology and year of publication. The following clinical information was collected: demographics, spinal abnormalities, and surgical indications, details and outcomes. RESULTS: Thirty-seven articles were included, with 23 describing surgical management of craniocervical manifestations seen in mucopolysaccharidosis. Radiological evidence of myelopathy at the craniocervical junction and/or progressive clinical neurological compromise were accepted as surgical indications. Prophylactic surgery was proposed by some authors. The recommended surgical technique and whether to stabilise and/or decompress varied between articles and LSD types. Twenty-one articles discussed thoracolumbar pathology, including thoracolumbar kyphosis and scoliosis. Radiological severity, progression of deformity, and presence of neurological deterioration were discussed as surgical indications. Most papers recommended circumferential arthrodesis via combined anterior and posterior approaches. CONCLUSION: The surgical management of spinal disorders in LSDs remains controversial. Centres managing these patients should be encouraged to have a standardised system of reporting outcomes, to facilitate recommendations for management of the spinal manifestations.

Clinical characteristics and surgical history of Taiwanese patients with mucopolysaccharidosis type II: data from the hunter outcome survey (HOS).

BACKGROUND: Mucopolysaccharidosis type II (MPS II) is the most frequently occurring MPS in Taiwan, with an incidence of 2.05 per 100,000 live male births, but little is known about clinical characteristics and surgical history in Taiwanese patients. METHODS: Medical history, demographics, signs and symptoms, and surgical history were analysed in all patients from Taiwanese centres in the Hunter Outcome Survey (HOS; NCT 03292887), a global, multicentre registry that collects real-world data on patients with MPS II. RESULTS: As of January 2016, 61 male Taiwanese patients were enrolled; 49% (24/49) had received at least one infusion of idursulfase. Median (10th, 90th percentiles) ages at signs and symptom onset and at diagnosis were 2.5 (0.2, 5.5) years (n = 55) and 3.5 (1.2, 11.9) years (n = 56), respectively. Hernia, facial features consistent with MPS II and claw hands were the earliest presenting signs and symptoms (median ages of 3.2 [0.4, 12.0] years, 4.3 [1.1, 12.0] years and 4.7 [2.5, 12.2] years [n = 45, 53 and 50], respectively). More than 75% of patients had undergone a surgical procedure, most commonly hernia repair (57% of patients). Median age at first surgery for hernia repair was 4.2 (0.5, 9.8) years (n = 35). Almost one-third (31.1%) of patients had at least one surgical procedure before diagnosis, and of the 20 procedures before diagnosis, 16 were hernia repair. CONCLUSIONS: This information from patients in HOS highlights the importance of both medical and surgical history in diagnosing MPS II in Taiwanese patients.

Primary disease recurrence­effects on paediatric renal transplantation outcomes.

Primary disease recurrence after renal transplantation is mainly diagnosed by examination of biopsy samples, but can also be associated with clinical symptoms. In some patients, recurrence can lead to graft loss (7-8% of all graft losses). Primary disease recurrence is generally associated with a high risk of graft loss in patients with focal segmental glomerulosclerosis, membranous proliferative glomerulonephritis, primary hyperoxaluria or atypical haemolytic uraemic syndrome. By contrast, disease recurrence is associated with a limited risk of graft loss in patients with IgA nephropathy, renal involvement associated with Henoch-Schönlein purpura, antineutrophil cytoplasmic antibody-associated glomerulonephritis or lupus nephritis. The presence of systemic diseases that affect the kidneys, such as sickle cell anaemia and diabetes mellitus, also increases the risk of delayed graft loss. This Review provides an overview of the epidemiology, pathophysiology and management of primary disease recurrence in paediatric renal graft recipients, and describes the overall effect on graft survival of each of the primary diseases listed above. With appropriate management, few paediatric patients should be excluded from renal transplantation programmes because of an increased risk of recurrence.

Ultrastructural change of ligamentum flavum in galactosialidosis.

PURPOSE: Galactosialidosis is an autosomal recessive lysosomal storage disease caused by deficiency of both α-neuraminidase and ß-galactosidase due to a defect of the protective protein/cathepsin A. Three clinical subtypes have been described, depending on the age of onset and severity of the symptoms: the early infantile, late infantile and juvenile/adult form. We report an adult-type patient who underwent surgery for galactosialidosis-related spinal deformity, and showed a favorable course thereafter. METHODS: The patient was a 50-year-old male, and he consulted our hospital with pain of the bilateral anterior thigh. Lumbar radiograph showed applanation and horn-like deformity of the L2 vertebral body, which is characteristic of this disease, narrowing of the L1/2 intervertebral space, and topical kyphosis. Fenestration between the L1/2, decompression of the L2 nerve root, and posterolateral fusion involving the T12 to L3 were performed. RESULTS: Immediately after surgery, pain of the lower limbs disappeared. During the 2-year postoperative follow-up, bone assimilation was achieved, showing a favorable course. Histological examination of the ligamentum flavum (LF) collected during surgery showed that the elastic fibers were thin, whereas the collagen fibers were abundant and dense. The ligament cells were swollen, and there were a large number of vacuoles in the cytoplasm. CONCLUSION: This is the first report on spinal surgery for adult-type galactosialidosis and histological examination of spinal LF.

Hematopoietic stem cell transplant for lysosomal storage diseases.

Hematopoietic stem cell transplantation (HSCT) for lysosomal storage diseases (LSD) has been performed for over 20 years. In that time, many advances have been made in understanding the unique pathophysiology of the various LSDs. We have also made advances in HSCT, particularly in the use of umbilical cord blood as a stem cell source. The goal of HSCT has always been to correct the deficient lysosomal enzyme through the engraftment of enzyme replete donor cells that include cells of the hematopoietic system and it's derivatives (i.e. brain microglia). In those LSDs that are accompanied by some form of neuro-degeneration as part of their phenotype, one of the primary endpoints of performing HSCT is to slow or arrest the neurodegenerative process. As a general rule, earlier HSCT leads to improved outcomes since irreversible organ and tissue damage has had less time to occur. Mostly through trial and error we have learned which LSDs respond best to HSCT and which have shown minimal improvement after HSCT. Due to the rare nature of LSDs, this learning process is not complete. Even after two decades of performing HSCT for LSDs, many experiences are still being published as case reports. In recent years, the advent of enzyme replacement therapy for several of the LSDs offers new avenues for treatments that can be complemented by HSCT. In this review, we discuss what is currently known of HSCT related outcomes in the treatment of LSDs.

Neural stem cell transplantation as a therapeutic approach for treating lysosomal storage diseases.

Treating the central nervous system manifestations of subjects with neuropathic lysosomal storage diseases remains a major technical challenge. This is because of the low efficiency by which lysosomal enzymes in systemic circulation are able to traverse the blood brain barrier into the central nervous system. Intracranial transplantation of neural stems cells genetically modified to overexpress the respective deficient enzymes represents a potential approach to addressing this group of diseases. The unique properties of neural stem cells and progenitor cells, such as their ability to migrate to distal sites, differentiate into various cell types and integrate within the host brain without disrupting normal function, making them particularly attractive therapeutic agents. In addition, neural stem cells are amenable to ex vivo propagation and modification by gene transfer vectors. In this regard, transplanted cells can serve not only as a source of lysosomal enzymes but also as a means to potentially repair the injured brain by replenishing the organ with healthy cells and effecting the release of neuroprotective factors. This review discusses some of the well-characterized neural stem cell types and their possible use in treating neuropathic lysosomal storage diseases such as the Niemann Pick A disease.

Neural stem cell-mediated therapy for rare brain diseases: perspectives in the near future for LSDs and MNDs.

Lysosomal storage diseases (LSDs) are genetically inherited disorders affecting most patients in pediatric age and progressively lead to severe, even lethal, multiorgan dysfunction and brain neurodegeneration. Motor neuron diseases (MNDs) or Amyotrophic Lateral Sclerosis (ALS)-related syndromes are neurodegenerative disorders occurring in the majority of cases sporadically and affect adult middle-aged patients. Despite being divergent in most pathological and physiological hallmarks, both MNDs and LSDs are characterized by tremendous clinical heterogeneity due to poor prognosis and variable onset of the symptoms. Moreover, both LSDs and MNDs are characterized by the concurrence of multiple pathogenetic processes, such as the development of inflammatory and excitotoxic environments. Furthermore, pharmacological, enzyme or genetic therapies have proven to be ineffective and no cure is currently available for the neurodegeneration in either LSD or ALS affected patients. Recent studies have identified non-neuronal cell types, such as astrocytes and microglia, as being involved in non cell-autonomous effects on MND or LSD progression. These findings have prompted the use of neural stem cells for the replacement of non-neuronal cells rather than neuronal cells, which may result in neuroprotection and immunomodulation. The choice of an appropriate tissue source and the establishment of standardized paradigms to culture human neural stem cells (hNSC) will allow their use for future clinical trials on both ALS and LSD affected patients and parallel drug screening studies with novel breakthroughs in the knowledge of neurodegenerative diseases.

Amnion-derived stem cells: in quest of clinical applications.

In the promising field of regenerative medicine, human perinatal stem cells are of great interest as potential stem cells with clinical applications. Perinatal stem cells could be isolated from normally discarded human placentae, which are an ideal cell source in terms of availability, the fewer number of ethical concerns, less DNA damage, and so on. Numerous studies have demonstrated that some of the placenta-derived cells possess stem cell characteristics like pluripotent differentiation ability, particularly in amniotic epithelial (AE) cells. Term human amniotic epithelium contains a relatively large number of stem cell marker-positive cells as an adult stem cell source. In this review, we introduce a model theory of why so many AE cells possess stem cell characteristics. We also describe previous work concerning the therapeutic applications and discuss the pluripotency of the AE cells and potential pitfalls for amnion-derived stem cell research.

Bone marrow transplantation in patients with storage diseases: a developing country experience.

Bone marrow transplantation (BMT) is a therapeutic option for patients with genetic storage diseases. Between 1979 and 2002, eight patients, four females and four males (1 to 13 years old) were submitted to this procedure in our center. Six patients had mucopolysaccharidosis (MPS I in 3; MPS III in one and MPS VI in 2), one had adrenoleukodystrophy (ALD) and one had Gaucher disease. Five patients had related and three unrelated BMT donor. Three patients developed graft versus host disease (two MPS I and one MPS VI) and died between 37 and 151 days after transplantation. Five patients survived 4 to 16 years after transplantation. Three patients improved (one MPS I; one MPS VI and the Gaucher disease patient), one patient had no disease progression (ALD) and in one patient this procedure did not change the natural course of the disease (MPS III).

Bone marrow transplantation in patients with storage diseases: a developing country experience

O transplante de medula óssea é uma opção terapêutica para os pacientes com doenças de acúmulo. Entre 1979 e 2002, oito pacientes, quatro femininos e quatro masculinos (entre um e 13 anos de idade) foram submetidos a este procedimento em nosso centro. Seis pacientes apresentavam mucopolissacaridose (MPS I em 3; MPS III em um e MPS VI em 2), um paciente apresentava adrenoleucodistrofia e um apresentava doença de Gaucher. Cinco pacientes receberam o transplante de doador aparentado e três de doador não aparentado. Três pacientes desenvolveram doença do enxerto versus hospedeiro (dois com MPS I e um com MPS VI) e faleceram entre 37 e 151 dias após o transplante. Cinco pacientes sobreviveram entre 4 e 16 anos após o transplante. Três tiveram melhora clínica (um MPS I, um MPS VI e o paciente com doença de Gaucher), um paciente não apresentou progressão da doença (adrenoleucodistrofia) e um paciente não teve alteração da história natural da doença (MPS III).

Current and emerging therapies for the lysosomal storage disorders.

Targeted treatments for the lysosomal storage disorders (LSDs), in the form of enzyme replacement and/or substrate depletion, have been shown to be relatively safe and effective in reversing core disease features in selected clinical subtypes (including Gaucher disease types I and III, Fabry disease and the Hurler-Scheie syndrome). These approaches have expanded the therapeutic options available to patients with rare genetic disorders, beyond palliative measures (such as liver or kidney transplantation for end-organ failure) and cellular replacement through bone marrow transplantation. Present efforts are focused on the development of novel strategies, including chaperone-mediated enzyme enhancement and genetically engineered stem cell therapy. In the coming decades, a broadening therapeutic horizon for patients with inborn errors of metabolism is anticipated, and the growing experience in the management of patients with LSDs will serve as an instructive model. Among the many challenges will be determination of the extent to which these therapies have modified the course of disease beyond merely extending the age of survival, but also enabling a meaningful patient quality of life, and the minimisation of current resource use. The projected lifetime acquisition costs of newly introduced therapeutic options also raises several issues, related to equitable access and the large opportunity costs for other therapeutic areas, that will need to be addressed by healthcare policy makers and third-party payers.

Successful hematopoietic stem cell transplantation in Farber disease.

Farber disease, a lysosomal storage disorder, has a dismal prognosis leading to death with progressive granulomatous inflammation, even in patients without central nervous system involvement (type 2/3). We report the first successful hematopoietic stem cell transplantations in 2 patients with Farber disease type 2/3, resulting in resolution of symptoms.

The status of hematopoietic stem cell transplantation in lysosomal storage disease.

Lysosomal storage diseases are a group of disorders which have in common an inherited defect in lysosomal function-in most cases, a missing intralysosomal enzyme. Research into potential treatment options for this group of disorders has focused on enzyme replacement. Over the past two decades, hematopoietic stem cell transplantation has been used with increasing frequency to treat patients with lysosomal storage disease by providing a population of cells with the capacity to produce the missing enzyme. The success of marrow transplantation depends on the specific enzyme deficiency and the stage of the disease. Generally, visceral symptoms can be improved, whereas skeletal lesions remain relatively unaffected. The effect on neurologic symptoms varies. Hematopoietic stem cell transplantation remains a viable treatment option in those lysosomal storage diseases where data supportive of disease stabilization or amelioration are known. Early transplantation is the goal so that enzyme replacement may occur before extensive central nervous system injury becomes evident. When inadequate clinical data are available, the decision to perform transplantation requires experimental data demonstrating that the enzyme in question is both excreted from normal cells and taken up by affected cells as evidenced by elimination of storage material in vitro.

[Treatment of patients with lysosomal storage diseases]. / Leczenie chorych na lizosomalne choroby spichrzeniowe.

A problem of management of patients with lysosomal storage diseases in own experience with over 100 children with such diseases has been discussed. Symptomatic therapy of carpal tunnel syndrome, Pudenz valves, splenectomies, plasty of hernia, locomotive rehabilitation and various forms of cooperation with patients' families have been used in the treatment. An attempt of the treatment of the storage diseases with implantation of fetal membranes has been undertaken in view of the fact, that such membranes are the source of deficit enzyme.

Long-term effects of bone marrow transplantation on lysosomal enzyme replacement in beta-glucuronidase-deficient mice.

This study uses bone marrow transplantation (BMT) between congenic strains of mice as an experimental model to examine enzyme replacement therapy of lysosomal storage diseases. Bone marrow cells from donor mice which have normal levels of the lysosomal enzyme beta-glucuronidase (Gus), which is heat-stable, rapidly repopulated the haematopoietic compartment of irradiated recipient mice which have only low levels of a thermolabile form of this enzyme. Gus activity was found to increase progressively in the tissues of the recipients, including the liver, heart and skeletal muscle. Elevated levels were also observed in the kidney and brain. The increase in enzyme activity in the host tissues was not due to the presence of contaminating blood cells, but rather to the acquisition of new, heat-stable enzyme from the donor bone marrow cells. High levels of Gus activity persisted for at least 72 weeks, showing the potential therapeutic value of BMT for enzyme deficiency diseases.