Mitochondrial dysfunction has been recognised a major contributory factor to the pathophysiology of a number of lysosomal storage disorders (LSDs). The cause of mitochondrial dysfunction in LSDs is ...as yet uncertain, but appears to be triggered by a number of different factors, although oxidative stress and impaired mitophagy appear to be common inhibitory mechanisms shared amongst this group of disorders, including Gaucher’s disease, Niemann–Pick disease, type C, and mucopolysaccharidosis. Many LSDs resulting from defects in lysosomal hydrolase activity show neurodegeneration, which remains challenging to treat. Currently available curative therapies are not sufficient to meet patients’ needs. In view of the documented evidence of mitochondrial dysfunction in the neurodegeneration of LSDs, along with the reciprocal interaction between the mitochondrion and the lysosome, novel therapeutic strategies that target the impairment in both of these organelles could be considered in the clinical management of the long-term neurodegenerative complications of these diseases. The purpose of this review is to outline the putative mechanisms that may be responsible for the reported mitochondrial dysfunction in LSDs and to discuss the new potential therapeutic developments.
The definition of neuronopathic Gaucher disease Schiffmann, Raphael; Sevigny, Jeff; Rolfs, Arndt ...
Journal of inherited metabolic disease,
September 2020, Letnik:
43, Številka:
5
Journal Article
Recenzirano
Odprti dostop
Neuronopathic Gaucher disease (nGD) has a very wide clinical and genotypic spectrum. However, there is no consensus definition of nGD, including no description of how best to diagnostically separate ...the acute form—Gaucher type 2—from the subacute or chronic form—Gaucher type 3. In this article, we define the various forms of Gaucher disease with particular emphasis on the presence of gaze palsy in all patients with nGD. This consensus definition will help in both clinical diagnosis and appropriate patient recruitment to upcoming clinical trials.
Neuronopathic Gaucher Disease (nGD) describes the condition of a subgroup of patients with the Lysosomal Storage Disorder (LSD), Gaucher disease with involvement of the central nervous system (CNS) ...which results from inherited deficiency of beta-glucosylceramidase. Although systemic manifestations of disease are now corrected by augmentation with macrophage-targeted therapeutic enzyme (enzyme replacement therapy, ERT), neurological disease progresses unpredictably as a result of failure of therapeutic enzyme to cross the blood-brain barrier (BBB). Without therapy, the systemic and neurological effects of the disease progress and shorten life: investigators, principally in Sweden and the UK, pioneered bone marrow transplantation (BMT; Haematopoietic Stem Cell Transplantation HSCT) to supply healthy marrow-derived macrophages and other cells, to correct the peripheral disease. Here we report the first long-term follow-up (over 20 years in all cases) of nine patients in the UK and Sweden who underwent HSCT in the 1970s and 1980s. This retrospective, multicentre observational study was undertaken to determine whether there are neurological features of Gaucher disease that can be corrected by HSCT and the extent to which deterioration continues after the procedure. Since intravenous administration of ERT is approved for patients with the neuronopathic disease and ameliorates many of the important systemic manifestations but fails to correct the neurological features, we also consider the current therapeutic positioning of HSCT in this disorder. In the nine patients here reported, neurological disease continued to progress after transplantation, manifesting as seizures, cerebellar disease and abnormalities of tone and reflexes. Although neurological disease progressed in this cohort of patients, there may be a future role for HSCT in the treatment of nGD. The procedure has the unique advantage of providing a life-long source of normally functioning macrophages in the bone marrow, and possibly other sites, after a single administration. HSCT moreover, clearly ameliorates systemic disease and this may be advantageous--especially where sustained provision of high-cost ERT cannot be guaranteed. Given the remaining unmet needs of patients with neuronopathic Gaucher disease and the greatly improved safety profile of the transplant procedure, HSCT could be considered to provide permanent correction of systemic disease, including bone disease not ameliorated by ERT, when combined with emerging therapies directed at the neurological manifestations of disease; this could include ex-vivo gene therapy approaches.
Background
Mutations in GBA cause Gaucher disease when biallelic and are strong risk factors for Parkinson's disease when heterozygous. GBA analysis is complicated by the nearby pseudogene. We aimed ...to design and validate a method for sequencing GBA using long reads.
Methods
We sequenced GBA on the Oxford Nanopore MinION as an 8.9 kb amplicon from 102 individuals, including patients with Parkinson's and Gaucher diseases. We used NanoOK for quality metrics, NGMLR to align data (after comparing with GraphMap), Nanopolish and Sniffles to call variants, and WhatsHap for phasing.
Results
We detected all known missense mutations in these samples, including the common p.N409S (N370S) and p.L483P (L444P) in multiple samples, and nine rarer ones, as well as a splicing and a truncating mutation, and intronic SNPs. We demonstrated the ability to phase mutations, confirm compound heterozygosity, and assign haplotypes. We also detected two known risk variants in some Parkinson's patients. Rare false positives were easily identified and filtered, with the Nanopolish quality score adjusted for the number of reads a very robust discriminator. In two individuals carrying a recombinant allele, we were able to detect and fully define it in one carrier, where it included a 55‐base pair deletion, but not in another one, suggesting a limitation of the PCR enrichment method. Missense mutations were detected at the correct zygosity, except for the case where the RecNciI one was missed.
Conclusion
The Oxford Nanopore MinION can detect missense mutations and an exonic deletion in this difficult gene, with the added advantages of phasing and intronic analysis. It can be used as an efficient research tool, but additional work is required to exclude all recombinants.
The GBA gene is important in Parkinson's and Gaucher disease, but difficult to sequence due to a highly homologous adjacent pseudogene. Here we present a novel method using long reads on the Oxford Nanopore MinION, which can detect missense mutations and an exonic deletion, with the added advantage of phasing and intronic analysis.
Neurological forms of Gaucher disease, the inherited disorder of β-Glucosylceramidase caused by bi-allelic variants in GBA1, is a progressive disorder which lacks a disease-modifying therapy. ...Systemic manifestations of disease are effectively treated with enzyme replacement therapy, however, molecules which cross the blood-brain barrier are still under investigation. Clinical trials of such therapeutics require robust, reproducible clinical endpoints to demonstrate efficacy and clear phenotypic definitions to identify suitable patients for inclusion in trials. The single consistent clinical feature in all patients with neuronopathic disease is the presence of a supranuclear saccadic gaze palsy, in the presence of Gaucher disease this finding serves as diagnostic of 'type 3' Gaucher disease.
We undertook a study to evaluate saccadic eye movements in Gaucher patients and to assess the role of the EyeSeeCam in measuring saccades. The EyeSeeCam is a video-oculography device which was used to run a protocol of saccade measures. We studied 39 patients with non-neurological Gaucher disease (type 1), 21 patients with type 3 (neurological) disease and a series of 35 healthy controls. Mean saccade parameters were compared across disease subgroups.
We confirmed the saccadic abnormality in patients with type 3 Gaucher disease and identified an unexpected subgroup of patients with type 1 Gaucher disease who demonstrated significant saccade parameter abnormalities. These patients also showed subtle neurological findings and shared a GBA1 variant.
This striking novel finding of a potentially attenuated type 3 Gaucher phenotype associated with a specific GBA1 variant and detectable saccadic abnormality prompts review of current disease classification. Further, this finding highlights the broad spectrum of neuronopathic Gaucher phenotypes relevant when designing inclusion criteria for clinical trials.
Gaucher disease is an inherited lysosomal storage disorder of which there are three subtypes. Type 1 disease has no neurological involvement and is treatable with enzyme replacement therapy. Type 2 ...disease results in infant death and type 3 disease is a heterogenous disorder characterised by progressive neurological decline throughout childhood and adult life. Endeavours to find a therapy to modify neurological disease are limited by a lack of meaningful clinical outcome measures which are acceptable to patients.
We present results from a pilot study utilising wearable technology to monitor physical activity as a surrogate of disease activity/severity paired with a mobile phone app allowing patients to complete self-reported outcome measures in the real world as opposed to the hospital environment. We demonstrate feasibility of the approach and highlight areas for development with this study of 21 patients, both children and adults.
We illustrate, where patients engage in the methodology, a rich dataset is obtainable and useful for proactive clinical care and for clinical trial outcome development.
The Gaucher Investigative Therapy Evaluation is a national clinical cohort of 250 patients aged 5-87 years with Gaucher disease in the United Kingdom-an ultra-rare genetic disorder. To inform ...clinical decision-making and improve pathophysiological understanding, we characterized the course of Gaucher disease and explored the influence of costly innovative medication and other interventions. Retrospective and prospective clinical, laboratory and radiological information including molecular analysis of the GBA1 gene and comprising > 2500 variables were collected systematically into a relational database with banking of collated biological samples in a central bioresource. Data for deep phenotyping and life-quality evaluation, including skeletal, visceral, haematological and neurological manifestations were recorded for a median of 17.3 years; the skeletal and neurological manifestations are the main focus of this study.
At baseline, 223 of the 250 patients were classified as type 1 Gaucher disease. Skeletal manifestations occurred in most patients in the cohort (131 of 201 specifically reported bone pain). Symptomatic osteonecrosis and fragility fractures occurred respectively in 76 and 37 of all 250 patients and the first osseous events occurred significantly earlier in those with neuronopathic disease. Intensive phenotyping in a subgroup of 40 patients originally considered to have only systemic features, revealed neurological involvement in 18: two had Parkinson disease and 16 had clinical signs compatible with neuronopathic Gaucher disease-indicating a greater than expected prevalence of neurological features. Analysis of longitudinal real-world data enabled Gaucher disease to be stratified with respect to advanced therapies and splenectomy. Splenectomy was associated with an increased hazard of fragility fractures, in addition to osteonecrosis and orthopaedic surgery; there were marked gender differences in fracture risk over time since splenectomy. Skeletal disease was a heavy burden of illness, especially where access to specific therapy was delayed and in patients requiring orthopaedic surgery.
Gaucher disease has been explored using real-world data obtained in an era of therapeutic transformation. Introduction of advanced therapies and repeated longitudinal measures enabled this heterogeneous condition to be stratified into obvious clinical endotypes. The study reveals diverse and changing phenotypic manifestations with systemic, skeletal and neurological disease as inter-related sources of disability.
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