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.

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Background: 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. Results: 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. Conclusions: 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.  

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Background: Gaucher disease type 2 (GD2) is defined by acute neurological decline, failure to thrive, and early demise. Currently, there is no clear standard for evaluating, staging, and counseling regarding neurological decline in GD2. Due to the high prevalence of progressive dysphagia secondary to acute neurological involvement, we aimed to identify key components of swallow function which could serve as markers of disease progression in GD2.

Methods: A post-hoc analysis of modified barium swallow studies was performed. Six parameters of swallowing were scored in a retrospective chart review of eleven infants with GD2. Mixed effects regression, principal component analysis (PCA), and a transition analysis were used to evaluate swallow function and model disease progression.

Results: All patients exhibited impaired swallow function. There was no association between any of the swallow parameters and age, indicating non-linear disease progression. PCA and transition analysis identified five parameters capturing multiple dimensions of swallowing which defined two distinct disease states.

Conclusion: A five-parameter swallow evaluation was sufficient to identify distinct states of GD2 and model prospective outcomes. This multi-dimensional evaluation could be a useful efficacy parameter for future therapeutic trials in GD2 and other neurodegenerative disorders of infancy.

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Therapeutic options for patients with nGD are lacking and the drug development process is hindered due to the nature of the disease. Aparito’s technology aims to provide the relevant stakeholders with the rich data sources that they need to address the disease. This can be further delivered as part of a global disease registry soon to be launched by the International Gaucher Alliance, which is also supported by Aparito. The registry approach will be recruiting patients remotely, and such data capture will be greatly facilitated with remote wearable and mobile health tools. This work also has the focus of developing a disease specific Patient Reported Outcome for inclusion in the registry.

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Gaucher disease (GD) is a rare lysosomal storage disorder that is divided into three subtypes based on presentation of neurological manifestations. Distinguishing between the types has important implications for treatment and counseling. Yet, patients with neuronopathic forms of GD, types 2 and 3, often present at young ages and can have overlapping phenotypes. It has been shown that new technologies employing artificial intelligence and facial recognition software can assist with dysmorphology assessments. Though classically not associated nor previously described with a dysmorphic facial phenotype, this study investigatedwhether a facial recognition platform could distinguish between photos of patients with GD2 and GD3 and discriminate between them and photos of healthy controls. Each cohort included over 100 photos. A cross validation scheme including a series of binary comparisons between groups was used. Outputs included a composite photo of each cohort and either a receiver operating characteristic curve or a confusion matrix. Binary comparisons showed that the software could correctly group photos at least 89% of the time.Multiclass comparison betweenGD2, GD3, and healthy controls demonstrated a mean accuracy of 76.6%, compared to a 37.7% chance for randomcomparison. Both GD2 and GD3 have now been added to the facial recognition platform as established syndromes that can be identified by the algorithm. These results suggest that facial recognition and artificial intelligence, though no substitute for other diagnostic methods, may aid in the recognition of neuronopathic GD. The algorithm, in concert with other clinical features, also appears to distinguish between young patients with GD2 and GD3, suggesting that this tool can help facilitate earlier implementation of appropriate management.

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Gaucher disease (OMIM#230800) is caused by β-glucosidase deficiency and primarily involves themononuclear phagocyte system (also called Reticuloendothelial System or Macrophage System). The disease is classified into three main phenotypes based on the presence or absence of neurological manifestations: non-neuronopathic (type 1), acute neuronopathic (type 2) and chronic neuronopathic (type 3). Typical manifestations include hepatosplenomegaly, skeletal deformities, hematological abnormalities, interstitial lung fibrosis and neurodegeneration in neuronopathic cases. Mesenteric lymphadenopathy with resultant protein losing enteropathy (PLE) has only been rarely described. Mesenteric lymphadenopathy may lead to intestinal lymphatic obstruction and secondary lymphangiectasia resulting in chronic diarrhea, abdominal pain andweight loss. Fecal protein loss with secondary hypoalbuminemia can be significant. We report a male with Chronic Neuronopathic Gaucher disease (GD) (homozygous for c.1448TNC (NM_000157.3) GBA mutation) who at 16 years of age developed intractable abdominal pain, diarrhea and weight loss. This was caused by PLE secondary to intestinal lymphangiectasia caused by calcified mesenteric lymphadenopathy despite prior long term enzyme replacement therapy (ERT) and/or substrate reduction therapy (SRT). His older similarly affected sister who had been receiving treatment with ERT and/or SRT remains stable on these treatments with no evidence ofmesenteric lymphadenopathy. Medical management with total parenteral nutrition, daily medium chain triglyceride-oil (MCT) supplementation, low dose oral budesonide, continued oral SRT and an increased dose of parenteral ERT has stabilized his condition with resolution of the gastrointestinal symptoms and appropriate weight gain.
 

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Gaucher disease, the inherited deficiency of the enzyme glucocerebrosidase, is themost common of the lysosomal storage disorders. Type 2 Gaucher disease, themost severe and progressive form,manifests either prenatally or in the first months of life, followed by death within the first years of life. The rarity of the many lysosomal storage disorders makes their diagnosis a challenge, especially in the newborn period when the focus is often on more prevalent illnesses. Thus, a heightened awareness of the presentation of these rare diseases is necessary to ensure their timely consideration. This review, designed to serve as a guide to physicians treating newborns and infants with Gaucher disease, discusses the presenting manifestations of Type 2 Gaucher disease, the diagnosticwork-up, associated genotypes and suggestions for management.We also address the ethical concerns thatmay arise with this progressive and lethal disorder, since currently available treatments may prolong life, but do not impact the neurological manifestations of the disease.

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Objective To identify relevant efficacy parameters essential in designing clinical trials for brain-penetrant therapies for Gaucher disease, we evaluated cognitive function longitudinally in 34 patients with Gaucher disease type 3 seen at the NIH Clinical Center.

Methods Individuals were tested with age-appropriate Wechsler Intelligence Scales administered between 1 and 18 times over 29 years. Variation in all IQ domains was not linear with time and was best characterized with the coefficient of variation (SD/mean) for each individual. Mixedeffects regressions were used to determine whether IQ was associated with clinical features. Models were controlled for variation in test version, participant identification, and test administrator.

Results Mean verbal, performance, and full-scale IQs were 81.77, 75.98, and 82.02, respectively, with a consistent discrepancy between verbal and performance IQs. Mean (SD) verbal, performance, and full-scale coefficient of variations were 0.07 (0.04), 0.09 (0.05), and 0.06 (0.02), respectively. IQ varied about a mean, with no clear trajectory, indicating no clear patterns of improvement or decline over time. EEG lateralization and behavioral issues were consistently associated with IQ.

Conclusions The observed variation in IQ in Gaucher disease type 3 across the cohort and within single individuals over time may be characteristic of other neuronopathic diseases. Therefore, to reliably use IQ as an efficacy measure in any clinical trial of neurotherapeutics, a normal variation range must be established to assess the clinical relevance of any IQ change.

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Background: 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 efectively 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 efcacy and clear phenotypic defnitions 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 fnding serves as diagnostic of ‘type 3’ Gaucher disease.

Methods: 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.

Results: We confrmed the saccadic abnormality in patients with type 3 Gaucher disease and identifed an unexpected subgroup of patients with type 1 Gaucher disease who demonstrated signifcant saccade parameter abnormalities. These patients also showed subtle neurological fndings and shared a GBA1 variant.

Conclusions: This striking novel fnding of a potentially attenuated type 3 Gaucher phenotype associated with a specifc GBA1 variant and detectable saccadic abnormality prompts review of current disease classifcation. Further, this fnding highlights the broad spectrum of neuronopathic Gaucher phenotypes relevant when designing inclusion criteria for clinical trials.

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Paediatric patients needed for a clinical research study testing an orally administered treatment in Gaucher disease types 1 & 3

This study will investigate if the investigational treatment, a substrate reduction therapy, works and its safety profile in paediatric patients with Gaucher disease type 1 & 3. Patients participating in the study will receive, based on their disease symptoms, either the study drug alone (cohort 1) or in combination with a currently approved enzyme replacement therapy (cohort 2). Patients may receive the study drug for up to 24 months. The safety of the study drug will be assessed through clinical lab evaluations, cardiological exams, hearing as well as neuropsychological tests. Efficacy will be evaluated through abdominal and bone images, and Gaucher Disease assessments.

Sixty patients will participate in this study that is currently conducted in multiple countries including Russia, Turkey, Canada, Argentina, Italy, Sweden, France, Spain, the United Kingdom, and Japan.

To participate in the study, patients should meet at least the following study criteria:

• be less than 18 years old
• have Gaucher disease type 1 or 3
• have received treatment with enzyme replacement therapy for at least 2 years and meet study specified Gaucher Disease treatment goals (cohort 1) or  have severe clinical manifestation of Gaucher Disease despite receiving adequate treatment with enzyme replacement therapy for at least 3 years, being at a stable dose for the past 6 months (cohort 2).

If you are interested in more information, contact your treating physician who could assess your eligibility for the study.

Further information can be obtained on www.clinicaltrials.gov, using study identifier NCT 03485677, or at www.clinicaltrialsregister.eu using study number EudraCT 2016-000301-37

This is a multicenter study to assess the safety and efficacy of taliglucerase alfa (60 units/kg) in previously untreated subjects of any age with Type 3 GD. Subjects will receive an infusion of taliglucerase alfa every 2 weeks for 12 months. Subjects who tolerate the infusions well, and who are treated in centers where home therapy is the SOC will be allowed to switch from site to home treatment at the discretion of the PI but after no less than 3 uneventful infusions at the site.  

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SRT for Neuronopathic GD: Sanofi Genzyme are currently in clinical trials with an SRT called Venglustat for type 3 Gaucher disease. Venglustat is being investigated as a potential oral substrate reduction therapy for GD3. Preclinical studies indicate the novel oral treatment is a glucosylceramide synthase inhibitor that reduces the synthesis of glucosylceramide. Preliminary results in phase II clinical trials show the pill to positively affect neurological features in adults with Gaucher disease type 3.  

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Gene therapy can be defined as the introduction of genetic material to cells of patients for therapeutic benefit. In simple terms, it involves providing a healthy functional copy of a gene to the patient's cells to compensate for a defective copy that causes the disease. Ideally this treatment would only need to be administered once in the lifetime of the patient. Even though the concept underlying gene therapy is straightforward, delivering genes into cells of a living organism is a very challenging process. Therefore, an essential component of gene therapy studies is the development of vectors that can efficiently deliver genetic material into cells.  

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Patients 12 years and older are needed for a clinical research study testing an orally administered treatment in Gaucher disease type 3.

This study will evaluate whether an investigational treatment, a substrate reduction therapy, is effective in treating patients 12 years and older with Gaucher disease type 3 while also further evaluating the study drug’s safety profile. This is a double blind, double dummy, randomised study which means that patients participating in the study will receive, either the study drug and placebo enzyme replacement therapy or enzyme replacement therapy and the placebo study drug, for a period of 52 weeks. Participants will not know if they received study drug or placebo during the initial 52 weeks of the study. All patients will receive the study drug during the extended treatment period of the study after completing the first 52 weeks. The extended treatment period will last a minimum of 52 weeks and a maximum of 130 weeks.

Further information can be obtained on www.clinicaltrials.gov, using study identifier NCT05222906, or at www.clinicaltrialsregister.eu using study number EudraCT 2021-005402-10