Literature

Paper 1 - Assessment of Bone Health...

Citation

Herrera S, Pérez-López J, Moltó-Abad M, et al.
Assessment of Bone Health in Patients with Type 1 Gaucher Disease Using Impact Microindentation
Journal of Bone and Mineral Research, 2017:32(7) 1575-1581

Study Aim

The aim of this study was to provide a wide-ranging assessment of bone health in a group of patients with Type 1 Gaucher Disease (GD1), including dual-energy X-ray absorptiometry (DXA/DEXA) imaging, impact microindentation and biochemical markers of bone turnover to measure material characteristics at a tissue level.

Methods

This was a cross-sectional study with patients with GD1 matched to control “healthy” participants. Participants were recruited between July 2015 and January 2016. In total 16 patients with GD1 were recruited to the study and provided consent, and 29 age- and gender-matched controls were recruited.

A variety of clinical characteristics were recorded for GD1 patients: age; gender; height and weight; chitotriosidase levels (an enzyme that is selectively activated in tissue macrophage, which is dramatically elevated in symptomatic Gaucher Disease patients); platelet count; haemoglobin concentration; age at diagnosis; disease severity (using the Zimran severity score index (SSI)). The type and duration of treatments; occurrence of splenectomy; focal bone lesions from previous MRI scans and incidence of avascular necrosis were also factors which were recorded.

Biochemical markers of bone turnover data which was collected included C-terminal telopeptide (CTX-I) and procollagen type 1N propeptide (P1NP). Bone Mineral Density (BMD) was measured at the hip and lumbar spine using DXA imaging whilst impact microindentation was used to measure Bone Material Strength index (BMSi). For control participants, demographic data (age; gender; height and weight) were collected along with DXA imaging and impact microindentation.

Results

Of the 16 patients with GD1, 12 were receiving enzyme replacement therapy (ERT) during the study period. The mean BMSi for GD1 patients was 72.74; the mean hip BMD was 0.717g/cm²; the mean lumbar spine BMD was 0.896g/cm². It was determined that 10 GD1 patients had osteopenia, 1 had osteoporosis and four had “normal” BMD scores. The BMSi values were significantly lower in patients with GD1 than in the 29 control participants. Patients with GD1 and high levels of the enzyme chitotriosidase had significantly lower values for their hip BMD values. There were no significant differences between control participants and GD1 patients in levels of CTX-I or P1NP. It was also found that for GD1 patients, there was not a significant difference in BMSi, lumbar BMD or hip BMD for patients who had received treatment versus those who had not.

Conclusion

The study found that patients with GD1 had a significantly lower value for BMSi than that of control participants. This is important as GD1 patients have a high prevalence of asymptomatic bone disease. The percentage of GD1 patients who had osteopenia in this study is consistent with that of previous studies; however, it is noted that sample sizes are small and too diverse to allow for thorough comparisons to other studies.

DXA scans are recommended for use in GD1 patients to assess the amount of minerals in the bone(s); however, it’s results can be jeopardised by factors such as bilateral hip prosthesis or degenerative lesions on the spine. In regard to bone turnover biomarkers (such as CTX-I or P1NP), due to the fact that studies have found inconsistent results, they are not currently used in clinical practice. Impact microindentation – a new tool to measure an aspect of the tissue properties of bone, affecting bone strength – is able to be used within clinical practice although it is difficult to determine which specific biomechanical properties are measured by the new technique.

A complete assessment and early diagnosis and management of bone disease is important in the GD1 patient population. The use of impact microindentation may help towards detecting early changes and it is an easier technique to implement in clinical practice. Further investigation into treatment effects i.e. of ERT, and better disease assessment using thorough evaluation of bone health, would be of benefit.

Paper 2 - Multiple intracranial aneurysms...

Citation

Reynolds M, Heiferman D, Boucher A, et al.
Multiple intracranial aneurysms in a patient with type 1 Gaucher disease: a case report and literature review.
British Journal of Neurosurgery, Published online 15^th Jan 2018

Study Aim

To present a possible link between Gaucher Disease (GD) and the formation of unruptured intracranial aneurysms (UIAs); and to propose screening of further patients and investigation of any links.

Methods

This is a report on an individual case study (and literature review) of an older GD patient with minimal symptoms and no enzyme replacement therapy (ERT). The patient was a 69-year-old female with Type 1 GD who had been diagnosed a year previously. She was an ex-smoker with hypertension (HTN) being evaluated for multiple UIAs discovered following an MRI scan.

Results

Except for a mild left sixth nerve palsy, all of the patients’ neurologic and ophthalmologic exams were normal. However, 15 UIAs were revealed following cerebral catheter angiography. The recommended treatment involved endoluminal flow diversion of the largest intracerebral aneurysms (IAs).

Conclusion

Currently, there is insufficient literature to confirm whether GD patients are more susceptible to the development of arterial aneurysms (in systemic or intracerebral circulations). In the past GD patients have developed splenic artery aneurysms; but this was thought to be due to splenomegaly and hypersplenism, causing vascular compression and resulting in arterial hypertension. It is possible that pro-inflammatory mediators, which result in the release of proteases which compromise the cerebrovasculature, together with neuroinflammation seen in GD may contribute to the development of IAs. However, it is worth noting that in this case study the patient also has other independent risk factors including a family history of subarachnoid haemorrhage, smoking and hypertension. As a result, any potential link between GD and multiple IAs may be coincidental. Further screening of patients with GD would be needed for more concrete conclusions to be made regards any links with the development of UIAs.

Paper 3 - Effect of Ambroxol...

Citation

Charkhand B, Scantlebury M, Narita A, Zimran A, & Al-Hertani W.
Effect of Ambroxol chaperone therapy on Glucosylsphingosine (Lyso-Gb1) levels in two Canadian patients with type 3 Gaucher disease.
Molecular Genetics and Metabolism Reports, 2019:20 100476

Study Aim

The aim of the study was to assess, in two Canadian patients with GD3, the effect of Ambroxol on glucosylsphingosine (Lyso-Gb1) levels and on the neurological morbidity.

Methods

This was a case report prepared on two individual subjects with Gaucher Disease type 3.  The first, a 15 year old male diagnosed, aged 1, with GD1; who had received imiglucerase (ERT) since diagnosis.  He had developed refractory epilepsy aged 10 and mild unsteadiness in gait aged 11.  Aged 12 his gait worsened and he became wheelchair dependent and unable to stand without support; which raised suspicion of GD3 instead of GD1.  Brain MRI normal; baseline Lyso-Gb1 on dried blood spot (DBS) 35.4ng/ml.

The second subject of the case report was a 21 year old female; diagnosed with GD1 aged 3 and started on imiglucerase (60IU/Kg) biweekly.  Aged 10, she started to experience neurological symptoms including refractory epilepsy, progressive ataxia and tremor; this led to suspicion of GD3.  A brain MRI was normal at age 10.  At age 18 the patient was wheelchair-bound with a history of frequent hospitalisations for status epilepticus.  Baseline Lyso-Gb1 on DBS was 31ng/ml.

Results

Patient 1 was started on Ambroxol 25mg/Kg/day. After 6 months of supplementation Lyso-Gb1 dropped to 17.5ng/ml (50.6% reduction).  After a further 6 months the Lyso-Gb1 level dropped again, to 10.5ng/ml – a total reduction, in 12 months, of 61.9%.  A similar reduction (60.9%) of Lyso-Gb1 was observed in CSF.  In functional terms, in the first 3 months after starting Ambroxol supplementation, the patient was able to ambulate for short time periods, due to improvement in his ataxia, without the use of a wheelchair.  Seizure type, frequency or duration were not observed to be changed; after 3 years of Ambroxol supplementation the patient’s seizures remain unchanged.  In the last 12 months of being on Ambroxol supplementation, the patient experienced a loss of noted improvements in ambulation; this was due to several new fractures of the femur, tibia and calcaneus causing pain, pain-anxiety and deconditioning due to fracture-related hospitalisations.  The patient had not experienced any fractures before he initially lost the ability to ambulate at the age of 12.

Patient 2 was started on Ambroxol supplementation (25mg/Kg/day) at age 18; after 6 months Lyso-Gb1 dropped to 13ng/ml (a 58% reduction); after a further 18 months the level dropped to 10ng/ml – a total reduction of 67.7% in 2 years.  Functionally the patient experienced significant improvements in her ataxia and ability to ambulate unassisted and she did not need her wheelchair, within the first 6 months of supplementation.  These improvements were stated to remain at the time the case study was written, 3 years after initiation of Ambroxol.  In regards to seizures, these were shorter in duration, with no hospitalisation required in the last 3 years for status epilepticus, although seizure type and frequency have no reported changes.

It is reported that both patients tolerated Ambroxol well, with no interruptions to supplementation treatment and no side effects.

Conclusion

The case study reported the experience of two patients with GD3 who were treated with Ambroxol alongside their ERT. In both patients, Lyso-Gb1 levels on DBS were found to have improved following Ambroxol supplementation.  Initially both patients demonstrated improvement in their ambulation, with Patient 1 losing this improvement due to new fractures.  Patient 1 had no notable changes in his seizures (type, frequency or duration).  In contrast, Patient 2 had a marked reduction in the duration of her seizures; with no hospital admissions in three years for status epilepticus. This improvement in seizures for Patient 2, along with the improvement in ambulation, led to the authors advising that a significant improvement in Patient 2’s quality of life was experienced.

The authors propose that the differences noted in patient responses to Ambroxol supplementation, is likely due to genotypic differences.  They also note that adding Ambroxol to their normal ERT treatment and epileptic medication, was not enough to prevent seizures completely in either of their patients.  The authors acknowledge that there are limitations to the study and that randomized clinical trials, with a larger number of patients are required to evaluate the findings found so far. However, they note that the observations of this case study are in line with other findings; and that in combination with ERT, Ambroxol may be a potential promising treatment for patients with GD3, depending on genotype.  A concern regarding future randomized clinical trials relates to the fact that due to the low cost of Ambroxol and the potential poor return on investment, industry sponsored trials may not be likely.

Paper 4 - Five-parameter evaluation...

Citation

Seehra G, Solomon B, Ryan E, et al.
Five-parameter evaluation of dysphagia: A novel prognostic scale for assessing neurological decline in Gaucher disease type 2.
Molecular Genetics and Metabolism, 2019:127 191-199

Study Aim

To identify key components of swallow function, which could serve as markers of disease progression in GD2.

Methods

This is a post-hoc analysis of modified barium swallow studies; with scoring of 6 parameters from retrospective chart reviews, statistical analysis and modelling of disease progression.  After obtaining informed parental consent, twenty-two patients with GD2 were enrolled in a natural history protocol.  Patients underwent a comprehensive evaluation including swallow studies.  Clinical indication informed which evaluations were performed at each visit. This study focuses on 11 patients who underwent swallow studies; 14 studies were performed on 11 patients, 2 with follow-up visits.

Swallow-function assessments consisted of oral administration (via patient utensils/bottles) of liquid and/or pureed food. Twelve of 14 studies were carried out by a single speech-language pathologist, who assessed and evaluated the clinical swallow at the National Institutes of Health (NIH) Clinical Centre.  The other 2 studies were carried out at other institutions, with results from outside medical records, before initial presentation to the NIH Clinical Centre.  The presence and identification of key swallowing features, as well as safety, informed the decision to perform the gold standard tool of a modified barium swallow (MBS).

The speech-language pathologist scored MBS results from medical records, using 6 parameters: aspiration and/or laryngeal penetration; ability to eat; oral phase dysphagia; head extension; dyssynchronization of ‘suck, swallow, and breathing’; and vocal/speech development.

Statistical testing that was carried out included a ‘mixed effects regression’ analysis, ‘principal component analysis’ and a ‘transition analysis’ using a ‘Hidden Markov Model’.

Results

The patients with GD2 who were assessed using MBS were eleven children – 9 females and 2 males.  Their ages ranged from 6 weeks to 4 years, at the time of their assessments.  Mutation analysis found that among the patients there were multiple genotypes, with only one genotype (RecTL/L444P) found in more than one patient.  Six of the 11 patients had a reported history of choking episodes; and a majority of the patients were noted to have symptoms of stridor and/or tracheomalacia. Eight patients were reported to have pulmonary findings – lung infiltrates on chest x-ray, episodes of pneumonia, or recurrent pneumonias.  Three of the patients eventually needed a tracheostomy.  Neurological involvement in the patients varied; 3 had abnormal EEGs; 5 had a history of seizures; and 6 had abnormal BAER findings.

Fourteen MBS studies were conducted on 11 children (1 child had 3 swallow studies; a second child had 2 swallow studies; whilst the remaining 9 children had 1 swallow study conducted each).  All patients were identified as having swallow dysfunction; 7 patients displayed pharyngeal dysphagia; 8 patients showed aspiration/penetration; whilst oral phase dysphagia was seen in 10 patients.  Vocal/speech development could not be assessed in all patients and due to missing scores this parameter was excluded from further analysis.

Conclusion

The authors write that the study “provides a comprehensive retrospective review of disease presentations and analysis of dysphagia in 11 patients with GD2.”  They note that a limitation of the study is the small sample size, but also that the study is a “valuable reference” for disease progressions and presentations.  They comment that the study is the first known to provide an in-depth analysis of swallow function, used as an indicator of neurological decline.  The statistical analysis carried out in the study validates the joint-use of 5 parameters to assess swallow impairment.  The statistical analysis supported the clinical observation, that the rate of neurological decline, in patients with GD2, cannot be predicted by age.  Transition analysis showed 2 distinct states of GD2; 4 of the 5 parameters displayed clear transition points from state 1 to state 2, with state 2 being considered a more severe disease state.  Additionally, transition probability revealed that the probability of moving from state 1 to state 2 was 100% and the probability of moving back to state 1 is 0%.  State 2 is suggested as representing end-stage disease as a result.  The authors suggest that MBS could help to identify compensatory procedures which may help patients to swallow safely.  They also suggest that clinical care could be guided using objective insights, provided by the evaluation of the MBS 5 parameter scoring system.