Objective
To develop recommendations for prevention and treatment of glucocorticoid‐induced osteoporosis (GIOP).
Methods
We conducted a systematic review to synthesize the evidence for the benefits ...and harms of GIOP prevention and treatment options. The Grading of Recommendations Assessment, Development and Evaluation methodology was used to rate the quality of evidence. We used a group consensus process to determine the final recommendations and grade their strength. The guideline addresses initial assessment and reassessment in patients beginning or continuing long‐term (≥3 months) glucocorticoid (GC) treatment, as well as the relative benefits and harms of lifestyle modification and of calcium, vitamin D, bisphosphonate, raloxifene, teriparatide, and denosumab treatment in the general adult population receiving long‐term GC treatment, as well as in special populations of long‐term GC users.
Results
Because of limited evidence regarding the benefits and harms of interventions in GC users, most recommendations in this guideline are conditional (uncertain balance between benefits and harms). Recommendations include treating only with calcium and vitamin D in adults at low fracture risk, treating with calcium and vitamin D plus an additional osteoporosis medication (oral bisphosphonate preferred) in adults at moderate‐to‐high fracture risk, continuing calcium plus vitamin D but switching from an oral bisphosphonate to another antifracture medication in adults in whom oral bisphosphonate treatment is not appropriate, and continuing oral bisphosphonate treatment or switching to another antifracture medication in adults who complete a planned oral bisphosphonate regimen but continue to receive GC treatment. Recommendations for special populations, including children, people with organ transplants, women of childbearing potential, and people receiving very high‐dose GC treatment, are also made.
Conclusion
This guideline provides direction for clinicians and patients making treatment decisions. Clinicians and patients should use a shared decision‐making process that accounts for patients’ values, preferences, and comorbidities. These recommendations should not be used to limit or deny access to therapies.
Introduction/Aims
Risdiplam is the newest available treatment for patients with spinal muscular atrophy (SMA). There is little information on its use in adults. We present the clinical experience of ...adults with SMA treated with risdiplam through the Early Access to Medicines Scheme (EAMS) in Northern Ireland.
Methods
All adults with Type 2 SMA attending the regional neuromuscular clinic were offered risdiplam treatment. Patients had assessments of respiratory function, the Epworth Sleepiness Scale (ESS), Quality of Life Measure for People with Slowly Progressive and Genetic Neuromuscular Disease (QOLM), and Egen Klassifikation 2 (EK2) every 3 mo and the Revised Upper Limb Module for SMA (RULM) at baseline and 6 mo. All assessments other than the RULM were carried out virtually.
Results
Six of seven patients who were offered risdiplam consented to treatment through the EAMS (five female, one male, mean age 33.7 y). It was generally well tolerated other than skin photosensitivity in all patients. All patients remained on therapy at 9 mo. All reported meaningful improvements in overall strength, sense of wellbeing, and speech quality. There was no change in respiratory function, daytime hypersomnolence, or upper limb function (all p > .05). There was improvement in the QOLM (p = .027) and EK2 (p = .009).
Discussion
Our study raises hopes that risdiplam may be efficacious in adults; however, more systematic studies in larger cohorts are needed before drawing any definitive conclusions. This study also demonstrated the feasibility of virtual assessments.
Amyotrophic lateral sclerosis (ALS), a common late-onset neurodegenerative disease, is associated with fronto-temporal dementia (FTD) in 3-10% of patients. A mutation in CHMP2B was recently ...identified in a Danish pedigree with autosomal dominant FTD. Subsequently, two unrelated patients with familial ALS, one of whom also showed features of FTD, were shown to carry missense mutations in CHMP2B. The initial aim of this study was to determine whether mutations in CHMP2B contribute more broadly to ALS pathogenesis.
Sequencing of CHMP2B in 433 ALS cases from the North of England identified 4 cases carrying 3 missense mutations, including one novel mutation, p.Thr104Asn, none of which were present in 500 neurologically normal controls. Analysis of clinical and neuropathological data of these 4 cases showed a phenotype consistent with the lower motor neuron predominant (progressive muscular atrophy (PMA)) variant of ALS. Only one had a recognised family history of ALS and none had clinically apparent dementia. Microarray analysis of motor neurons from CHMP2B cases, compared to controls, showed a distinct gene expression signature with significant differential expression predicting disassembly of cell structure; increased calcium concentration in the ER lumen; decrease in the availability of ATP; down-regulation of the classical and p38 MAPK signalling pathways, reduction in autophagy initiation and a global repression of translation. Transfection of mutant CHMP2B into HEK-293 and COS-7 cells resulted in the formation of large cytoplasmic vacuoles, aberrant lysosomal localisation demonstrated by CD63 staining and impairment of autophagy indicated by increased levels of LC3-II protein. These changes were absent in control cells transfected with wild-type CHMP2B.
We conclude that in a population drawn from North of England pathogenic CHMP2B mutations are found in approximately 1% of cases of ALS and 10% of those with lower motor neuron predominant ALS. We provide a body of evidence indicating the likely pathogenicity of the reported gene alterations. However, absolute confirmation of pathogenicity requires further evidence, including documentation of familial transmission in ALS pedigrees which might be most fruitfully explored in cases with a LMN predominant phenotype.
Objective
To develop recommendations for prevention and treatment of glucocorticoid‐induced osteoporosis (GIOP).
Methods
We conducted a systematic review to synthesize the evidence for the benefits ...and harms of GIOP prevention and treatment options. The Grading of Recommendations Assessment, Development and Evaluation methodology was used to rate the quality of evidence. We used a group consensus process to determine the final recommendations and grade their strength. The guideline addresses initial assessment and reassessment in patients beginning or continuing long‐term (≥3 months) glucocorticoid (GC) treatment, as well as the relative benefits and harms of lifestyle modification and of calcium, vitamin D, bisphosphonate, raloxifene, teriparatide, and denosumab treatment in the general adult population receiving long‐term GC treatment, as well as in special populations of long‐term GC users.
Results
Because of limited evidence regarding the benefits and harms of interventions in GC users, most recommendations in this guideline are conditional (uncertain balance between benefits and harms). Recommendations include treating only with calcium and vitamin D in adults at low fracture risk, treating with calcium and vitamin D plus an additional osteoporosis medication (oral bisphosphonate preferred) in adults at moderate‐to‐high fracture risk, continuing calcium plus vitamin D but switching from an oral bisphosphonate to another antifracture medication in adults in whom oral bisphosphonate treatment is not appropriate, and continuing oral bisphosphonate treatment or switching to another antifracture medication in adults who complete a planned oral bisphosphonate regimen but continue to receive GC treatment. Recommendations for special populations, including children, people with organ transplants, women of childbearing potential, and people receiving very high‐dose GC treatment, are also made.
Conclusion
This guideline provides direction for clinicians and patients making treatment decisions. Clinicians and patients should use a shared decision‐making process that accounts for patients' values, preferences, and comorbidities. These recommendations should not be used to limit or deny access to therapies.
Background: The evidence base for the diagnosis and management of amyotrophic lateral sclerosis (ALS) is weak.
Objectives: To provide evidence‐based or expert recommendations for the diagnosis and ...management of ALS based on a literature search and the consensus of an expert panel.
Methods: All available medical reference systems were searched, and original papers, meta‐analyses, review papers, book chapters and guidelines recommendations were reviewed. The final literature search was performed in February 2011. Recommendations were reached by consensus.
Recommendations: Patients with symptoms suggestive of ALS should be assessed as soon as possible by an experienced neurologist. Early diagnosis should be pursued, and investigations, including neurophysiology, performed with a high priority. The patient should be informed of the diagnosis by a consultant with a good knowledge of the patient and the disease. Following diagnosis, the patient and relatives/carers should receive regular support from a multidisciplinary care team. Medication with riluzole should be initiated as early as possible. Control of symptoms such as sialorrhoea, thick mucus, emotional lability, cramps, spasticity and pain should be attempted. Percutaneous endoscopic gastrostomy feeding improves nutrition and quality of life, and gastrostomy tubes should be placed before respiratory insufficiency develops. Non‐invasive positive‐pressure ventilation also improves survival and quality of life. Maintaining the patient’s ability to communicate is essential. During the entire course of the disease, every effort should be made to maintain patient autonomy. Advance directives for palliative end‐of‐life care should be discussed early with the patient and carers, respecting the patient’s social and cultural background.
To discover novel genes underlying amyotrophic lateral sclerosis (ALS), we aggregated exomes from 3,864 cases and 7,839 ancestry-matched controls. We observed a significant excess of rare ...protein-truncating variants among ALS cases, and these variants were concentrated in constrained genes. Through gene level analyses, we replicated known ALS genes including SOD1, NEK1 and FUS. We also observed multiple distinct protein-truncating variants in a highly constrained gene, DNAJC7. The signal in DNAJC7 exceeded genome-wide significance, and immunoblotting assays showed depletion of DNAJC7 protein in fibroblasts in a patient with ALS carrying the p.Arg156Ter variant. DNAJC7 encodes a member of the heat-shock protein family, HSP40, which, along with HSP70 proteins, facilitates protein homeostasis, including folding of newly synthesized polypeptides and clearance of degraded proteins. When these processes are not regulated, misfolding and accumulation of aberrant proteins can occur and lead to protein aggregation, which is a pathological hallmark of neurodegeneration. Our results highlight DNAJC7 as a novel gene for ALS.
Amyotrophic lateral sclerosis is a progressive neurodegenerative disease of motor neurons. About 25 genes have been verified as relevant to the disease process, with rare and common variation ...implicated. We used next generation sequencing and repeat sizing to comprehensively assay genetic variation in a panel of known amyotrophic lateral sclerosis genes in 1126 patient samples and 613 controls. About 10% of patients were predicted to carry a pathological expansion of the C9orf72 gene. We found an increased burden of rare variants in patients within the untranslated regions of known disease-causing genes, driven by SOD1, TARDBP, FUS, VCP, OPTN and UBQLN2. We found 11 patients (1%) carried more than one pathogenic variant (P = 0.001) consistent with an oligogenic basis of amyotrophic lateral sclerosis. These findings show that the genetic architecture of amyotrophic lateral sclerosis is complex and that variation in the regulatory regions of associated genes may be important in disease pathogenesis.
Previous associations between mitochondrial DNA (mtDNA) and idiopathic Parkinson disease (PD) have been inconsistent and contradictory. Our aim was to resolve these inconsistencies and determine ...whether mtDNA has a significant role in the risk of developing PD.
Two-stage genetic association study of 138 common mtDNA variants in 3,074 PD cases and 5,659 ethnically matched controls followed by meta-analysis of 6,140 PD cases and 13,280 controls.
In the association study, m.2158T>C and m.11251A>G were associated with a reduced risk of PD in both the discovery and replication cohorts. None of the common European mtDNA haplogroups were consistently associated with PD, but pooling of discovery and replication cohorts revealed a protective association with "super-haplogroup" JT. In the meta-analysis, there was a reduced risk of PD with haplogroups J, K, and T and super-haplogroup JT, and an increase in the risk of PD with super-haplogroup H.
In a 2-stage association study of mtDNA variants and PD, we confirm the reduced risk of PD with super-haplogroup JT and resolve this at the J1b level. Meta-analysis explains the previous inconsistent associations that likely arise through sampling effects. The reduced risk of PD with haplogroups J, K, and T is mirrored by an increased risk of PD in super-haplogroup HV, which increases survival after sepsis. Antagonistic pleiotropy between mtDNA haplogroups may thus be shaping the genetic landscape in humans, leading to an increased risk of PD in later life.
Summary Background Parkinson's disease has been reported in a small number of patients with chromosome 22q11.2 deletion syndrome. In this study, we screened a series of large, independent Parkinson's ...disease case-control studies for deletions at 22q11.2. Methods We used data on deletions spanning the 22q11.2 locus from four independent case-control Parkinson's disease studies (UK Wellcome Trust Case Control Consortium 2, Dutch Parkinson's Disease Genetics Consortium, US National Institute on Aging, and International Parkinson's Disease Genomics Consortium studies), which were independent of the original reports of chromosome 22q11.2 deletion syndrome. We did case-control association analysis to compare the proportion of 22q11.2 deletions found, using the Fisher's exact test for the independent case-control studies and the Mantel-Haenszel test for the meta-analyses. We retrieved clinical details of patients with Parkinson's disease who had 22q11.2 deletions from the medical records of these patients. Findings We included array-based copy number variation data from 9387 patients with Parkinson's disease and 13 863 controls. Eight patients with Parkinson's disease and none of the controls had 22q11.2 deletions (p=0·00082). In the 8451 patients for whom age at onset data were available, deletions at 22q11.2 were associated with Parkinson's disease age at onset (Mann-Whitney U test p=0·001). Age at onset of Parkinson's disease was lower in patients carrying a 22q11.2 deletion (median 37 years, 95% CI 32·0–55·5; mean 42·1 years SD 11·9) than in those who did not carry a deletion (median 61 years, 95% CI 60·5–61·0; mean 60·3 years SD 12·8). A 22q11.2 deletion was present in more patients with early-onset (p<0·0001) and late-onset Parkinson's disease (p=0·016) than in controls, and in more patients with early-onset than late-onset Parkinson's disease (p=0·005). Interpretation Clinicians should be alert to the possibility of 22q11.2 deletions in patients with Parkinson's disease who have early presentation or features associated with the chromosome 22q11.2 deletion syndrome, or both. Funding UK Medical Research Council, UK Wellcome Trust, Parkinson's UK, Patrick Berthoud Trust, National Institutes of Health, “Investissements d'Avenir” ANR-10-IAIHU-06, Dutch Parkinson Foundation (Parkinson Vereniging), Neuroscience Campus Amsterdam, National Institute for Health Research, National Institute on Aging, National Institutes of Health.
The expansion of a hexanucleotide repeat GGGGCC in C9orf72 is the most common known cause of ALS accounting for ~ 40% familial cases and ~ 7% sporadic cases in the European population. In most ...people, the repeat length is 2, but in people with ALS, hundreds to thousands of repeats may be observed. A small proportion of people have an intermediate expansion, of the order of 20 to 30 repeats in size, and it remains unknown whether intermediate expansions confer risk of ALS in the same way that massive expansions do. We investigated the association of this intermediate repeat with ALS by performing a meta-analysis of four previously published studies and a new British/Alzheimer's Disease Neuroimaging Initiative dataset of 1295 cases and 613 controls. The final dataset comprised 5071 cases and 3747 controls. Our meta-analysis showed association between ALS and intermediate C9orf72 repeats of 24 to 30 repeats in size (random-effects model OR = 4.2, 95% CI = 1.23-14.35, p-value = 0.02). Furthermore, we showed a different frequency of the repeat between the northern and southern European populations (Fisher's exact test p-value = 5 × 10
). Our findings provide evidence for the association between intermediate repeats and ALS (p-value = 2 × 10
) with direct relevance for research and clinical practice by showing that an expansion of 24 or more repeats should be considered pathogenic.
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