Spinocerebellar ataxia type 5 (SCA-5) is a predominantly slowly progressive adult onset ataxia. We describe a child with a presentation of ataxic cerebral palsy (CP) and developmental delay at 6 ...months of age. Genetic testing confirmed a c.812C>T p.(Thr271Ile) mutation within the
SPTBN2
gene. Seven previous cases of infantile onset SCA-5 are reported in the literature, four of which had a CP presentation. Early onset of SCA-5 presents with ataxic CP and is a rare cause of cerebral palsy.
Mutations in the sarcomeric protein titin, encoded by
TTN
, are emerging as a common cause of myopathies. The diagnosis of a
TTN
-related myopathy is, however, often not straightforward due to ...clinico-pathological overlap with other myopathies and the prevalence of
TTN
variants in control populations. Here, we present a combined clinico-pathological, genetic and biophysical approach to the diagnosis of
TTN
-related myopathies and the pathogenicity ascertainment of
TTN
missense variants. We identified 30 patients with a primary
TTN
-related congenital myopathy (CM) and two truncating variants, or one truncating and one missense
TTN
variant, or homozygous for one
TTN
missense variant. We found that
TTN
-related myopathies show considerable overlap with other myopathies but are strongly suggested by a combination of certain clinico-pathological features. Presentation was typically at birth with the clinical course characterized by variable progression of weakness, contractures, scoliosis and respiratory symptoms but sparing of extraocular muscles. Cardiac involvement depended on the variant position. Our biophysical analyses demonstrated that missense mutations associated with CMs are strongly destabilizing and exert their effect when expressed on a truncating background or in homozygosity. We hypothesise that destabilizing
TTN
missense mutations phenocopy truncating variants and are a key pathogenic feature of recessive titinopathies that might be amenable to therapeutic intervention.
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.
Background
Corticosteroid treatment is considered the 'gold standard' for Duchenne muscular dystrophy (DMD); however, it is also known to induce osteoporosis and thus increase the risk of vertebral ...fragility fractures. Good practice in the care of those with DMD requires prevention of these adverse effects. Treatments to increase bone mineral density include bisphosphonates and vitamin D and calcium supplements, and in adolescents with pubertal delay, testosterone. Bone health management is an important part of lifelong care for patients with DMD.
Objectives
To assess the effects of interventions to prevent or treat osteoporosis in children and adults with DMD taking long‐term corticosteroids; to assess the effects of these interventions on the frequency of vertebral fragility fractures and long‐bone fractures, and on quality of life; and to assess adverse events.
Search methods
On 12 September 2016, we searched the Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, Embase, and CINAHL Plus to identify potentially eligible trials. We also searched the Web of Science ISI Proceedings (2001 to September 2016) and three clinical trials registries to identify unpublished studies and ongoing trials. We contacted correspondence authors of the included studies in the review to obtain information on unpublished studies or work in progress.
Selection criteria
We considered for inclusion in the review randomised controlled trials (RCTs) and quasi‐RCTs involving any bone health intervention for corticosteroid‐induced osteoporosis and fragility fractures in children, adolescents, and adults with a confirmed diagnosis of DMD. The interventions might have included oral and intravenous bisphosphonates, vitamin D supplements, calcium supplements, dietary calcium, testosterone, and weight‐bearing activity.
Data collection and analysis
Two review authors independently assessed reports and selected potential studies for inclusion, following standard Cochrane methodology. We contacted study authors to obtain further information for clarification on published work, unpublished studies, and work in progress.
Main results
We identified 18 potential studies, of which two, currently reported only as s, met the inclusion criteria for this review. Too little information was available for us to present full results or adequately assess risk of bias. The participants were children aged five to 15 years with DMD, ambulant and non‐ambulant. The interventions were risedronate versus no treatment in one trial (13 participants) and whole‐body vibration versus a placebo device in the second (21 participants). Both studies reported improved bone mineral density with the active treatments, with no improvement in the control groups, but the s did not compare treatment and control conditions. All children tolerated whole‐body vibration treatment. No study provided information on adverse events. Two studies are ongoing: one investigating whole‐body vibration, the other investigating zoledronic acid.
Authors' conclusions
We know of no high‐quality evidence from RCTs to guide use of treatments to prevent or treat corticosteroid‐induced osteoporosis and reduce the risk of fragility fractures in children and adults with DMD; only limited results from two trials reported in s were available. We await formal trial reports. Findings from two ongoing relevant studies and two trials, for which only s are available, will be important in future updates of this review.
OBJECTIVE:To study the clinical and radiologic spectrum and genotype–phenotype correlation of 4H (hypomyelination, hypodontia, hypogonadotropic hypogonadism) leukodystrophy caused by mutations in ...POLR3A or POLR3B.
METHODS:We performed a multinational cross-sectional observational study of the clinical, radiologic, and molecular characteristics of 105 mutation-proven cases.
RESULTS:The majority of patients presented before 6 years with gross motor delay or regression. Ten percent had an onset beyond 10 years. The disease course was milder in patients with POLR3B than in patients with POLR3A mutations. Other than the typical neurologic, dental, and endocrine features, myopia was seen in almost all and short stature in 50%. Dental and hormonal findings were not invariably present. Mutations in POLR3A and POLR3B were distributed throughout the genes. Except for French Canadian patients, patients from European backgrounds were more likely to have POLR3B mutations than other populations. Most patients carried the common c.1568T>A POLR3B mutation on one allele, homozygosity for which causes a mild phenotype. Systematic MRI review revealed that the combination of hypomyelination with relative T2 hypointensity of the ventrolateral thalamus, optic radiation, globus pallidus, and dentate nucleus, cerebellar atrophy, and thinning of the corpus callosum suggests the diagnosis.
CONCLUSIONS:4H is a well-recognizable clinical entity if all features are present. Mutations in POLR3A are associated with a more severe clinical course. MRI characteristics are helpful in addressing the diagnosis, especially if patients lack the cardinal non-neurologic features.
Drug repurposing could provide novel treatment options for Duchenne muscular dystrophy. Because tamoxifen—an oestrogen receptor regulator—reduced signs of muscular pathology in a Duchenne muscular ...dystrophy mouse model, we aimed to assess the safety and efficacy of tamoxifen in humans as an adjunct to corticosteroid therapy over a period of 48 weeks.
We did a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial at 12 study centres in seven European countries. We enrolled ambulant boys aged 6·5–12·0 years with a genetically confirmed diagnosis of Duchenne muscular dystrophy and who were on stable corticosteroid treatment for more than 6 months. Exclusion criteria included ophthalmological disorders, including cataracts, and haematological disorders. We randomly assigned (1:1) participants using an online randomisation tool to either 20 mg tamoxifen orally per day or matched placebo, stratified by centre and corticosteroid intake. Participants, caregivers, and clinical investigators were masked to treatment assignments. Tamoxifen was taken in addition to standard care with corticosteroids, and participants attended study visits for examinations every 12 weeks. The primary efficacy outcome was the change from baseline to week 48 in scores on the D1 domain of the Motor Function Measure in the intention-to-treat population (defined as all patients who fulfilled the inclusion criteria and began treatment). This study is registered with ClinicalTrials.gov (NCT03354039) and is completed.
Between May 24, 2018, and Oct 14, 2020, 95 boys were screened for inclusion, and 82 met inclusion criteria and were initially enrolled into the study. Three boys were excluded after initial screening due to cataract diagnosis or revoked consent directly after screening, but before randomisation. A further boy assigned to the placebo group did not begin treatment. Therefore, 40 individuals assigned tamoxifen and 38 allocated placebo were included in the intention-to-treat population. The primary efficacy outcome did not differ significantly between tamoxifen (–3·05%, 95% CI –7·02 to 0·91) and placebo (–6·15%, –9·19 to –3·11; 2·90% difference, –3·02 to 8·82, p=0·33). Severe adverse events occurred in two participants: one participant who received tamoxifen had a fall, and one who received placebo suffered a panic attack. No deaths or life-threatening serious adverse events occurred. Viral infections were the most common adverse events.
Tamoxifen was safe and well tolerated, but no difference between groups was reported for the primary efficacy endpoint. Slower disease progression, defined by loss of motor function over time, was indicated in the tamoxifen group compared with the placebo group, but differences in outcome measures were neither clinically nor statistically significant. Currently, we cannot recommend the use of tamoxifen in daily clinical practice as a treatment option for boys with Duchenne muscular dystrophy due to insufficient clinical evidence.
Thomi Hopf Foundation, ERA-Net, Swiss National Science Foundation, Duchenne UK, Joining Jack, Duchenne Parent Project, Duchenne Parent Project Spain, Fondation Suisse de Recherche sur les Maladies Musculaires, Association Monegasque contre les Myopathies.
A case of central hypoventilation syndrome was identified in a child with brainstem and cervical cord injury following Haemophilus influenzae type b meningitis and extensive herpes simplex infection. ...This process resulted in a spastic tetraplegia, and the child continues to require respiratory support. Possible mechanisms of causation are discussed including an evolving, progressive inflammatory or vasculitic process in the setting of transient immunosuppression.
ObjectiveTo describe age and time at key stages in the Duchenne muscular dystrophy (DMD) prediagnosis pathway at selected centres to identify opportunities for service improvement.DesignA multicentre ...retrospective national audit.SettingNine tertiary neuromuscular centres across the UK and Ireland. A prior single-centre UK audit of 20 patients with no DMD family history provided benchmark criteria.PatientsPatients with a definitive diagnosis of DMD documented within 3 years prior to December 2018 (n=122).Main outcome measuresMean age (months) at four key stages in the DMD diagnostic pathway and mean time (months) of presentational and diagnostic delay, and time from first reported symptoms to definitive diagnosis. Type of symptoms was also recorded.ResultsOverall, mean age at definitive diagnosis, age at first engagement with healthcare professional (HCP) and age at first reported symptoms were 53.9±29.7, 49.9±28.9 and 36.4±26.8 months, respectively. The presentational delay and time to diagnosis were 21.1 (±21.1) and 4.6 (±7.9) months, respectively. The mean time from first reported symptoms to definitive diagnosis was 24.2±20.9. The percentages of patients with motor and/or non-motor symptoms recorded were 88% (n=106/121) and 47% (n=57/121), respectively.ConclusionsMajority of data mirrored the benchmark audit. However, while the time to diagnosis was shorter, a presentational delay was observed. Failure to recognise early symptoms of DMD could be a contributing factor and represents an unmet need in the diagnosis pathway. Methods determining how to improve this need to be explored.
Summary
Purpose
To evaluate adherence to prescribed antiepileptic drugs (AEDs) in children with epilepsy using a combination of adherence‐assessment methods.
Methods
A total of 100 children with ...epilepsy (≤17 years old) were recruited. Medication adherence was determined via parental and child self‐reporting (≥9 years old), medication refill data from general practitioner (GP) prescribing records, and via AED concentrations in dried blood spot (DBS) samples obtained from children at the clinic and via self‐ or parental‐led sampling in children's own homes. The latter were assessed using population pharmacokinetic modeling. Patients were deemed nonadherent if any of these measures were indicative of nonadherence with the prescribed treatment. In addition, beliefs about medicines, parental confidence in seizure management, and the presence of depressed mood in parents were evaluated to examine their association with nonadherence in the participating children.
Key Findings
The overall rate of nonadherence in children with epilepsy was 33%. Logistic regression analysis indicated that children with generalized epilepsy (vs. focal epilepsy) were more likely (odds ratio OR 4.7, 95% confidence interval CI 1.37–15.81) to be classified as nonadherent as were children whose parents have depressed mood (OR 3.6, 95% CI 1.16–11.41).
Significance
This is the first study to apply the novel methodology of determining adherence via AED concentrations in clinic and home DBS samples. The present findings show that the latter, with further development, could be a useful approach to adherence assessment when combined with other measures including parent and child self‐reporting. Seizure type and parental depressed mood were strongly predictive of nonadherence.
The objective of this study is to analyse retrospective, observational, longitudinal growth (weight, height and BMI) data in ambulatory boys aged 5-12 years with Duchenne muscular dystrophy (DMD).
We ...considered glucocorticoids (GC) use, dystrophin isoforms and amenability to exon 8, 44, 45, 51 and 53 skipping drug subgroups, and the impact of growth on loss of ambulation. We analysed 598 boys, with 2604 observations. This analysis considered patients from the UK NorthStar database (2003-2020) on one of five regimes: "GC naïve", "deflazacort daily" (DD), "deflazacort intermittent" (DI), "prednisolone daily" (PD) and "prednisolone intermittent" (PI). A random slope model was used to model the weight, height and BMI SD scores (using the UK90).
The daily regime subgroups had significant yearly height stunting compared to the GC naïve subgroup. Notably, the average height change for the DD subgroup was 0.25 SD (95% CI - 0.30, - 0.21) less than reference values. Those with affected expression of Dp427, Dp140 and Dp71 isoforms were 0.77 (95% CI 0.3, 1.24) and 0.82 (95% CI 1.28, 0.36) SD shorter than those with Dp427 and/or Dp140 expression affected respectively. Increased weight was not associated with earlier loss of ambulation, but taller boys still ambulant between the age of 10 and 11 years were more at risk of losing ambulation.
These findings may provide further guidance to clinicians when counselling and discussing GCs commencement with patients and their carers and may represent a benchmark set of data to evaluate the effects of new generations of GC.
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