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Aims: Limb‐girdle congenital myasthenic syndrome (LG‐CMS) is a genetically heterogeneous disorder characterised by muscle weakness and fatigability. The LG‐CMS gene DPAGT1 codes for an essential enzyme of the glycosylation pathway, a posttranslational modification mechanism shaping the structure and function of proteins. In DPAGT1‐related LG‐CMS, decreased glycosylation of the acetylcholine receptor (AChR) reduces its localization at the neuromuscular junction (NMJ) and results in diminished neuromuscular transmission. LG‐CMS patients also show tubular aggregates on muscle biopsy, but the origin and potential contribution of the aggregates to disease development are not understood. Here, we describe two LG‐CMS patients with the aim of providing a molecular diagnosis and to shed light on the pathways implicated in tubular aggregate formation. Methods: Following clinical examination of the patients, we performed next‐generation sequencing (NGS) to identify the genetic causes, analysed the biopsies at the histological and ultrastructural levels, investigated the composition of the tubular aggregates and performed experiments on protein glycosylation. Results: We identified novel pathogenic DPAGT1 variants in both patients and pyridostigmine treatment quantitatively improved muscle force and function. The tubular aggregates contained proteins of the sarcoplasmic reticulum (SR) and structurally conformed to the aggregates observed in tubular aggregate myopathy (TAM). TAM arises from overactivation of the plasma membrane calcium channel ORAI1, and functional studies on muscle extracts from our LG‐CMS patients evidenced abnormal ORAI1 glycosylation. Conclusions: We expand the genetic variant spectrum of LG‐CMS and provide a genotype/phenotype correlation for pathogenic DPAGT1 variants. The discovery of ORAI1 hypoglycosylation in our patients highlights a physiopathological link between LG‐CMS and TAM. [ABSTRACT FROM AUTHOR]

We sought to devise a rational, systematic approach for defining/grouping survival motor neuron‐targeted disease‐modifying treatment (DMT) scenarios. The proposed classification is primarily based on a two‐part differentiation: initial DMT, and persistence/discontinuation of subsequent DMT(s). Treatment categories were identified: monotherapy add‐on, transient add‐on, combination with onasemnogene abeparvovec, bridging to onasemnogene abeparvovec, and switching to onasemnogene abeparvovec. We validated this approach by applying the classification to the 443 patients currently in the RESTORE registry and explored the demographics of these different groups of patients. This work forms the basis to explore the safety and efficacy profile of the different combinations of DMT in SMA. [ABSTRACT FROM AUTHOR]

Angelman Syndrome is a rare neurodevelopmental disorder characterized by developmental delay, lack of speech, seizures, intellectual disability, characteristic behavior, and movement disorders. Clinical gait analysis provides the opportunity for movement quantification to investigate an observed maladaptive change in gait pattern and offers an objective outcome of change. Pressure‐sensor‐based technology, inertial and activity monitoring, and instrumented gait analysis (IGA) were employed to define motor abnormalities in Angelman syndrome. Temporal–spatial gait parameters of persons with Angelman Syndrome (pwAS) show deficiencies in gait performance through walking speed, step length, step width, and walk ratio. pwAS walk with reduced step lengths, increased step width, and greater variability. Three‐dimensional motion kinematics showed increased anterior pelvic tilt, hip flexion, and knee flexion. PwAS have a walk ratio more than two standard deviations below controls. Dynamic electromyography showed prolonged activation of knee extensors, which was associated with a decreased range of motion and the presence of hip flexion contractures. Use of multiple gait tracking modalities revealed that pwAS exhibit a change in gait pattern to a flexed knee gait pattern. Cross‐sectional studies of individuals with AS show a regression toward this maladaptive gait pattern over development in pwAS ages 4‐11. PwAS unexpectedly did not have spasticity associated with change in gait pattern. Multiple quantitative measures of motor patterning may offer early biomarkers of gait decline consistent with critical periods of intervention, insight into appropriate management strategies, objective primary outcomes, and early indicators of adverse events. [ABSTRACT FROM AUTHOR]

In the last decade, there has been a dramatic increase in the number of families resorting to internet‐based public appeals to fund access to novel, highly expensive, or experimental therapies for rare disorders. Medical crowdfunding may provide a means to fund treatments or interventions, but it raises individual and societal ethical questions. In this review, we consider the ethical challenges crowdfunding poses in paediatric neurology, drawing on the example of gene therapy for spinal muscular atrophy. We discuss physician responsibilities, and how neurologists should respond to crowdfunding that they encounter in clinical practice. We also briefly consider actions that can be taken by clinicians, charities, and crowdfunding websites to reduce harms. The best way to mitigate these harms may be to target the high costs and restrictive criteria that limit access to many novel treatments, and to optimize treatment utility, for instance by newborn screening. What this paper adds: Crowdfunding is a social phenomenon arising from families' inability to access desired treatment.Treatments sought by crowdfunding range from those that are clearly beneficial (but unaffordable) to those that would be ineffective and potentially harmful.Crowdfunding carries a range of harms and risks to families and children and has wider social impact. What this paper adds: Crowdfunding is a social phenomenon arising from families' inability to access desired treatment.Treatments sought by crowdfunding range from those that are clearly beneficial (but unaffordable) to those that would be ineffective and potentially harmful.Crowdfunding carries a range of harms and risks to families and children and has wider social impact. [ABSTRACT FROM AUTHOR]

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Objective: Spinal muscular atrophy (SMA) is a common genetic cause of infant mortality. Nusinersen treatment ameliorates the clinical outcome of SMA, however, some patients respond well, while others have limited response. We investigated microRNAs in blood samples from SMA patients and their response to nusinersen treatment evaluating the potential of circulating microRNAs as biomarkers for SMA. Methods: In a discovery cohort study, microRNA next‐generation sequencing was performed in blood samples from SMA patients (SMA type 2, n = 10; SMA type 3, n = 10) and controls (n = 7). The dysregulated microRNAs were further analysed in the therapeutic response cohort comprised of SMA type 1 patients (n = 22) who had received nusinersen treatment, at three time points along the treatment course (baseline, 2 and 6 months of treatment). The levels of the studied microRNAs were correlated to the SMA clinical outcome measures. Results: In the discovery cohort, 69 microRNAs were dysregulated between SMA patients and controls. In the therapeutic response cohort, the baseline plasma levels of miR‐107, miR‐142‐5p, miR‐335‐5p, miR‐423‐3p, miR‐660‐5p, miR‐378a‐3p and miR‐23a‐3p were associated with the 2 and 6 months response to nusinersen treatment. Furthermore, the levels of miR‐107, miR‐142‐5p, miR‐335‐5p, miR‐423‐3p, miR‐660‐5p and miR‐378‐3p at 2 months of treatment were associated with the response after 6 months of nusinersen treatment. Interpretation: Blood microRNAs could be used as biomarkers to indicate SMA patients' response to nusinersen and to monitor the efficacy of the therapeutic intervention. In addition, some of these microRNAs provide insight into processes involved in SMA that could be exploited as novel therapeutic targets. [ABSTRACT FROM AUTHOR]

Introduction/Aims: Limb girdle muscular dystrophy type 2B (LGMDR2) and facioscapulohumeral muscular dystrophy (FSHD) are genetic muscular dystrophies with an increasing number of potential therapeutic approaches. The aim of this study is to report the data of exploratory digital outcomes extracted from wearable magneto‐inertial sensors used in a non‐controlled environment for ambulant patients with FSHD and LGMDR2 in a short‐term, multicenter clinical study. Methods: Digital outcomes (stride length, stride speed, and walk parameters in a non‐controlled environment) were used as exploratory outcomes in the open‐label study ATYR1940‐C‐004 in ambulant patients during the 3 mo of ATYR1940 treatment and 1 mo of follow‐up. Activity and gait variables were calculated from the data recorded in 30‐day sub‐periods using the sensors. For each sub‐period, activity and gait parameters were compared between FSHD and LGMDR2 patients. Change from baseline over the 4‐mo study period was assessed. Results: Ten patients (5 FSHD, 5 LGMDR2) were ambulant and compliant for analysis. Gait parameters, but not activity variables, were significantly lower in LGMDR2 compared to FSHD patients at baseline. Longitudinal analyses showed a slight but significant decrease in stride speed at month 4 for all subjects. Activity variables such as total number of strides per day were highly variable from month to month in individual patients, and no visit effects were found for this variable. Discussion The present study suggests that home‐recorded stride speed constitutes a precise and sensitive outcome in ambulant patients with FSHD and LGMDR2. [ABSTRACT FROM AUTHOR]

Introduction/Aims: Mutations amenable to skipping of specific exons have been associated with different motor progression in Duchenne muscular dystrophy (DMD). Less is known about their association with long‐term respiratory function. In this study we investigated the features of respiratory progression in four DMD genotypes relevant in ongoing exon‐skipping therapeutic strategies. Methods: This was a retrospective longitudinal study including DMD children followed by the UK NorthStar Network and international AFM Network centers (May 2003 to October 2020). We included boys amenable to skip exons 44, 45, 51, or 53, who were older than 5 years of age and ambulant at first recorded visit. Subjects who were corticosteroid‐naive or enrolled in interventional clinical trials were excluded. The progression of respiratory function (absolute forced vital capacity [FVC] and calculated as percent predicted [FVC%]) was compared across the four subgroups (skip44, skip45, skip51, skip53). Results: We included 142 boys in the study. Mean (standard deviation) age at first visit was 8.6 (2.5) years. Median follow‐up was 3 (range, 0.3‐8.3) years. In skip45 and skip51, FVC% declined linearly from the first recorded visit. From the age of 9 years, FVC% declined linearly in all genotypes. Skip44 had the slowest (2.7%/year) and skip51 the fastest (5.9%/year) annual FVC% decline. The absolute FVC increased progressively in skip44, skip45, and skip51. In skip53, FVC started declining from 14 years of age. Discussion The progression of respiratory dysfunction follows different patterns for specific genotype categories. This information is valuable for prognosis and for the evaluation of exon‐skipping therapies. [ABSTRACT FROM AUTHOR]

Spinal muscular atrophy (SMA) is a rare, progressive neuromuscular disease characterized by loss of motor neurons and muscle atrophy. Untreated infants with type 1 SMA do not achieve major motor milestones, and death from respiratory failure typically occurs before 2 years of age. Individuals with types 2 and 3 SMA exhibit milder phenotypes and have better functional and survival outcomes. Herein, a systematic literature review was conducted to identify factors that influence the prognosis of types 1, 2, and 3 SMA. In untreated infants with type 1 SMA, absence of symptoms at birth, a later symptom onset, and a higher survival of motor neuron 2 (SMN2) copy number are all associated with increased survival. Disease duration, age at treatment initiation, and, to a lesser extent, baseline function were identified as potential treatment‐modifying factors for survival, emphasizing that early treatment with disease‐modifying therapies (DMT) is essential in type 1 SMA. In patients with types 2 and 3 SMA, factors considered prognostic of changes in motor function were SMN2 copy number, age, and ambulatory status. Individuals aged 6–15 years were particularly vulnerable to developing complications (scoliosis and progressive joint contractures) which negatively influence functional outcomes and may also affect the therapeutic response in patients. Age at the time of treatment initiation emerged as a treatment‐effect modifier on the outcome of DMTs. Factors identified in this review should be considered prior to designing or analyzing studies in an SMA population, conducting population matching, or summarizing results from different studies on the treatments for SMA. [ABSTRACT FROM AUTHOR]

Objective: To understand the natural disease upper limb progression over 3 years of ambulatory and non‐ambulatory patients with Duchenne muscular dystrophy (DMD) using functional assessments and quantitative magnetic resonance imaging (MRI) and to exploratively identify prognostic factors. Methods: Forty boys with DMD (22 non‐ambulatory and 18 ambulatory) with deletions in dystrophin that make them eligible for exon 53‐skipping therapy were included. Clinical assessments, including Brooke score, motor function measure (MFM), hand grip and key pinch strength, and upper limb distal coordination and endurance (MoviPlate), were performed every 6 months and quantitative MRI of fat fraction (FF) and lean muscle cross sectional area (flexor and extensor muscles) were performed yearly. Results: In the whole population, there were strong nonlinear correlations between outcome measures. In non‐ambulatory patients, annual changes over the course of 3 years were detected with high sensitivity standard response mean (|SRM| ≥0.8) for quantitative MRI‐based FF, hand grip and key pinch, and MFM. Boys who presented with a FF<20% and a grip strength >27% were able to bring a glass to their mouth and retained this ability in the following 3 years. Ambulatory patients with grip strength >35% of predicted value and FF <10% retained ambulation 3 years later. Interpretation: We demonstrate that continuous decline in upper limb strength, function, and MRI measured muscle structure can be reliably measured in ambulatory and non‐ambulatory boys with DMD with high SRM and strong correlations between outcomes. Our results suggest that a combination of grip strength and FF can be used to predict important motor milestones. [ABSTRACT FROM AUTHOR]

Background: Duchenne muscular dystrophy (DMD) is a lethal muscle disease detected in approximately 1:5000 male births. DMD is caused by mutations in the DMD gene, encoding a critical protein that links the cytoskeleton and the extracellular matrix in skeletal and cardiac muscles. The primary consequence of the disrupted link between the extracellular matrix and the myofibre actin cytoskeleton is thought to involve sarcolemma destabilization, perturbation of Ca2+ homeostasis, activation of proteases, mitochondrial damage, and tissue degeneration. A recently emphasized secondary aspect of the dystrophic process is a progressive metabolic change of the dystrophic tissue; however, the mechanism and nature of the metabolic dysregulation are yet poorly understood. In this study, we characterized a molecular mechanism of metabolic perturbation in DMD. Methods: We sequenced plasma miRNA in a DMD cohort, comprising 54 DMD patients treated or not by glucocorticoid, compared with 27 healthy controls, in three groups of the ages of 4–8, 8–12, and 12–20 years. We developed an original approach for the biological interpretation of miRNA dysregulation and produced a novel hypothesis concerning metabolic perturbation in DMD. We used the mdx mouse model for DMD for the investigation of this hypothesis. Results: We identified 96 dysregulated miRNAs (adjusted P‐value <0.1), of which 74 were up‐regulated and 22 were down‐regulated in DMD. We confirmed the dysregulation in DMD of Dystro‐miRs, Cardio‐miRs, and a large number of the DLK1‐DIO3 miRNAs. We also identified numerous dysregulated miRNAs yet unreported in DMD. Bioinformatics analysis of both target and host genes for dysregulated miRNAs predicted that lipid metabolism might be a critical metabolic perturbation in DMD. Investigation of skeletal muscles of the mdx mouse uncovered dysregulation of transcription factors of cholesterol and fatty acid metabolism (SREBP‐1 and SREBP‐2), perturbation of the mevalonate pathway, and the accumulation of cholesterol in the dystrophic muscles. Elevated cholesterol level was also found in muscle biopsies of DMD patients. Treatment of mdx mice with Simvastatin, a cholesterol‐reducing agent, normalized these perturbations and partially restored the dystrophic parameters. Conclusions: This investigation supports that cholesterol metabolism and the mevalonate pathway are potential therapeutic targets in DMD. [ABSTRACT FROM AUTHOR]

Objective: This study was undertaken to determine whether a low residual quantity of dystrophin protein is associated with delayed clinical milestones in patients with DMD mutations. Methods: We performed a retrospective multicentric cohort study by using molecular and clinical data from patients with DMD mutations registered in the Universal Mutation Database–DMD France database. Patients with intronic, splice site, or nonsense DMD mutations, with available muscle biopsy Western blot data, were included irrespective of whether they presented with severe Duchenne muscular dystrophy (DMD) or milder Becker muscular dystrophy (BMD). Patients were separated into 3 groups based on dystrophin protein levels. Clinical outcomes were ages at appearance of first symptoms; loss of ambulation; fall in vital capacity and left ventricular ejection fraction; interventions such as spinal fusion, tracheostomy, and noninvasive ventilation; and death. Results: Of 3,880 patients with DMD mutations, 90 with mutations of interest were included. Forty‐two patients expressed no dystrophin (group A), and 31 of 42 (74%) developed DMD. Thirty‐four patients had dystrophin quantities < 5% (group B), and 21 of 34 (61%) developed BMD. Fourteen patients had dystrophin quantities ≥ 5% (group C), and all but 4 who lost ambulation beyond 24 years of age were ambulant. Dystrophin quantities of <5%, as low as <0.5%, were associated with milder phenotype for most of the evaluated clinical outcomes, including age at loss of ambulation (p < 0.001). Interpretation: Very low residual dystrophin protein quantity can cause a shift in disease phenotype from DMD toward BMD. ANN NEUROL 2021;89:280–292 [ABSTRACT FROM AUTHOR]

The coronavirus disease 2019 (COVID-19) pandemic has resulted in reorganization of healthcare settings affecting the delivery of clinical care to patients with spinal muscular atrophy (SMA). There is a concern that patients with SMA may be at increased risk of manifesting severe symptoms of COVID-19. Currently approved therapies for SMA improve survival and motor function; however, their delivery requires an increased exposure to the health system and a dedicated healthcare team. In this study, we discuss consensus recommendations pertaining to care of SMA patients during the pandemic. We highlight that SMA treatments should not be perceived as elective. Decisions regarding the delay of treatments should be made with consideration of the potential risks of COVID-19 exposure and the risk of that delay. We emphasize the importance of collaborative treatment decisions between the patient, family, and healthcare provider, considering any geographic- or institution-specific policies and precautions for COVID-19. [ABSTRACT FROM AUTHOR]

Aim: To determine factors associated with acquisition of a sitting position in patients with spinal muscular atrophy type 1 (SMA1) treated with nusinersen.Method: Using data from the registry of patients with SMA1 treated with nusinersen, we compared the subgroups of sitters and non-sitters after 14 months of therapy as a function of baseline level, SMN2 copy number, age at treatment initiation, and improvement at 2 and 6 months post-treatment initiation. We used Hammersmith Infant Neurological Examination, Section 2 (HINE-2) and Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders for motor evaluation.Results: Fifty children (22 females, 28 males), mean age 22 months (SD 20.7; range 2.5-102.8mo) were treated. Data on sitting position acquisition were collected for 47 patients at month 14. Fifteen patients were able to sit unassisted; 11 of 15 had a baseline HINE-2 score of at least 2 points and 11 of 14 had an improvement over baseline of at least 2 points at month 6. Patients who improved by 2 or more points at month 6 were three times more likely to be sitters at month 14 than those who did not.Interpretation: High baseline motor function and improvement in HINE-2 score after 6 months of treatment are associated with the probability of acquiring a sitting position in patients with SMA1 treated with nusinersen.What This Paper Adds: Fifteen of 47 patients with spinal muscular atrophy could sit unaided 14 months after treatment with nusinersen. The number of SMN2 copies were not predictive of acquisition of a sitting position. Baseline condition and clinical response after 6 months of treatment were most predictive of sitting position acquisition. [ABSTRACT FROM AUTHOR]

Objective: Recently, the ASC-1 complex has been identified as a mechanistic link between amyotrophic lateral sclerosis and spinal muscular atrophy (SMA), and 3 mutations of the ASC-1 gene TRIP4 have been associated with SMA or congenital myopathy. Our goal was to define ASC-1 neuromuscular function and the phenotypical spectrum associated with TRIP4 mutations.Methods: Clinical, molecular, histological, and magnetic resonance imaging studies were made in 5 families with 7 novel TRIP4 mutations. Fluorescence activated cell sorting and Western blot were performed in patient-derived fibroblasts and muscles and in Trip4 knocked-down C2C12 cells.Results: All mutations caused ASC-1 protein depletion. The clinical phenotype was purely myopathic, ranging from lethal neonatal to mild ambulatory adult patients. It included early onset axial and proximal weakness, scoliosis, rigid spine, dysmorphic facies, cutaneous involvement, respiratory failure, and in the older cases, dilated cardiomyopathy. Muscle biopsies showed multiminicores, nemaline rods, cytoplasmic bodies, caps, central nuclei, rimmed fibers, and/or mild endomysial fibrosis. ASC-1 depletion in C2C12 and in patient-derived fibroblasts and muscles caused accelerated proliferation, altered expression of cell cycle proteins, and/or shortening of the G0/G1 cell cycle phase leading to cell size reduction.Interpretation: Our results expand the phenotypical and molecular spectrum of TRIP4-associated disease to include mild adult forms with or without cardiomyopathy, associate ASC-1 depletion with isolated primary muscle involvement, and establish TRIP4 as a causative gene for several congenital muscle diseases, including nemaline, core, centronuclear, and cytoplasmic-body myopathies. They also identify ASC-1 as a novel cell cycle regulator with a key role in cell proliferation, and underline transcriptional coregulation defects as a novel pathophysiological mechanism. ANN NEUROL 2020;87:217-232. [ABSTRACT FROM AUTHOR]

Spinal muscular atrophy (SMA) is a recessive disorder caused by a mutation in the survival motor neuron 1 gene (SMN1); it affects 1 in 11 000 newborn infants. The most severe and most common form, type 1 SMA, is associated with early mortality in most cases and severe disability in survivors. Nusinersen, an antisense oligonucleotide, promotes production of full-length protein from the pseudogene SMN2. Nusinersen treatment prolongs survival of patients with type 1 SMA and allows motor milestone acquisition. Patients with type 2 SMA also show progress on different motor scales after nusinersen treatment. Nusinersen was recently approved by the European Medicines Agency and the US Food and Drug Administration; it is now reimbursed in several European countries and in the USA. In Australia, the transition from expanded access programme to commercial availability is coming soon. In New Zealand, an expanded access programme is opened, and in Canada price negotiation for the treatment is in progress. In this review we exemplify the clinical benefit of nusinersen in subgroups of patients with SMA. Nusinersen represents the first efficacious marked approved drug in type 1 and type 2 SMA. Different knowledge gaps, such as results in older patients, in patients with permanent ventilation, in patients with neonatal forms, or in patients after spinal fusion, still need to be addressed. WHAT THIS PAPER ADDS: Identifies gaps in knowledge about the efficacy of nusinersen in broader populations of patients with spinal muscular atrophy. Identifies open questions in populations of patients where proof of efficacy is available. [ABSTRACT FROM AUTHOR]

Quantitative NMRI and 31P NMRS indices are reported in the forearms of 24 patients with Duchenne muscular dystrophy (DMD) (6-18 years, 14 non-ambulant) amenable to exon 53 skipping therapy and in 12 age-matched male controls (CONT). Examinations carried out at 3 T comprised multi-slice 17-echo measurements of muscle water T2 and heterogeneity, three-point Dixon imaging of fat fraction in flexor and extensor muscles (FLEX, EXT), and non-localised spectroscopy of phosphate metabolites. We studied four imaging indices, eight metabolic ratios combining ATP, phosphocreatine, phosphomonoesters and phosphodiesters, the cytosolic inorganic phosphate (Pia) and an alkaline (Pib) pool present in dystrophic muscle, and average pH. All indices differed between DMD and CONT, except for muscle water T2. Measurements were outside the 95th percentile of age-matched CONT values in over 65% of cases for percentage fat signal (%F), and in 78-100% of cases for all spectroscopic indices. T2 was elevated in one-third of FLEX measurements, whereas %pixels > 39 ms and T2 heterogeneity were abnormal in one-half of the examinations. The FLEX muscles had higher fat infiltration and T2 than EXT muscle groups. All indices, except pH, correlated with patient age, although the correlation was negative for T2. However, in non-ambulant patients, the correlation with years since loss of ambulation was stronger than the correlation with age, and the slope of evolution per year was steeper after loss of ambulation. All indices except Pi/gATP differed between ambulant and non-ambulant patients; however, T2 and %pixels > 39 ms were highest in ambulant patients, possibly owing to the greater extent of inflammatory processes earlier in the disease. All other indices were worse in non-ambulant subjects. Quantitative measurements obtained from patients at different disease stages covered a broad range of abnormalities that evolved with the disease, and metabolic indices were up to 10-fold above normal from the onset, thus establishing a variety of potential markers for future therapy. Copyright © 2015 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Aim An international Clinical Outcomes Group consisting of clinicians, scientists, patient advocacy groups, and industries identified a need for a scale to measure motor performance of the upper limb. We report the steps leading to the development of the Performance of the Upper Limb ( PUL), a tool specifically designed for assessing upper limb function in ambulant and non-ambulant patients with Duchenne muscular dystrophy ( DMD). Method The development of the PUL followed a number of steps, from the systematic review and a preliminary study exploring the suitability of the existing measures, to the application of a pilot version in a multicentric setting, with Rasch analysis of the preliminary results, leading to a revised pro forma. Results The PUL was specifically designed for DMD, with a conceptual framework reflecting the progression of weakness and natural history of functional decline in DMD. Modern psychometric methods were used to create a scale with robust internal reliability, validity, and hierarchical scalability; males with DMD and their families were involved iteratively throughout the process of the clinician-reported outcome assessment tool development to establish clinical meaningfulness and relevance of individual PUL items to activities of daily living. Interpretation The module was developed using innovative approaches and will be useful for designing clinical trials. [ABSTRACT FROM AUTHOR]

In the past, preventive health concerning sexuality of people with intellectual disabilities was addressed through surgical sterilization as part of nationwide eugenic programs in many countries. For more than 30 years now, it has come progressively to light in the scientific literature that, besides major ethical and legal problems, these programs also failed to assess many of the individual's needs in sexual health. The fact that an increasing number of people with intellectual disabilities live in the community rather than in institutions has heightened public awareness that these individuals have sexual expectancies, desires, and needs that must be supported through both education and health services. The emergence of AIDS, including descriptions of cases among people with intellectual disabilities, has further demonstrated that surgical sterilization cannot be considered a global option to achieve preventive sexual health. The aim of this paper is to review scientific studies that have assessed the expectancies and support needs of persons with intellectual disabilities in terms of sexual health. These needs vary widely from one individual to another, according to life milieu, level of disability, and potential comorbidity. From this review, it appears that hygiene management, global gynecological care, and prevention of unplanned pregnancy, sexually transmitted diseases, and abuse have been frequently identified as areas in which the presence of intellectual disability dictates specific support needs. Different approaches that have been evaluated to address these issues will also be discussed. MRDD Research Reviews 2006;12:48–56. © 2006 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Patients with Duchenne muscular dystrophy (DMD) commonly show specific cognitive deficits in addition to a severe muscle impairment caused by the absence of dystrophin expression in skeletal muscle. These cognitive deficits have been related to the absence of dystrophin in specific regions of the central nervous system, notably cerebellar Purkinje cells (PCs). Dystrophin has recently been involved in GABAA receptors clustering at postsynaptic densities, and its absence, by disrupting this clustering, leads to decreased inhibitory input to PC. We performed an in vivo electrophysiological study of the dystrophin‐deficient muscular dystrophy X‐linked (mdx) mouse model of DMD to compare PC firing and local field potential (LFP) in alert mdx and control C57Bl/10 mice. We found that the absence of dystrophin is associated with altered PC firing and the emergence of fast (~160–200 Hz) LFP oscillations in the cerebellar cortex of alert mdx mice. These abnormalities were not related to the disrupted expression of calcium‐binding proteins in cerebellar PC. We also demonstrate that cerebellar long‐term depression is altered in alert mdx mice. Finally, mdx mice displayed a force weakness, mild impairment of motor coordination and balance during behavioural tests. These findings demonstrate the existence of cerebellar dysfunction in mdx mice. A similar cerebellar dysfunction may contribute to the cognitive deficits observed in patients with DMD. [ABSTRACT FROM AUTHOR]

View Supplementary Video 1 [ABSTRACT FROM AUTHOR]

This commentary is on the original article by Alfano et al. on pages 303–309 of this issue. [ABSTRACT FROM AUTHOR]

Presents a study that determined to what extent the expression of calretinin in a specific neuronal cell type, the cerebellar granule cells, contributes to the phenotype detected in calretinin knockout (Cr) mice. Generation of Cr-rescue mouse; Restoration of a WT Purkinje cell firing and granule cell excitability; Normal motor coordination exhibited by Cr-rescue mice; Conclusions and significance of the study.