Duchenne muscular dystrophy Yiu, Eppie M; Kornberg, Andrew J
Journal of paediatrics and child health,
August 2015, Letnik:
51, Številka:
8
Journal Article
Recenzirano
Duchenne muscular dystrophy, an X‐linked disorder, has an incidence of one in 5000 boys and presents in early childhood with proximal muscle weakness. Untreated boys become wheelchair bound by the ...age of 12 years and die of cardiorespiratory complications in their late teens to early 20s. The use of corticosteroids, non‐invasive respiratory support, and active surveillance and management of associated complications have improved ambulation, function, quality of life and life expectancy. The clinical features, investigations and management of Duchenne muscular dystrophy are reviewed, as well as the latest in some of the novel therapies.
Acute generalised muscle weakness in children is a paediatric emergency with a broad differential diagnosis. A careful history and neurologic examination guides timely investigation and management. ...We review some of the more common causes of acute generalised muscle weakness in children, highlighting key history and examination findings, along with an approach to lesion localisation to guide differential diagnosis and further investigation.
Guillain-Barré syndrome (GBS) is a rare, but potentially fatal, immune-mediated disease of the peripheral nerves and nerve roots that is usually triggered by infections. The incidence of GBS can ...therefore increase during outbreaks of infectious diseases, as was seen during the Zika virus epidemics in 2013 in French Polynesia and 2015 in Latin America. Diagnosis and management of GBS can be complicated as its clinical presentation and disease course are heterogeneous, and no international clinical guidelines are currently available. To support clinicians, especially in the context of an outbreak, we have developed a globally applicable guideline for the diagnosis and management of GBS. The guideline is based on current literature and expert consensus, and has a ten-step structure to facilitate its use in clinical practice. We first provide an introduction to the diagnostic criteria, clinical variants and differential diagnoses of GBS. The ten steps then cover early recognition and diagnosis of GBS, admission to the intensive care unit, treatment indication and selection, monitoring and treatment of disease progression, prediction of clinical course and outcome, and management of complications and sequelae.
Introduction/Aims
Boys with Duchenne muscular dystrophy (DMD) are at increased risk of fracture. This study investigated the incidence of fractures, factors contributing to risk of first fracture ...with emphasis on body mass index (BMI), and the impact of fractures on functional capacity in an Australian cohort of boys with DMD.
Methods
A retrospective cohort study included boys with DMD who attended a pediatric neuromuscular clinic from 2011 to 2018. Information regarding fractures, anthropometry measurements, body composition and functional assessment was collected. Factors associated with first fracture risk were analyzed with Cox‐proportional hazards. Longitudinal analysis of function post‐fracture was also conducted.
Results
This study included 155 boys with DMD. At least one fracture occurred in 71 (45%) boys; overall incidence of fractures was 399‐per‐10,000 persons‐years. The first fracture was vertebral in 55%; 41% had non‐vertebral fractures and 4% had both. Vertebral fractures occurred in significantly older (12.28 vs 9.28 y) boys with longer exposure to glucocorticoids (5.45 vs 2.50 y) compared to non‐vertebral fractures. Boys with a history of fracture(s) had a steeper rate of functional decline (measured by Northstar Ambulatory Assessment score) than those with no recorded fractures.
Discussion
A high fracture burden was observed in a large Australian cohort of boys with DMD. Further investigation is required to understand preventative strategies and modifiable risk factors to reduce the incidence of fractures in DMD. The impact on fractures on ambulatory capacity should be closely monitored.
Abstract The nutritional implications of spinal muscular atrophy (SMA) are profound. Disease modifying therapies (DMT) have improved clinical outcomes. This review describes the impact of DMT on ...nutrition outcomes. A systematic search strategy was applied across seven databases until May 2023. Eligible studies measured nutrition outcomes in individuals with SMA on DMT (nusinersen, risdiplam or onasemnogene abeparvovec OA) compared to untreated comparators. Nutrition outcomes included anthropometry, feeding route, swallowing dysfunction, dietary intake, dietetic intervention, nutritional biochemistry, metabolism, gastrointestinal issues and energy expenditure. Articles retrieved were screened in duplicate, data were extracted and appraised systematically. Sixty three articles from 54 studies were included; 41% ( n = 22) investigated nusinersen in pediatric participants with SMA type 1. Anthropometry ( n = 18), feeding route ( n = 39), and swallowing dysfunction ( n = 18) were the most commonly reported outcomes. In combined pediatric and adult cohorts, BMI z‐score remained stable post nusinersen therapy. The proportion of children with SMA requiring enteral nutrition was stable post nusinersen therapy. Ability to thrive at age 1.5 years was higher in children treated in early infancy with OA compared to historical controls. Significant heterogeneity existed across study population characteristics and outcome measures. Nusinersen may prevent deterioration in some nutrition outcomes; and OA in early infancy may be associated with improved nutrition outcomes. Timing of DMT initiation is an important consideration for future nutrition research. Studies investigating nutrition as a primary outcome of DMT, using consistent outcome measures are required for nutritional management strategies for this cohort to be appropriately tailored.
ATL1102 is a 2'MOE gapmer antisense oligonucleotide to the CD49d alpha subunit of VLA-4, inhibiting expression of CD49d on lymphocytes, reducing survival, activation and migration to sites of ...inflammation. Children with DMD have dystrophin deficient muscles susceptible to contraction induced injury, which triggers the immune system, exacerbating muscle damage. CD49d is a biomarker of disease severity in DMD, with increased numbers of high CD49d expressing T cells correlating with more severe and progressive weakess, despite corticosteroid treatment.
This Phase 2 open label study assessed the safety, efficacy and pharmacokinetic profile of ATL1102 administered as 25 mg weekly by subcutaneous injection for 24 weeks in 9 non-ambulatory boys with DMD aged 10-18 years. The main objective was to assess safety and tolerability of ATL1102. Secondary objectives included the effect of ATL1102 on lymphocyte numbers in the blood, functional changes in upper limb function as assessed by Performance of Upper Limb test (PUL 2.0) and upper limb strength using MyoGrip and MyoPinch compared to baseline.
Eight out of nine participants were on a stable dose of corticosteroids. ATL1102 was generally safe and well tolerated. No serious adverse events were reported. There were no participant withdrawals from the study. The most commonly reported adverse events were injection site erythema and skin discoloration. There was no statistically significant change in lymphocyte count from baseline to week 8, 12 or 24 of dosing however, the CD3+CD49d+ T lymphocytes were statistically significantly higher at week 28 compared to week 24, four weeks past the last dose (mean change 0.40x109/L 95%CI 0.05, 0.74; p = 0.030). Functional muscle strength, as measured by the PUL2.0, EK2 and Myoset grip and pinch measures, and MRI fat fraction of the forearm muscles were stable throughout the trial period.
ATL1102, a novel antisense drug being developed for the treatment of inflammation that exacerbates muscle fibre damage in DMD, appears to be safe and well tolerated in non-ambulant boys with DMD. The apparent stabilisation observed on multiple muscle disease progression parameters assessed over the study duration support the continued development of ATL1102 for the treatment of DMD.
Clinical Trial Registration. Australian New Zealand Clinical Trials Registry Number: ACTRN12618000970246.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background. Treatment of genetic degenerative ataxia is currently based on symptom management and maintenance of function. However, utilization of rehabilitation is limited due to a lack of evidence ...supporting its efficacy. Objective. This systematic review evaluated rehabilitation interventions for individuals with genetic degenerative ataxia. In addition, long-term outcomes from rehabilitation and optimal duration and intensity of rehabilitation were examined. Methods. A comprehensive search of 4 databases (MEDLINE, CINAHL, PEDro, and Cochrane) identified randomized, nonrandomized controlled, and cohort studies published from inception through to January 2016. The studies included at least one measure examining function, ataxia, balance, or gait. Methodological quality was assessed with the Australian National Health and Medical Research Council (NHMRC) Hierarchy of Evidence and the randomized controlled trials were rated according to the PEDro scale. Results. Seventeen studies met eligibility criteria. Five randomized controlled trials were included; however, the majority were classified as level III-3 and IV studies. Of 292 participants included, 148 had autosomal dominant ataxia, and 85 had autosomal recessive ataxia. Rehabilitation interventions included coordination and balance training, multifaceted inpatient rehabilitation, a cycling regime, balance exercises with technology assisted biofeedback, respiratory muscle training, and treadmill training. Two studies examined adjuncts to rehabilitation. Fifteen of the 17 studies demonstrated a statistically significant improvement in at least 1 outcome measuring ataxia, function, gait, or balance. Less than half of the studies included assessment of long-term outcomes and follow-up time frames varied considerably. Conclusion. There is consistent evidence that rehabilitation improves function, mobility, ataxia, and balance in genetic degenerative ataxia.
OBJECTIVE:To investigate differences in nerve cross-sectional area (CSA) as measured by peripheral nerve ultrasound in children with Charcot-Marie-Tooth disease type 1A (CMT1A) compared to healthy ...controls.
METHODS:This was a cross-sectional, matched, case-control study. CSA of the median, ulnar, tibial, and sural nerves was measured by peripheral nerve ultrasound. The mean difference in CSA between children with CMT1A and controls at each nerve site was determined. The relationship between nerve CSA and age/body metrics, and between nerve CSA and neurologic disability in CMT1A, was also evaluated.
RESULTS:Twenty-nine children with CMT1A and 29 age- and sex-matched controls were enrolled. Nerve CSA was significantly increased in children with CMT1A compared to controls (1.9- to 3.5-fold increase, p < 0.001). The increase in nerve CSA with age was disproportionately greater in those with CMT1A. Nerve CSA showed a strong positive linear correlation with age, height, and weight in both the CMT1A and control groups. Disease severity correlated with both nerve CSA and age.
CONCLUSIONS:Children with CMT1A have significantly increased nerve CSA compared to controls, and the increase in nerve CSA with age is disproportionately greater in CMT1A, suggesting ongoing nerve hypertrophy throughout childhood. Nerve CSA correlates with neurologic disability. These findings demonstrate the utility of peripheral nerve ultrasound as a diagnostic tool in pediatric neuropathies, and as an outcome measure in natural history studies and clinical trials in CMT1A.
CLASSIFICATION OF EVIDENCE:This study provides Class IV evidence that measurement of nerve CSA by peripheral nerve ultrasound accurately identifies patients with CMT1A.
Objective
Friedreich ataxia (FRDA) is an inherited neurodegenerative disease characterized by ataxia and cardiomyopathy. Homozygous GAA trinucleotide repeat expansions in the first intron of FXN ...occur in 96% of affected individuals and reduce frataxin expression. Remaining individuals are compound heterozygous for a GAA expansion and a FXN point/insertion/deletion mutation. We examined disease‐causing mutations and the impact on frataxin structure/function and clinical outcome in FRDA.
Methods
We compared clinical information from 111 compound heterozygotes and 131 individuals with homozygous expansions. Frataxin mutations were examined using structural modeling, stability analyses and systematic literature review, and categorized into four groups: (1) homozygous expansions, and three compound heterozygote groups; (2) null (no frataxin produced); (3) moderate/strong impact; and (4) minimal impact. Mean age of onset and the presence of cardiomyopathy and diabetes mellitus were compared using regression analyses.
Results
Mutations in the hydrophobic core of frataxin affected stability whereas surface residue mutations affected interactions with iron sulfur cluster assembly and heme biosynthetic proteins. The null group of compound heterozygotes had significantly earlier age of onset and increased diabetes mellitus, compared to the homozygous expansion group. There were no significant differences in mean age of onset between homozygotes and the minimal and moderate/strong impact groups.
Interpretation
In compound heterozygotes, expression of partially functional mutant frataxin delays age of onset and reduces diabetes mellitus, compared to those with no frataxin expression from the non‐expanded allele. This integrated analysis of categorized frataxin mutations and their correlation with clinical outcome provide a definitive resource for investigating disease pathogenesis in FRDA. Ann Neurol 2016;79:485–495
Auditory neuropathy (AN) is a hearing disorder that affects neural activity in the VIIIth cranial nerve and central auditory pathways. Progressive forms have been reported in a number of ...neurodegenerative diseases and may occur as a result of both the deafferentiation and desynchronisation of neuronal processes. The purpose of this study was to describe changes in auditory function over time in a patient with axonal neuropathy and to explore the effect of auditory intervention.
We tracked auditory function in a child with progressive AN associated with Charcot-Marie-Tooth (Type 2C) disease, evaluating hearing levels, auditory-evoked potentials, and perceptual abilities over a 3-year period. Furthermore, we explored the effect of auditory intervention on everyday listening and neuroplastic development.
While sound detection thresholds remained constant throughout, both electrophysiologic and behavioural evidence suggested auditory neural degeneration over the course of the study. Auditory brainstem response amplitudes were reduced, and perception of auditory timing cues worsened over time. Functional hearing ability (speech perception in noise) also deteriorated through the first 1.5 years of study until the child was fitted with a "remote-microphone" listening device, which subsequently improved binaural processing and restored speech perception ability to normal levels.
Despite the deterioration of auditory neural function consistent with peripheral axonopathy, sustained experience with the remote-microphone listening system appeared to produce neuroplastic changes, which improved the patient's everyday listening ability-even when not wearing the device.
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