Progress in the treatment of Friedreich ataxia

Friedreich ataxia (FRDA) is a progressive neurological disorder affecting approximately 1 in 29,000 individuals of European descent. At present, there is no approved pharmacological treatment for this condition however research into treatment of FRDA has advanced considerably over the last two decades since the genetic cause was identified. Current proposed treatment strategies include decreasing oxidative stress, increasing cellular frataxin, improving mitochondrial function as well as modulating frataxin controlled metabolic pathways. Genetic and cell based therapies also hold great promise. Finally, physical therapies are being explored as a means of maximising function in those affected by FRDA

Fracture risk and impact in boys with Duchenne muscular dystrophy: A retrospective cohort study

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

Diagnosis and management of Guillain-Barré syndrome in ten steps

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

Guía basada en la evidencia. Diagnóstico y manejo del síndrome de Guillain-Barré en diez pasos = Evidence based guidelines. Diagnosis and management of Guillain-Barré syndrome in ten steps

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 in 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

Diagnosis and management of Guillain–Barré syndrome in ten steps

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

Novel genes and therapies in neurogenetic disorders

© 2103 Dr. Eppie M. YiuPublications included in thesis:Yiu, E. M., & Ryan, M. M. (2012). Demyelinating prenatal and infantile developmental neuropathies. Journal of the Peripheral Nervous System, 17(1), 32-52. DOI: 10.1111/j.1529-8027.2012.00379.xYiu, E. M., & Ryan, M. M. (2012). Genetic axonal neuropathies and neuronopathies of pre-natal and infantile onset. Journal of the Peripheral Nervous System, 17(3), 285-300. DOI: 10.1111/j.1529-8027.2012.00412.xKennerson, M. L., Yiu, E.M., Chuang, D. T., Kidambi, A., Tso, S-C., Ly, C., et al. (2013). A new locus for X-linked dominant Charcot-Marie-Tooth Disease (CMTX6) is caused by mutations in the pyruvate dehydrogenase kinase isoenzyme 3 (PDK3) gene. Human Molecular Genetics., 22(7), 1404-1416. DOI: 10.1093/hmg/dds557Neurogenetics has increasing relevance in the field of clinical neurology. Rapid advances in genetic techniques have led to an explosion in the ability to diagnose previously undefined disorders, understand their pathobiology, and ultimately develop disease-modifying therapies. This PhD encompasses a number of these aspects, and consists of three studies in two neurogenetic disorders: Friedreich ataxia (FRDA) and Charcot-Marie-Tooth disease (CMT). The first study describes an open-label clinical trial of resveratrol as a treatment for FRDA. This study evaluated the effect of two different doses of resveratrol, 1 g/day and 5 g/day, over a 12 week treatment period in individuals with FRDA. Whilst there was no change in the primary outcome measure, lymphocyte frataxin levels, improvements in a number of clinical and biologic secondary outcome measures including neurologic disability, hearing, speech and oxidative stress were noted in those receiving high-dose resveratrol (5 g/day). Resveratrol had a good safety profile. Though dose-related gastrointestinal side effects were common, no participants in this study experienced serious adverse events. These findings indicate that high-dose resveratrol is a potential disease-modifying therapy for FRDA, and that a randomised clinical trial is warranted to further establish its efficacy. The second study describes the detailed clinical and neurophysiologic characterisation of a large X-linked CMT pedigree, which led to the identification of a novel CMT locus (CMTX6) and gene (PDK3). This new CMT subtype is characterised by a slowly progressive axonal sensorimotor neuropathy with onset during childhood in affected males, with milder features in carrier females. The third study evaluated the utility of high-resolution peripheral nerve ultrasound in paediatric CMT1A and demonstrated a marked increase in nerve cross-sectional area in children with CMT1A compared to controls at all ages, including those as young as 19 months of age. This study also showed that peripheral nerve size correlates with both age and disease severity in CMT1A, and that the increase in nerve size with age in CMT1A is disproportionately greater than that seen in healthy controls, indicating that ongoing pathological nerve hypertrophy occurs throughout childhood. Peripheral nerve ultrasound, a non-invasive, safe and well tolerated imaging technique, may therefore have a role as an adjunctive diagnostic tool in CMT1A, as well as a biomarker of disease progression in natural history studies and future clinical trials. Whilst FRDA and CMT represent only a proportion of all neurogenetic disorders, the challenges and lessons learned in the diagnosis, monitoring and evaluation of potential disease-modifying therapies in the clinical trial setting are applicable to a wide range of neurogenetic conditions, and provide hope for individuals and families affected by these disorders

Duchenne muscular dystrophy

Duchenne muscular dystrophy (DMD), an X-linked disorder, is the most common muscular dystrophy in children, presenting in early childhood and characterized by proximal muscle weakness and calf hypertrophy in affected boys. Patients usually become wheelchair-bound by the age of 12 years, and die of cardiorespiratory complications in their late teens to early twenties. Advances in the management of DMD, including treatment with corticosteroids and the use of intermittent positive pressure ventilation have provided improvements in function, ambulation, quality of life and life expectancy, although novel therapies still aim to provide a cure for this devastating disorder. The clinical features, investigations, and management of DMD are reviewed, as well as the latest in some of the novel therapies

Remediation of Perceptual Deficits in Progressive Auditory Neuropathy: A Case Study

Background: 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. Methods: 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. Results: 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. Conclusions: 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