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 disseminated encephalomyelitis (ADEM) is an immune-mediated demyelinating CNS disorder with predilection to early childhood. ADEM is generally considered a monophasic disease. However, ...recurrent ADEM has been described and defined as multiphasic disseminated encephalomyelitis. ADEM often occurs postinfectiously, although a causal relationship has never been established. ADEM and multiple sclerosis are currently viewed as distinct entities, generally distinguishable even at disease onset. However, pathologic studies have demonstrated transitional cases of yet unclear significance. ADEM is clinically defined by acute polyfocal neurologic deficits including encephalopathy. MRI typically demonstrates reversible, ill-defined white matter lesions of the brain and often also the spinal cord, along with frequent involvement of thalami and basal ganglia. CSF analysis may reveal a mild pleocytosis and elevated protein, but is generally negative for intrathecal oligoclonal immunoglobulin G synthesis. In the absence of a specific diagnostic test, ADEM is considered a diagnosis of exclusion, and ADEM mimics, especially those requiring a different treatment approach, have to be carefully ruled out. The role of biomarkers, including autoantibodies like anti–myelin oligodendrocyte glycoprotein, in the pathogenesis and diagnosis of ADEM is currently under debate. Based on the presumed autoimmune etiology of ADEM, the current treatment approach consists of early immunotherapy. Outcome of ADEM in pediatric patients is generally favorable, but cognitive deficits have been reported even in the absence of other neurologic sequelae. This review summarizes the current knowledge on epidemiology, pathology, clinical presentation, neuroimaging features, CSF findings, differential diagnosis, therapy, and outcome, with a focus on recent advances and controversies.
Disturbed mitochondrial fusion and fission have been linked to various neurodegenerative disorders. In siblings from two unrelated families who died soon after birth with a profound ...neurodevelopmental disorder characterized by pontocerebellar hypoplasia and apnoea, we discovered a missense mutation and an exonic deletion in the SLC25A46 gene encoding a mitochondrial protein recently implicated in optic atrophy spectrum disorder. We performed functional studies that confirmed the mitochondrial localization and pro-fission properties of SLC25A46. Knockdown of slc24a46 expression in zebrafish embryos caused brain malformation, spinal motor neuron loss, and poor motility. At the cellular level, we observed abnormally elongated mitochondria, which was rescued by co-injection of the wild-type but not the mutant slc25a46 mRNA. Conversely, overexpression of the wild-type protein led to mitochondrial fragmentation and disruption of the mitochondrial network. In contrast to mutations causing non-lethal optic atrophy, missense mutations causing lethal congenital pontocerebellar hypoplasia markedly destabilize the protein. Indeed, the clinical severity appears inversely correlated with the relative stability of the mutant protein. This genotype-phenotype correlation underscores the importance of SLC25A46 and fine tuning of mitochondrial fission and fusion in pontocerebellar hypoplasia and central neurodevelopment in addition to optic and peripheral neuropathy across the life span.
Chromatin fibers must fold or coil in the process of chromosome condensation. Patterns of coiling have been demonstrated for reconstituted chromatin, but the actual trajectories of fibers in ...condensed states of chromosomes could not be visualized because of the high density of the material. We have exploited partial decondensation of mitotic chromosomes to reveal their internal structure at sub-nucleosomal resolution by cryo-electron tomography, without the use of stains, fixatives, milling, or sectioning. DNA gyres around nucleosomes were visible, allowing the nucleosomes to be identified and their orientations to be determined. Linker DNA regions were traced, revealing the trajectories of the chromatin fibers. The trajectories were irregular, with almost no evidence of coiling and no short- or long-range order of the chromosomal material. The 146-bp core particle, long known as a product of nuclease digestion, is identified as the native state of the nucleosome, with no regular spacing along the chromatin fibers.
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•Chromosomes were decondensed and recondensed in a physiologically relevant manner•Cryo-ET revealed linker DNA and nucleosomes as double-layer discs•Trajectories of chromatin fibers were irregular, unrelated to previous proposals•Condensation occurred without higher-order structure in the regions examined
Partial decondensation of mitotic chromosomes and cryo-electron tomography revealed the internal structure of the chromosomal material. Nucleosomes and linker DNA segments between them were observed, permitting chromatin fibers to be traced over distances of 10 kb (50 nucleosomes) or more. Patterns of coiling or folding in specific gene regions can now be determined.
Summary Background Charcot–Marie–Tooth disease type 1A (CMT1A) is the most common inherited nerve disorder. CMT1A is characterised by peripheral nerve demyelination, weakness, and impaired motor ...function and is caused by the duplication of PMP22 , the gene that encodes peripheral myelin protein 22. High-dose ascorbic acid has been shown to have remyelinating potential and to correct the phenotype of a transgenic mouse model of CMT1A by decreasing expression of PMP22 . We tested the efficacy and safety of ascorbic acid supplementation in children with CMT1A. Methods This 12-month, randomised, double-blind, placebo-controlled trial undertaken between June, 2007, and December, 2008, assessed high-dose oral ascorbic acid (about 30 mg/kg/day) in 81 children with CMT1A (2–16 years). Randomisation was done on a 1:1 ratio by a computer-generated algorithm. All investigators and participants were blinded to treatment allocation with the exception of the trial pharmacist. The primary efficacy outcome was median nerve motor conduction velocity (m/s) at 12 months. Secondary outcomes were foot and hand strength, motor function, walking ability, and quality of life. Compliance was measured by plasma ascorbic acid concentration, pill count, and medication diary entries. Analysis was by intention to treat. This trial is registered with the Australian New Zealand Clinical Trials Registry, number 12606000481572. Findings 81 children were randomly assigned to receive high-dose ascorbic acid (n=42) or placebo (n=39). 80 children completed 12 months of treatment. The ascorbic acid group had a small, non-significant increase in median nerve motor conduction velocity compared with the placebo group (adjusted mean difference 1·7 m/s, 95% CI −0·1 to 3·4; p=0·06). There was no measurable effect of ascorbic acid on neurophysiological, strength, function, or quality of life outcomes. Two children in the ascorbic acid group and four children in the placebo group reported gastrointestinal symptoms. There were no serious adverse events. Interpretation 12 months of treatment with high-dose ascorbic acid was safe and well tolerated but none of the expected efficacy endpoints were reached. Funding University of Sydney Research and Development Scheme; National Health and Medical Research Council of Australia; James N Kirby Foundation; New South Wales Podiatrists Registration Board; Australian Podiatry Education and Research Foundation; Charcot–Marie–Tooth Association of Australia.
We report a child from Southern Australia (New South Wales) who presented during a La Niña event with encephalopathy and acute flaccid paralysis. Magnetic resonance imaging suggested Japanese ...encephalitis (JE). Steroids and intravenous immunoglobulin did not improve symptoms. Therapeutic plasma exchange (TPE) resulted in rapid improvement and tracheostomy decannulation. Our case illustrates the complex pathophysiology of JE, its' geographic expansion into Southern Australia and potential use of TPE for neuroinflammatory sequelae.
Aicardi-Goutières syndrome (AGS) is a genetic encephalopathy whose clinical features mimic those of acquired in utero viral infection. AGS exhibits locus heterogeneity, with mutations identified in ...genes encoding the 3′→5′ exonuclease TREX1 and the three subunits of the RNASEH2 endonuclease complex. To define the molecular spectrum of AGS, we performed mutation screening in patients, from 127 pedigrees, with a clinical diagnosis of the disease. Biallelic mutations in
TREX1, RNASEH2A, RNASEH2B, and
RNASEH2C were observed in 31, 3, 47, and 18 families, respectively. In five families, we identified an
RNASEH2A or
RNASEH2B mutation on one allele only. In one child, the disease occurred because of a de novo heterozygous
TREX1 mutation. In 22 families, no mutations were found. Null mutations were common in
TREX1, although a specific missense mutation was observed frequently in patients from northern Europe. Almost all mutations in
RNASEH2A, RNASEH2B, and
RNASEH2C were missense. We identified an
RNASEH2C founder mutation in 13 Pakistani families. We also collected clinical data from 123 mutation-positive patients. Two clinical presentations could be delineated: an early-onset neonatal form, highly reminiscent of congenital infection seen particularly with
TREX1 mutations, and a later-onset presentation, sometimes occurring after several months of normal development and occasionally associated with remarkably preserved neurological function, most frequently due to
RNASEH2B mutations. Mortality was correlated with genotype; 34.3% of patients with
TREX1, RNASEH2A, and
RNASEH2C mutations versus 8.0%
RNASEH2B mutation–positive patients were known to have died (
P=.001). Our analysis defines the phenotypic spectrum of AGS and suggests a coherent mutation-screening strategy in this heterogeneous disorder. Additionally, our data indicate that at least one further AGS-causing gene remains to be identified.
Objective
To study the epilepsy syndromes among the severe epilepsies of infancy and assess their incidence, etiologies, and outcomes.
Methods
A population‐based cohort study was undertaken of severe ...epilepsies with onset before age 18 months in Victoria, Australia. Two epileptologists reviewed clinical features, seizure videos, and electroencephalograms to diagnose International League Against Epilepsy epilepsy syndromes. Incidence, etiologies, and outcomes at age 2 years were determined.
Results
Seventy‐three of 114 (64%) infants fulfilled diagnostic criteria for epilepsy syndromes at presentation, and 16 (14%) had "variants" of epilepsy syndromes in which there was one missing or different feature, or where all classical features had not yet emerged. West syndrome (WS) and "WS‐like" epilepsy (infantile spasms without hypsarrhythmia or modified hypsarrhythmia) were the most common syndromes, with a combined incidence of 32.7/100 000 live births/year. The incidence of epilepsy of infancy with migrating focal seizures (EIMFS) was 4.5/100 000 and of early infantile epileptic encephalopathy (EIEE) was 3.6/100 000. Structural etiologies were common in "WS‐like" epilepsy (100%), unifocal epilepsy (83%), and WS (39%), whereas single gene disorders predominated in EIMFS, EIEE, and Dravet syndrome. Eighteen (16%) infants died before age 2 years. Development was delayed or borderline in 85 of 96 (89%) survivors, being severe–profound in 40 of 96 (42%). All infants with EIEE or EIMFS had severe–profound delay or were deceased, but only 19 of 64 (30%) infants with WS, "WS‐like," or "unifocal epilepsy" had severe–profound delay, and only two of 64 (3%) were deceased.
Significance
Three quarters of severe epilepsies of infancy could be assigned an epilepsy syndrome or "variant syndrome" at presentation. In this era of genomic testing and advanced brain imaging, diagnosing epilepsy syndromes at presentation remains clinically useful for guiding etiologic investigation, initial treatment, and prognostication.
Recessive SLC25A46 mutations cause a spectrum of neurodegenerative disorders with optic atrophy as a core feature. We report a patient with optic atrophy, peripheral neuropathy, ataxia, but not ...cerebellar atrophy, who is on the mildest end of the phenotypic spectrum. By studying seven different nontruncating mutations, we found that the stability of the SLC25A46 protein inversely correlates with the severity of the disease and the patient's variant does not markedly destabilize the protein. SLC25A46 belongs to the mitochondrial transporter family, but it is not known to have transport function. Apart from this possible function, SLC25A46 forms molecular complexes with proteins involved in mitochondrial dynamics and cristae remodeling. We demonstrate that the patient's mutation directly affects the SLC25A46 interaction with MIC60. Furthermore, we mapped all of the reported substitutions in the protein onto a 3D model and found that half of them fall outside of the signature carrier motifs associated with transport function. We thus suggest that there are two distinct molecular mechanisms in SLC25A46‐associated pathogenesis, one that destabilizes the protein while the other alters the molecular interactions of the protein. These results have the potential to inform clinical prognosis of such patients and indicate a pathway to drug target development.
This study identifies a novel missense mutation in the SLC25A46 gene causing optic atrophy, peripheral neuropathy, ataxia, but not cerebellar atrophy. Stability of the SLC25A46 protein inversely correlates with disease severity. The patient's p.R257Q variant does not markedly destabilize the protein. Instead, it affects the SLC25A46 interaction with MIC60 involved in mitochondrial dynamics and cristae remodeling. These results provide further insight into the genotype‐phenotype correlation for mutations in the gene and may inform clinical prognosis of such patients.
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