Papers by Andrew Kornberg
Dysembryoplastic neuroepithelial tumors (DNETs) are benign supratentorial tumors based in the cer... more Dysembryoplastic neuroepithelial tumors (DNETs) are benign supratentorial tumors based in the cerebral cortex. They usually are found in children and young adults with seizures that tend to become refractory to medical treatment. In the vast majority of cases resection results in good seizure control, and adjuvant therapy is not required. When tumors thought to be DNETs are not resected due to their proximity to eloquent cortex, lack of change in the clinical and neuroimaging features over time supports the diagnosis of DNET. The authors report on a patient in whom a pilocytic astrocytoma developed within a DNET, raising questions regarding the classification of these lesions and the need for lifelong clinical and imaging surveillance. This paper adds to the growing body of literature about the biological behavior of these lesions.
We report a third patient with typical cap myopathy due to a heterozygous TPM3 mutation, confirmi... more We report a third patient with typical cap myopathy due to a heterozygous TPM3 mutation, confirming the importance of this causal association. The p.R168C TPM3 mutation we identified has been reported in two previous patients. The histological changes associated with this mutation vary widely from typical cap myopathy with near complete type 1 predominance (two patients), to typical congenital fibre-type disproportion without protein inclusions (one patient). We performed 2D-gel electrophoresis using muscle biopsies from two patients with the p.R168C mutation and show that mutant protein accounts for around 50% of alpha-tropomyosin(slow) in sarcomeres, consistent with a dominant negative mechanism of disease pathogenesis.
Journal of Medical Genetics
BackgroundUBA5 is the activating enzyme of UFM1 in the ufmylation post-translational modification... more BackgroundUBA5 is the activating enzyme of UFM1 in the ufmylation post-translational modification system. Different neurological phenotypes have been associated with UBA5 pathogenic variants including epilepsy, intellectual disability, movement disorders and ataxia.Methods and resultsWe describe a large multigenerational consanguineous family presenting with a severe congenital neuropathy causing early death in infancy. Whole exome sequencing and linkage analysis identified a novel homozygous UBA5 NM_024818.3 c.31C>T (p.Arg11Trp) mutation. Protein expression assays in mouse tissue showed similar levels of UBA5 in peripheral nerves to the central nervous system. CRISPR-Cas9 edited HEK (human embrionic kidney) cells homozygous for the UBA5 p.Arg11Trp mutation showed reduced levels of UBA5 protein compared with the wild-type. The mutant p.Arg11Trp UBA5 protein shows reduced ability to activate UFM1.ConclusionThis report expands the phenotypical spectrum of UBA5 mutations to include ...
Journal of Neurology, Neurosurgery & Psychiatry
BackgroundAge has been independently associated with higher rates of treatment discontinuation in... more BackgroundAge has been independently associated with higher rates of treatment discontinuation in multiple sclerosis.ObjectiveThe current study examines the impact of age on persistence for all reimbursed DMTs for RRMS in Australia.MethodsThe Pharmaceutical Benefits Scheme (PBS) 10% sample supplied by the Department of Human Services was used in this study. Eligible patients must have received a script for a reimbursed DMT for RRMS between September 2011 and February 2016. Patients were classified into five age-groups (ages 18–30; 31–40; 41–50; 51–60; 61+) and defined as persistent if their DMT script was filled within 4 months. Persistence was derived using the Kaplan-Meier method and hazard ratios (HR) to represent the relative rate of drop-off of different age groups.ResultsPatients aged 18–30 (n=250) had a 44% increased risk of discontinuation (HR 1.44 (95%CI: 1.22–1.72) compared to the ‘all ages’ cohort (n=1,866); no significant difference was observed for any other age group (...
The Lancet. Child & adolescent health, 2018
Infantile spasms constitute a severe form of epileptic encephalopathy. In the International Colla... more Infantile spasms constitute a severe form of epileptic encephalopathy. In the International Collaborative Infantile Spasms Study (ICISS), we showed that combining vigabatrin with hormonal therapy was more effective than hormonal therapy alone at stopping spasms between days 14 and 42 of treatment. In this planned follow-up, we aimed to assess whether combination therapy was associated with improved developmental and epilepsy outcomes at 18 months of age. In ICISS, a multicentre, open-label, randomised controlled trial, infants were enrolled from 102 hospitals (three in Australia, 11 in Germany, two in New Zealand, three in Switzerland, and 83 in the UK). Eligible infants had a clinical diagnosis of infantile spasms and a hypsarrhythmic (or similar) electroencephalogram (EEG) no more than 7 days before enrolment. Participants were randomly assigned (1:1) by a secure website to receive hormonal therapy with vigabatrin or hormonal therapy alone. If parents consented, there was an addit...
Human mutation, Jan 3, 2018
Recessive SLC25A46 mutations cause a spectrum of neurodegenerative disorders with optic atrophy a... more 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 non-truncating 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 ...
Journal of neurology, neurosurgery, and psychiatry, Aug 26, 2017
We have undertaken a clinic-based survey of neuromyelitis optica spectrum disorders (NMOSDs) in A... more We have undertaken a clinic-based survey of neuromyelitis optica spectrum disorders (NMOSDs) in Australia and New Zealand to establish incidence and prevalence across the region and in populations of differing ancestry. NMOSD is a recently defined demyelinating disease of the central nervous system (CNS). The incidence and prevalence of NMOSD in Australia and New Zealand has not been established. Centres managing patients with demyelinating disease of the CNS across Australia and New Zealand reported patients with clinical and laboratory features that were suspicious for NMOSD. Testing for aquaporin 4 antibodies was undertaken in all suspected cases. From this group, cases were identified who fulfilled the 2015 Wingerchuk diagnostic criteria for NMOSD. A capture-recapture methodology was used to estimate incidence and prevalence, based on additional laboratory identified cases. NMOSD was confirmed in 81/170 (48%) cases referred. Capture-recapture analysis gave an adjusted incidence ...
Physical & Occupational Therapy In Pediatrics, 2017
To report the effects of below-knee serial casting in two boys with Duchenne muscular dystrophy w... more To report the effects of below-knee serial casting in two boys with Duchenne muscular dystrophy who presented with well-preserved strength and calf shortening. Bilateral below-knee serial casts were applied over two weeks with follow-up of daily stretching and wearing of customized night splints. Outcome measures were performed at baseline, 1, 3, 6, and 12 months post-casting. These included measures of calf length, leg strength, motor function, endurance, and spatio-temporal gait parameters. Both boys completed serial casting with gains in muscle length. No adverse effects on strength or motor function were observed over a 12-month follow-up period.
Nature communications, Jan 31, 2017
Duchenne muscular dystrophy (DMD) is characterized by muscle degeneration and progressive weaknes... more Duchenne muscular dystrophy (DMD) is characterized by muscle degeneration and progressive weakness. There is considerable inter-patient variability in disease onset and progression, which can confound the results of clinical trials. Here we show that a common null polymorphism (R577X) in ACTN3 results in significantly reduced muscle strength and a longer 10 m walk test time in young, ambulant patients with DMD; both of which are primary outcome measures in clinical trials. We have developed a double knockout mouse model, which also shows reduced muscle strength, but is protected from stretch-induced eccentric damage with age. This suggests that α-actinin-3 deficiency reduces muscle performance at baseline, but ameliorates the progression of dystrophic pathology. Mechanistically, we show that α-actinin-3 deficiency triggers an increase in oxidative muscle metabolism through activation of calcineurin, which likely confers the protective effect. Our studies suggest that ACTN3 R577X gen...
Neurology, 2016
The International Pediatric Multiple Sclerosis Study Group held its inaugural educational program... more The International Pediatric Multiple Sclerosis Study Group held its inaugural educational program, "The World of Pediatric MS: A Global Update," in September 2014 to discuss advances and challenges in the diagnosis and management of pediatric multiple sclerosis (MS) and other neuroinflammatory CNS disorders. Highlights included a discussion on the revised diagnostic criteria, which enable the differentiation of MS, acute disseminated encephalomyelitis, neuromyelitis optica, and other neuroinflammatory disorders. While these criteria currently identify clinical and MRI features for a particular diagnosis, advances in biomarkers may prove to be useful in the future. An update was also provided on environmental factors associated with pediatric MS risk and possibly outcomes, notably vitamin D deficiency. However, optimal vitamin D intake and its role in altering MS course in children have yet to be established. Regarding MS outcomes, our understanding of the cognitive consequences of early-onset MS has grown. However, further work is needed to define the course of cognitive function and its long-term outcome in diverse patient samples and to develop strategies for effective cognitive rehabilitation specifically tailored to children and adolescents. Finally, treatment strategies were discussed, including a need to consider additional drug treatment options and paradigms (escalation vs induction), although treatment should be tailored to the individual child. Of critical importance, clinical trials of newer MS agents in children are required. Although our understanding of childhood MS has improved, further research is needed to have a positive impact for children and their families. Neurology ® 2016;87 (Suppl 2):S110-S116 GLOSSARY ADEM 5 acute disseminated encephalomyelitis; ADS 5 acute demyelinating syndrome; AQP4 5 aquaporin-4; CI 5 confidence interval; CIS 5 clinically isolated syndrome; DMT 5 disease-modifying treatment; EDSS 5 Expanded Disability Status Scale; EMA 5 European Medicines Agency; FDA 5 Food and Drug Administration; IPMSSG 5 International Pediatric MS Study Group; MOG 5 myelin oligodendrocyte glycoprotein; MS 5 multiple sclerosis; NMO 5 neuromyelitis optica; NMOSD 5 neuromyelitis optica spectrum disorder; RDA 5 Recommended Dietary Allowance. Advances in our understanding of epidemiology, pathogenesis, and treatment in multiple sclerosis (MS) have been rapid in the last few years and will have a positive effect for children with the disease. Such progress in the diagnosis and management of pediatric MS and neuroinflammatory disorders includes the following: 1. Revised diagnostic criteria for MS, acute disseminated encephalomyelitis (ADEM), and neuromyelitis optica (NMO) across the age spectrum. 2. Improved understanding of the cognitive consequences of MS onset during childhood. 3. Additional drug treatment options, including immunosuppressant, immunomodulatory, and oral medications, and awareness of the need for clinical trials of these agents in children.
Brain, 2016
Disturbed mitochondrial fusion and fission have been linked to various neurodegenerative disorder... more 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 nonlethal 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.
Advances in Neurology, Feb 1, 1995
J Neurol Sci, 2001
We previously found that serums with anti-sulfatide antibodies have several different patterns of... more We previously found that serums with anti-sulfatide antibodies have several different patterns of binding to neural tissue. In this study, Ž. we asked whether serums with anti-myelin associated glycoprotein MAG antibodies also have similar variations in patterns of tissue binding. We examined binding to peripheral nerve in 49 serums with IgM anti-MAG antibodies and 13 serums with IgM anti-sulfoglu-Ž. curonyl paragloboside SGPG antibodies but no MAG binding. We correlated patterns of binding with titers of IgM binding to MAG and SGPG measured by ELISA methods. Our results show that IgM in most anti-MAG serums stained areas of non-compact myelin, including the periaxonal and outer myelin membranes and Schmidt-Lanterman incisures. However, other patterns included IgM binding to areas of compact myelin and to non-myelin structures including axons and endoneurial macrophages. IgM in anti-SGPG serums bound Ž. to axons or macrophages, but rarely to myelin-related structures. A total of 11r62 18% of serums had IgM binding to axons, six with Ž. anti-MAG antibodies and five with anti-SGPG antibodies. The majority of these serums 73% had SGPG titers greater than MAG titers when measured by ELISA. We conclude that anti-MAG serums have several different binding patterns to neural tissue, including axonal binding, especially when anti-MAG antibodies cross-react with SGPG. These different binding patterns may relate to the ability of anti-MAG serum IgM to bind both MAG and SGPG or to other molecules with a sulfated glucuronic acid epitope that are present in peripheral nerve.
J Clin Neurosci, 2007
The aim of the study is to evaluate the prognostic power of the first video-electroencephalograph... more The aim of the study is to evaluate the prognostic power of the first video-electroencephalography, executed in the neonatal period, on the neurodevelopmental outcome of preterm infants with seizures. Methods: We analyzed all preterm infants consecutively admitted to the neonatal intensive care unit (NICU) of the University Hospital of Parma, in the period January 1999-June 2003. Thirty-five newborns were selected according to the following criteria: (1) gestational age below 37 weeks, (2) repeated neonatal EEG-confirmed seizures, (3) need for chronic anticonvulsant therapy, (4) at least one Video-EEG performed during the neonatal period, (5) neurological follow-up up to 24 months of corrected gestational age. We evaluated: the background activity (scored following age-dependent criteria), the spreading of the electrical discharge, the duration of the electroclinical seizures, the amplitude and the polarity of the electrical discharge. Statistical analysis was performed using the Statistical Package for the Social Sciences (SPSS) program, version 8.0. For unpaired data we used Student's t-test and nominal data were analyzed using the v 2 test. Results: An abnormal Video-EEG recording is significantly associated with a poor neurodevelopmental outcome (p < 0.006). The findings significantly related to an adverse outcome were: an abnormal background EEG activity (p = 0.000), spread of the electrical discharge to the hemisphere (p = 0.025), and seizures lasting more than 10 minutes (p = 0.02). Conclusions: The neurophysiological findings of the first EEG performed during the neonatal period, could be strong predictors of neurodevelopmental outcome in preterm infants with seizures.
Bailliere S Clinical Neurology, Nov 1, 1995
Immune-mediated motor neuropathies are most often disorders manifest clinically by slowly progres... more Immune-mediated motor neuropathies are most often disorders manifest clinically by slowly progressive, asymmetrical, distal weakness, starting in the hands more often than the legs. In some cases, electrophysiological findings show multifocal conduction block along the length of motor axons. Other patients have findings consistent with only axonal loss. Laboratory testing is unremarkable except for high-titre serum autoantibodies to GM1 and other neural antigens. Diagnosis of immune-mediated motor neuropathies provides an opportunity for effective immunomodulating therapy that can significantly improve quality of life in affected patients. The identification of antigenic targets of serum autoantibodies in patients with motor neuropathies lends hope that immunotherapies to specifically treat the autoimmune disorder can be developed.
Human mutation, Jul 2, 2016
Congenital disorders of glycosylation (CDG) arise from pathogenic mutations in over one hundred g... more Congenital disorders of glycosylation (CDG) arise from pathogenic mutations in over one hundred genes leading to impaired protein or lipid glycosylation. ALG1 encodes a β1,4 mannosyltransferase that catalyzes the addition of the first of nine mannose moieties to form a dolichol-lipid linked oligosaccharide intermediate (DLO) required for proper N-linked glycosylation. ALG1 mutations cause a rare autosomal recessive disorder termed ALG1-CDG. To date thirteen mutations in eighteen patients from fourteen families have been described with varying degrees of clinical severity. We identified and characterized thirty-nine previously unreported cases of ALG1-CDG from thirty-two families and add twenty-six new mutations. Pathogenicity of each mutation was confirmed based on its inability to rescue impaired growth or hypoglycosylation of a standard biomarker in an alg1-deficient yeast strain. Using this approach we could not establish a rank order comparison of biomarker glycosylation and pat...
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Papers by Andrew Kornberg