Publications by authors named "Alfred P Born"

11 Publications

  • Page 1 of 1

Prolonged fasting-induced hyperketosis, hypoglycaemia and impaired fat oxidation in child and adult patients with spinal muscular atrophy type II.

Acta Paediatr 2021 Aug 18. Epub 2021 Aug 18.

Department of Biomedical Sciences, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.

Aim: This study explored hypoglycaemia and metabolic crises, including hyperketosis, in patients with spinal muscular atrophy (SMA).

Methods: The study comprised four adolescents aged 15-17 and six adults aged 19-37 with SMA type II and eight adult controls aged 21-41, who were recruited by the Rigshospitalet, Denmark, from May 1st to October 30th 2017. We used stable isotope technique and indirect calorimetry to investigate fat and glucose metabolism during a 24-h fast or until hypoglycaemia occurred.

Results: All patients with SMA II developed moderate to severe hyperketosis and 60% had symptoms of hypoglycaemia or blood glucose levels below 3 mmol/L. None of the controls developed hyperketosis or hypoglycaemia. Plasma bicarbonate decreased, in line with increased ketone bodies, indicating the start of metabolic acidosis in patients with SMA II. Increased fat production and utilisation were seen in healthy controls during the fasting period, but were absent in patients with SMA II, indicating blunted fat oxidation.

Conclusion: Low skeletal muscle mass was the best explanation for why patients with SMA II had an increased risk of hypoglycaemia, hyperketosis, metabolic acidosis and disturbed fat and glucose metabolism during fasting. These risks have implications for children facing surgery and those with severe illnesses.
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http://dx.doi.org/10.1111/apa.16074DOI Listing
August 2021

Nutritional screening of children and adolescents with cerebral palsy: a scoping review.

Dev Med Child Neurol 2021 Jul 11. Epub 2021 Jul 11.

Department of Neuropaediatrics, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.

Aim: To examine nutritional screening methods for children and adolescents with cerebral palsy.

Method: A scoping review was performed using established methodologies. In June 2020 we searched PubMed, Embase, CINAHL Complete, and the Cochrane Central Register of Controlled Trials to identify articles on tools/methods for nutritional screening of our target groups.

Results: Thirty studies were included, containing various tools/methods used to identify under- and/or overnutrition by weight/height, circumferences, skinfolds, questionnaires, and/or technically advanced or invasive methods. Questionnaires, weight/height, circumferences, and skinfolds were considered feasible based on clinical utility, whereas bioelectrical impedance analysis and blood samples were not.

Interpretation: We identified two screening tools for undernutrition that include no physical measurements, but did not find any screening tools for overweight and obesity. Most of the studies recommended one or more methods, indicating that determining nutritional status most likely includes a combination of methods, not all of which may be feasible in clinical practice.
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http://dx.doi.org/10.1111/dmcn.14981DOI Listing
July 2021

Glucocorticoid treatment for non-cerebral diseases in children and adolescents is associated with differences in uncinate fasciculus microstructure.

Pediatr Res 2021 Mar 31. Epub 2021 Mar 31.

Danish Research Centre for Magnetic Resonance, Centre for Functional and Diagnostic Imaging and Research, Copenhagen University Hospital - Amager and Hvidovre, Copenhagen, Denmark.

Background: Evidence suggests that fronto-limbic brain regions and connecting white matter fibre tracts in the left hemisphere are more sensitive to glucocorticoids than in the right hemisphere. It is unknown whether treatment with glucocorticoids in childhood is associated with microstructural differences of the uncinate fasciculus and cingulum bundle, which connect fronto-limbic brain regions. Here, we tested the hypothesis that prior glucocorticoid treatment would be associated with differences in fractional anisotropy (FA) of the left relative to right uncinate fasciculus and cingulum bundle.

Methods: We performed diffusion-weighted imaging in 28 children and adolescents aged 7-16 years previously treated with glucocorticoids for nephrotic syndrome or rheumatic disease and 28 healthy controls.

Results: Patients displayed significantly different asymmetry in the microstructure of uncinate fasciculus with higher left but similar right uncinate fasciculus FA and axial diffusivity compared to controls. No apparent differences were observed for the cingulum. Notably, higher cumulative glucocorticoid doses were significantly associated with higher uncinate fasciculus FA and axial diffusivity bilaterally.

Conclusions: Our findings indicate that previous glucocorticoid treatment for non-cerebral diseases in children and adolescents is associated with long-term changes in the microstructure of the uncinate fasciculi, and that higher cumulative glucocorticoid doses have a proportional impact on the microstructure.

Impact: It is unknown if treatment with glucocorticoids in childhood have long-term effects on fronto-limbic white matter microstructure. The study examined if children and adolescents previously treated with glucocorticoids for nephrotic syndrome or rheumatic disorder differed in fronto-limbic white matter microstructure compared to healthy controls. The nephrotic and rheumatic patients had higher left but similar right uncinate fasciculus FA and axial diffusivity. Higher bilateral uncinate fasciculus FA and axial diffusivity was associated with higher cumulative glucocorticoid doses. We revealed new evidence suggesting that previous glucocorticoid treatment for non-cerebral diseases in children and adolescents is associated with long-term changes in uncinate fasciculi microstructure.
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http://dx.doi.org/10.1038/s41390-021-01394-wDOI Listing
March 2021

Combined Muscle Biopsy and Comprehensive Electrophysiology in General Anesthesia is Valuable in Diagnosis of Neuromuscular Disease in Children.

Neuropediatrics 2021 Mar 11. Epub 2021 Mar 11.

Department of Paediatrics, Copenhagen University Hospital, Rigshospitalet, Denmark.

Aim:  The diagnostic workup in patients with delayed motor milestones suspected of having either myopathy or a congenital myasthenic syndrome is complex. Our hypothesis was that performance of a muscle biopsy and neurophysiology including stimulated single-fiber electromyography during an anesthetic procedure, combined with genetic testing has a high diagnostic quality.

Materials And Methods:  Clinical and paraclinical data were retrospectively collected from 24 patients aged from 1 month to 10 years (median: 5.2 years).

Results:  Neurophysiology examination was performed in all patients and was abnormal in 11 of 24. No patients had findings suggestive of a myasthenic syndrome. Muscle biopsy was performed in 21 of 24 and was normal in 16. Diagnostic findings included nemaline rods, inclusion bodies, fiber size variability, and type-II fiber atrophy. Genetic testing with either a gene panel or exome sequencing was performed in 18 of 24 patients, with pathogenic variants detected in , , , , , and genes.

Conclusion:  Results supporting a neuromuscular abnormality were found in 15 of 24. In six patients (25%), we confirmed a genetic diagnosis and 12 had a clinical neuromuscular diagnosis. The study suggests that combined use of neurophysiology and muscle biopsy in cases where genetic testing does not provide a diagnosis can be useful in children with delayed motor milestones and clinical evidence of a neuromuscular disease.
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http://dx.doi.org/10.1055/s-0041-1726120DOI Listing
March 2021

Incidence of pediatric neuromyelitis optica spectrum disorder and myelin oligodendrocyte glycoprotein antibody-associated disease in Denmark 2008‒2018: A nationwide, population-based cohort study.

Mult Scler Relat Disord 2019 Aug 5;33:162-167. Epub 2019 Jun 5.

Danish Multiple Sclerosis Center, Department of Neurology, Rigshospitalet, University of Copenhagen, Denmark.

Background: The incidence of pediatric neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease have not been reported previously. Our aim was to estimate the incidence of pediatric NMOSD and the occurrence of anti-MOG antibody-associated disease in Denmark during 2008-18, and to evaluate the diagnostic usefulness of antibodies against MOG and aquaporin-4 (AQP4) in children <18 years.

Methods: We undertook a nationwide, population-based, multicenter cohort study using data from the Danish National Patient Register, the Danish Multiple Sclerosis Registry, and laboratories providing anti-AQP4 and anti-MOG antibody analyses. Diagnoses were confirmed by review of the medical records, including blinded MRI review in most children with acute disseminated encephalomyelitis (ADEM).

Results: In children with acquired demyelinating syndromes, anti-AQP4 antibodies were detected in 4% and anti-MOG antibodies in 18%, including in the two children with ADEM who relapsed. We identified four children with NMOSD, equivalent to an incidence of 0.031/100,000 (95% confidence interval = 0.011‒0.082). In anti-MOG antibody-positive children, 32% relapsed during follow-up.

Conclusions: Pediatric NMOSD and MOG antibody-associated disease are rare, but one-third of anti-MOG-positive children relapsed. In pediatric ADEM, only anti-MOG antibody-positive children relapsed, but the overall risk of relapse after pediatric ADEM was low.
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http://dx.doi.org/10.1016/j.msard.2019.06.002DOI Listing
August 2019

Implications of the International Paediatric Multiple Sclerosis Study Group consensus criteria for paediatric acute disseminated encephalomyelitis: a nationwide validation study.

Dev Med Child Neurol 2018 11 10;60(11):1123-1131. Epub 2018 May 10.

Department of Paediatrics, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.

Aim: The International Paediatric Multiple Sclerosis Study Group (IPMSSG) has proposed criteria for acute disseminated encephalomyelitis (ADEM) not evaluated in clinical practice. Our objective was to assess epidemiological implications of the IPMSSG criteria for ADEM in a cohort study using prospectively collected data.

Method: We identified all diagnosed cases of ADEM in Denmark between 2008 and 2015 from the Danish National Patient Register by International Classification of Diseases 10 codes assigned to acute demyelinating episodes, and we reviewed all medical records to validate ADEM.

Results: We found 52 children up to the age of 18 years with a verified clinical diagnosis of ADEM (incidence rate 0.54/100 000 person-years; all had abnormal brain magnetic resonance imaging). Only 18 (35%) fulfilled the IPMSSG criteria regarding encephalopathy and polyfocal neurological deficits. Among all 52 children with ADEM, 33 per cent had clinical sequelae after a median follow-up of 4 years 6 months (range: 10mo-8y 3mo). Surprisingly, none progressed to multiphasic ADEM or multiple sclerosis, but median age at end of follow-up was only 10 years 9 months (range: 2y-24y 3mo).

Interpretation: Among 52 children with ADEM, none converted to multiphasic ADEM or multiple sclerosis (median follow-up: 4y 6mo; range: 10mo-8y 3mo). Applying the IPMSSG criteria to all children with a diagnosis of ADEM leaves 65 per cent of the cases without a diagnosis and lowers the incidence rate of paediatric ADEM.

What This Paper Adds: The incidence of paediatric acute disseminated encephalomyelitis (ADEM) was 0.54 per 100 000 person-years in children younger than 18 years. Only 35 per cent of children with ADEM fulfilled the International Paediatric Study Group consensus criteria. ADEM in clinical practice was primarily based on magnetic resonance imaging findings. Paediatric neurologists diagnosed ADEM in the absence of encephalopathy. None of the children with ADEM progressed to multiple sclerosis/multiphasic ADEM during follow-up.
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http://dx.doi.org/10.1111/dmcn.13798DOI Listing
November 2018

Total brain, cortical, and white matter volumes in children previously treated with glucocorticoids.

Pediatr Res 2018 04 10;83(4):804-812. Epub 2018 Jan 10.

Danish Research Centre for Magnetic Resonance, Centre for Functional and Diagnostic Imaging and Research, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark.

BackgroundPerinatal exposure to glucocorticoids and elevated endogenous glucocorticoid levels during childhood can have detrimental effects on the developing brain. Here, we examined the impact of glucocorticoid treatment during childhood on brain volumes.MethodsA total of 30 children and adolescents with rheumatic or nephrotic disease previously treated with glucocorticoids and 30 controls matched on age, sex, and parent education underwent magnetic resonance imaging (MRI) of the brain. Total cortical gray and white matter, brain, intracranial volume, and total cortical thickness and surface area were derived from MRI scans.ResultsPatients had significantly smaller gray and white matter and total brain volumes relative to healthy controls. Brain volume differences disappeared when accounting for intracranial volume, as patients had relatively smaller intracranial volumes. Group differences were mainly driven by the children with rheumatic disease. Total cortical thickness and cortical surface area did not significantly differ between groups. We found no significant associations between glucocorticoid-treatment variables and volumetric measures.ConclusionObserved smaller total brain, cortical gray, and white matter volumes in children and adolescents previously treated with glucocorticoids compared with that in healthy controls may reflect both developmental and degenerative processes. Prospective longitudinal studies are warranted to clarify whether findings are related to treatment or disease.
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http://dx.doi.org/10.1038/pr.2017.312DOI Listing
April 2018

Gene Panel Testing in Epileptic Encephalopathies and Familial Epilepsies.

Mol Syndromol 2016 Sep 20;7(4):210-219. Epub 2016 Aug 20.

Danish Epilepsy Centre, Filadelfia, Dianalund, Denmark.

In recent years, several genes have been causally associated with epilepsy. However, making a genetic diagnosis in a patient can still be difficult, since extensive phenotypic and genetic heterogeneity has been observed in many monogenic epilepsies. This study aimed to analyze the genetic basis of a wide spectrum of epilepsies with age of onset spanning from the neonatal period to adulthood. A gene panel targeting 46 epilepsy genes was used on a cohort of 216 patients consecutively referred for panel testing. The patients had a range of different epilepsies from benign neonatal seizures to epileptic encephalopathies (EEs). Potentially causative variants were evaluated by literature and database searches, submitted to bioinformatic prediction algorithms, and validated by Sanger sequencing. If possible, parents were included for segregation analysis. We identified a presumed disease-causing variant in 49 (23%) of the 216 patients. The variants were found in 19 different genes including and . Patients with neonatal-onset epilepsies had the highest rate of positive findings (57%). The overall yield for patients with EEs was 32%, compared to 17% among patients with generalized epilepsies and 16% in patients with focal or multifocal epilepsies. By the use of a gene panel consisting of 46 epilepsy genes, we were able to find a disease-causing genetic variation in 23% of the analyzed patients. The highest yield was found among patients with neonatal-onset epilepsies and EEs.
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http://dx.doi.org/10.1159/000448369DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5073625PMC
September 2016

New hyperekplexia mutations provide insight into glycine receptor assembly, trafficking, and activation mechanisms.

J Biol Chem 2013 Nov 9;288(47):33745-33759. Epub 2013 Oct 9.

Epilepsy Research Centre, Melbourne Brain Centre, Austin Health, Heidelberg 3084, Victoria, Australia.

Hyperekplexia is a syndrome of readily provoked startle responses, alongside episodic and generalized hypertonia, that presents within the first month of life. Inhibitory glycine receptors are pentameric ligand-gated ion channels with a definitive and clinically well stratified linkage to hyperekplexia. Most hyperekplexia cases are caused by mutations in the α1 subunit of the human glycine receptor (hGlyR) gene (GLRA1). Here we analyzed 68 new unrelated hyperekplexia probands for GLRA1 mutations and identified 19 mutations, of which 9 were novel. Electrophysiological analysis demonstrated that the dominant mutations p.Q226E, p.V280M, and p.R414H induced spontaneous channel activity, indicating that this is a recurring mechanism in hGlyR pathophysiology. p.Q226E, at the top of TM1, most likely induced tonic activation via an enhanced electrostatic attraction to p.R271 at the top of TM2, suggesting a structural mechanism for channel activation. Receptors incorporating p.P230S (which is heterozygous with p.R65W) desensitized much faster than wild type receptors and represent a new TM1 site capable of modulating desensitization. The recessive mutations p.R72C, p.R218W, p.L291P, p.D388A, and p.E375X precluded cell surface expression unless co-expressed with α1 wild type subunits. The recessive p.E375X mutation resulted in subunit truncation upstream of the TM4 domain. Surprisingly, on the basis of three independent assays, we were able to infer that p.E375X truncated subunits are incorporated into functional hGlyRs together with unmutated α1 or α1 plus β subunits. These aberrant receptors exhibit significantly reduced glycine sensitivity. To our knowledge, this is the first suggestion that subunits lacking TM4 domains might be incorporated into functional pentameric ligand-gated ion channel receptors.
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http://dx.doi.org/10.1074/jbc.M113.509240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3837119PMC
November 2013

Ketogenic diet in 3 cases of childhood refractory status epilepticus.

Eur J Paediatr Neurol 2013 Nov 14;17(6):531-6. Epub 2013 Jun 14.

Department of Paediatrics, Hillerød Hospital, 3400 Hillerød, Denmark. Electronic address:

Introduction: Refractory status epilepticus (RSE) in children is associated with a significant risk of death or neurological morbidity. Recently attention has been drawn to the ketogenic diet (KD) as an acute treatment, as it has shown promise in controlling seizures in otherwise refractory status epilepticus in several cases. We have listed these and reviewed all cases of KD used in RSE at our centre. KD was given as 4:1 fat:carbohydrate-protein solution.

Results: A 3-year-old girl with RSE due to Hemiconvulsion-Hemiplegia Epilepsy syndrome. KD was instigated on day 6. Seizures stopped with ketosis on day 7. A 10-year-old boy rapidly developing RSE. After months a mitochondrial disorder was discovered. KD was tried twice with severe side-effects but no seizure control. 11-year-old healthy boy with RSE as FIRES. On KD seizures stopped for 24 h one day after reaching ketosis. He improved over 3-4 weeks.

Discussion: KD was efficient in two of three cases of RSE. The non-responder had severe side-effects and proved to have a mitochondrial disorder which is arguably a contraindication for KD. More studies are needed to prove efficacy of KD in RSE, to define optimal timing of KD and possible contraindications for KD in RSE.
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http://dx.doi.org/10.1016/j.ejpn.2013.05.001DOI Listing
November 2013

Changes in BOLD and ADC weighted imaging in acute hypoxia during sea-level and altitude adapted states.

Neuroimage 2005 Dec 10;28(4):947-55. Epub 2005 Aug 10.

Danish Research Centre for Magnetic Resonance, Copenhagen University Hospital Hvidovre, Denmark.

Acute normobaric hypoxia as well as longstanding hypobaric hypoxia induce pronounced physiological changes and may eventually lead to impairment of cerebral function. The aim of the present study is to investigate the effect of hypoxia on the cerebral activation response as well as to explore possible structural changes as measured by diffusion weighted imaging. Eleven healthy sea-level residents were studied after 5 weeks of adaptation to high altitude conditions at Chacaltaya, Bolivia (5260 m). The subjects were studied immediately after return to sea-level in hypoxic and normoxic conditions, and the examinations repeated 6 months later after re-adaptation to sea-level conditions. The BOLD response, measured at 1.5 T, was severely reduced during acute hypoxia both in the altitude and sea-level adapted states (50% reduction during an average S(a)O(2) of 75%). On average, the BOLD response magnitude was 23% lower in altitude than sea-level adaptation in the normoxic condition, but in the hypoxic condition, no significant differences were found. A small but statistically significant decrease in the apparent diffusion coefficient (ADC) was seen in some brain regions during acute hypoxia, whereas ADC was slightly elevated in high altitude as compared to sea-level adaptation. It is concluded that hypoxia significantly diminishes the BOLD response, and the mechanisms underlying this finding are discussed. Furthermore, altitude adaptation may influence both the magnitude of the activation-related response, as well as micro-structural features.
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http://dx.doi.org/10.1016/j.neuroimage.2005.06.032DOI Listing
December 2005
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