Publications by authors named "Kirsten Svenstrup"

18 Publications

  • Page 1 of 1

Novel Homozygous Truncating Variant Widens the Spectrum of Early-Onset Multisystemic SYNE1 Ataxia.

Cerebellum 2021 Jul 28. Epub 2021 Jul 28.

Department of Neurology, University of Copenhagen, Rigshospitalet, Inge Lehmanns Vej 8, 2100, Copenhagen, Denmark.

Pathogenic variants in the SYNE1 gene are associated with a phenotypic spectrum spanning from late-onset, slowly progressive, relatively pure ataxia to early-onset, fast progressive multisystemic disease. Since its first description in 2007 as an adult-onset ataxia in French Canadian families, subsequent identification of patients worldwide has widened the clinical spectrum and increased the number of identified pathogenic variants. We report a 20-year-old Faroese female with early-onset progressive gait problems, weakness, dysphagia, slurred speech, orthostatic dizziness, and urge incontinence. Neurological examination revealed mild cognitive deficits, dysarthria, broken slow pursuit, hypometric saccades, weakness with spasticity, hyperreflexia, absent ankle reflexes, ataxia, and wide-based, spastic gait. Magnetic resonance imaging displayed atrophy of the cerebellum, brainstem, and spinal cord. Severely prolonged central motor conduction time and lower motor neuron involvement was demonstrated electrophysiologically. Fluorodeoxyglucose-positron emission tomography (FDG-PET) scan showed hypometabolism of the cerebellum and right frontal lobe. Muscle biopsy revealed chronic neurogenic changes and near-absent immunostaining for Nesprin-1. Next-generation sequencing revealed a previously undescribed homozygous truncating, likely pathogenic variant in the SYNE1 gene. The patient's mother and paternal grandfather were heterozygous carriers of the variant. Her father's genotype was unobtainable. We expand the list of likely pathogenic variants in SYNE1 ataxia with a novel homozygous truncating variant with proximity to the C-terminus and relate it to a phenotype comprising early-onset cerebellar deficits, upper and lower motor neuron involvement and cognitive deficits. Also, we report novel findings of focally reduced frontal lobe FDG-PET uptake and motor evoked potential abnormalities suggestive of central demyelination.
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http://dx.doi.org/10.1007/s12311-021-01308-wDOI Listing
July 2021

Prediction of survival in amyotrophic lateral sclerosis: a nationwide, Danish cohort study.

BMC Neurol 2021 Apr 17;21(1):164. Epub 2021 Apr 17.

Department of Neuroanaesthesiology, Neuroscience Centre, Rigshospitalet, Copenhagen, Denmark.

Introduction: Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease with great heterogeneity. Biological prognostic markers are needed for the patients to plan future supportive treatment, palliative treatment, and end-of-life decisions. In addition, prognostic markers are greatly needed for the randomization in clinical trials.

Objective: This study aimed to test the ALS Functional Rating Scale-Revised (ALSFRS-R) progression rate (ΔFS) as a prognostic marker of survival in a Danish ALS cohort.

Methods: The ALSFRS-R score at test date in association with duration of symptoms, from the onset of symptoms until test date, (defined as ΔFS') was calculated for 90 Danish patients diagnosed with either probable or definite sporadic ALS. Median survival time was then estimated from the onset of symptoms until primary endpoint (either death or tracheostomy). ΔFS' was subjected to survival analysis using Cox proportional hazards modelling, log-rank test, and Kaplan-Meier survival analysis.

Results And Conclusions: Both ΔFS' and age was found to be strong predictors of survival of the Danish ALS cohort. Both variables are easily obtained at the time of diagnosis and could be used by clinicians and ALS patients to plan future supportive and palliative treatment. Furthermore, ΔFS', is a simple, prognostic marker that predicts survival in the early phase of disease as well as at later stages of the disease.
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http://dx.doi.org/10.1186/s12883-021-02187-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8052712PMC
April 2021

Complement Profiles in Patients with Amyotrophic Lateral Sclerosis: A Prospective Observational Cohort Study.

J Inflamm Res 2021 23;14:1043-1053. Epub 2021 Mar 23.

Laboratory of Molecular Medicine, Department of Clinical Immunology, Section 7631, Diagnostic Centre, Rigshospitalet, Copenhagen, Denmark.

Background: The complement system has been suggested to be involved in the pathophysiology of amyotrophic lateral sclerosis (ALS), a progressive motor neuron disease. In the present study, we compared levels of selected complement markers to clinical outcome in ALS patients.

Methods: This observational, explorative cohort study included 92 ALS patients, 61 neurological controls (NCs) admitted for suspected aneurysmal subarachnoid haemorrhage, and 96 neurologically healthy controls (NHCs). Peripheral blood and cerebrospinal fluid (CSF) were obtained for the measurement of ficolin-1, -2, and -3; collectin-11, MBL, MASP-3, MAP-1, C4, C3, PTX-3, and complement activation products C4c, C3bc, and sC5b-9. We recorded clinical outcomes of ALS patients for 24 to 48 months after inclusion in order to analyse the effects of the complement markers on survival time.

Results: Compared with both control groups, ALS patients exhibited increased collectin-11, C4 and sC5b-9 in plasma, as well as increased ficolin-3 in CSF. Ficolin-2 was significantly decreased in plasma of the ALS patients compared with NHCs, but not with NCs. The concentration of collectin-11, C3 and C3bc correlated negatively with the revised ALS functional rating scale (ALSFRS-R). No association was found between levels of complement markers and survival as estimated by hazard ratios.

Conclusion: ALS patients exhibit aberrant expression of selected mediators of the lectin complement pathway as well as increased activation of the terminal complement pathway, corroborating the notion that the complement system might be involved in the pathophysiology of ALS.
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http://dx.doi.org/10.2147/JIR.S298307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8005270PMC
March 2021

TDP-43-specific Autoantibody Decline in Patients With Amyotrophic Lateral Sclerosis.

Neurol Neuroimmunol Neuroinflamm 2021 03 24;8(2). Epub 2020 Dec 24.

From the Research Laboratory for Stereology and Neuroscience (A.K.N., J.F., S.O., B.P., S.A., T.B.), and Department of Neurology (K.S., K.W.), Bispebjerg-Frederiksberg Hospital, University Hospital of Copenhagen; Neuromuscular Clinic (K.S.), Department of Neurology, Rigshospitalet, Copenhagen; Institute of Clinical Medicine (B.P.), Faculty of Health and Medical Sciences, University of Copenhagen; and Copenhagen Center for Translational Research (S.A., T.B.), Copenhagen University Hospital, Bispebjerg and Frederiksberg, Denmark.

Objective: We hypothesize alterations in the quality and quantity of anti-43-kDa TAR DNA-binding protein (TDP-43) naturally occurring autoantibodies (NAbs) in patients with amyotrophic lateral sclerosis (ALS); therefore, we assessed relative binding properties of anti-TDP-43 NAbs composite in plasma from patients with ALS in comparison with healthy individuals.

Methods: ELISA competition assay was used to explore the apparent avidity/affinity of anti-TDP-43 NAbs in plasma from 51 normal controls and 30 patients with ALS. Furthermore, the relative levels of anti-TDP-43 NAbs within the immunoglobulin (Ig) classes of IgG (isotype IgG1-4) and IgMs were measured using classical indirect ELISA. The occurring results were hereafter correlated with the measures of disease duration and disease progression.

Results: High-avidity/affinity anti-TDP-43 NAbs levels were significantly reduced in plasma samples from patients with ALS. In addition, a significant decrease in relative levels of anti-TDP-43 IgG3 and IgM NAbs and a significant increase in anti-TDP-43 IgG4 NAbs were observed in ALS plasma vs controls. Furthermore, a decrease in global IgM and an increase in IgG4 levels were observed in ALS. These aberrations of humoral immunity correlated with disease duration, but did not correlate with ALS Functional Rating Scale-Revised scores.

Conclusions: Our results may suggest TDP-43-specific immune aberrations in patients with ALS. The skewed immune profiles observed in patients with ALS could indicate a deficiency in the clearance capacity and/or blocking of TDP-43 transmission and propagation. The decrease in levels of high affinity/avidity anti-TDP-43 NAbs and IgMs correlates with disease progression and may be disease predictors.
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http://dx.doi.org/10.1212/NXI.0000000000000937DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768943PMC
March 2021

Amyotrophic lateral sclerosis in the Faroe Islands - a genealogical study.

Amyotroph Lateral Scler Frontotemporal Degener 2020 Sep 4:1-5. Epub 2020 Sep 4.

Department of Occupational Medicine and Public Health, the Faroese Hospital System, Tórshavn, Faroe Islands.

In the Faroe Islands, a clustering of amyotrophic lateral sclerosis (ALS) was observed on the geographically isolated island, Suðuroy. This study aims to estimate the frequency of familial ALS (fALS) in the Faroes including 43 patients diagnosed with ALS. Patients with fALS were identified through medical records and the Faroese Multi Generation Register. Firstly, fALS was recognized when occurring between first- or second-degree relatives. Secondly, families and individuals with fALS were recognized through pedigrees (≥3 cases within 3 generations). The prevalence of ALS was 3 times higher in Suðuroy compared to the nationwide prevalence. The frequency of fALS was at least 14% ( = 6) and mean survival time was 1.7 years shorter for fALS compared to sporatic ALS ( = 0.01. SD = 0.5, range 1.0-2.2). This study is suggestive of familial clustering in excess of expected for ALS and supports a genetic contribution to ALS in the Faroe Islands albeit environmental exposure within families cannot be excluded.
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http://dx.doi.org/10.1080/21678421.2020.1813311DOI Listing
September 2020

Peripheral neuropathy in hereditary spastic paraplegia caused by REEP1 variants.

J Neurol 2019 Mar 12;266(3):735-744. Epub 2019 Jan 12.

Department of Neurology, Rigshospitalet, Neuromuscular Research Center, University of Copenhagen, Copenhagen, Denmark.

SPG31 is a hereditary spastic paraplegia (HSP) caused by pathogenic variants in the REEP1 gene. The phenotype (SPG31) has occasionally been described with peripheral nervous system involvement, in additional to the gradually progressing lower limb spasticity that characterizes HSP. The objective of this study was to characterize patients with pathogenic REEP1 variants and neurophysiologically assess the extent of peripheral nerve involvement in this patient group. Thirty-eight index cases were molecular-genetically tested, yielding two previously reported pathogenic REEP1 variants and a novel missense variant, in a total of four index patients. Three of four probands and five additional family members underwent nerve conduction studies, electromyography, quantitative sensory testing, and examination of the autonomic nervous system. None of the examined patients had completely unremarkable results of peripheral nerve studies. Most showed electrophysiological signs of carpal tunnel syndrome, and one patient demonstrated a multifocal compression neuropathy. Autonomic testing revealed no severe dysfunction, and findings were limited to adrenergic function. HSP caused by pathogenic REEP1 variants may be accompanied by a generally mild and subclinical polyneuropathy with a predisposition to compression neuropathy, and should be considered in such cases.
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http://dx.doi.org/10.1007/s00415-019-09196-1DOI Listing
March 2019

Genetic analysis of Charcot-Marie-Tooth disease in Denmark and the implementation of a next generation sequencing platform.

Eur J Med Genet 2019 Jan 11;62(1):1-8. Epub 2018 Apr 11.

Dept. of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark.

Charcot-Marie-Tooth disease (CMT) is a heterogeneous group of hereditary polyneuropathies. Variants in more than 80 different genes have been associated with the disorder. In recent years, the introduction of next generation sequencing (NGS) techniques have completely changed the genetic diagnostic approach from the analysis of a handful of genes to the analysis of all genes associated with CMT in a single run. In this study we describe the CMT diagnostics in Denmark in 1992-2012, prior to the implementation of NGS, by combining laboratory- and national registry data. We investigate the effect of implementing a targeted NGS approach of 63 genes associated with CMT in the diagnostic laboratory setting. This was performed by analyzing a cohort of 195 samples from patients previously analyzed by Sanger sequencing and quantitative analysis for the common causes of CMT without reaching a molecular diagnosis. A total of 1442 CMT analyses were performed in Denmark in the period 1992-2012; a disease-causing variant was detected in 21.6% of the cases. Interestingly, the diagnosis was genetically confirmed in significantly more women than men; 25.9% compared to18.5%. In our study cohort, we found a 5.6% increase in the diagnostic yield with the introduction of a targeted NGS approach.
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http://dx.doi.org/10.1016/j.ejmg.2018.04.003DOI Listing
January 2019

July 2017 ENCALS statement on edaravone.

Amyotroph Lateral Scler Frontotemporal Degener 2017 11 4;18(7-8):471-474. Epub 2017 Oct 4.

ad Department of Neurology-Stroke Unit and Laboratory of Neuroscience, Department of Pathophysiology and Transplantation , Center for Neurotechnology and Brain Therapeutics, Università degli Studi di Milano, IRCCS Istituto Auxologico Italiano , Milan , Italy.

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http://dx.doi.org/10.1080/21678421.2017.1369125DOI Listing
November 2017

SCA28: Novel Mutation in the AFG3L2 Proteolytic Domain Causes a Mild Cerebellar Syndrome with Selective Type-1 Muscle Fiber Atrophy.

Cerebellum 2017 02;16(1):62-67

Danish Dementia Research Centre, Neurogenetics Clinic, Department of Neurology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.

The spinocerebellar ataxias (SCA) are a group of rare inherited neurodegenerative diseases characterized by slowly progressive cerebellar ataxia, resulting in unsteady gait, clumsiness, and dysarthria. The disorders are predominantly inherited in an autosomal dominant manner. Mutations in the gene AFG3L2 that encodes a subunit of the mitochondrial m-AAA protease have previously been shown to cause spinocerebellar ataxia type 28 (SCA28). Here, we present the clinical phenotypes of three patients from a family with autosomal dominant cerebellar ataxia and show by molecular genetics and in silico modelling that this is caused by a novel missense mutation in the AFG3L2 gene. Furthermore, we show, for the first time, fluorodeoxyglucose-positron emission tomography (FDG-PET) scans of the brain and selective type I fiber atrophy of skeletal muscle of SCA28 patients indicating non-nervous-system involvement in SCA28 as well.
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http://dx.doi.org/10.1007/s12311-016-0765-1DOI Listing
February 2017

[Genetic counselling is relevant in familial as well as sporadic cases of amyotrophic lateral sclerosis].

Ugeskr Laeger 2014 Oct;176(43)

Klinisk Genetisk Klinik, Rigshospitalet, Blegdamsvej 9, 2100 København Ø.

Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disease of upper and lower motor neurons which often results in death from respiratory failure within 2-4 years. It has been estimated that 5-10% of ALS patients have a family history with ALS. The genetic background of the disorder is heterogeneous, and recently molecular genetic testing has become increasingly relevant, also in the clinical evaluation. As several genes have been identified in which the pathogenic mutations are characterized by reduced age-dependent penetrance, genetic testing can be relevant to consider, also in isolated cases.
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October 2014

Intravenous immunoglobulin treatment in a patient with adrenomyeloneuropathy.

BMC Neurol 2012 Sep 26;12:108. Epub 2012 Sep 26.

Kennedy Centre, Copenhagen University Hospital, Rigshospitalet, Gl, Landevej 7, Copenhagen, 2600, Glostrup, Denmark.

Background: Adrenomyeloneuropathy (AMN) is one of several phenotypes of the adrenoleukodystrophy spectrum caused by mutations in the ABCD1 gene on the X chromosome. An inflammatory component is part of the disease complex ranging from severe childhood CNS demyelination to spinal cord and peripheral nerve degeneration.

Case Presentation: We present a patient with clinical progressive AMN and severe lower limb pain. Longitudinal brain magnetic resonance spectroscopy showed a constant slightly elevated myoinositol/total creatine ratio during the five year treatment period, probably reflecting demyelination, microglial activation and gliosis, indicating an inflammatory response. The pain was refractory to conventional therapy but intravenous immunoglobulin (IVIG) treatment was highly efficient.

Conclusion: IVIG may be considered as a last resort for treatment of refractory pain in AMN patients with indications of an inflammatory component.
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http://dx.doi.org/10.1186/1471-2377-12-108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3517486PMC
September 2012

ATXN2 with intermediate-length CAG/CAA repeats does not seem to be a risk factor in hereditary spastic paraplegia.

J Neurol Sci 2012 Oct 3;321(1-2):100-2. Epub 2012 Aug 3.

Danish Dementia Research Centre, Neurogenetics Clinic, Department of Neurology, Rigshospitalet, Copenhagen University Hospital, Denmark.

Hereditary spastic paraplegia (HSP) confines a group of heterogeneous neurodegenerative disorders characterized by progressive spasticity and lower limb weakness. Age of onset is highly variable even in familial cases with known mutations suggesting that the disease is modulated by other yet unknown parameters. Although progressive gait disturbances, lower limb spasticity and extensor plantar responses are hallmarks of HSP these characteristics are also found in other neurodegenerative disorders, e.g. amytrophic lateral sclerosis (ALS). HSP has been linked to ALS and frontotemporal degeneration with motor neuron disease (FTD-MND), since TDP-43 positive inclusions have recently been found in an HSP subtype, and TDP-43 are found in abundance in pathological inclusions of both ALS and FTD-MND. Furthermore, ataxin-2 (encoded by the gene ATXN2), a polyglutamine containing protein elongated in spinocerebellar ataxia type 2, has been shown to be a modulator of TDP-43 induced toxicity in ALS animal and cell models. Finally, it has been shown that ATXN2 with non-pathogenic intermediate-length CAG/CAA repeat elongations (encoding the polyglutamine tract) is a genetic risk factor of ALS. Considering the similarities in the disease phenotype and the neuropathological link between ALS and HSP we hypothesized that intermediate-length CAG/CAA repeats in ATXN2 could be a modulator of HSP. We show that in a cohort of 181 HSP patients 4.9 % of the patients had intermediate-length CAG/CAA repeats in ATXN2 which was not significantly different from the frequencies in a Danish control cohort or in American and European control populations. However, the mean age of onset was significantly lower in HSP patients with intermediate-length CAG/CAA repeats in ATXN2 compared to patients with normal length repeats. Based on these results we conclude that ATXN2 is most likely not a risk factor of HSP, whereas it might serve as a modulator of age of onset.
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http://dx.doi.org/10.1016/j.jns.2012.07.036DOI Listing
October 2012

Clinical and molecular characterization of limb-girdle muscular dystrophy due to LAMA2 mutations.

Muscle Nerve 2011 Nov 26;44(5):703-9. Epub 2011 Sep 26.

Neuromuscular Center, Department of Neurosciences, University of Padova, Padova 35128, Italy.

Introduction: In this study we describe the clinical and molecular characteristics of limb-girdle muscular dystrophy (LGMD) due to LAMA2 mutations.

Methods: Five patients clinically diagnosed with LGMD and showing brain white matter hyperintensities on MRI were evaluated using laminin α2 genetic and protein testing.

Results: The patients had slowly progressive, mild muscular dystrophy with various degrees of CNS involvement. Epilepsy was observed in 2, and subtle symptoms of CNS involvement (mild deficit in executive functions and low IQ scores) were noted in 3 patients. Novel LAMA2 mutations were identified in all patients. The amount of laminin α2 protein in the muscle biopsies ranged from trace to about 50% compared with controls.

Conclusions: This study represents the largest series of LGMD laminin α2-deficient patients and expands the clinical phenotype associated with LAMA2 mutations. The findings suggest that brain MRI could be included in the diagnostic work-up of patients with undiagnosed LGMD.
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http://dx.doi.org/10.1002/mus.22132DOI Listing
November 2011

Hereditary spastic paraplegia caused by the PLP1 'rumpshaker mutation'.

J Neurol Neurosurg Psychiatry 2010 Jun 1;81(6):666-72. Epub 2009 Dec 1.

Section of Neurogenetics, Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark.

Background: Hereditary spastic paraplegia (HSP) is a group of clinically and genetically heterogeneous neurodegenerative disorders characterised by progressive spasticity and weakness in the lower limbs. Mutations in PLP1 on the X chromosome cause spastic paraplegia type 2 (SPG2) or the allelic Pelizaeus-Merzbacher Disease (PMD). The PLP1 protein is a major myelin protein involved in stabilisation and maintenance of the myelin sheath. The function of the protein has been studied in the rumpshaker mouse, which is a model of SPG2/PMD.

Objective: To characterise the phenotype of patients with the 'rumpshaker mutation.'

Patients: A family with HSP caused by the 'rumpshaker mutation.'

Results: The patients showed nystagmus during infancy and had early onset of HSP. They had normal cognition, and cerebral MRI showed relatively unspecific white matter abnormalities on T2 sequences without clear progression. Urinary urgency was reported among the female carriers. MRS of both patients showed increased myo-inositol in the white matter, while decreased N-acetylaspartate was found exclusively in the oldest patient. All evoked potential examinations were compatible with severe central demyelination, while no signs of peripheral demyelination or axonal degeneration were found. (18)F-FDG-PET scans were normal.

Conclusion: The phenotypes of the patients reported here are the mildest described to be caused by the rumpshaker mutation and represent the mildest form among the spectrum of PLP1 related disorders. No definite symptoms in the female carriers could be ascribed to the mutation. These data suggest the pathology to be an underlying dysmyelinating disorder in combination with a central axonal degeneration.
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http://dx.doi.org/10.1136/jnnp.2009.180315DOI Listing
June 2010

Sequence variants in SPAST, SPG3A and HSPD1 in hereditary spastic paraplegia.

J Neurol Sci 2009 Sep 6;284(1-2):90-5. Epub 2009 May 6.

Section of Neurogenetics, Department of Cellular and Molecular Medicine, University of Copenhagen, Denmark.

Hereditary spastic paraplegia (HSP) is a group of clinically and genetically heterogeneous neurodegenerative disorders characterized by progressive spasticity and weakness in the lower limbs. The most common forms of autosomal dominant HSP, SPG4 and SPG3, are caused by sequence variants in the SPAST and SPG3A genes, respectively. The pathogenic variants are scattered all over these genes and many variants are unique to a specific family. The phenotype in SPG4 patients can be modified by a variant in SPAST (p.Ser44Leu) and recently, a variant in HSPD1, the gene underlying SPG13, was reported as a second genetic modifier in SPG4 patients. In this study HSP patients were screened for variants in SPG3A, SPAST and HSPD1 in order to identify disease causing variations. SPAST was sequenced in all patients whereas subsets were sequenced in HSPD1 and in selected exons of SPG3A. SPG4 patients and their HSP relatives were genotyped for the modifying variant in HSPD1. We report six new sequence variants in SPAST including a fourth non synonymous sequence variant in exon 1 and two synonymous changes of which one has been found in a HSP patient previously, but never in controls. Of the novel variants in SPAST four were interpreted as disease causing. In addition one new disease causing sequence variant and one non pathogenic non synonymous variant were found in SPG3A. In HSPD1 we identified a sporadic patient homozygote for the potential modifying variation. The effect of the modifying HSPD1 variation was not supported by identification in one SPG4 family.
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http://dx.doi.org/10.1016/j.jns.2009.04.024DOI Listing
September 2009

A novel mutation in the HSPD1 gene in a patient with hereditary spastic paraplegia.

J Neurol 2007 Jul 10;254(7):897-900. Epub 2007 Apr 10.

Research Unit for Molecular Medicine, Faculty of Health Sciences Aarhus University Hospital , Skejby Sygehus, Brendstrupgaardsvej, 8200, Aarhus N, Denmark,

A mutation in the HSPD1 gene has previously been associated with an autosomal dominant form of spastic paraplegia in a French family. HSPD1 encodes heat shock protein 60, a molecular chaperone involved in folding and quality control of mitochondrial proteins. In the present work we have investigated 23 Danish index patients with hereditary spastic paraplegia (HSP) for mutations in the HSPD1 gene. One patient was found to be heterozygous for a c.1381C > G missense mutation encoding the mutant heat shock protein 60 p.Gln461Glu. The mutation was also present in two unaffected brothers, but absent in 400 unrelated Danish individuals. We found that the function of the p.Gln461Glu heat shock protein 60 was mildly compromised. The c.1381C > G mutation likely represents a novel low-penetrance HSP allele.
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http://dx.doi.org/10.1007/s00415-006-0470-yDOI Listing
July 2007

Postnatal development of beta-cells in rats. Proposed explanatory model.

APMIS 2002 May;110(5):372-8

Bartholin Instituttet, H:S Kommunehospitalet, H:S Bispebjerg Hospital, Copenhagen, Denmark.

The previously shown wave of beta-cell apoptosis and the apparent plateau in the beta-cell mass in the third week of life in rats are still unexplained events. Using a novel design-based stereological method we investigated the postnatal development of the beta-cell population in Sprague-Dawley rats. The total beta-cell mass increased from postnatal day 4 until day 16, to be followed by a plateau until day 24, after which it increased further. This plateau was caused by beta-cell hypotrophia as well as decreased net beta-cell formation. The beta-cell mass per unit body weight (the relative beta-cell mass) was five times higher at birth compared with the adult constant level that was reached at approximately 24 days of age. We propose an explanatory model for the postnatal development of the beta-cell population in rats. According to this model, beta-cells in the early postnatal period are immature, i.e. are not susceptible to the mechanism that in later life maintains a constant relative beta-cell mass. Within the following weeks the number of mature beta-cells increases, and from approximately day 24 and onwards the beta-cell population is dominated by mature beta-cells that adjust to match the body weight, keeping a constant relative beta-cell mass. Findings of an apoptotic wave, a plateau phase in the total beta-cell mass development, a period with beta-cell hypotrophia, and the disappearance of insulin-like growth factor II positive beta-cells at postnatal day 21 all fit well in the model.
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http://dx.doi.org/10.1034/j.1600-0463.2002.100502.xDOI Listing
May 2002
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