Lis Hasholt

IT University of Copenhagen, København, Capital Region, Denmark

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Publications (75)271.19 Total impact

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    ABSTRACT: Objective: Ceramides are precursors of complex sphingolipids (SLs), which are important for normal functioning of both the developing and mature brain. Altered SL levels have been associated with many neurodegenerative disorders, including epilepsy, although few direct links have been identified between genes involved in SL metabolism and epilepsy. Methods: We used quantitative real-time PCR, Western blotting, and enzymatic assays to determine the mRNA, protein, and activity levels of ceramide synthase 2 (CERS2) in fiibroblasts iso-lated from parental control subjects and from a patient diagnosed with progres-sive myoclonic epilepsy (PME). Mass spectrometry and fluorescence microscopy were used to examine the effects of reduced CERS2 activity on cel-lular lipid composition and plasma membrane functions. Results: We identify a novel 27 kb heterozygous deletion including the CERS2 gene in a proband diagnosed with PME. Compared to parental controls, levels of CERS2 mRNA, protein, and activity were reduced by ~50% in fibroblasts isolated from this proband, resulting in significantly reduced levels of ceramides and sphingomye-lins containing the very long-chain fatty acids C24:0 and C26:0. The change in SL composition was also reflected in a reduction in cholera toxin B immuno-fluorescence, indicating that membrane composition and function are altered. Interpretation: We propose that reduced levels of CERS2, and consequently diminished levels of ceramides and SLs containing very long-chain fatty acids, lead to development of PME.
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    ABSTRACT: Objective: Ceramides are precursors of complex sphingolipids (SLs), which are important for normal functioning of both the developing and mature brain. Altered SL levels have been associated with many neurodegenerative disorders, including epilepsy, although few direct links have been identified between genes involved in SL metabolism and epilepsy. Methods: We used quantitative real-time PCR, Western blotting, and enzymatic assays to determine the mRNA, protein, and activity levels of ceramide synthase 2 (CERS2) in fiibroblasts iso-lated from parental control subjects and from a patient diagnosed with progres-sive myoclonic epilepsy (PME). Mass spectrometry and fluorescence microscopy were used to examine the effects of reduced CERS2 activity on cel-lular lipid composition and plasma membrane functions. Results: We identify a novel 27 kb heterozygous deletion including the CERS2 gene in a proband diagnosed with PME. Compared to parental controls, levels of CERS2 mRNA, protein, and activity were reduced by ~50% in fibroblasts isolated from this proband, resulting in significantly reduced levels of ceramides and sphingomye-lins containing the very long-chain fatty acids C24:0 and C26:0. The change in SL composition was also reflected in a reduction in cholera toxin B immuno-fluorescence, indicating that membrane composition and function are altered. Interpretation: We propose that reduced levels of CERS2, and consequently diminished levels of ceramides and SLs containing very long-chain fatty acids, lead to development of PME.
    02/2014; 1(2):88-98. DOI:10.1002/acn3.28
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    ABSTRACT: Activation of caspase-6 in the striatum of both presymptomatic and affected persons with Huntington's disease (HD) is an early event in the disease pathogenesis. However, little is known about the role of caspase-6 outside the central nervous system (CNS) and whether caspase activation might play a role in the peripheral phenotypes, such as muscle wasting observed in HD. We assessed skeletal muscle tissue from HD patients and well-characterized mouse models of HD. Cleavage of the caspase-6 specific substrate lamin A is significantly increased in skeletal muscle obtained from HD patients as well as in muscle tissues from two different HD mouse models. p53, a transcriptional activator of caspase-6, is upregulated in neuronal cells and tissues expressing mutant huntingtin. Activation of p53 leads to a dramatic increase in levels of caspase-6 mRNA, caspase-6 activity and cleavage of lamin A. Using mouse embryonic fibroblasts (MEFs) from YAC128 mice, we show that this increase in caspase-6 activity can be mitigated by pifithrin-α (pifα), an inhibitor of p53 transcriptional activity, but not through the inhibition of p53's mitochondrial pro-apoptotic function. Remarkably, the p53-mediated increase in caspase-6 expression and activation is exacerbated in cells and tissues of both neuronal and peripheral origin expressing mutant huntingtin (Htt). These findings suggest that the presence of the mutant Htt protein enhances p53 activity and lowers the apoptotic threshold, which activates caspase-6. Furthermore, these results suggest that this pathway is activated both within and outside the CNS in HD and may contribute to both loss of CNS neurons and muscle atrophy.
    Human Molecular Genetics 09/2013; DOI:10.1093/hmg/ddt458 · 6.68 Impact Factor
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    ABSTRACT: Metabolic dysfunction and mitochondrial involvement are recognised as part of the pathology in Huntington's Disease (HD). Post-mortem examinations of the striatum from end-stage HD patients have shown a decrease in the in vitro activity of complexes II, III and IV of the electron transport system (ETS). In different models of HD, evidence of enzyme defects have been reported in complex II and complex IV using enzyme assays. However, such assays are highly variable and results have been inconsistent. We investigated the integrated ETS function ex vivo using a sensitive high-resolution respirometric (HRR) method. The O2 flux in a whole-cell sample combined with the addition of mitochondrial substrates, uncouplers and inhibitors enabled us to accurately quantitate the function of individual mitochondrial complexes in intact mitochondria, while retaining mitochondrial regulation and compensatory mechanisms. We used HRR to examine the mitochondrial function in striata from 12-week old R6/2 mice expressing exon 1 of human HTT with 130 CAG repeats. A significant reduction in complex II and complex IV flux control ratios was found in the R6/2 mouse striatum at 12 weeks of age compared to controls, confirming previous findings obtained with spectrophotometric enzyme assays.
    04/2013; 5. DOI:10.1371/currents.hd.d8917b4862929772c5a2f2a34ef1c201
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    ABSTRACT: AIMS: To investigate in prion diseases the in-situ localization of prion protein oligomers sharing a common epitope with amyloid oligomers involved in a range of neurodegenerative diseases. METHODS AND RESULTS: We performed immunohistochemistry on sporadic Creutzfeldt-Jakob disease (sCJD) (n = 9) and hereditary Gerstmann-Sträussler-Scheinker disease (GSS) (n = 1) specimens with the anti-oligomer antibody A11 to determine the localization of reactive species. We found that A11 reactivity in the sCJD specimens was localized to the cerebral and cerebellar cortices both in spongiform and adjacent, non-spongiform areas, reminiscent of multicentric or diffuse plaques. In the GSS specimens, we found that staining was closely associated with kuru-like plaques, and that A11-reactive species colocalized with protease-resistant prion protein (Prp(Sc) ). We also observed sporadic neuronal cytosolic staining in both types of specimen. CONCLUSIONS: We confirm that intracellular and extracellular A11-reactive species are present in situ in sCJD cases and GSS, and that immunoreactivity for A11 and Prp(Sc) overlaps. We argue that the A11-reactive species are indeed composed of oligomeric Prp(Sc) , and suggest that the toxic effects of Prp(Sc) oligomers could be related to the generic oligomeric conformation recognized by A11.
    Histopathology 01/2013; 62(7). DOI:10.1111/his.12097 · 3.30 Impact Factor
  • Journal of Neurology Neurosurgery & Psychiatry 08/2012; 83(Suppl 1):A11-A11. DOI:10.1136/jnnp-2012-303524.35 · 5.58 Impact Factor
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    ABSTRACT: 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.
    Journal of the neurological sciences 08/2012; 321(1-2):100-2. DOI:10.1016/j.jns.2012.07.036 · 2.26 Impact Factor
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    ABSTRACT: Frontotemporal dementia is the second most common form of young-onset dementia after Alzheimer's disease, and several genetic forms of frontotemporal dementia are known. A rare genetic variant is caused by a point mutation in the CHMP2B gene. CHMP2B is a component of the ESCRT-III complex, which is involved in endosomal trafficking of proteins targeted for degradation in lysosomes. Mutations in CHMP2B result in abnormal endosomal structures in patient fibroblasts and patient brains, probably through a gain-of-function mechanism, suggesting that the endosomal pathway plays a central role in the pathogenesis of the disease. In the present study, we used lentiviral vectors to efficiently knockdown CHMP2B by delivering microRNA embedded small hairpin RNAs. We show that CHMP2B can be efficiently knocked down in patient fibroblasts using an RNA interference approach and that the knockdown causes reversal of the abnormal endosomal phenotype observed in patient fibroblasts. This is the first description of a treatment that reverses the cellular pathology caused by mutant CHMP2B and suggests that RNA interference might be a feasible therapeutic strategy. Furthermore, it provides the first proof of a direct link between the disease-causing mutation and the cellular phenotype in cells originating from CHMP2B mutation patients.
    The Journal of Gene Medicine 08/2012; 14(8):521-9. DOI:10.1002/jgm.2649 · 1.95 Impact Factor
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    ABSTRACT: Fabry disease, an X-linked lysosomal storage disorder, results from the deficient activity of α-galactosidase A (α-Gal A). In affected males, the clinical diagnosis is confirmed by the markedly decreased α-Gal A activity. However, in female heterozygotes, the α-Gal A activity can range from low to normal due to random X-chromosomal inactivation, and diagnostic confirmation requires identification of the family's α-Gal A gene mutation. In a young female who had occasional acroparesthesias, corneal opacities, and 15 to 50% of the lower limit of normal leukocyte α-Gal A activity, α-Gal A sequencing in two expert laboratories did not identify a confirmatory mutation, presenting a diagnostic dilemma. A renal biopsy proved diagnostic and renewed efforts to detect an α-Gal A mutation. Subsequent gene dosage analyses identified a large α-Gal A deletion confirming her heterozygosity, and she was started on enzyme replacement therapy. Thus, gene dosage analyses can detect large deletions (>50bp) in suspect heterozygotes for X-linked and autosomal dominant diseases that are "sequencing cryptic," resolving molecular diagnostic dilemmas.
    Molecular Genetics and Metabolism 05/2011; 104(3):314-8. DOI:10.1016/j.ymgme.2011.05.008 · 2.83 Impact Factor
  • Parkinsonism & Related Disorders 02/2011; 17(5):398-9. DOI:10.1016/j.parkreldis.2011.01.016 · 4.13 Impact Factor
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    ABSTRACT: Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurodegenerative disease caused by an expanded CAG trinucleotide repeat in the SCA1 gene on chromosome 6. We screened 40 probands with ataxia for the CAG repeat expansion and found five probands with SCA1 representing five different families. The SCA1 gene was analysed in 50 members of these families, and the CAG repeat expansion was found in all 17 affected persons and in 14 unaffected at-risk individuals. The range of expansion was 41–53 repeat units, while the range of normal alleles was 22–36 repeat units. We found pronounced inter- and intrafamilial phenotypical variation. One of the families had a comparatively mild phenotype which correlates with a CAG repeat length in the low end of the range of expansions and a late age at onset. With few exceptions, normal alleles of the SCA1 gene have one to three CAT interruptions in the middle of the CAG repeat, while all expanded alleles are uninterrupted. We report the hitherto longest normal uninterrupted allele of 22 repeat units and stress the importance of analysis for the presence of CAT interruptions in the diagnosis of SCA1.
    European Journal of Neurology 01/2011; 4(6):586 - 592. DOI:10.1111/j.1468-1331.1997.tb00410.x · 3.85 Impact Factor
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    ABSTRACT: We studied systemic and brain glucose and lactate metabolism in Huntington's disease (HD) patients in response to ergometer cycling. Following termination of exercise, blood glucose increased abruptly in control subjects, but no peak was seen in any of the HD patients (2.0 ± 0.5 vs. 0.0 ± 0.2mM, P < 2 × 10(-6)). No difference was seen in brain metabolism parameters. Reduced hepatic glucose output in the HD mouse model R6/2 following a lactate challenge, combined with reduced phosphoenolpyruvate carboxykinase and increased pyruvate kinase activity in the mouse liver suggest a reduced capacity for gluconeogenesis in HD, possibly contributing to the clinical symptoms of HD. We propose that blood glucose concentration in the recovery from exercise can be applied as a liver function test in HD patients.
    Neurobiology of Disease 12/2010; 40(3):656-62. DOI:10.1016/j.nbd.2010.08.009 · 5.20 Impact Factor
  • NeuroImage 08/2010; 52. DOI:10.1016/j.neuroimage.2010.04.211 · 6.13 Impact Factor
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    ABSTRACT: Fabry disease, an X-linked storage disorder caused by defective lysosomal enzyme alpha-galactosidase A activity, may resemble sarcomere-gene-associated hypertrophic cardiomyopathy (HCM). The 'cardiac variant' of Fabry disease which only affects the heart may be missed unless specifically tested for. We evaluated 90 consecutively recruited HCM probands and their relatives. Probands without sarcomere-gene mutations were tested for alpha-galactosidase A gene (GLA) mutations. Of the 90 families, 31 (34%) had sarcomere gene mutations and were therefore excluded. In the remaining 59 probands, 3 (5%) had GLA mutations as follows. The first proband, a female with asymmetric septal hypertrophy (ASH), a significant left ventricular outflow tract gradient, and chronic obstructive pulmonary disease, was heterozygous for a novel missense mutation (p.N139S). The second proband, a male with ASH and multiple episodes of ventricular tachycardia, was hemizygous for a missense mutation (p.A156T). His daughter was heterozygous, but had normal enzyme activity. The third proband was a female with ASH, and no other indices of Fabry disease. She was heterozygous for a GLA missense mutation (p.G271S). She had one affected daughter but her two other children were unaffected. The affected daughter had three children, of whom two were also affected--a boy aged 8 and a daughter aged 10 years. This is the first report of systematic mutation screening of GLA in HCM patients without sarcomere gene mutations. GLA mutations were found in 3/90 (3%) of HCM families and in 2/20 (10%) of females without sarcomere-gene mutations. None of the probands presented other indices of Fabry disease. This, in combination with putative reversibility of cardiac changes by enzyme replacement therapy, supports systematic testing for Fabry disease. Enzyme measurements are sufficient in men, but genetic testing is needed in women.
    European Journal of Heart Failure 06/2010; 12(6):535-40. DOI:10.1093/eurjhf/hfq073 · 6.58 Impact Factor
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    ABSTRACT: Fabry disease is an X-linked inherited lysosomal disorder with dysfunction of the lysosomal enzyme alpha-galactosidase A causing accumulation of glycolipids in multiple organs including the nervous system. Pain and somatosensory disturbances are prominent manifestations of this disease. Until recently disease manifestations in female carriers of Fabry disease have been questioned. To explore the frequency of symptoms and the functional and structural involvement of the nervous system in female patients we examined the presence of pain, manifestations of peripheral neuropathy and nerve density in skin biopsies in 19 female patients with Fabry disease and 19 sex- and age-matched controls. Diaries, quantitative sensory testing, neurophysiologic tests and skin biopsies were performed. Daily pain was present in 63% of patients, with a median VAS score of 4.0. Tactile detection threshold and pressure pain threshold were lower and cold detection thresholds increased in patients. Sensory nerve action potential amplitude and maximal sensory conduction velocity were not different, whereas there was a highly significant reduction in intraepidermal nerve fiber density. We found no correlation between pain VAS score, quantitative sensory testing and intraepidermal nerve fiber density. Our study demonstrates that careful evaluation of symptoms in female Fabry patients is important as small fiber disease manifestations are present, which in some cases is only detected by skin biopsy.
    Pain 09/2009; 145(1-2):237-45. DOI:10.1016/j.pain.2009.06.032 · 5.84 Impact Factor
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    ABSTRACT: Fabry disease is a genetic lysosomal disorder with dysfunction of the lysosomal enzyme alpha-galactosidase A causing accumulation of glycolipids in multiple organs including the nervous system and with neuropathy as a prominent manifestation. Neurological symptoms include pain and autonomic dysfunction. This study examined peripheral autonomic nerve function in 19 female patients with Fabry disease and 19 sex and age-matched controls by measuring (1) sweat production following acetylcholine challenge; (2) the sympathetically mediated vasoconstrictor responses to inspiratory gasp, stress, and the cold pressor test; and (3) cutaneous blood flow following capsaicin. The vasoconstrictor response to inspiratory gasp was increased in Fabry patients compared to controls (p = 0.03), while the response to cold and mental stress did not change. Female patients with Fabry disease had a reduced sweat response to iontophoresis of acetylcholine (p = 0.04) and a smaller capsaicin-induced flare compared to controls. These findings suggest that female patients both have an impaired C-fiber function and local abnormalities in blood vessels and sweat glands.
    Journal of the Peripheral Nervous System 09/2009; 14(3):159-64. DOI:10.1111/j.1529-8027.2009.00227.x · 2.50 Impact Factor
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    ABSTRACT: Huntington's disease (HD) is an autosomal, dominantly inherited, neurodegenerative disorder characterised by neurological, cognitive and psychiatric symptoms. HD has been associated with diabetes mellitus, which is, to some extent, supported by studies in transgenic HD mice. In transgenic mice, the severity of the diabetic phenotype appears to correlate with the length of a polyglutamine expansion in the protein huntingtin. In the present study, we investigated the association between diabetes mellitus and HD by performing an oral glucose-tolerance test (OGTT) to evaluate the glucose-tolerance status and OGTT-related insulin release in 14 HD patients. Furthermore, we expressed N-terminal huntingtin fragments with different polyglutamine lengths in an insulinoma-cell line (INS-1E) to investigate how mutant huntingtin influences glucose-stimulated insulin release in vitro. We found no difference between a group of early- and middle-stage HD patients and a large group of control individuals in any of the assessed variables. However, the glucose-stimulated induction of insulin release was significantly reduced in the insulinoma-cell line expressing highly expanded huntingtin compared to cells expressing huntingtin with modestly elongated polyglutamine stretches. These data indicate that insulin release from beta-cells expressing mutant huntingtin appears to be polyglutamine length-dependent, and that polyglutamine lengths within the range normally found in adult onset HD do not influence insulin release. This challenges the assumption of an increased risk of diabetes among HD patients, although our results do not exclude a changed glucose tolerance in end-stage HD patients or in patients with juvenile onset HD. It also raises the question of which extent transgenic mice models reflect the pathology of human HD in this regard.
    Journal of Neuroendocrinology 08/2009; 21(9):770-6. DOI:10.1111/j.1365-2826.2009.01898.x · 3.51 Impact Factor
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    ABSTRACT: The autosomal dominant spinocerebellar ataxias, commonly referred to as SCAs, are clinically and genetically heterogeneous neurodegenerative disorders. Twenty-eight genetic subtypes have been identified, of which 7 are caused by expansion of a CAG trinucleotide repeat that encodes a polyglutamine tract in the respective proteins. SCA17 is caused by a CAG/CAA repeat expansion in the TATA box-binding protein-gene (TBP). In some cases the clinical phenotype of SCA17 overlaps that of Huntington's disease (HD), hence the use of the term Huntington's disease-like. We screened 89 patients with a Huntington's disease-like phenotype without the HD-gene mutation and 178 patients with genetically unclassified cerebellar ataxia for the mutation in TBP. A 33-year old woman presenting with an HD like phenotype with a de novo 54 CAG/CAA repeat expansion was identified. Her normal allele included 38 repeats. The patient's mother and father both carried normal range repeats, 38/38 and 33/39 respectively. Analysis of the repeat structures revealed that the expansion had occurred upon expansion of the longer paternal allele. We conclude that, however rare, SCA17 must be considered as a cause of Huntington's disease-like phenotypes and ataxia syndromes, also in isolated cases.
    Parkinsonism & Related Disorders 08/2009; 16(1):12-5. DOI:10.1016/j.parkreldis.2009.06.006 · 4.13 Impact Factor
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    ABSTRACT: Viral vectors have been used in several different settings for the delivery of small hairpin (sh) RNAs. However, most vectors have utilized ubiquitously-expressing polymerase (pol) III promoters to drive expression of the hairpin as a result of the strict requirement for precise transcriptional initiation and termination. Recently, pol II promoters have been used to construct vectors for RNA interference (RNAi). By embedding the shRNA into a micro RNA-context (miRNA) the endogenous miRNA processing machinery is exploited to achieve the mature synthetic miRNA (smiRNA), thereby expanding the possible promoter choices and eventually allowing cell type specific down-regulation of target genes. In the present study, we constructed lentiviral vectors expressing smiRNAs under the control of pol II promoters to knockdown gene expression in cell culture and in the brain. We demonstrate robust knockdown of green fluorescent protein using lentiviral vectors driving RNAi from the ubiquitously-expressing promoter of the cytomegalovirus (CMV) and, in addition, we show for the first time neuron-specific knockdown in the brain using a neuron-specific promoter. Furthermore, we show that the expression pattern of the presumed ubiquitously-expressing CMV promoter changes over time from being expressed initially in neurons and glial cells to being expressed almost exclusively in neurons in later stages. In the present study, we developed vectors for cell-specific RNAi for use in the brain. This offers the possibility of specifically targeting RNAi to a subset of cells in a complex tissue and may prove to be of great importance in the design of future gene therapeutic paradigms.
    The Journal of Gene Medicine 07/2009; 11(7):559-69. DOI:10.1002/jgm.1333 · 1.95 Impact Factor
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    ABSTRACT: 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.
    Journal of the neurological sciences 06/2009; 284(1-2):90-5. DOI:10.1016/j.jns.2009.04.024 · 2.26 Impact Factor

Publication Stats

862 Citations
271.19 Total Impact Points

Institutions

  • 1990–2013
    • IT University of Copenhagen
      København, Capital Region, Denmark
  • 1993
    • Ruhr-Universität Bochum
      Bochum, North Rhine-Westphalia, Germany
  • 1988
    • Institute of Sports Medicine Copenhagen
      København, Capital Region, Denmark