Agnieszka Ługowska | Institute of Psychiatry and Neurology (original) (raw)
Papers by Agnieszka Ługowska
Postępy Psychiatrii i Neurologii, 2019
Purpose: To assess the relationship between serum inflammatory markers (interleukin 6, high sensi... more Purpose: To assess the relationship between serum inflammatory markers (interleukin 6, high sensitivity C-reactive protein [hsCRP] and chitotriosidase activity) and the extent of carotid atherosclerotic lesions in subjects with various types of dementia. Methods: Four hundreds persons with dementia (166 diagnosed as probable Alzheimer's disease, 85 as vascular dementia [VaD], 149 as mixed dementia [MD] and 180 controls) were observed. In all persons carotid intima-media thickness (IMT) was measured and all were subjected to a general medical and neurological evaluation, neuroimaging examination (computed tomography and magnetic resonance) and comprehensive neuropsychological examination. The pro-inflammatory markers interleukin-6 (IL-6) and hsCRP, and anti-inflammatory markers (paraoxonase-1 activity and HDL cholesterol level), were determined in blood serum. Chitotriosidase activity-an indicator of chronic macrophage activation-was also determined. Results: A higher frequency of carotid atherosclerosis was observed in the whole group of dementia and in the VaD and MD groups as compared to the controls. A significant positive correlation of IMT with the inflammatory indicators IL-6 and hsCRP was found. A negative correlation of IMT with inflammatory markers (paraoxonase-1 activity and HDL cholesterol level) was observed. Chitotriosidase activity was significantly elevated, as compared with the controls, in the whole group with dementia and in the MD group, and depended on the degree of carotid stenosis. Conclusions: Serum IL-6, hsCRP and chitotriosidase activity can be considered as markers of the extent of carotid arteriosclerosis in dementia, especially in patients with dementia with vascular lesions. High chitotriosidase activity may indicate chronic macrophage activation in the course of dementia development.
PubMed, Oct 1, 1995
Inherited lysosomal storage disorders are caused by the deficiency or importantly lowered activit... more Inherited lysosomal storage disorders are caused by the deficiency or importantly lowered activity of one of the lysosomal enzymes, leading to the storage in the lysosomes the not degraded high-molecular substrates, among others: mucopolysaccharides, glycolipids, oligosaccharides and glycoproteins. Thin-layer chromatography of urine oligosaccharides allows reliable and fast diagnosis of some lysosomal storage disorders e.g. alpha-mannosidosis, fucosidosis, sialidosis, galactosialidosis, Schindler disease, GM1-gangliosidosis, GM2-gangliosidosis (Sandhoff type), Pompe disease, Salla disease, mucolipidosis II and III. We are presenting a modification of the Humbel and Collart's method of TLC of urine oligosaccharides. The principle of our modification is to introduce of the preliminary desalting step of the urine on the columns containing anionit BioRad AG 1 x 8 and cationit Dowex 50 x 8-200.
Gene, Sep 1, 2013
A case of late onset GM2 gangliosidodis with spinal muscular atrophy phenotype followed by cerebe... more A case of late onset GM2 gangliosidodis with spinal muscular atrophy phenotype followed by cerebellar and extrapyramidal symptoms is presented. Genetic analysis revealed compound heterozygous mutation in exon 10 of the HEXA gene. Patient has normal intelligence and emotional reactivity. Neuroimaging tests of the brain showed only cerebellar atrophy consistent with MR spectroscopy (MRS) abnormalities. (18) F-fluorodeoxyglucose positron emission tomography (18)F-FDG PET/CT of the brain revealed glucose hypometabolism in cerebellum and in temporal and occipital lobes bilaterally.
Analytical Biochemistry, May 1, 2017
Acid sphingomyelinase deficiency (ASMd, Niemann-Pick disease A/B) and Niemann-Pick type C disease... more Acid sphingomyelinase deficiency (ASMd, Niemann-Pick disease A/B) and Niemann-Pick type C disease (NPC) share core clinical symptoms. Initial diagnostic discrimination of these two rare lysosomal storage diseases is thus difficult. As sphingomyelin accumulates in ASMd as well as NPC, lysosphingomyelin (sphingosylphosphorylcholine) and its m/z 509 analog were suggested as biomarkers for both diseases. Herein we present results of simultaneous LC-ESI-MS/MS measurements of lysosphingomyelin and lysosphingomyelin 509 in plasma and dried blood spots (DBS) collected from ASMd and NPC patients and suggest that the plasma but not DBS levels of the two analytes allow differential biochemical screening of ASMd and NPC.
Metabolic Brain Disease, Dec 28, 2022
Ceroid lipofuscinosis type 3 (CLN3) is an autosomal recessive, neurodegenerative metabolic diseas... more Ceroid lipofuscinosis type 3 (CLN3) is an autosomal recessive, neurodegenerative metabolic disease. Typical clinical symptoms include progressive visual loss, epilepsy of unknown etiology and dementia. Presence of lipofuscin deposits with typical pattern of 'fingerprints' and vacuolized lymphocytes suggest the diagnosis of CLN3. Cause of CLN3 are mutations in the CLN3 gene, among which the most frequently found is the large deletion 1.02 kb spreading on exons 7 and 8. We present 4 patients from 2 families, in whom the deterioration of visual quality and acuity was observed as first clinical sign, when they were a few years old and it was successively accompanied by symptoms of neurologic deterioration (like generalized convulsions with consciousness impairment). In all patients the 1.02 kb deletion in the CLN3 gene was detected in homoor heterozygosity with other CLN3 pathogenic variant. Ultrastructural studies revealed abnormal structures corresponding to 'fingerprint' profiles (FPPs) in conjunctival endothelial cells. It should be emphasized that in patients with blindness of unknown cause the diagnosis of ceroid lipofuscinosis should be considered and in older children-especially CLN3. The facility of the analysis for the presence of 1.02 kb deletion and economic costs are a solid argument for intensive use of this test in the diagnostic procedure of CLN3.
Metabolic Brain Disease, Jun 13, 2019
Niemann-Pick type C disease (NPC) is a genetically determined neurodegenerative metabolic disease... more Niemann-Pick type C disease (NPC) is a genetically determined neurodegenerative metabolic disease resulting from the mutations in the NPC1 or NPC2 genes. It belongs to the lysosomal storage diseases and its main cause is impaired cholesterol transport in late endosomes or lysosomes. NPC is inherited in an autosomal recessive trait. Due to the wide range in age of onset, often unspecific clinical picture and varying dynamics of disease progression, the diagnosis is very difficult and long-lasting. The most characteristic visceral symptoms are hepato-or hepatosplenomegaly, which may appear independently of neurological or psychiatric symptoms at various stages of the disease. Available biochemical biomarkers should be tested as early as possible in patients presenting with hepato-or hepatosplenomegaly, long-lasting cholestatic jaundice in neonates or infantile patients, as well as in individuals at any age with: vertical supranuclear gaze palsy (VSGP), ataxia, dystonia, frontotemporal dementia and untreatable schizophrenia or psychosis. Research on biomarkers which can detect NPC patients (Cholestan-3β, 5α, 6β-triol, 7-ketocholesterol, lysosphingomyelin isoforms and bile acid metabolites) is still ongoing, although they are not specific for the NPC disease only. This mini review describes currently used diagnostic methods.
Progress in Neuro-psychopharmacology & Biological Psychiatry, Jul 1, 2019
The aim of this study was to assess the influence of chronic restraint stress on amphetamine (AMP... more The aim of this study was to assess the influence of chronic restraint stress on amphetamine (AMPH)related appetitive 50-kHz ultrasonic vocalisations (USVs) in rats differing in freezing duration in a contextual fear test (CFT), i.e. HR (high-anxiety responsive) and LR (low-anxiety responsive) rats. The LR and the HR rats, previously exposed to an AMPH binge experience, differed in sensitivity to AMPH's rewarding effects, measured as appetitive vocalisations. Moreover, chronic restraint stress attenuated AMPH-related appetitive vocalisations in the LR rats but had no influence on the HR rats' behaviour. To specify, the restraint LR rats vocalised appetitively less in the AMPH-associated context and after an AMPH challenge than the control LR rats. This phenomenon was associated with a decrease in the mRNA level for D2 dopamine receptor in the amygdala and its protein expression in the basal amygdala (BA) and opposite changes in the nucleus accumbens (NAc)-an increase in the mRNA level for D2 dopamine receptor and its protein expression in the NAc shell, compared to control conditions. Moreover, we observed that chronic restraint stress influenced epigenetic regulation in the LR and the HR rats differently. The contrasting changes were observed in the dentate gyrus (DG) of the hippocampus-the LR rats presented a decrease, but the HR rats showed an increase in H3K9 trimethylation. The restraint LR rats also showed higher miR-494 and miR-34c levels in the NAc than the control LR group. Our study provides behavioural and biochemical data concerning the role of differences in fear-conditioned response in stress vulnerability and AMPHassociated appetitive behaviour. The LR rats were less sensitive to the rewarding effects of AMPH when previously exposed to chronic stress that was accompanied by changes in D2 dopamine receptor expression and epigenetic regulation in mesolimbic areas.
Metabolic Brain Disease
Ceroid lipofuscinosis type 3 (CLN3) is an autosomal recessive, neurodegenerative metabolic diseas... more Ceroid lipofuscinosis type 3 (CLN3) is an autosomal recessive, neurodegenerative metabolic disease. Typical clinical symptoms include progressive visual loss, epilepsy of unknown etiology and dementia. Presence of lipofuscin deposits with typical pattern of ‘fingerprints’ and vacuolized lymphocytes suggest the diagnosis of CLN3. Cause of CLN3 are mutations in the CLN3 gene, among which the most frequently found is the large deletion 1.02 kb spreading on exons 7 and 8. We present 4 patients from 2 families, in whom the deterioration of visual quality and acuity was observed as first clinical sign, when they were a few years old and it was successively accompanied by symptoms of neurologic deterioration (like generalized convulsions with consciousness impairment). In all patients the 1.02 kb deletion in the CLN3 gene was detected in homo- or heterozygosity with other CLN3 pathogenic variant. Ultrastructural studies revealed abnormal structures corresponding to ‘fingerprint’ profiles (...
Microbios, 1990
From a heterogenous cell population of Caulobacter crescentus a deoxyribonucleoprotein fraction (... more From a heterogenous cell population of Caulobacter crescentus a deoxyribonucleoprotein fraction (DNP) was obtained by the modified technique of Sjåstad et al. (1982). Under the electron microscope DNP had a smooth fibrillar structure. The chemical properties of the proteins associated with the DNA were similar to those of other bacteria. An abundant, heat-stable, basic and DNA-binding protein, termed HCc, which has a molecular weight of 13.4 kD may be an analogue of the HU-histone-like protein from Escherichia coli.
PubMed, 2005
The metachromatic leukodystrophy (MLD)--causing mutation c.1204 + 1G > A damages an intron-exon s... more The metachromatic leukodystrophy (MLD)--causing mutation c.1204 + 1G > A damages an intron-exon splice site recognition sequence. This results in a complete loss of enzymatic activity of arylsulfatase A (ARSA) protein molecules. We have found a late-infantile type MLD-patient to be homozygous for this mutation, which was not reported earlier, but is consistent with previous suggestions. Interestingly, the cerebral magnetic resonance imaging (MRI) in this patient displayed linear or punctuate structures radiating in the demyelinated white matter, which resembled the patterns described in Pelizaeus-Merzbacher disease. It should be emphasised that whenever a cerebral MRI demonstrates the "tigroid" or "leopard-skin" demyelination pattern not only Pelizaeus-Merzbacher disease, but also metachromatic leukodystrophy diagnosis should be considered; this suggests the necessity of ARSA activity estimations in patients with such specific MRI patterns.
Gene, Sep 1, 2013
Metachromatic leukodystrophy (MLD) is a severe, neurodegenerative, metabolic disease which is cau... more Metachromatic leukodystrophy (MLD) is a severe, neurodegenerative, metabolic disease which is caused by deficient activity of arylsulfatase A (ARSA). Sulfatides and other substrates of ARSA are stored in central and peripheral nervous systems, and in some other organs. Accumulated sulfatides are especially toxic to oligodendrocytes and Schwann cells leading to progressive demyelination. The kind of apolipoprotein E (apoE) isoform is of essential significance for the modulation of sulfatide quantity in the brain as apoE4 contains more sulfatides than apoE3. Taking into consideration the fact that apoE4 leads to the loss of sulfatides in CSF of Alzheimer's disease patients, we examined if apoE isoforms display any impact on clinical outcome in patients with different forms of MLD in whom sulfatides accumulate. The significant association of age at the onset of MLD symptoms with APOE ε2/ε3/ε4 and LRP1 c.766C>T polymorphisms was shown in multivariate stepwise regression analysis, in which other factors known to affect age at onset of the disease, i.e. clinical type of MLD, family connection of the patient and sex were also analyzed. As expected, the clinical type of MLD explained about 80% of the variance of the dependent variable. The impact of both polymorphisms on age of onset of the disease was considerably lower: 2.0% in the case of APOE polymorphism and 1.0% in the case of LRP1 polymorphism. Thus, the clinical outcome in MLD patients is related principally to the genotype of the ARSA gene, while the polymorphisms in the APOE and LRP1 genes are only slightly modifying factors.
Clinical Genetics, Apr 12, 2005
The occurrence and genotype-phenotype correlations of the eight most common mutations in the aryl... more The occurrence and genotype-phenotype correlations of the eight most common mutations in the arylsulfatase A (ARSA) gene were studied in 43 unrelated Polish patients suffering from different types of metachromatic leukodystrophy (MLD). Screening for mutations p.R84Q, p.S96F, c.459+1G>A, p.I179S, p.A212V, c.1204+1G>A, p.P426L, and c.1401-1411del allowed the identification of 53.5% of the mutant alleles. In the whole investigated group of patients, mutations c.459+1G>A and p.P426L were the most frequent, 19 and 17%, respectively. The prevalence of the third most frequent mutation, i.e. p.I179S (13%), seems to be higher than that in other populations. The incidence of c.1204+1G>A was 5%, which is higher than reported earlier (2%). It seems that p.I179S and c.1204+1G>A are more prevalent in MLD patients from Poland than from other countries. In the group examined by us, mutations p.R84Q, p.S96F, p.A212V, and c.1401-1411del were not detected; thus, 46.5% of MLD alleles remained unidentified. This indicates that other, novel or already described, but rare, mutations exist in Polish population. In late infantile homozygotes for c.459+1G>A and one homozygote for c.1204+1G>A, first clinical symptom was motor deterioration. In adult homozygotes for p.P426L, the disease onset manifested as gait disturbances, followed by choreoathetotic movements, difficulties in swallowing, dysarthria, tremor, and nystagmus. In the carriers of the p.I179S mutation, the hallmark of the clinical picture was psychotic disturbances.
Clinical Genetics, Jun 28, 2008
Metachromatic leukodystrophy (MLD) is an autosomal, recessively inherited, lysosomal storage dise... more Metachromatic leukodystrophy (MLD) is an autosomal, recessively inherited, lysosomal storage disease caused by arylsulfatase A (ASA) activity deficit. Arylsulfatase A initiates the degradation of sulfatide (cerebroside sulfate), which is an essential component of myelin. The main clinical symptoms are caused by progressive demyelination. At least 34 MLD-related ASA mutations are known to date. I179S (E3P799) is a disease-related mutation, described for the first time by Fluharty in 1991. This aberration appears to substantially reduce, but not completely eliminate ASA activity, and was detected in individuals with late-onset (juvenile or adult) forms of MLD. This paper deals with the peculiar clinical course in three unrelated juveniles with late-onset MLD carrying the I179S mutations on one allele. In the three described patients with the I179S mutation, psychiatric disturbances and intellectual impairment dominated the clinical picture, while the neurological lesions progressed more slowly. Although the symptoms appeared rather early, making it possible to classify this as the juvenile type of MLD, the clinical picture was more that of the adult type. Although the mutations on the second allele in our patients are unknown, one can speculate, that the mutation I179S plays an important role in the characteristic clinical course (psychiatric impairment, slower neurological deterioration, but relatively early onset). It seems that I179S mutation on one allele with another mutation on the other allele reduces ASA activity, but the enzyme can still cope with a part of the substrate influx, leading to late-juvenile-onset MLD with such strikingly similar phenotypes remaining a little bit of the adult (psychiatric) type. This could be one more argument in favour of phenotype-genotype correlation in patients with MLD.
Clinical Biochemistry, Mar 1, 2000
PLOS ONE, Oct 30, 2015
The pathophysiological role of human chitinases and chitinase-like proteins (CLPs) is not fully u... more The pathophysiological role of human chitinases and chitinase-like proteins (CLPs) is not fully understood. We aimed to determine the levels of neutrophil-derived chitotriosidase (CHIT1), acidic mammalian chitinase (AMCase) and chitinase 3-like protein 1 (YKL-40) in patients with type 2 diabetes (T2D) and verify their association with metabolic and clinical conditions of these patients. Methods Neutrophils were obtained from the whole blood by gradient density centrifugation from 94 T2D patients and 40 control subjects. The activities of CHIT1 and AMCase as well as leukocyte elastase (LE) were measured fluorometrically and concentration of YKL-40 immunoenzymatically. Also, routine laboratory parameters in serum/plasma were determined by standard methods. Results The levels of all three examined proteins were about 2-times higher in diabetic patients in comparison to control subjects. They were significantly correlated with the activity of LE and increased progressively across tertiles of LE activity. Moreover, the activities of CHIT1 and AMCase were significantly correlated with each other. Metabolic compensation of diabetes did not influence the levels of these proteins. In the subgroup of patients with inflammatory evidence only YKL-40 concentration was significantly higher compared to those without inflammation. The highest levels of all three proteins were observed in patients with macroangiopathies. Insulin therapy was associated with lower levels of examined proteins.
Clinical Biochemistry, Jun 1, 1997
Use of sulfatide excretion in differentiating MLD/PD-heterozygotes from MLD-patients and PD/PD-ho... more Use of sulfatide excretion in differentiating MLD/PD-heterozygotes from MLD-patients and PD/PD-homozygotes. Sulfatide was extracted from urine sediment with chlorotom/methanol (2:1, v/v). The quantity of sulfatide was measured densitometrically (lambda = 580 nm) after thin-layer chromatography. ASA and beta-galactosidase activities were assayed enzymatically. MLD/PD-heterozygotes excreted sulfatide in the range of 4.8-36.3 nmol/mg lipid (mean +/- SD = 17.8 +/- 10.7), whereas sulfatide in MLD-patients ranged from 74.3-411.6 nmol/mg lipid (mean +/- SD = 184.5 +/- 130.8) and in PD/PD-hormozygotes sulfatide excretion remained in normal range of 0.0-5.9 nmol/mg lipid (mean +/- SD = 1.64 +/- 2.12). ASA activities in these groups were very low or lowered. The quantitative measurement of sulfatide in urine allows differentiation between MLD/PD-heterozygotes and MLD-heterozygotes, as well as between MLD/PD-heterozygotes with very low ASA activity and MLD-patients or PD/PD-hormozygotes. The quantitative measurement of sulfatide in urine differs between MLD-carriers and controls.
Clinical Genetics, Oct 7, 2007
Gaucher disease is generally caused by a deficiency of the lysosomal enzyme glucocerebrosidase. T... more Gaucher disease is generally caused by a deficiency of the lysosomal enzyme glucocerebrosidase. The degradation of glycosphingolipids requires also the participation of sphingolipid activator proteins. The prosaposin PSAP gene codes for a single protein which undergoes post‐translational cleavage to yield four proteins named saposins A, B, C and D. Saposin (SAP‐) C is required for glucosylceramide degradation, and its deficiency results in a variant form of Gaucher disease. In this report, we present clinical, biochemical, and molecular findings in a 36‐year‐old man and his 30‐year‐old sister with non‐neuronopathic Gaucher disease due to SAP‐C deficiency. Very high levels of chitotriosidase activity, chemokine CCL18, and increased concentration of glucosylceramide in plasma and normal β‐glucosidase activity in skin fibroblasts were observed in the patients. A molecular genetics study of the PSAP gene enabled the identification of one missense mutation, p.L349P, located in the SAP‐C domain and another mutation, p.M1L, located in the initiation codon of the prosaposin precursor protein. The presented findings describe the first cases where the non‐neuronopathic Gaucher disease has been definitely demonstrated to be a consequence of SAP‐C deficiency. Three previously described cases in the literature displayed a Gaucher type 3 phenotype.
Pediatria polska, Feb 1, 2013
Postępy Psychiatrii i Neurologii, 2019
Purpose: To assess the relationship between serum inflammatory markers (interleukin 6, high sensi... more Purpose: To assess the relationship between serum inflammatory markers (interleukin 6, high sensitivity C-reactive protein [hsCRP] and chitotriosidase activity) and the extent of carotid atherosclerotic lesions in subjects with various types of dementia. Methods: Four hundreds persons with dementia (166 diagnosed as probable Alzheimer's disease, 85 as vascular dementia [VaD], 149 as mixed dementia [MD] and 180 controls) were observed. In all persons carotid intima-media thickness (IMT) was measured and all were subjected to a general medical and neurological evaluation, neuroimaging examination (computed tomography and magnetic resonance) and comprehensive neuropsychological examination. The pro-inflammatory markers interleukin-6 (IL-6) and hsCRP, and anti-inflammatory markers (paraoxonase-1 activity and HDL cholesterol level), were determined in blood serum. Chitotriosidase activity-an indicator of chronic macrophage activation-was also determined. Results: A higher frequency of carotid atherosclerosis was observed in the whole group of dementia and in the VaD and MD groups as compared to the controls. A significant positive correlation of IMT with the inflammatory indicators IL-6 and hsCRP was found. A negative correlation of IMT with inflammatory markers (paraoxonase-1 activity and HDL cholesterol level) was observed. Chitotriosidase activity was significantly elevated, as compared with the controls, in the whole group with dementia and in the MD group, and depended on the degree of carotid stenosis. Conclusions: Serum IL-6, hsCRP and chitotriosidase activity can be considered as markers of the extent of carotid arteriosclerosis in dementia, especially in patients with dementia with vascular lesions. High chitotriosidase activity may indicate chronic macrophage activation in the course of dementia development.
PubMed, Oct 1, 1995
Inherited lysosomal storage disorders are caused by the deficiency or importantly lowered activit... more Inherited lysosomal storage disorders are caused by the deficiency or importantly lowered activity of one of the lysosomal enzymes, leading to the storage in the lysosomes the not degraded high-molecular substrates, among others: mucopolysaccharides, glycolipids, oligosaccharides and glycoproteins. Thin-layer chromatography of urine oligosaccharides allows reliable and fast diagnosis of some lysosomal storage disorders e.g. alpha-mannosidosis, fucosidosis, sialidosis, galactosialidosis, Schindler disease, GM1-gangliosidosis, GM2-gangliosidosis (Sandhoff type), Pompe disease, Salla disease, mucolipidosis II and III. We are presenting a modification of the Humbel and Collart's method of TLC of urine oligosaccharides. The principle of our modification is to introduce of the preliminary desalting step of the urine on the columns containing anionit BioRad AG 1 x 8 and cationit Dowex 50 x 8-200.
Gene, Sep 1, 2013
A case of late onset GM2 gangliosidodis with spinal muscular atrophy phenotype followed by cerebe... more A case of late onset GM2 gangliosidodis with spinal muscular atrophy phenotype followed by cerebellar and extrapyramidal symptoms is presented. Genetic analysis revealed compound heterozygous mutation in exon 10 of the HEXA gene. Patient has normal intelligence and emotional reactivity. Neuroimaging tests of the brain showed only cerebellar atrophy consistent with MR spectroscopy (MRS) abnormalities. (18) F-fluorodeoxyglucose positron emission tomography (18)F-FDG PET/CT of the brain revealed glucose hypometabolism in cerebellum and in temporal and occipital lobes bilaterally.
Analytical Biochemistry, May 1, 2017
Acid sphingomyelinase deficiency (ASMd, Niemann-Pick disease A/B) and Niemann-Pick type C disease... more Acid sphingomyelinase deficiency (ASMd, Niemann-Pick disease A/B) and Niemann-Pick type C disease (NPC) share core clinical symptoms. Initial diagnostic discrimination of these two rare lysosomal storage diseases is thus difficult. As sphingomyelin accumulates in ASMd as well as NPC, lysosphingomyelin (sphingosylphosphorylcholine) and its m/z 509 analog were suggested as biomarkers for both diseases. Herein we present results of simultaneous LC-ESI-MS/MS measurements of lysosphingomyelin and lysosphingomyelin 509 in plasma and dried blood spots (DBS) collected from ASMd and NPC patients and suggest that the plasma but not DBS levels of the two analytes allow differential biochemical screening of ASMd and NPC.
Metabolic Brain Disease, Dec 28, 2022
Ceroid lipofuscinosis type 3 (CLN3) is an autosomal recessive, neurodegenerative metabolic diseas... more Ceroid lipofuscinosis type 3 (CLN3) is an autosomal recessive, neurodegenerative metabolic disease. Typical clinical symptoms include progressive visual loss, epilepsy of unknown etiology and dementia. Presence of lipofuscin deposits with typical pattern of 'fingerprints' and vacuolized lymphocytes suggest the diagnosis of CLN3. Cause of CLN3 are mutations in the CLN3 gene, among which the most frequently found is the large deletion 1.02 kb spreading on exons 7 and 8. We present 4 patients from 2 families, in whom the deterioration of visual quality and acuity was observed as first clinical sign, when they were a few years old and it was successively accompanied by symptoms of neurologic deterioration (like generalized convulsions with consciousness impairment). In all patients the 1.02 kb deletion in the CLN3 gene was detected in homoor heterozygosity with other CLN3 pathogenic variant. Ultrastructural studies revealed abnormal structures corresponding to 'fingerprint' profiles (FPPs) in conjunctival endothelial cells. It should be emphasized that in patients with blindness of unknown cause the diagnosis of ceroid lipofuscinosis should be considered and in older children-especially CLN3. The facility of the analysis for the presence of 1.02 kb deletion and economic costs are a solid argument for intensive use of this test in the diagnostic procedure of CLN3.
Metabolic Brain Disease, Jun 13, 2019
Niemann-Pick type C disease (NPC) is a genetically determined neurodegenerative metabolic disease... more Niemann-Pick type C disease (NPC) is a genetically determined neurodegenerative metabolic disease resulting from the mutations in the NPC1 or NPC2 genes. It belongs to the lysosomal storage diseases and its main cause is impaired cholesterol transport in late endosomes or lysosomes. NPC is inherited in an autosomal recessive trait. Due to the wide range in age of onset, often unspecific clinical picture and varying dynamics of disease progression, the diagnosis is very difficult and long-lasting. The most characteristic visceral symptoms are hepato-or hepatosplenomegaly, which may appear independently of neurological or psychiatric symptoms at various stages of the disease. Available biochemical biomarkers should be tested as early as possible in patients presenting with hepato-or hepatosplenomegaly, long-lasting cholestatic jaundice in neonates or infantile patients, as well as in individuals at any age with: vertical supranuclear gaze palsy (VSGP), ataxia, dystonia, frontotemporal dementia and untreatable schizophrenia or psychosis. Research on biomarkers which can detect NPC patients (Cholestan-3β, 5α, 6β-triol, 7-ketocholesterol, lysosphingomyelin isoforms and bile acid metabolites) is still ongoing, although they are not specific for the NPC disease only. This mini review describes currently used diagnostic methods.
Progress in Neuro-psychopharmacology & Biological Psychiatry, Jul 1, 2019
The aim of this study was to assess the influence of chronic restraint stress on amphetamine (AMP... more The aim of this study was to assess the influence of chronic restraint stress on amphetamine (AMPH)related appetitive 50-kHz ultrasonic vocalisations (USVs) in rats differing in freezing duration in a contextual fear test (CFT), i.e. HR (high-anxiety responsive) and LR (low-anxiety responsive) rats. The LR and the HR rats, previously exposed to an AMPH binge experience, differed in sensitivity to AMPH's rewarding effects, measured as appetitive vocalisations. Moreover, chronic restraint stress attenuated AMPH-related appetitive vocalisations in the LR rats but had no influence on the HR rats' behaviour. To specify, the restraint LR rats vocalised appetitively less in the AMPH-associated context and after an AMPH challenge than the control LR rats. This phenomenon was associated with a decrease in the mRNA level for D2 dopamine receptor in the amygdala and its protein expression in the basal amygdala (BA) and opposite changes in the nucleus accumbens (NAc)-an increase in the mRNA level for D2 dopamine receptor and its protein expression in the NAc shell, compared to control conditions. Moreover, we observed that chronic restraint stress influenced epigenetic regulation in the LR and the HR rats differently. The contrasting changes were observed in the dentate gyrus (DG) of the hippocampus-the LR rats presented a decrease, but the HR rats showed an increase in H3K9 trimethylation. The restraint LR rats also showed higher miR-494 and miR-34c levels in the NAc than the control LR group. Our study provides behavioural and biochemical data concerning the role of differences in fear-conditioned response in stress vulnerability and AMPHassociated appetitive behaviour. The LR rats were less sensitive to the rewarding effects of AMPH when previously exposed to chronic stress that was accompanied by changes in D2 dopamine receptor expression and epigenetic regulation in mesolimbic areas.
Metabolic Brain Disease
Ceroid lipofuscinosis type 3 (CLN3) is an autosomal recessive, neurodegenerative metabolic diseas... more Ceroid lipofuscinosis type 3 (CLN3) is an autosomal recessive, neurodegenerative metabolic disease. Typical clinical symptoms include progressive visual loss, epilepsy of unknown etiology and dementia. Presence of lipofuscin deposits with typical pattern of ‘fingerprints’ and vacuolized lymphocytes suggest the diagnosis of CLN3. Cause of CLN3 are mutations in the CLN3 gene, among which the most frequently found is the large deletion 1.02 kb spreading on exons 7 and 8. We present 4 patients from 2 families, in whom the deterioration of visual quality and acuity was observed as first clinical sign, when they were a few years old and it was successively accompanied by symptoms of neurologic deterioration (like generalized convulsions with consciousness impairment). In all patients the 1.02 kb deletion in the CLN3 gene was detected in homo- or heterozygosity with other CLN3 pathogenic variant. Ultrastructural studies revealed abnormal structures corresponding to ‘fingerprint’ profiles (...
Microbios, 1990
From a heterogenous cell population of Caulobacter crescentus a deoxyribonucleoprotein fraction (... more From a heterogenous cell population of Caulobacter crescentus a deoxyribonucleoprotein fraction (DNP) was obtained by the modified technique of Sjåstad et al. (1982). Under the electron microscope DNP had a smooth fibrillar structure. The chemical properties of the proteins associated with the DNA were similar to those of other bacteria. An abundant, heat-stable, basic and DNA-binding protein, termed HCc, which has a molecular weight of 13.4 kD may be an analogue of the HU-histone-like protein from Escherichia coli.
PubMed, 2005
The metachromatic leukodystrophy (MLD)--causing mutation c.1204 + 1G > A damages an intron-exon s... more The metachromatic leukodystrophy (MLD)--causing mutation c.1204 + 1G > A damages an intron-exon splice site recognition sequence. This results in a complete loss of enzymatic activity of arylsulfatase A (ARSA) protein molecules. We have found a late-infantile type MLD-patient to be homozygous for this mutation, which was not reported earlier, but is consistent with previous suggestions. Interestingly, the cerebral magnetic resonance imaging (MRI) in this patient displayed linear or punctuate structures radiating in the demyelinated white matter, which resembled the patterns described in Pelizaeus-Merzbacher disease. It should be emphasised that whenever a cerebral MRI demonstrates the "tigroid" or "leopard-skin" demyelination pattern not only Pelizaeus-Merzbacher disease, but also metachromatic leukodystrophy diagnosis should be considered; this suggests the necessity of ARSA activity estimations in patients with such specific MRI patterns.
Gene, Sep 1, 2013
Metachromatic leukodystrophy (MLD) is a severe, neurodegenerative, metabolic disease which is cau... more Metachromatic leukodystrophy (MLD) is a severe, neurodegenerative, metabolic disease which is caused by deficient activity of arylsulfatase A (ARSA). Sulfatides and other substrates of ARSA are stored in central and peripheral nervous systems, and in some other organs. Accumulated sulfatides are especially toxic to oligodendrocytes and Schwann cells leading to progressive demyelination. The kind of apolipoprotein E (apoE) isoform is of essential significance for the modulation of sulfatide quantity in the brain as apoE4 contains more sulfatides than apoE3. Taking into consideration the fact that apoE4 leads to the loss of sulfatides in CSF of Alzheimer's disease patients, we examined if apoE isoforms display any impact on clinical outcome in patients with different forms of MLD in whom sulfatides accumulate. The significant association of age at the onset of MLD symptoms with APOE ε2/ε3/ε4 and LRP1 c.766C>T polymorphisms was shown in multivariate stepwise regression analysis, in which other factors known to affect age at onset of the disease, i.e. clinical type of MLD, family connection of the patient and sex were also analyzed. As expected, the clinical type of MLD explained about 80% of the variance of the dependent variable. The impact of both polymorphisms on age of onset of the disease was considerably lower: 2.0% in the case of APOE polymorphism and 1.0% in the case of LRP1 polymorphism. Thus, the clinical outcome in MLD patients is related principally to the genotype of the ARSA gene, while the polymorphisms in the APOE and LRP1 genes are only slightly modifying factors.
Clinical Genetics, Apr 12, 2005
The occurrence and genotype-phenotype correlations of the eight most common mutations in the aryl... more The occurrence and genotype-phenotype correlations of the eight most common mutations in the arylsulfatase A (ARSA) gene were studied in 43 unrelated Polish patients suffering from different types of metachromatic leukodystrophy (MLD). Screening for mutations p.R84Q, p.S96F, c.459+1G>A, p.I179S, p.A212V, c.1204+1G>A, p.P426L, and c.1401-1411del allowed the identification of 53.5% of the mutant alleles. In the whole investigated group of patients, mutations c.459+1G>A and p.P426L were the most frequent, 19 and 17%, respectively. The prevalence of the third most frequent mutation, i.e. p.I179S (13%), seems to be higher than that in other populations. The incidence of c.1204+1G>A was 5%, which is higher than reported earlier (2%). It seems that p.I179S and c.1204+1G>A are more prevalent in MLD patients from Poland than from other countries. In the group examined by us, mutations p.R84Q, p.S96F, p.A212V, and c.1401-1411del were not detected; thus, 46.5% of MLD alleles remained unidentified. This indicates that other, novel or already described, but rare, mutations exist in Polish population. In late infantile homozygotes for c.459+1G>A and one homozygote for c.1204+1G>A, first clinical symptom was motor deterioration. In adult homozygotes for p.P426L, the disease onset manifested as gait disturbances, followed by choreoathetotic movements, difficulties in swallowing, dysarthria, tremor, and nystagmus. In the carriers of the p.I179S mutation, the hallmark of the clinical picture was psychotic disturbances.
Clinical Genetics, Jun 28, 2008
Metachromatic leukodystrophy (MLD) is an autosomal, recessively inherited, lysosomal storage dise... more Metachromatic leukodystrophy (MLD) is an autosomal, recessively inherited, lysosomal storage disease caused by arylsulfatase A (ASA) activity deficit. Arylsulfatase A initiates the degradation of sulfatide (cerebroside sulfate), which is an essential component of myelin. The main clinical symptoms are caused by progressive demyelination. At least 34 MLD-related ASA mutations are known to date. I179S (E3P799) is a disease-related mutation, described for the first time by Fluharty in 1991. This aberration appears to substantially reduce, but not completely eliminate ASA activity, and was detected in individuals with late-onset (juvenile or adult) forms of MLD. This paper deals with the peculiar clinical course in three unrelated juveniles with late-onset MLD carrying the I179S mutations on one allele. In the three described patients with the I179S mutation, psychiatric disturbances and intellectual impairment dominated the clinical picture, while the neurological lesions progressed more slowly. Although the symptoms appeared rather early, making it possible to classify this as the juvenile type of MLD, the clinical picture was more that of the adult type. Although the mutations on the second allele in our patients are unknown, one can speculate, that the mutation I179S plays an important role in the characteristic clinical course (psychiatric impairment, slower neurological deterioration, but relatively early onset). It seems that I179S mutation on one allele with another mutation on the other allele reduces ASA activity, but the enzyme can still cope with a part of the substrate influx, leading to late-juvenile-onset MLD with such strikingly similar phenotypes remaining a little bit of the adult (psychiatric) type. This could be one more argument in favour of phenotype-genotype correlation in patients with MLD.
Clinical Biochemistry, Mar 1, 2000
PLOS ONE, Oct 30, 2015
The pathophysiological role of human chitinases and chitinase-like proteins (CLPs) is not fully u... more The pathophysiological role of human chitinases and chitinase-like proteins (CLPs) is not fully understood. We aimed to determine the levels of neutrophil-derived chitotriosidase (CHIT1), acidic mammalian chitinase (AMCase) and chitinase 3-like protein 1 (YKL-40) in patients with type 2 diabetes (T2D) and verify their association with metabolic and clinical conditions of these patients. Methods Neutrophils were obtained from the whole blood by gradient density centrifugation from 94 T2D patients and 40 control subjects. The activities of CHIT1 and AMCase as well as leukocyte elastase (LE) were measured fluorometrically and concentration of YKL-40 immunoenzymatically. Also, routine laboratory parameters in serum/plasma were determined by standard methods. Results The levels of all three examined proteins were about 2-times higher in diabetic patients in comparison to control subjects. They were significantly correlated with the activity of LE and increased progressively across tertiles of LE activity. Moreover, the activities of CHIT1 and AMCase were significantly correlated with each other. Metabolic compensation of diabetes did not influence the levels of these proteins. In the subgroup of patients with inflammatory evidence only YKL-40 concentration was significantly higher compared to those without inflammation. The highest levels of all three proteins were observed in patients with macroangiopathies. Insulin therapy was associated with lower levels of examined proteins.
Clinical Biochemistry, Jun 1, 1997
Use of sulfatide excretion in differentiating MLD/PD-heterozygotes from MLD-patients and PD/PD-ho... more Use of sulfatide excretion in differentiating MLD/PD-heterozygotes from MLD-patients and PD/PD-homozygotes. Sulfatide was extracted from urine sediment with chlorotom/methanol (2:1, v/v). The quantity of sulfatide was measured densitometrically (lambda = 580 nm) after thin-layer chromatography. ASA and beta-galactosidase activities were assayed enzymatically. MLD/PD-heterozygotes excreted sulfatide in the range of 4.8-36.3 nmol/mg lipid (mean +/- SD = 17.8 +/- 10.7), whereas sulfatide in MLD-patients ranged from 74.3-411.6 nmol/mg lipid (mean +/- SD = 184.5 +/- 130.8) and in PD/PD-hormozygotes sulfatide excretion remained in normal range of 0.0-5.9 nmol/mg lipid (mean +/- SD = 1.64 +/- 2.12). ASA activities in these groups were very low or lowered. The quantitative measurement of sulfatide in urine allows differentiation between MLD/PD-heterozygotes and MLD-heterozygotes, as well as between MLD/PD-heterozygotes with very low ASA activity and MLD-patients or PD/PD-hormozygotes. The quantitative measurement of sulfatide in urine differs between MLD-carriers and controls.
Clinical Genetics, Oct 7, 2007
Gaucher disease is generally caused by a deficiency of the lysosomal enzyme glucocerebrosidase. T... more Gaucher disease is generally caused by a deficiency of the lysosomal enzyme glucocerebrosidase. The degradation of glycosphingolipids requires also the participation of sphingolipid activator proteins. The prosaposin PSAP gene codes for a single protein which undergoes post‐translational cleavage to yield four proteins named saposins A, B, C and D. Saposin (SAP‐) C is required for glucosylceramide degradation, and its deficiency results in a variant form of Gaucher disease. In this report, we present clinical, biochemical, and molecular findings in a 36‐year‐old man and his 30‐year‐old sister with non‐neuronopathic Gaucher disease due to SAP‐C deficiency. Very high levels of chitotriosidase activity, chemokine CCL18, and increased concentration of glucosylceramide in plasma and normal β‐glucosidase activity in skin fibroblasts were observed in the patients. A molecular genetics study of the PSAP gene enabled the identification of one missense mutation, p.L349P, located in the SAP‐C domain and another mutation, p.M1L, located in the initiation codon of the prosaposin precursor protein. The presented findings describe the first cases where the non‐neuronopathic Gaucher disease has been definitely demonstrated to be a consequence of SAP‐C deficiency. Three previously described cases in the literature displayed a Gaucher type 3 phenotype.
Pediatria polska, Feb 1, 2013