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LITAF and TNF alpha genes sequence variants in the patients with Charcot-Marie-Tooth disease

100%

Sinkiewicz-Darol E., Potulska-Chromik A., Kostera-Pruszczyk A., Kabzinska D., Kochanski A.

Acta Neurobiologiae Experimentalis

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2011

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tom 71

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nr 1

Recently it has been reported that Charcot-Marie-Tooth disease may coexist with chronic inflammatory neuropathy and central demyelination. There is a question, whether CMT and inflammatory disease detected in one family share a common pathogenesis or result from the random coincidence of two disorders. There is a possibility that mutations/sequence variants in the gene coding for immune response mediators (LITAF, TNF alpha) may modify the CMT phenotype. To test this hypothesis, we have sequenced the coding sequence of LITAF gene and the promoter sequence of TNF alpha gene in two families with Charcot-Marie-Tooth disease coexisting with chronic inflammatory demyelinating polyneuropathy (CIDP) and primary progressive multiple sclerosis (PPMS). The genetic analysis has revealed three sequence variants: c.274A>G (Ile92Val) and in c.334G>A (Gly112Ser) in the LITAF gene and one SNP -308G>A in the promoter region of TNF alpha gene. The sequence variants c.334G>A (Gly112Ser) in the LITAF gene and -308G>A in the TNF alpha gene were detected in family with Charcot-Marie-Tooth type 1C and primary progressive multiple sclerosis (PPMS). The sequence variants c.274A>G (Ile92Val) in the LITAF gene and -308G>A in the TNF alpha gene were detected in family with Charcot-Marie-Tooth type 1A and chronic inflammatory polyradiculoneuropathy (CIDP). In agreement with previously published data we suggest that the sequence variants in the genes coding for inflammatory mediators may contribute to the clinical variability of CMT.

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How accurate is spirometry at predicting restrictive pulmonary impairment in children with myasthenia gravis

100%

Zielonka T., Kostera-Pruszczyk A., Ryniewicz B., Korczynski P., Szyluk B.

Journal of Physiology and Pharmacology. Supplement

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2006

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tom 57

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nr 4

409-416

Myasthenia gravis (MG) is an autoimmune disorder of the neuromuscular junction. Clinical symptoms are caused by weakness and increased fatigability of various muscle groups. Myasthenia may lead to significant respiratory dysfunction. The aim of our study was to estimate lung function in children with MG. We tested 23 non-smoking patients (18 girls and 5 boys) aged 7-18 years. Whole-body plethysmography and spirometry were performed in all patients. In 33% of the patients a decrease in VC <80% of predicted value was observed (VC = 89 ±19%), but the analysis of TLC revealed restrictive pattern only in one patient (TLC = 102 ±17%). In more than 75% of the children the value of RV above 120% of predicted value was found (RV = 146 ±54%). Spirometric obstructive pattern measured by FEV1%VC <70% was not observed, although in 56% of the patients airway resistance was increased (Raw = 132 ±44%). In 45% of the patients a decrease of PEF (76 ±14%) was observed. In MG children true restrictive pulmonary impairment is rarely observed and a decrease in VC in these patents seems to result mainly from functional restriction provoked by an increase in RV. Spirometry is not an optimum method to assess functional changes in MG patients. The assessment of additional measures such as TLC, RV, and Raw is desirable.

3

A novel homozygous mutation in the WNK1/HSN2 gene causing hereditary sensory neuropathy type 2

100%

Potulska-Chromik A., Kabzinska D., Lipowska M., Kostera-Pruszczyk A., Kochanski A.

Acta Biochimica Polonica

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2012

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tom 59

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nr 3

Hereditary sensory and autonomic neuropathy type 2 is a rare disorder caused by recessive mutations in the WNK1/HSN2 gene located on chromosome 12p13.33. Phenotype of the patients is characterized by severe sensory loss affecting all sensory modalities. We report a novel homozygous Lys179fsX182 (HSN2); Lys965fsX968 (WNK1/HSN2) mutation causing an early childhood onset hereditary sensory and autonomic neuropathy type 2, with acromutilations in upper and lower limbs, and autonomic dysfunction. To the best of our knowledge this is the first genetically proven case of hereditary sensory and autonomic neuropathy type 2 originating from East Europe.

4

Chronic progressive external ophthalmoplegia in Polish patients – clinical and genetic characteristics

86%

Kierdaszuk B., Kaliszewska M., Tonska K., Bartnik E., Kaminska A. M., Kostera-Pruszczyk A.

Acta Neurobiologiae Experimentalis

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2017

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tom 77

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nr Suppl.1

INTRODUCTION: Mitochondrial encephalomyopathies comprise a group of heterogeneous disorders which may result from mutations in mitochondrial (mtDNA) and nuclear genome (nDNA). From a variety of symptoms progressive external ophthalmoplegia (PEO) seems to be the most common. AIM(S): The aim of this study was the clinical and genetic characteristics of Polish patients with progressive external ophthalmoplegia. METHOD(S): Clinical, electrophysiological, neuroradiological and morphological data of 45 patients aged 11 to 76 years were analyzed. Genetic studies of mtDNA were performed in all patients. Among nDNA genes POLG was studied in 15 and C10orf2 in 6 patients. RESULTS: 16 patients with ptosis and PEO were included to chronic progressive external ophthalmoplegia (CPEO) group and 13 with ptosis, PEO and limb or trunk muscles’ weakness to CPEO+ group. There were 11 patients with PEO and the central nervous system impairment classified as mitochondrial encephalomyopathy (ME), 4 patients with Kearns-Sayre syndrome (KSS) and one patient with sensory ataxic neuropathy, dysarthria, ophthalmoparesis (SANDO) syndrome. Genetic studies of mtDNA revealed already known single or multiple mtDNA deletions in all patients and in most cases they were detected in the muscle tissue. Genetic analysis of nDNA genes confirmed mutations in POLG gene in 6 patients. There were 3 CPEO patients with p.[Arg309Leu];[Gln968Glu], p.[Ala518Thr];[=] and p.[Trp748Ser];[Ser998Pro] mutations, and 2 CPEO+ patients with p.[Thr251Ile;Pro587Leu];[Thr251Ile;Pro587Leu] and p.[Thr251Ile;Pro587Leu];[Lys1191Asn] mutations. In patient with SANDO syndrome the mutation p.[Arg290Cys];[Arg309Cys] in POLG gene was confirmed. Additionally the analysis of the C10orf2 gene proved the mutation p.[Arg374Gln];[=] in one CPEO patient CONCLUSIONS: Genetic studies of both mtDNA and nDNA are necessary for diagnosis of chronic progressive external ophthalmoplegia and its genetic counseling.

5

Sympathetic skin response in obstructive sleep apnea syndrome

86%

Zakrzewska-Pniewska B., Przybylowski T., Byskiniewicz K., Kostera-Pruszczyk A., Droszcz W., Emeryk-Szajewska B.

Acta Neurobiologiae Experimentalis

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1998

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tom 58

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nr 2

6

Phenotype modifiers of spinal muscular atrophy: the number of SMN2 gene copies, deletion in the NAIP gene and probably gender influence the course of the disease

72%

Jedrzejowska M., Milewski M., Zimowski J., Borkowska J., Kostera-Pruszczyk A., Sielska D., Jurek M., Hausmanowa-Petrusewicz I.

Acta Biochimica Polonica

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2009

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tom 56

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nr 1

103-108

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder caused by mutations of the SMN1 gene. It is characterized by significant phenotype variability. In this study, we analyzed possible phenotype modifiers of the disease the size of the deletion in the SMA region, the number of SMN2 gene copies, as well as the effect of gender. Among the factors analyzed, two seem to influence the SMA phenotype: the number of SMN2 gene copies and a deletion in the NAIP gene. A higher number of SMN2 copies makes the clinical symptoms more benign, and the NAIP gene deletion is associated with a more severe phenotype. The influence of gender remains unclear. In a group of 1039 patients, 55% of whom were male, the greatest disproportion was in the SMA1 (F/M=0.78) and SMA3b (F/M=0.45) forms. In SMA1 a deletion in the NAIP gene was seen twice as frequently in girls compared to boys. In three patients, we observed genotypes atypical for the chronic forms of SMA: two patients with SMA3a and 3b had a deletion of the NAIP gene, and a third patient with SMA2 had one copy of the SMN2 gene.

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Myofibrillar myopathies in Poland: Clinical, histopathological and genetic studies

72%

Potulska-Chromik A., Fichna J., Karolczak J., Berdynski M., Miszta P., Sikorska A., Redowicz M. J., Kostera-Pruszczyk A., Kaminska A.

Acta Neurobiologiae Experimentalis

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2017

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tom 77

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nr Suppl.1

INTRODUCTION: Myofibrillar myopathies (MFMs) are hereditary muscle diseases characterized by distinctive histopathology of myofibrillar disintegration and abnormal protein aggregation. Seven genes: DES, CRYAB, MYOT, FLNC, LDB3, BAG3, PLEC encoding proteins associated with Z disc are considered responsible for MFMs. However in about half of patients, the gene defect is still unknown. AIM(S): The aim of this study was to describe the clinical and histopathological features of genetically confirmed MFM. METHOD(S): 13 patients from 4 families with MFM were systematically identified and clinically studied. The families were not known to be related. In all suspected MFM patients (one proband from each family) disintegration of myofibrils and accumulation of degradation products into inclusions containing desmin were detected in muscle biopsy. However differentiation between MFM subtypes on the basis of clinical/ pathological phenotype alone was impossible. Therefore, subtype identification was performed using molecular studies. RESULTS: All patients presented with progressive muscle weakness with distal-proximal distribution in the lower limbs. CK was normal or slightly elevated. Finally three mutations were identified: two in DES: (Q348P) and (A357_E359del) and one in CRYAB (D109A). In two families with desminopathy caused by A357_E359del mutation cardiac arrhythmias was observed (paternal uncle with similar symptoms died due to cardiac arrhythmia). Dilated cardiomyopathy was confirmed by echocardiography in family with CRYAB D109A. In this family respiratory insufficiency as well as early cataract were diagnosed. CONCLUSIONS: Molecular identification of MFM is crucial for final diagnosis. The awareness of MFM type could be life-saving by means of appropriate treatment such as 1) inserting of a pacemaker in case of significant heart conduction defects and arrhythmia or 2) initiation of noninvasive ventilation in case of chronic respiratory failure.

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FKRP gene mutations and candidate disease-modifying genes in Polish patients with limb-girdle muscular dystrophy – results of whole exome sequencing study

72%

Macias A., Fichna J., Korostynski M., Piechota M., Potulska-Chromik A., Redowicz M. J., Zekanowski C., Kaminska A. M., Kostera-Pruszczyk A.

Acta Neurobiologiae Experimentalis

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2017

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tom 77

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nr Suppl.1

INTRODUCTION: Limb-girdle muscular dystrophies (LGMD) are hereditary progressive disorders of skeletal muscles. Currently 33 LGMD types are recognized. For up to 50% of LGMD patients the causal genetic defect remains unknown. There is considerable phenotypic variability, even among patients with identical causal mutation. Mutations in fukutin-related protein (FKRP) gene are responsible for an autosomal recessive type 2 I of LGMD, which is a relatively frequent type of LGMD in Europe. AIM(S): The aim of this work was to assess frequency of LGMD2I in Polish LGMD patients, characterize the pathogenic mutations, clinical phenotype and possible disease modifying genes. METHOD(S): The study involved 85 patients with LGMD diagnosis based on clinical assessment and muscle biopsy. Whole exome sequencing of peripheral blood DNA was performed. Filtering of the identified variants was based on allele frequency, association with Human Phenotype Ontology terms and predicted pathogenicity. Selected variants were confirmed using a direct fluorescence‑based sequencing. RESULTS: Homozygous or compound heterozygous mutations in FKRP gene were found in 7/85 patients. L276I mutation was the most common one – found in 6/7 LGMD2I patients, 3 of them were homozygous. We could observe considerable phenotypic variability. Candidate disease-modifying genes were COL6A3, COL12A1, PLEC, SYNE1. In 2 patients with particularly severe course of the disease, heterozygous mutation in genes involved In glycosylation process was found (LARGE, ISPD, ITGA7). Two patients were found to be heterozygous for mutations in DYSF gene. CONCLUSIONS: LGMD2I is a common type of LGMD in Polish population. The most common mutation in FKRP gene is L276I. Heterozygocity for mutations in other LGMD genes is high in this group of patients. New generation sequencing methods are a valuable tool for identifying causal mutations, but also for finding candidate disease‑modifying genes, which can help to elucidate mechanisms of LGMD.

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Nuclear genes involved in mitochondrial diseases with mitochondrial DNA instability in adults

59%

Rusecka J., Kierdaszuk B., Kaliszewska M., Rydzanicz M., Stawinski P., Gambin T., Kostera-Pruszczyk A., Bartnik E., Kaminska A., Ploski R., Tonska K.

Acta Biochimica Polonica

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2018

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tom 65

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nr S2

10

NGS as a diagnostic tool for unexplained limb-girdle muscles weakness: Results of European MYO-SEQ project in 75 Polish patients

52%

Lusakowska A., Johnson K., Topf A., Bertoli M., Phillips L., Straub V., Lek M., Xu L., MacArthur D. G., Macias A., Potulska-Chromik A., Kierdaszuk B., Janiszewska K., Arendt E., Grochowski P., Kaminska A., Kostera-Pruszczyk A.

Acta Neurobiologiae Experimentalis

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2017

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tom 77

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nr Suppl.1

INTRODUCTION: Hereditary muscle disorders are a genetically heterogeneous group of rare diseases with overlapping phenotypes causing difficulties in establishing a diagnosis. Genetic testing isthe only reliable tool to confirm a prompt diagnosis.Genetically confirmed diagnosisisrequired forthe future targeted therapies and the genetic counselling. Department of Neurology, Warsaw Medical University, participated in a European multicenter project MYO‑SEQ led by Institute of Genetic Medicine, Newcastle University. AIM(S): The main aim of the project was to establish accurate diagnoses in patients with unexplained limb-girdle muscle weakness by applying New Generation Sequencing(NGS). MATERIAL Patients included in the study were at least 10 years old, presented with unexplained limb-girdle or respiratory muscle weakness and/or elevated serum CK activity. Based on these criteria we identified 75 patients treated at our Department of Neurology. METHOD(S): With the patients’ consent, their encoded DNA samples and anonymous clinical data were sent to the MYO‑SEQ coordinating center for a whole exome sequencing using NGS. A detailed analysis of potential mutations was restricted to 169 gene associated with neuromuscular disorders. When the molecular result were obtained, a detail clinical-genetic analysis was done. RESULTS: In total of 75 tested samples, 50 (66,7%) showed specific mutations responsible for the patients’ symptoms, including 45 (60,0%) with mutation in a single gene. In 5 samples (6,7%), mutations in more than one gene were found. In two patients the treatable diseases were identified: Pompe disease and congenital myasthenic syndrome. In 25 (33,3%) samples, no strong candidate gene was identified. CONCLUSIONS: NGS offers an accurate and reliable methodology to establish a diagnosis in rare inherited muscle diseases.When the new molecular therapies become available, NGS test should be included in a standard diagnostic procedure of myopathies.

Ograniczanie wyników

LITAF and TNF alpha genes sequence variants in the patients with Charcot-Marie-Tooth disease

How accurate is spirometry at predicting restrictive pulmonary impairment in children with myasthenia gravis

A novel homozygous mutation in the WNK1/HSN2 gene causing hereditary sensory neuropathy type 2

Chronic progressive external ophthalmoplegia in Polish patients – clinical and genetic characteristics

Sympathetic skin response in obstructive sleep apnea syndrome

Phenotype modifiers of spinal muscular atrophy: the number of SMN2 gene copies, deletion in the NAIP gene and probably gender influence the course of the disease

Myofibrillar myopathies in Poland: Clinical, histopathological and genetic studies

FKRP gene mutations and candidate disease-modifying genes in Polish patients with limb-girdle muscular dystrophy – results of whole exome sequencing study

Nuclear genes involved in mitochondrial diseases with mitochondrial DNA instability in adults

NGS as a diagnostic tool for unexplained limb-girdle muscles weakness: Results of European MYO-SEQ project in 75 Polish patients