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

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

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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.

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Myofibrillar myopathies in Poland: Clinical, histopathological and genetic studies

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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

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

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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

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

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

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