Wyniki wyszukiwania - Biblioteka Nauki

1

Wtrętowe zapalenie mięśni (WZM). Wprowadzenie

100%

Hausmanowa-Petrusewicz I.

Aktualności Neurologiczne

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2005

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tom 5

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nr 4

242-243

2

Laminopatie – układ integrujący i ciągle intrygujący

100%

Hausmanowa-Petrusewicz I.

Aktualności Neurologiczne

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2006

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tom 6

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nr 1

24-31

EN

Lamins – proteins with intermediate filaments – are components of the internal membrane and internal structures of cell nucleus. Some lamins are encoded by the LMNA gene, located at the long arm of the chromosome 1 – 1q21-23. Mutations of this gene are responsible for several diseases in humans. Some of these diseases have been described long ago – they were considered very rare, they were not diagnosed properly or their pathogenesis was unclear. Other diseases of this class only recently have appeared in medical handbooks. The key event in our understanding of laminopathies was elucidation in 1994 of the Emery-Dreifuss syndrome, well known to clinicians but rarely described hitherto. It is characterized by the triad of symptoms: early articular contractures (mainly of the cubital, talocrural and cervical vertebral joints), moderate atrophy and weakness of the brachial and peroneal muscle groups, and cardiomyopathy with conduction block, developing at the age of 20. The latter is the main life-threatening factor in Emery-Dreifuss syndrome patients. It became clear that the development of this condition depends on mutation of the STA gene, located at the long arm of the X chromosome (Xq28). The product of this gene is a protein included in the internal nuclear membrane, of molecular weight 34 kDa, called “emerin” in memory of Alan Emery. Its discovery marked a breakthrough in myology (hitherto it was believed that cell nucleus does not play any significant role in human pathology), paving the way for subsequent important discoveries. Among other things, it turned out that the Emery-Dreifuss dystrophy phenotype is not always associated with mutation of the STA gene or with emerin deficit. Growing interest in emerinopathy contributed to gathering of a fairly large number of patients featuring a similar phenotype but entirely different genotypic profile. The most important observation was that some patients phenotypically consistent with the Emery-Dreifuss syndrome are afflicted with one of the many possible mutations of the LMNA gene. The disease has an autosomal dominant inheritance pattern (rarely autosomal recessive). The product of the LMNA gene are lamins A/C. The gene has 12 exons and depending on location of the mutation, several entirely different syndromes may develop. Thereof, the most important are: 1. Emery-Dreifuss syndrome, featuring the same triad as the Emery-Dreifuss syndrome associated with emerinopathy; 2. limb-girdle muscular dystrophy type 1B, characterized by an autosomal dominant pattern of inheritance; 3. isolated, i.e. idiopathic dilated cardiomyopathy, characterized by an autosomal dominant inheritance pattern; 4. Charcot-Marie-Tooth disease type 2B with axonal conduction disorders, characterized by an autosomal dominant inheritance pattern; 5. familial partial lipodystrophy (Dunnigan type), featuring an autosomal dominant inheritance pattern; 6. mandibuloacral dysplasia (MAD) – a rare yet very severe disease, featuring autosomal recessive inheritance pattern; 7. Hutchinson-Gilford progeria, characterized by premature senescence of children, featuring autosomal dominant inheritance. In the field of laminopathies, which constitute a relatively novel area of research in medicine, we are struck by prominent role of cell nucleus and various mutations at several exons of the LMNA gene, resulting in different nosologic entities. From the clinician’s perspective, laminopathies (or nucleopathies in general) constitute a heterogenous group of hereditary diseases which damage skeletal muscles, cardiac muscle, connective tissue, nerves and bones. An interesting problem is “tissue specificity” of particular laminopathies, in spite of their presence in every tissue.

PL

Laminy - białka z pośrednimi filamentami - wchodzą w skład wewnętrznej błony i wewnętrznych struktur jądra komórkowego. Niektóre laminy są kodowane przez gen LMNA, który jest zlokalizowany na długim ramieniu chromosomu 1. - 1q21-23. Mutacje tego genu są odpowiedzialne za cały szereg chorób człowieka. Część tych chorób opisano już dawno - uważano je za bardzo rzadkie, nie zawsze były rozpoznawane lub miały niejasną patogenezę, inne pojawiły się w podręcznikach medycyny dopiero teraz. Prologiem do poznania laminopatii było wyjaśnienie w 1994 roku znanego klinicystom, ale rzadko opisywanego zespołu Emery’ego-Dreifussa. Charakteryzuje go triada następujących objawów: wczesne przykurcze stawowe, głównie stawu łokciowego, skokowego i kręgosłupa szyjnego, umiarkowany zanik i nieznaczne osłabienie mięśni grupy ramieniowo-strzałkowej oraz kardiomiopatia z blokiem przewodzenia, która objawia się około 20. r.ż. Właśnie ona stanowi najistotniejsze zagrożenie dla życia pacjentów z zespołem Emery’ego-Dreifussa. Pojawienie się choroby okazało się zależne od mutacji genu STA, zlokalizowanego na długim ramieniu chromosomu X (Xq28). Produktem tego genu jest białko wewnętrznej błony jądrowej o ciężarze 34 kDa, nazwane na cześć Alana Emery’ego „emeryną”. Jego odkrycie było przełomem w miologii (do tego momentu uważano, iż jądro komórkowe nie odgrywa w ludzkiej patologii poważniejszej roli), stanowiło katalizator dalszych istotnych odkryć. Okazało się między innymi, że fenotyp dystrofii Emery’ego-Dreifussa nie zawsze idzie w parze z mutacją genu STA czy też z deficytem emeryny. Zainteresowanie emerynopatią przyczyniło się do zebrania dużej liczby chorych o podobnym fenotypie, ale całkiem innej charakterystyce genotypowej. Najważniejsze było stwierdzenie, że część pacjentów fenotypowo odpowiadających kryteriom zespołu Emery’ego-Dreifussa ma jedną z licznych możliwych mutacji genu LMNA. Choroba dziedziczy się w sposób autosomalny dominujący (rzadko recesywny). Produktem genu LMNA są laminy A/C. Gen ma 12 eksonów i w zależności od lokalizacji mutacji powstają bardzo rozmaite zespoły chorobowe. Najważniejsze z nich to: 1. zespół Emery’ego-Dreifussa z triadą taką samą jak w zespole Emery’ego-Dreifussa związanym z emerynopatią: 2. obręczowo-kończynowa dystrofia typu 1B, dziedzicząca się autosomalnie dominująco: 3. izolowana, tzw. idiopatyczna kardiomiopatia rozstrzeniowa, dziedzicząca się autosomalnie dominująco: 4. choroba Charcota-Marie’a-Tootha typu 2B z aksonalnymi zmianami przewodzenia, dziedzicząca się w sposób autosomalny recesywny: 5. rodzinna lipodystrofia typu Dunnigana (FPLD), dziedzicząca się w sposób autosomalny dominujący: 6. dysplazja żuchwowo-obojczykowa (MAD) - jest schorzeniem rzadkim, ale bardzo ciężkim, dziedziczy się autosomalnie recesywnie: 7. progeria Hutchinsona-Gilforda, charakteryzująca się przedwczesnym starzeniem dzieci, dziedzicząca się autosomalnie dominująco. W laminopatiach, które stanowią względnie nowy przedmiot badań medycyny, uderza olbrzymia rola jądra komórkowego i rozmaite mutacje w różnych eksonach LMNA powodujące różne zespoły chorobowe. Z punktu widzenia klinicysty laminopatie (a może w ogóle nukleopatie) są heterogenną grupą chorób dziedzicznych, które uszkadzają mięsień szkieletowy, sercowy, tkankę łączną, nerwy, kościec. Intrygującym problemem jest „tkankowa swoistość” laminopatii, pomimo ich obecności w każdej tkance.

3

The involvement of oxidative stress in determining the severity and progress of pathological processes in dystrophin-deficient muscles.

63%

Niebrój-Dobosz I. , Hausmanowa-Petrusewicz I.

Acta Biochimica Polonica

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2005

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tom 52

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nr 2

449-452

EN

In both forms of muscular dystrophy, the severe Duchenne’s muscular dystrophy (DMD) with lifespan shortened to about 20 years and the milder Becker dystrophy (BDM) with normal lifespan, the gene defect is located at chromosome locus Xp21. The location is the same in the experimental model of DMD in the mdx mice. As the result of the gene defect a protein called dystrophin is either not synthesized, or is produced in traces. Although the structure of this protein is rather well established there are still many controversies about the dystrophin function. The most accepted suggestion supposes that it stabilizes sarcolemma in the course of the contraction-relaxation cycle. Solving the problem of dystrophin function is a prerequisite for introduction of an effective therapy. Among the different factors which might be responsible for the appearance and progress of dystrophic changes in muscles there is an excessive action of oxidative stress. In this review data indicating the influence of oxidative stress on the severity of the pathologic processes in dystrophy are discussed. Several pieces of data indicating the action of oxidative damage to different macromolecules in DMD/BDM are presented. Special attention is devoted to the degree of oxidative damage to muscle proteins, the activity of neuronal nitric oxide synthase (nNOS) and their involvement in defining the severity of the dystrophic processes. It is indicated that the severity of the morbid process is related to the degree of oxidative damage to muscle proteins and the decrease of the nNOS activity in muscles. Estimation of the degree of the destructive action of oxidative stress in muscular dystrophy may be a useful marker facilitating introduction of an effective antioxidant therapy and regulation of nNOS activity.

4

Dziedziczna miopatia wtrętowa

63%

Zaremba J. , Hausmanowa-Petrusewicz I.

Aktualności Neurologiczne

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2005

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tom 5

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nr 4

261-264

EN

The hereditary inclusion body myopathies (hIBM) are discussed: 1) The recessive autosomally transmitted form – hIBM2 with characteristic sparing quadriceps femoris muscle, affecting Persian (Iranien) Jews, some Jewish population in Egypt, Afganistan and Kurdic-Iranian Jews; also relatively frequent in Japan. hIBM2 is caused by mutations in the gene of bifunctional enzyme UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase, localized on chromosome 9p12-p11. The onset of the disorder occurs usually between 20th and 35th year of life. Characteristic in histological picture of the muscle are rimmed vacuoles and cytoplasmic inclusions; 2) The autosomal dominant form hIBM3. Characteristic of the disorder are congenital joint contractures, external ophthalmoplegia, proximal muscle weakness and rimmed vacuoles – as in IBM2. A causative mutation was identified in the myosin heavy chain gene MYHC2A localized on chromosome 17p13.1 Some hereditary myopathies occurring in isolated populations in Europe as e.g. Welander distal myopathy or Udd tibial dystrophy are also considered to be variants of hIBM.

PL

Omówione są wrodzone miopatie wtrętowe: 1) Dziedzicząca się recesywnie autosomalnie (hIBM2) z charakterystycznym zaoszczędzeniem m. czworogłowego uda, występująca u Perskich (Irańskich) Żydów, czasem również u Żydów w Egipcie, Afganistanie lub u kurdo-irańskich Żydów; jest także dość częsta w Japonii. Przyczyną hIBM2 są mutacje w genie dwufunkcyjnego enzymu epimerazy UDP-N-acetyloglukozaminy/kinazy N-acetylomannozaminy (GNE), który został zlokalizowany na chromosomie 9p12-p11. Początek choroby przypada zazwyczaj na trzecią lub czwartą dekadę życia. W obrazie histologicznym mięśni bardzo charakterystyczna jest obecność obrzeżonych wakuoli i cytoplasmatycznych wtrętów; 2) Autosomalna dominująca postać (hIBM3) cechująca się wrodzonymi przykurczami w stawach, oftalmoplegią zewnętrzną, osłabieniem mięśni dosiebnych kończyn i obrzeżonymi wakuolami jak w hIBM2. Przyczyną hIBM3 są mutacje w genie ciężkiego łańcucha miozyny IIa (MYHC2A), który został zlokalizowany na chromosomie 17p13. Ponadto pewne miopatie, występujące w Europie w izolowanych, etnicznych grupach są zaliczane do wtrętowych (np. miopatia odsiebna Welander, dystrofia piszczelowa Udda).

5

MU firing characteristics in human dystrophic muscle

51%

Piotrkiewicz M. , Filipiuk M. , Hausmanowa-Petrusewicz I.

Acta Neurobiologiae Experimentalis

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1993

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tom 53

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nr 1

313-318

EN

During isometric contractions of constant force surface EMG as well as intramuscular MU potentials from extensor digitorum communis and biceps brachii muscles were recorded on magnetic tape for furthr off-line analysis. Surface EMG power spectra were computed and transformed so as to reveal low-frequency peaks which might correspond to MU firing rates. From intramuscular recordings, single MU action potentials were identified with an aid of semi-automatic recognition program. For each single MU action potential train (MUAPT) statistical parameteres of interspike intervals (ISIs) were determined and related to the measured muscle force level. Sixty four MUAPTs from 9 patients and 55 MUAPTs from 4 normals were analysed so far. The estimates of MU firing rate from surface and needle EMG corresponded well to each other. The MU firing rates were higher in muscular dystrophy and this difference was more pronounced for higher levels of muscle force. The tendency towards mean MU firing rate increase is stronger for the patients with more advanced disease. The typical dependency of standard deviation of ISIs on their mean value may be axpproximated by two lines of different slope. There were reported experimental data indicating that the breaking point of this dependency may be an estimate of AHP duration in motoneurones. Our results for dystrophic muscle showed a shift of this point towards shorter ISIs, as compared to normals.This suggests that inmuscular dystrophy also motoneurones may be altered, either by the disease itself or as a compensation for changes in muscular part of a MU.

6

A severe recessive and a mild dominant form of Charcot-Marie-Tooth disease associated with a newly identified Glu222Lys GDAP1 gene mutation

45%

Kabzińska D. , Kotruchow K. , Cegielska J. , Hausmanowa-Petrusewicz I. , Kochański A.

Acta Biochimica Polonica

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2014

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tom 61

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nr 4

739-744

EN

Charcot-Marie-Tooth (CMT) disease caused by mutations in the GDAP1 gene has been shown to be inherited via traits that may be either autosomal recessive (in the majority of cases) [CMT4A] or autosomal dominant [CMT2K]. CMT4A disease is characterized by an early onset, and a severe clinical course often leading to a loss of ambulation, whereas CMT2K is characterized by a mild clinical course of benign axonal neuropathy beginning even in the 6th decade of life. Clinical data from a GDAP1 mutated patient suggests that the presence of a particular mutation is associated with a certain trait of inheritance. The association of a particular GDAP1 gene mutation and a dominant or recessive trait of inheritance is of special importance for genetic counseling and the prenatal diagnostics as regards severe forms of CMT. In the present study we report on two CMT families in which a newly identified Glu222Lys mutation within the GDAP1 gene segregates both in autosomal dominant and recessive traits. Our study shows that at least some GDAP1 gene mutations may segregate with the CMT phenotype as both dominant and recessive traits. Thus, genetic counseling for CMT4A/CMT2K families requires more extensive data on GDAP1 phenotype-genotype correlations.

7

Matrix metalloproteinases in serum of Emery-Dreifuss muscular dystrophy patients

45%

Niebroj-Dobosz I. , Madej-Pilarczyk A. , Marchel M. , Sokołowska B. , Hausmanowa-Petrusewicz I.

Acta Biochimica Polonica

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2009

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tom 56

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nr 4

717-722

EN

In the pathogenesis of dilated cardiomyopathy (DCM) in Emery-Dreifuss muscular dystrophy (EDMD) matrix metalloproteinases (MMPs) are supposed to be involved and may have diagnostic/prognostic value. Serum levels of MT1-MMP, MMP-2 and MMP-9 were quantified by ELISA and zymography in 22 EDMD patients and 15 age-matched controls. In the autosomal-dominant EDMD MMP-2 and MT1-MMP were increased in all cases, and MMP-9 was increased in two of the eight examined patients. In the X-linked EDMD MMP-2 expression was increased in all the cases, MMP-9 level was elevated in 3 of the 14 cases, and MT1-MMP was decreased in eight of these patients. There was no evident correlation between the MMPs level and the different cardiac parameters including left-ventricular end-diastolic diameter, left atrial diameter and left ventricular ejection fraction in either form of EDMD. The presented results indicate that a changed level of matrix metalloproteinases, especially that of MMP-2 in serum, may be of value for detection of cardiac involvement in EDMD patients, especially in those patients with no evident subjective cardiac symptoms. Further follow-up studies of MMPs are needed to check if their determination is of value for monitoring of the progression of atrial/ventricular dilatation. MMPs determinations may also be useful for monitoring DCM treatment by synthetic MMPs inhibitors.

8

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

32%

Jędrzejowska 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

EN

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.

9

Interrelationship between gene, its product and phenotype in Duchenne and Becker muscular dystrophy

32%

Hausmanowa-Petrusewicz I. , Zaremba J. , Fidzianska A. , Badurska B. n. , Bisko M. , Borkowska J. , Lusakowska A. , Zimowski J.

Acta Neurobiologiae Experimentalis

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1993

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tom 53

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nr 1

297-303

EN

DNA analysis> was carried out in 113 patiens of 103 families. In 58 families (55%) deletions were found using different cDNA probes. The attempt of studying the correlation between mental retardation in patients and the exon deletions was made. Dystrophin was evaluated in 80 patients including 12 affected females. One girl had chromosomal translocation X;22 and was a true DMD case. An unusual pedigree typical of X-linked transmission with affected subjects showing clinical features of DMD but with normally expressed dystrophin is presented. Owing to DNA and dystrophin analysis the correct diagnosis in some doubtful cases of muscular dystrophies could be established and some unusual pedigrees detected.