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A Fidzianska

Publications and source records attributed to A Fidzianska.

16 recordsLinked to original sources
PubMed2006

Early onset Charcot-Marie-Tooth disease caused by a homozygous Leu239Phe mutation in the GDAP1 gene.

Mutations in the ganglioside -induced differentiation-associated protein 1 (GDAP1) gene are common a cause of the Charcot-Marie-Tooth (CMT4A) disease with autosomal recessive mode of inheritance. To date more than twenty mutations in the GDAP1 gene have been reported in patients suffering from the demyelinating, axonal or mixed form of Charcot-Marie-Tooth disease. Only in a few CMT4A affected patients sural nerve biopsy findings have been provided. We report a homozygous Leu239Phe mutation in the GDAP1 gene in a 39-year-old female with a severe form of mixed axonal and demyelinating Charcot-Marie-Tooth disease.

Adult↗
PubMed2005

In vivo and in vitro examination of the functional significances of novel lamin gene mutations in heart failure patients.

CONTEXT: Lamin A/C (LMNA) gene variations have been reported in more than one third of genotyped families with dilated cardiomyopathy (DCM). However, the relationship between LMNA mutation and the development of DCM is poorly understood. METHODS AND RESULTS: We found that end stage DCM patients carrying LMNA mutations displayed either dramatic ultrastructural changes of the cardiomyocyte nucleus (D192G) or nonspecific changes (R541S). Overexpression of the D192G lamin C dramatically increased the size of intranuclear speckles and reduced their number. This phenotype was only partially reversed by coexpression of the D192G and wild type lamin C. Moreover, the D192G mutation precludes insertion of lamin C into the nuclear envelope when co-transfected with the D192G lamin A. By contrast, the R541S phenotype was entirely reversed by coexpression of the R541S and wild type lamin C. As lamin speckle size is known to be correlated with regulation of transcription, we assessed the SUMO1 distribution pattern in the presence of mutated lamin C and showed that D192G lamin C expression totally disrupts the SUMO1 pattern. CONCLUSION: Our in vivo and in vitro results question the relationship of causality between LMNA mutations and the development of heart failure in some DCM patients and therefore, the reliability of genetic counselling. However, LMNA mutations producing speckles result not only in nuclear envelope structural damage, but may also lead to the dysregulation of cellular functions controlled by sumoylation, such as transcription, chromosome organisation, and nuclear trafficking.

Animals↗
PubMed2003

Expression of emerin and lamins in muscle of patients with different forms of Emery-Dreifuss muscular dystrophy.

Emerin and lamins are nuclear proteins, which are missing or defective in Emery-Dreifuss muscular dystrophy (EDMD). The aim of this study was to test the expression of these proteins in skeletal muscles in the X-linked (X-EDMD) and autosomal dominant (AD-EDMD) form. The study group consisted of 11 patients with X-EDMD, 11 patients of the AD-EDMD and 20 age-matched normal subjects. Expression of emerin and lamins in muscles were analyzed by Western blotting and the immunocytochemical technique. Using the Western blotting procedure emerin was detected in traces in the X-linked form. In the majority of these cases (6/11) it was connected with a decreased concentration of lamin A, in four patients a lowered concentration of lamin C was present. Lamin B2 was either normal (8/11), or decreased (3/11). Deficit of lamin A was a characteristic feature for AD-EDMD in the majority of these cases (9/11), while in two of these patients a decrease of lamin C, in four cases a lowered level of emerin was also present. In one AD-EDMD patient of a decrease of lamin C, but normal lamin A was present. Following the immunocytochemical examination the decrease of lamin A/C in X-EDMD and of emerin in AD-EDMD was also observed. The above mentioned data demonstrated that in X-EDMD and AD-EDMD the deficit of the appropriate proteins is not restricted either to emerin or lamins. The defect is more widespread and results in disruption of several nuclear proteins. This study also indicated that for the diagnostic EDMD purposes the immunocytochemical detection of emerin/lamins has to be accomplished by quantitative immunochemical analyses of the above mentioned proteins.

Adolescent↗
PubMed2000

Congenital fascial dystrophy: abnormal composition of the fascia.

BACKGROUND: A scleroderma-like genetic disease, congenital fascial dystrophy, probably a variant of stiff skin syndrome described by Esterly and McKusick, was found to be related to genetically determined fascial abnormalities. Our previous electronmicroscopic study disclosed as a main pathologic finding presence of giant amianthoid-like collagen fibrils in the affected fascia. OBJECTIVE: The aim of the present study was to disclose the collagen abnormalities in the affected and control fascias and in the patient's fibroblast cultures derived from the skin and fascia. METHODS: The study was performed by histologic, immunohistochemical, and electronmicroscopic techniques. Immunohistochemical studies were done with the use of monoclonal antibodies: anti-collagens I, III, IV, and VI, anti-laminin, anti-fibronectin, anti-desmin, anti-spectrin, anti-vimentin, anti-laminin, anti-heparan sulfate, and anti-alpha-actinin. Electronmicroscopic studies were performed on the fascia sections and on cultured fibroblasts. RESULTS: The main abnormality leading to giant collagen fibril formation was presence of myofibroblasts, absence of collagen III, and overproduction of spectrin and collagen type VI, mainly its filamentous form. CONCLUSION: Our findings suggest that the abnormal composition of the fascia could depend on modulation of fibroblasts into myofibroblasts capable of producing spectrin and long-spacing collagen.

Child↗
PubMed1999

Calpain III mutation analysis of a heterogeneous limb-girdle muscular dystrophy population.

OBJECTIVE: To determine the frequency of calpain III mutations in a heterogeneous limb-girdle muscular dystrophy (LGMD) population. BACKGROUND: Mutations of the calpain III gene have been shown to cause a subset of autosomal recessive LGMDs. Patient populations studied to date have been primarily of French and Spanish origin, in which calpain III may cause 30% of autosomal recessive MDs. The incidence of calpain III mutations in non-French/Spanish MD patients has not been studied thoroughly. No sensitive and specific biopsy screening methods for detecting patients with abnormal calpain III protein are available. Thus, detection of patients relies on direct detection of gene mutations. METHODS: The authors studied the calpain III gene in 107 MD patient muscle biopsies exhibiting normal dystrophin. Muscle biopsy RNA was produced for each patient, and the entire calpain III complementary DNA was screened for mutations by reverse-transcriptase PCR/single-strand conformation polymorphism using three different conditions. RESULTS: The authors identified nine patients (eight unrelated) with causative mutations. Six of the seven distinct mutations identified are novel mutations and have not been described previously. CONCLUSION: The results suggest that approximately 9.2% of patients in the heterogeneous population with an LGMD diagnosis will show mutations of the calpain III gene. Interestingly, two patients were heterozygous for a single mutation at the DNA level, whereas only the mutant allele was observed at the RNA level. This suggests that there are undetectable, nondeletion mutations that ablate expression of the calpain III gene.

Adolescent↗
PubMed1998

A dystrophin missense mutation showing persistence of dystrophin and dystrophin-associated proteins yet a severe phenotype.

A muscle biopsy from an X-linked muscular dystrophy pedigree showed normal dystrophin and dystrophin-associated proteins. Linkage to multiple markers within the dystrophin gene (LOD=2.7, theta=0) indicated a primary dystrophinopathy. Sequencing of the entire dystrophin RNA revealed a single missense mutation (D3335H) in the unique carboxyl-terminal domain. This is the first report showing that a relatively severe dystrophinopathy can occur despite the correct localization of dystrophin and dystrophin-associated proteins.

Amino Acid Sequence↗
PubMed1995

An X:autosome translocation stabilizes truncated dystrophin: implications for lack of truncated dystrophins in Duchenne muscular dystrophy.

We report a 5-year-old girl with clinical symptoms of typical Duchenne muscular dystrophy in males. The girl showed dramatic elevations of serum creatine kinase, and muscle biopsy histopathology consistent with a severe dystrophic myopathy. Cytogenetic analysis revealed an X:22 translocation (46,X,t [X;22] [p21.2;11.2]). Dystrophin immunofluoresence studies showed strong membrane immunostaining of dystrophin with antibodies directed against the amino terminus of the protein, but vastly reduced immunostaining with carboxyl-terminal antibodies. Immunoblot studies showed a major immunoreactive protein of approximately 350 kDa at approximately 20% levels. Nested RT-PCR analysis of the dystrophin mRNA in the patient's muscle showed the RNA to be positive for primers covering the first 85% of the dystrophin coding sequence, and negative for the carboxyl-terminal 15%. Taken together, our data suggests that the translocation breakpoint occurs towards the 3' end of the gene. The translocated dystrophin gene is still expressed into a truncated dystrophin protein associated with the plasma membrane. Our results are consistent with the translocation resulting in a more stable abnormal dystrophin mRNA.

Antibodies, Monoclonal↗
PubMed1993

Hyperkalemic periodic paralysis: rapid molecular diagnosis and relationship of genotype to phenotype in 12 families.

We studied mutations of the adult voltage-gated skeletal muscle sodium channel gene in 12 families, from diverse ethnic backgrounds, with hyperkalemic periodic paralysis (HyperPP). We describe a novel procedure, using ligase chain reaction (LCR), to simultaneously identify two different point mutations (previously described) and one rare, apparently benign polymorphism that results in a nonconservative amino acid substitution. Three of 12 families showed the Met1592Val mutation, and six of 12 had the Thr704Met mutation. The mutation in three of the 12 families was not identified. In one of these three families, the disease was not linked to the adult voltage-gated sodium channel gene, suggesting the existence of a clinically similar but genetically distinct form of HyperPP. Genotype/phenotype correlations based on patient records and interviews in these families showed the variable and subjective nature of the illness, although the clinical distinctions between hyperkalemic periodic paralysis and paramyotonia congenita were reinforced by the molecular data.

Adolescent↗
PubMed1993

Molecular genetic and genetic correlations in sodium channelopathies: lack of founder effect and evidence for a second gene.

We present a correlation of molecular genetic data (mutations) and genetic data (dinucleotide-repeat polymorphisms) for a cohort of seven hyperkalemic periodic paralysis (HyperPP) and two paramyotonia congenita (PC) families from diverse ethnic backgrounds. We found that each of three previously identified point mutations of the adult skeletal muscle sodium-channel gene occurred on two different dinucleotide-repeat haplotypes. These results indicate that dinucleotide-repeat haplotypes are not predictive of allelic heterogeneity in sodium channelopathies, contrary to previous suggestions. In addition, we identified a HyperPP pedigree in which the dominant disorder was not linked to the sodium-channel gene. Thus, a second locus can give rise to a similar clinical phenotype. Some individuals in this pedigree exhibited a base change causing the nonconservative substitution of an evolutionarily conserved amino acid. Because this change was not present in 240 normal chromosomes and was near another HyperPP mutation, is fulfilled the most commonly used criteria for being a mutation rather than a polymorphism. However, linkage studies using single-strand conformation polymorphism-derived and sequence-derived haplotypes excluded this base change as a causative mutation: these data serve as a cautionary example of potential pitfalls in the delineation of change-of-function point mutations.

Adult↗
PubMed1992

Phagocytic capacity of human muscle fibers.

Isolated dead muscle cell fragments (apoptotic bodies [ABs]) were investigated by electron microscopy in different stages of phagocytosis. Phagocytosis of ABs was carried out by neighboring muscle cells. The mechanism of internalization took place in both mature and immature muscle cells and consisted of the progressive engulfment of ABs within cytoplasmic vacuoles and craters. In addition, concentrated microfilaments formed a dense ring in the muscle cytoplasm adjacent to the engulfed ABs. The above combination of membrane evagination and phagocytic vacuole formation as well as the extensive microfilament organization at the site of AB engulfment were analogous to the cytoplasmic response seen in the tissue of mononuclear phagocytic cells.

Humans↗
PubMed1983

A morphological study of non-Japanese congenital muscular dystrophy associated with cerebral lesions.

Clinical and morphological findings in five patients, three girls and two boys, afflicted with congenital muscular dystrophy (CMD) and cerebral lesions are reported. Four of these patients represented two pairs of siblings, and all patients had died in early infancy. Three of the patients had muscle hypotonia in early infancy, two siblings died with a necrotizing myopathy before neuromuscular symptoms became clinically apparent. Two siblings had intractable grand mal seizures, one other boy had polymicrogyria, and a single child had internal hydrocephalus. Muscle morphology in all patients was compatible with CMD, showing a necrotizing component in two male sibs. Electron microscopy of muscle only revealed non-specific ultrapathology. The association of CMD with cerebral lesions renders prognosis unfavourable. The data presented do not permit the delineation of a precise nosological form of cerebro-muscular disease but may comprise several entities. The association of CMD and cerebral lesions may often occur in families, apparently following an autosomal-recessive mode of inheritance. It may not be identical to the Fukuyama type of CMD, and it is definitely different from the "muscle, eye and brain disease" in Finnish children. It seems to be similar to CMD with cerebral lesions observed in non-Japanese siblings, but whether it is actually the same disease remains unclear. At least the association of CMD and cerebral lesions indicate an unfavourable clinical prognosis.

Brain↗
PubMed1982

Congenital muscular dystrophy (CMD) - a collagen formative disease?

Muscle biopsies of 5 patients with congenital muscular dystrophy (CMD) (8 months to 3 years old) were examined by electron microscopy to determine ultrastructural abnormalities of the muscle as well as of the connective tissue cells. Two populations of muscle fibers were observed in each biopsy. Besides muscle fibers with normal or enlarged diameters there were frequently very small muscle cells indicating immaturity. The most interesting findings in each biopsy were myofibroblast-like cells exhibiting active protein synthesis. Large amounts of collagen fibrils with abnormal diameters as well as accumulation of elastic fibrils within the endomysium in CMD suggest abnormalities in collagen synthesis.

Biopsy↗
PubMedDate not supplied

Mallory body-like inclusions in a hereditary congenital neuromuscular disease.

Subsequent to an earlier report on clinical and light microscopic data, peculiar Mallory body-like inclusions are described in muscle fibers of three genetically linked children. These Mallory body-like inclusions were unlike other well-defined intramuscular inclusions, such as nemaline, cytoplasmic, fingerprint, or sarcoplasmic bodies, but morphologically quite similar to hepatic Mallory bodies, because they were composed of three components: granular material and two types of filaments. Evidence is presented that these inclusions may contain desmin, the intermediate filament type characteristic of muscle. The exclusive appearance of these Mallory body-like inclusions in muscle biopsy specimens from three genetically related children of a large kinship emphasizes the uniqueness of these Mallory body-like inclusions in these muscle fibers as well as the special form of this congenital neuromuscular disorder.

Adolescent↗