Facioscapulohumeral muscular dystrophy type 1A in northwestern Tuscany: a molecular genetics-based epidemiological and genotype-phenotype study.

Facioscapulohumeral muscular dystrophy type 1A (FSHD1A) is an autosomal dominant inherited disorder characterized by early involvement of facial and scapular muscles with eventual spreading to pelvic and lower limb muscles. A high degree of clinical variability with respect to age at onset, severity, and pattern of muscle involvement, both between and within families, is present. For this reason, diagnosis of FSHD1A can be sometimes difficult and molecular diagnosis is then necessary. A clinical and molecular genetic-based epidemiological investigation has been carried out in the territory of northwestern Tuscany in central Italy to calculate the prevalence rate of FSHD1A as of March, 2004. The molecular diagnosis has been based on the detection of large deletions of variable size of kpnI repeat units on chromosome 4q35. Results have been compared to those of a previous study conducted in the same area in 1981 (in the premolecular diagnosis era). The minimum prevalence rate was 4.60 x 10(-5) inhabitants, a value four times higher compared to our previous study. No significant correlation between fragment size and clinical severity has been observed. This study confirms in an Italian population a prevalence rate of FSHD1A similar to that observed in other populations. Furthermore, it underlines the usefulness of routine adoption of the genetic testing in confirming clinical suspicion of FSHD1A as well as in correctly diagnosing atypical and otherwise misclassified cases.

Molecular and prospective phenotypic characterization of a pedigree with familial Alzheimer's disease and a missense mutation in codon 717 of the beta-amyloid precursor protein gene.

We present prospective clinical and neuropathologic details of a pedigree segregating familial Alzheimer's disease (FAD) associated with a mutation (G----A substitution) at nucleotide 2149 in exon 17 of the amyloid precursor protein (APP) gene. This mutation, which is predicted to cause the missense substitution of isoleucine for valine at codon 717 of APP, cosegregated perfectly with the FAD trait (lod score = 3.49 at theta = 0.00). The earliest clinical manifestations of the disease relate to deficits in memory function, cognitive processing speed, and attention to complex cognitive sets. These changes occurred in the absence of changes in nonmemory language and visuospatial functions. The neuropathologic features of FAD associated with the APP717 mutation in this family include severe neuronal loss, abundant neurofibrillary tangles, amyloid plaques, and amyloid angiopathy. These results provide independent confirmation that mutations in the APP gene are linked to the FAD trait in some families.

Indium-111 imaging of an inflammatory abdominal aortic aneurysm.

Indium-111-labeled leukocyte scanning has been shown to be a highly sensitive and specific imaging modality in the detection of abscess formation. Leukocyte infiltration occurs in a variety of inflammatory states as well as some noninflammatory states, leading to false-positive results. We report a case of an inflammatory abdominal aortic aneurysm imaged by 111In. It is not clear whether the activity noted is due to the inflammatory nature of the aneurysm or to hemorrhage present within the wall of the aneurysm.

Mild phenotype associated with inv dup 8 (q21.2-q22.3) of maternal origin.

We report on a girl with a de novo inverted duplication of chromosome 8 (q21.2-q22.3) associated with a mild phenotype. We were able to establish the maternal origin of the rearranged chromosome. We discuss the correlation between genotype and phenotype on the basis of a review of the findings from individuals with partial dup(8q).

A novel but non-pathogenic mutation in exon 4 of the human amyloid precursor protein (APP) gene.

Mutations in the beta-amyloid precursor protein (APP) gene have been associated with both familial Alzheimer disease (FAD) and with hereditary cerebral haemorrhage. The polymerase chain reaction was used to both amplify and sequence exon 4 of the APP gene from genomic DNA of subjects with FAD and normal control subjects. A novel, rare, conservative DNA sequence variant was discovered at nucleotide 459 of codon 153 (valine) in exon 4 of the APP gene in an affected member of a large FAD pedigree. Segregation studies indicate that this mutation is likely to be non-pathogenic, but must be recognized and discriminated from pathogenic mutations during sequencing studies of the APP gene in patients with FAD.

Establishment and characterization of two cell lines derived from human glioblastoma multiforme.

We established and characterized two cell lines derived from glioblastoma multiforme. Both cell lines exhibited tumor cell morphology and growth kinetics and showed variable expression of glial fibrillary acidic protein (GFAP), S-100, fibronectin and vimentin. Cytofluorimetrical analysis of tumor samples showed a diploid DNA distribution, whereas permanent culture cells evolved to the hyperdiploid DNA content. Karyotype studies revealed cytogenetical abnormalities described in glial tumors including gain of chromosome 7, loss of chromosome 10 and presence of double minutes (DMs). Enhanced expression of Ha-ras and c-myc genes resulted from high p-21 and p-62 levels. The contemporary presence of TGF-alpha and EGF-Rc transcripts suggested an autocrine mechanism in the cell lines growth.

Morphine-augmented cholescintigraphy with a false-negative result and an apparent ectopic gallbladder.

Morphine-augmented cholescintigraphy has been shown to be a highly sensitive and specific means of evaluating acute cholecystitis. False-negative results do occur infrequently, however, and such a case is reported. In addition, this case initially demonstrated an apparent ectopic gallbladder, and thus anomalies in location of the gallbladder will be discussed.

Macrovascular pulmonary arteriovenous malformations demonstrated by radionuclide method.

Pulmonary arteriovenous malformations (AVMs) are abnormal vascular communications that allow unoxygenated blood to pass from the venous to the arterial circulation. Usually congenital in origin and twice as likely in women, hemoptysis, dyspnea, and chest pain are the common presenting complaints in AVM. A case of pulmonary AVMs that were demonstrated on a radionuclide angiogram is presented. Pulmonary AVMs were suspected after finding radioactivity in both kidneys on a perfusion lung scan.

Facioscapulohumeral Muscular Dystrophy: More Complex than it Appears.

Facioscapulohumeral muscular dystrophy (FSHD) has been classified as an autosomal dominant myopathy, linked to rearrangements in an array of 3.3 kb tandemly repeated DNA elements (D4Z4) located at the 4q subtelomere (4q35). For the last 20 years, the diagnosis of FSHD has been confirmed in clinical practice by the detection of one D4Z4 allele with a reduced number (≤8) of repeats at 4q35. Although wide inter- and intra-familial clinical variability was found in subjects carrying D4Z4 alleles of reduced size, this DNA testing has been considered highly sensitive and specific. However, several exceptions to this general rule have been reported. Specifically, FSHD families with asymptomatic relatives carrying D4Z4 reduced alleles, FSHD genealogies with subjects affected with other neuromuscular disorders and FSHD affected patients carrying D4Z4 alleles of normal size have been described. In order to explain these findings, it has been proposed that the reduction of D4Z4 repeats at 4q35 could be pathogenic only in certain chromosomal backgrounds, defined as "permissive" specific haplotypes. However, our most recent studies show that the current DNA signature of FSHD is a common polymorphism and that in FSHD families the risk of developing FSHD for carriers of D4Z4 reduced alleles (DRA) depends on additional factors besides the 4q35 locus. These findings highlight the necessity to re-evaluate the significance and the predictive value of DRA, not only for research but also in clinical practice. Further clinical and genetic analysis of FSHD families will be extremely important for studies aiming at dissecting the complexity of FSHD.

New molecular findings in congenital myopathies due to selenoprotein N gene mutations.

Selenoprotein N-related myopathy (SEPN1-RM) is an early-onset muscle disorder that can manifest clinically as congenital muscular dystrophy with spinal rigidity and can result in specific pathological entities such as multiminicore disease, desmin-related myopathy with Mallory body-like inclusions, and congenital fiber-type disproportion. Here we describe the clinical, histopathological, muscle magnetic resonance imaging (MRI) and genetic findings of three Italian SEPN1-RM families. Proband 1 is a 31-year-old female who was floppy at birth and developed axial and mild lower limb-girdle weakness. The second proband is a 13-year-old boy with RSMD1. Probands 3 and 4 were brothers showing clinical phenotype of congenital myopathy. Muscle MRI demonstrated selective involvement of sartorius, gluteal muscles and distal gastrocnemius and sparing of rectus femoris and gracilis. Muscle histopathology showed in proband 1 myopathic changes with mild connective tissue increase and some fibres lacking the Z-line, while probands 2 and 3 had multiminicores. SEPN1 gene analysis revealed five mutations, three of which are novel. Proband 1 was a compound heterozygote for a 92-bp (exon 1) and a 1-bp deletion (exon 9); proband 2 had a 99-bp deletion and a 10-bp duplication in exon 1, and proband 3 presented a novel homozygous mutation in intron 10 acceptor splice site.

Altered gene silencing and human diseases.

Epigenetic regulation of gene expression is mediated through several mechanisms, including modifications in DNA methylation, covalent modifications of core nucleosomal histones, rearrangement of histones and RNA interference. It is now clear that deregulation of epigenetic mechanisms cooperates with genetic alterations in the development and progression of several Mendelian disorders. Here, we summarize the recent findings that highlight how certain inherited diseases, such as Rett syndrome, Immunodeficiency-centromeric instability-facial anomalies syndrome, and facioscapulohumeral muscular dystrophy, result from altered gene silencing.

Molecular basis of facioscapulohumeral muscular dystrophy.

Facioscapulohumeral muscular dystrophy (FSHD), the third most common myopathy, is an autosomal dominant disease with an insidious onset and progression. Almost all FSHD patients carry deletions of an integral number of tandem 3.3 kb repeats, termed D4Z4, located on chromosome 4q35. In FSHD patients a deletion of the integral number of D4Z4 repeats generates a fragment that is usually smaller than 35 kb (fewer than 11 repeats), whereas in normal controls the size usually ranges from 50 to 300 kb (between 11 and 150 units). D4Z4 is a repetitive element with heterochromatic features. Recently, 4q35 genes located upstream of D4Z4 have been found to be inappropriately overexpressed specifically in FSHD muscle. An element within D4Z4 has been shown to behave as a silencer that provides a binding site for a transcriptional repressing complex. These results suggest a model in which deletion of D4Z4 leads to the inappropriate transcriptional derepression of 4q35 genes, resulting in disease.

Wegener granulomatosis of the colon: CT and histologic correlation.

Wegener granulomatosis is a systemic vasculitis with distinct clinical and histologic features often characterized with involvement of the upper airway, lung, and kidneys. The reported incidence of gastrointestinal involvement is relatively rare, with histologic confirmation often lacking. We report a case in which gastrointestinal involvement was the principal feature, with CT and histologic correlation.

Multicentric chondrosarcomas associated with Ollier's disease. Review and case report.

The malignant transformation of enchondromas in patients with Ollier's Disease is a well known occurrence although few studies have prospectively followed patients with this disease and reviewed the frequency of this process. When malignant degeneration occurs, usually only one focus is noted even though others potentially may be involved. This paper represents a case report in which two separate locations of chondrosarcoma were found. Discussion includes chondrosarcomatous transformation of enchondromas, radiographic findings in this transformation, and treatment of multicentric chondrosarcomas in a patient with Ollier's Disease.

Maternal derivation of inv dup (22) and clinical variation in cat-eye syndrome.

Cytogenetic analysis in a male child with dismorphies and renal anomalies showed an extra bisatellited chromosome. In situ hybridization and an analysis of cytogenetic polymorphisms revealed that the abnormal chromosome derived from a single maternal chromosome 22.

Expressing the human genome.

We have searched the human genome for genes encoding new proteins that may be involved in three nuclear gene expression processes: transcription, pre-messenger RNA splicing and polyadenylation. A plethora of potential new factors are implicated by sequence in nuclear gene expression, revealing a substantial but selective increase in complexity compared with Drosophila melanogaster and Caenorhabditis elegans. Although the raw genomic information has limitations, its availability offers new experimental approaches for studying gene expression.

Deletion of specific sequences or modification of centromeric chromatin are responsible for Y chromosome centromere inactivation.

Stable dicentric chromosomes behave as monocentrics because one of the centromeres is inactive. The cause of centromere inactivation is unknown; changes in centromere chromatin conformation and loss of centromeric DNA elements have been proposed as possible mechanisms. We studied the phenomenon of inactivation in two Y centromeres, having as a control genetically identical active Y centromeres. The two cases have the following karyotypes: 45, X/46,X,i(Y)(q12) and 46,XY/47,XY,+t(X;Y) (p22.3;p11.3). The analysis of the behavior of the active and inactive Y chromosome centromeres after Da-Dapi staining, CREST immunofluorescence, and in situ hybridization with centromeric probes leads us to conclude that, in the case of the isochromosome, a true deletion of centromeric chromatin is responsible for its stability, whereas in the second case, stability for its stability, whereas in the second case, stability of the dicentric (X;Y) is the result of centromere chromatin modification.