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At least 721 records · Page 40Linked to original sources
PubMed2006

Transient progeroid phenotype and lipodystrophy in mosaic polyploidy.

Wiedemann-Rautenstrauch syndrome is a rare disorder with a progressive course and early lethality. Severe mental and growth retardation, muscle hypotonia, a progeroid face, wrinkled skin, relative macrocephaly with late closure of the anterior fontanel, arachnodactyly and congenital heart defects are also typical. We report on a female infant with all the characteristic features of this syndrome after birth. Chromosomal studies on peripheral leukocytes showed a normal karyotype. In view of an abnormal lipid distribution and lipodystrophy, metabolic studies for congenital disorders of glycosylation have been performed with normal results. At the age of 2 years 6 months the progeroid signs were no longer present, and the patient had a striking improvement in her psychomotor development. As there are overlapping features in Wiedemann-Rautenstrauch syndrome and in mosaic polyploidy, including psychomotor retardation, reduced peripheral muscle bulk, arachnodactyly and lipodystrophy, chromosome analysis was performed in the fibroblast culture of our patient. A mosaic triploidy/tetraploidy was detected in 60% and 14% of the cells, respectively. We therefore recommend chromosome analysis of fibroblasts from patients with a neonatal presentation of progeroid features and lipodystrophy.

Abnormalities, Multiple↗
PubMed2020

Tissue specificity of senescent cell accumulation during physiologic and accelerated aging of mice.

Senescent cells accumulate with age in vertebrates and promote aging largely through their senescence-associated secretory phenotype (SASP). Many types of stress induce senescence, including genotoxic stress. ERCC1-XPF is a DNA repair endonuclease required for multiple DNA repair mechanisms that protect the nuclear genome. Humans or mice with reduced expression of this enzyme age rapidly due to increased levels of spontaneous, genotoxic stress. Here, we asked whether this corresponds to an increased level of senescent cells. p16Ink4a and p21Cip1 mRNA were increased ~15-fold in peripheral lymphocytes from 4- to 5-month-old Ercc1-/∆ and 2.5-year-old wild-type (WT) mice, suggesting that these animals exhibit a similar biological age. p16Ink4a and p21Cip1 mRNA were elevated in 10 of 13 tissues analyzed from 4- to 5-month-old Ercc1-/∆ mice, indicating where endogenous DNA damage drives senescence in vivo. Aged WT mice had similar increases of p16Ink4a and p21Cip1 mRNA in the same 10 tissues as the mutant mice. Senescence-associated β-galactosidase activity and p21Cip1 protein also were increased in tissues of the progeroid and aged mice, while Lamin B1 mRNA and protein levels were diminished. In Ercc1-/Δ mice with a p16Ink4a luciferase reporter, bioluminescence rose steadily with age, particularly in lung, thymus, and pancreas. These data illustrate where senescence occurs with natural and accelerated aging in mice and the relative extent of senescence among tissues. Interestingly, senescence was greater in male mice until the end of life. The similarities between Ercc1-/∆ and aged WT mice support the conclusion that the DNA repair-deficient mice accurately model the age-related accumulation of senescent cells, albeit six-times faster.

Aging↗
PubMed2024

The Ercc1-/Δ mouse model of XFE progeroid syndrome undergoes accelerated retinal degeneration.

Age-related macular degeneration (AMD) is a major cause of vision loss in older adults. AMD is caused by degeneration in the macula of the retina. The retina is the highest oxygen consuming tissue in our body and is prone to oxidative damage. DNA damage is one hallmark of aging implicated in loss of organ function. Genome instability has been associated with several disorders that result in premature vision loss. We hypothesized that endogenous DNA damage plays a causal role in age-related retinal changes. To address this, we used a genetic model of systemic depletion of expression of the DNA repair enzyme ERCC1-XPF. The neural retina and retinal pigment epithelium (RPE) from Ercc1-/Δ mice, which models a human progeroid syndrome, were compared to age-matched wild-type (WT) and old WT mice. By 3-months-of age, Ercc1-/Δ mice presented abnormal optokinetic and electroretinogram responses consistent with photoreceptor dysfunction and visual impairment. Ercc1-/Δ mice shared many ocular characteristics with old WT mice including morphological changes, elevated DNA damage markers (γ-H2AX and 53BP1), and increased cellular senescence in the neural retinal and RPE, as well as pathological angiogenesis. The RPE is essential for the metabolic health of photoreceptors. The RPE from Ercc1-/Δ mice displayed mitochondrial dysfunction causing a compensatory glycolytic shift, a characteristic feature of aging RPE. Hence, our study suggests spontaneous endogenous DNA damage promotes the hallmarks of age-related retinal degeneration.

Animals↗
PubMed2005

Homozygous and compound heterozygous mutations in ZMPSTE24 cause the laminopathy restrictive dermopathy.

Restrictive dermopathy (RD) is a lethal human genetic disorder characterized by very tight, thin, easily eroded skin, rocker bottom feet, and joint contractures. This disease was recently reported to be associated with a single heterozygous mutation in ZMPSTE24 and hypothesized to be a digenic disorder (Navarro et al, Lamin A and ZMPSTE24 (FACE-1) defects cause nuclear disorganization and identify restrictive dermopathy as a lethal neonatal laminopathy. Hum Mol Genet 13:2493-2503, 2004). ZMPSTE24 encodes an enzyme necessary for the correct processing and maturation of lamin A, an intermediate filament component of the nuclear envelope. Here we present four unrelated patients with homozygous mutations in ZMPSTE24 and a fifth patient with compound heterozygous mutations in ZMPSTE24. Two of the three different mutations we found are novel, and all are single base insertions that result in messenger RNA frameshifts. As a consequence of the presumed lack of ZMPSTE24 activity, prelamin A, the unprocessed toxic form of lamin A, was detected in the nuclei of both cultured cells and tissue from RD patients, but not in control nuclei. Abnormally aggregated lamin A/C was also observed. These results indicate that RD is an autosomal recessive laminopathy caused by inactivating ZMPSTE24 mutations that result in defective processing and nuclear accumulation of prelamin A.

Cell Nucleus↗
PubMed2004

The De Barsy syndrome.

BACKGROUND: In 1968, De Barsy reported on a girl exhibiting an aged aspect, 'dwarfism, oligophrenia, and degeneration of the elastic tissue in cornea and skin'. The disorder was recognized as a subgroup of cutis laxa syndrome and termed De Barsy-Moens-Dierckx syndrome. The pathogenesis of the disorder is unknown. METHODS: To improve the comprehension of the pathogenetic mechanisms involved in the De Barsy syndrome, we performed an ultrastructural, morphometric, immunocytochemical study on a skin biopsy of a boy with the De Barsy phenotype, who has been clinically followed for 12 years from birth. Moreover, the lysyl oxidase activity was measured on skin fibroblasts cultured in vitro. RESULTS: Light and electron microscopy, morphometry, and immunocytochemical observations showed a significant reduction of the elastic fibers in the papillary and in the reticular dermis of patient compared to an age-matched control (p < 0.05). By contrast, the collagen structure, content, and the distribution were normal, as well as lysyl oxidase activity in the medium of in vitro fibroblasts (12,323 DPM/10(6) cells). The immunoreaction for antibodies recognizing fibrillin-1, neutrophilic elastase, and tumor necrosis factor-alpha was stronger, whereas that for antibodies against transforming growth factor-beta was less pronounced in the dermis of the De Barsy boy compared to control. CONCLUSIONS: Clinical, phenotypic, and structural data were consistent with the diagnosis of De Barsy syndrome. This is the first case described in Italy. Clinical and structural data confirm that the elastic component is mostly affected in this disorder. Moreover, ultrastructural and immunochemical findings suggest that both elastic fiber degradative and very likely synthetic processes are involved.

Abnormalities, Multiple↗
PubMed2004

Acrogeria with decreased gene expression of alpha1 (I) and alpha1 (III) collagen in cultured dermal fibroblasts.

We report a case of acrogeria. A 47-year-old Japanese man presented with micrognathism, thin lips, radial wrinkles around his month, atrophy of skin and subcutaneous tissue, and mottled hyperpigmentation on his extremities. A biopsy of the lesional skin showed flat epidermis and atrophy of the dermal layer. The in vitro life span of the patient's fibroblasts (18+/-2.2 PDL) was significantly shorter than that of control fibroblasts (42+/-3.5 PDL). The early-passage fibroblasts from the patient showed abnormal morphology which was also seen in the late-passage (in vitro aging) of normal fibroblasts. In northern blotting analysis of cultured dermal fibroblasts, mRNA levels of alpha1 (I) collagen and alpha1 (III) collagen were markedly reduced. These results revealed that patient fibroblasts might be in severe senescence in vitro and contribute to the phenotypes of this premature aging syndrome.

Biopsy, Needle↗
PubMed1980

Familial acrogeria (Gottron).

A mother and her oldest son suffering from acrogeria are described; in the mother the disease was complicated by elastosis perforans serpiginosa. Microscopic and ultramicroscopic details are given.

Adult↗
PubMed1976

A syndrome of generalized elastic fiber deficiency with leprechaunoid features: a distinct genetic disease with an autosomal recessive mode of inheritance.

Three male infants with generalized elastolysis and leprechaunoid features from two related and consanguineous parents of Italian origin died in the first year of life following severe cardio-pulmonary complications. While these children showed a decrease in elastic fibers, no degeneration was noted and histochemical as well as systemic metabolic studies were negative. It is postulated that this disease is a variant of cutis laxa or at least that the absence of granular degeneration of the elastic fibers described by Goltz is a secondary manifestation present only in older children. Prenatal diagnosis of this syndrome is not yet possible since no intracellular or biochemical changes have been identified. In view of the familial occurrence of this syndrome, and the association of specific clinical and pathological findings, we suggest that we are dealing with a distinct hereditary disorder of the connective tissue.

Abnormalities, Multiple↗
PubMed1984

Mandibuloacral dysplasia: a rare progeroid syndrome. Two brothers confirm autosomal recessive inheritance.

Mandibuloacral Dysplasia would appear to be a very rare syndrome, probably because it is usually mistakenly diagnosed. This article describes the case histories of two brothers, confirming Welsh's (1975) earlier hypothesis concerning autosomal recessive inheritance and makes certain observations which should be helpful in diagnosing this rare hereditary syndrome.

Abnormalities, Multiple↗
PubMed1986

Ehlers-Danlos features with progeroid facies and mild mental retardation. Further delineation of the syndrome.

A syndrome characterized by progeroid facies, multiple nevi, mild mental retardation, skin hyperextensibility, bruisability, moderate skin fragility, joint hypermobility principally in digits, is described in two unrelated patients. Electron microscopy of the skin showed some fragmentation of the elastic fibers' portion and moderate electrodensity in the amorphous portion. Since a practically identical constellation of clinical features was previously reported in three patients, the individualization of a distinct connective tissue disorder, probably autosomal dominant, with variable expressivity is concluded.

Adolescent↗
PubMed1997

Clinical manifestation of a severe neonatal progeroid syndrome.

A girl with a progeroid appearance, with prominent occiput, blepharophimosis, cataract, arthrogryposis of the upper limbs and severe pulmonary stenosis is described. She died aged less than 6 months. An older sister was born 3 years before with the same appearance and underwent the same fatal evolution. The clinical appearance of this reported patient is compared to the previously published cases with severe neonatal progeroid syndromes.

Cutis Laxa↗
PubMed2006

The laminopathies: a clinical review.

The laminopathies are a diverse group of conditions caused by mutations in the LMNA gene (MIM*150330). LMNA encodes the nuclear envelope proteins lamin A and lamin C by utilization of an alternative splice site in exon 10. The human LMNA gene was identified in 1986 but it was another 13 years before it was found to be the causative gene for a disease, namely Emery Dreifuss muscular dystrophy. Since then, a further eight clearly defined phenotypes have been associated with LMNA mutations. The diversity of these phenotypes is striking with features such as premature ageing, axonal neuropathy, lipodystrophy and myopathy being seen. These phenotypes and the emerging genotype/phenotype correlations are the subject of this review.

Abnormalities, Multiple↗