scholarly journals Atypical Progeroid Syndrome due to Heterozygous Missense LMNA Mutations

2009 ◽  
Vol 94 (12) ◽  
pp. 4971-4983 ◽  
Author(s):  
Abhimanyu Garg ◽  
Lalitha Subramanyam ◽  
Anil K. Agarwal ◽  
Vinaya Simha ◽  
Benjamin Levine ◽  
...  
Keyword(s):  
Clinical Features ◽  
Trichostatin A ◽  
Epifluorescence Microscopy ◽  
Lamin A ◽  
Metabolic Complications ◽  
Prelamin A ◽  
Progeroid Syndrome ◽  
Number Of Patients ◽  
Hands And Feet ◽  
Mandibuloacral Dysplasia

Context: Hutchinson-Gilford progeria syndrome (HGPS) and mandibuloacral dysplasia are well-recognized allelic autosomal dominant and recessive progeroid disorders, respectively, due to mutations in lamin A/C (LMNA) gene. Heterozygous LMNA mutations have also been reported in a small number of patients with a less well-characterized atypical progeroid syndrome (APS). Objective: The objective of the study was to investigate the underlying genetic and molecular basis of the phenotype of patients presenting with APS. Results: We report 11 patients with APS from nine families, many with novel heterozygous missense LMNA mutations, such as, P4R, E111K, D136H, E159K, and C588R. These and previously reported patients now reveal a spectrum of clinical features including progeroid manifestations such as short stature, beaked nose, premature graying, partial alopecia, high-pitched voice, skin atrophy over the hands and feet, partial and generalized lipodystrophy with metabolic complications, and skeletal anomalies such as mandibular hypoplasia and mild acroosteolysis. Skin fibroblasts from these patients when assessed for lamin A/C expression using epifluorescence microscopy revealed variable nuclear morphological abnormalities similar to those observed in patients with HGPS. However, these nuclear abnormalities in APS patients could not be rescued with 48 h treatment with farnesyl transferase inhibitors, geranylgeranyl transferase inhibitors or trichostatin-A, a histone deacetylase inhibitor. Immunoblots of cell lysates from fibroblasts did not reveal prelamin A accumulation in any of these patients. Conclusions: APS patients have a few overlapping but some distinct clinical features as compared with HGPS and mandibuloacral dysplasia. The pathogenesis of clinical manifestations in APS patients seems not to be related to accumulation of mutant farnesylated prelamin A.

scholarly journals Atypical progeroid syndrome (p.E262K LMNA mutation): a rare cause of short stature and osteoporosis

2021 ◽  
Vol 2021 ◽  
Author(s):  
Marina Yukina ◽  
Nurana Nuralieva ◽  
Ekaterina Sorkina ◽  
Ekaterina Troshina ◽  
Anatoly Tiulpakov ◽  
...  
Keyword(s):  
Short Stature ◽  
De Novo ◽  
Age Of Onset ◽  
Gene Mutations ◽  
List Type ◽  
Metabolic Complications ◽  
Progeroid Syndrome ◽  
Progeria Syndrome ◽  
Mandibuloacral Dysplasia ◽  
Hutchinson Gilford Progeria Syndrome

Summary Lamin A/C (LMNA) gene mutations cause a heterogeneous group of progeroid disorders, including Hutchinson–Gilford progeria syndrome, mandibuloacral dysplasia, atypical progeroid syndrome (APS) and generalized lipodystrophy-associated progeroid syndrome (GLPS). All of those syndromes are associated with some progeroid features, lipodystrophy and metabolic complications but vary differently depending on a particular mutation and even patients carrying the same gene variant are known to have clinical heterogeneity. We report a new 30-year-old female patient from Russia with an APS and generalized lipodystrophy (GL) due to the heterozygous de novo LMNA p.E262K mutation and compare her clinical and metabolic features to those of other described patients with APS. Despite many health issues, short stature, skeletal problems, GL and late diagnosis of APS, our patient seems to be relatively metabolically healthy for her age when compared to previously described patients with APS. Learning points Atypical progeroid syndromes (APS) are rare and heterogenic with different age of onset and degree of metabolic disorders, which makes this diagnosis very challenging for clinicians and may be missed until the adulthood. The clinical picture of the APS depends on a particular mutation in the LMNA gene, but may vary even between the patients with the same mutation. The APS due to a heterozygous LMNA p.E262K mutation, which we report in this patient, seems to have association with the generalized lipodystrophy, short stature and osteoporosis, but otherwise, it seems to cause relatively mild metabolic complications by the age of 30. The patients with APS and lipodystrophy syndromes require a personalized and multidisciplinary approach, and so they should be referred to highly specialized reference-centres for diagnostics and treatment as early as possible. Because of the high heterogeneity of such a rare disease as APS, every patient’s description is noteworthy for a better understanding of this challenging syndrome, including the analysis of genotype-phenotype correlations.

scholarly journals Severe Mandibuloacral Dysplasia-Associated Lipodystrophy and Progeria in a Young Girl with a Novel Homozygous Arg527Cys LMNA Mutation

2008 ◽  
Vol 93 (12) ◽  
pp. 4617-4623 ◽  
Author(s):  
Anil K. Agarwal ◽  
Irina Kazachkova ◽  
Svetlana Ten ◽  
Abhimanyu Garg
Keyword(s):  
Joint Stiffness ◽  
Nuclear Lamina ◽  
Lamin A ◽  
Prelamin A ◽  
Farnesyl Transferase ◽  
Mandibular Hypoplasia ◽  
Lmna Mutation ◽  
Geranylgeranyl Transferase ◽  
Mandibuloacral Dysplasia

Context: Mandibuloacral dysplasia (MAD) is a rare autosomal recessive progeroid syndrome due to mutations in genes encoding nuclear lamina proteins, lamins A/C (LMNA) or prelamin A processing enzyme, and zinc metalloproteinase (ZMPSTE24). Objective: The aim of the study was to investigate the underlying genetic and molecular basis of the phenotype of a 7-yr-old girl with MAD belonging to a consanguineous pedigree and with severe progeroid features and lipodystrophy. Design and Patient: The patient developed mandibular hypoplasia during infancy and joint stiffness, skin thinning, and mottled hyperpigmentation at 15 months. Progressive clavicular hypoplasia, acroosteolysis, and severe loss of hair from the temporal and occipital areas were noticed at 3 yr. At 5 yr, cranial sutures were still open and lipodystrophy of the limbs was prominent. GH therapy from the ages of 3–7 yr did not improve the short stature. Severe joint contractures resulted in abnormal posture and decreased mobility. We studied her skin fibroblasts for nuclear morphology and immunoblotting and determined the in vitro effects of various pharmacological interventions on fibroblasts. Results: LMNA gene sequencing revealed a homozygous missense mutation, c.1579C>T, p.Arg527Cys. Immunoblotting of skin fibroblast lysate with lamin A/C antibody revealed no prelamin A accumulation. Immunofluorescence staining of the nuclei for lamin A/C in fibroblasts revealed marked nuclear morphological abnormalities. This abnormal phenotype could not be rescued with inhibitors of farnesyl transferase, geranylgeranyl transferase, or histone deacetylase. Conclusion: Severe progeroid features in MAD could result from LMNA mutation, which does not lead to accumulation of prenylated lamin A or prelamin A.

scholarly journals Compound Heterozygosity for Mutations in LMNA in a Patient with a Myopathic and Lipodystrophic Mandibuloacral Dysplasia Type A Phenotype

2007 ◽  
Vol 92 (11) ◽  
pp. 4467-4471 ◽  
Author(s):  
Francesca Lombardi ◽  
Francesca Gullotta ◽  
Marta Columbaro ◽  
Antonio Filareto ◽  
Monica D’Adamo ◽  
...  
Keyword(s):  
Histone H3 ◽  
Type A ◽  
Lamin A ◽  
Tail Domain ◽  
Lmna Gene ◽  
Partial Loss ◽  
Metabolic Complications ◽  
Heterochromatin Protein ◽  
Normal Expression ◽  
Mandibuloacral Dysplasia

Abstract Context: Mandibuloacral dysplasia type A (MADA; OMIM 248370) is a rare progeroid syndrome characterized by dysmorphic craniofacial and skeletal features, lipodystrophy, and metabolic complications. Most Italian patients carry the same homozygous missense mutation (p.R527H) in the C-terminal tail domain of the LMNA gene, which encodes lamin A/C, an intermediate filament component of the nuclear envelope. Objective: The objective of the study was to identify novel LMNA mutations in individuals with clinical characteristics (bird-like facies, mandibular and clavicular hypoplasia, acroosteolysis, lipodystrophy, alopecia) observed in other well-known patients. Design: The LMNA gene was sequenced. Functional properties of the mutant alleles were investigated. Patient: We report a 27-yr-old Italian woman showing a MADA-like phenotype. Features include a hypoplastic mandible, acroosteolysis, pointed nose, partial loss of sc fat, and a progeric appearance. Due to the absence of clavicular dysplasia and normal metabolic profiles, generally associated with muscle hyposthenia and generalized hypotonia, this phenotype can be considered an atypical laminopathy. Results: We identified a patient compound heterozygote for the p.R527H and p.V440M alleles. The patient’s cells showed nuclear shape abnormalities, accumulation of pre-lamin A, and irregular lamina thickness. Lamins A and C showed normal expression and localization. The electron microscopy detected heterochromatin defects with a pattern similar to those observed in other laminopathies. However, chromatin analysis showed a normal distribution pattern of the major heterochromatin proteins: heterochromatin protein-1β and histone H3 methylated at lysine 9. Conclusions: The clinical and cellular features of this patient show overlapping laminopathy phenotypes that could be due to the combination of p.R527H and p.V440M alleles.

Alterations of nuclear envelope and chromatin organization in mandibuloacral dysplasia, a rare form of laminopathy

2005 ◽  
Vol 23 (2) ◽  
pp. 150-158 ◽  
Author(s):  
Ilaria Filesi ◽  
Francesca Gullotta ◽  
Giovanna Lattanzi ◽  
Maria Rosaria D'Apice ◽  
Cristina Capanni ◽  
...  
Keyword(s):  
Nuclear Envelope ◽  
Protein A ◽  
Nuclear Architecture ◽  
Mendelian Inheritance ◽  
Premature Aging ◽  
Lamin A ◽  
Lamin B ◽  
Lamin B Receptor ◽  
Epigenetic Events ◽  
Mandibuloacral Dysplasia

Autosomal recessive mandibuloacral dysplasia [mandibuloacral dysplasia type A (MADA); Online Mendelian Inheritance in Man (OMIM) no. 248370 ] is caused by a mutation in LMNA encoding lamin A/C. Here we show that this mutation causes accumulation of the lamin A precursor protein, a marked alteration of the nuclear architecture and, hence, chromatin disorganization. Heterochromatin domains are altered or completely lost in MADA nuclei, consistent with the finding that heterochromatin-associated protein HP1β and histone H3 methylated at lysine 9 and their nuclear envelope partner protein lamin B receptor (LBR) are delocalized and solubilized. Both accumulation of lamin A precursor and chromatin defects become more severe in older patients. These results strongly suggest that altered chromatin remodeling is a key event in the cascade of epigenetic events causing MADA and could be related to the premature-aging phenotype.

Clinical features and neuroimaging findings in acute cerebral infarction patients using RAPID Artificial Intelligent (RAPID AI) Software Analysis – a series of 54 cases (Preprint)

2021 ◽  
Author(s):  
Ngoc Huy Nguyen ◽  
Minh Van Hoang ◽  
An Quang Nguyen ◽  
Luc Quang Tran ◽  
Thong Van Nguyen
Keyword(s):  
Cerebral Infarction ◽  
Clinical Features ◽  
Cerebral Circulation ◽  
Clinical Signs ◽  
Acute Cerebral Infarction ◽  
Stroke Patients ◽  
Permanent Disability ◽  
Artificial Intelligent ◽  
Software Analysis ◽  
Number Of Patients

BACKGROUND Stroke is the second leading cause of death and the leading cause of permanent disability globally. Vietnam is a developing country with a high prevalence of stroke. OBJECTIVE This study aimed to present the clinical features and neuroimaging findings in acute cerebral infarction patients using RAPID Artificial Intelligent (RAPID AI) Software Analysis METHODS A case series of 54 stroke patients based on data from the electronic medical records who admitted between October 2019 and October 2020, for whom Rapid AI was used to analyze images of stroke. RESULTS The results showed that the mean age of patients was 73.39 ± 12.46 years and males comprised 57.4 of the sample. The most common risk factor identified was hypertension (75.9%), followed by atrial fibrillation (24%), diabetes (20%), alcohol (15%), and smoking (9%). The most common clinical signs were hemiparesis in 76% of the patients, followed by dysphasia in 50% and memory loss in 28% of the sample. 7% presented with dizziness and 7% with headache. 6% were unconscious on admission. ASPECTS evaluation showed that 24 (44%) patients had good ASPECTS scores of 8-10, 17 (32%) patients had ASPECTS scores of 5-7, and 13 (24%) patients had ASPECTS scores of 0-4. The number of patients with an infarct core volume <70 mL was 50 (93%), while a mismatch volume of >15 mL was observed in 31 (55%) patients and 22 (41%) patients had a mismatch ratio >1.8. The assessment of CT imaging of thrombi showed 51 cases of anterior cerebral circulation, including 13 (24%) cases diagnosed as ICA, 30 (76%) cases diagnosed as MCA, and 8 (15%) cases diagnosed as SA. There were 10 cases of MCA-M1 (19%), 7 cases of MCA-M2 and MCA-M4 (13%) cases and 6 cases of MCA-M3 (11%), respectively. There were three cases of posterior cerebral circulation, comprising one case of Posterior cerebral artery (PCA) and two cases of Basilar artery (BA) territory infarction. CONCLUSIONS A collection of clinical features and neuroradiological assessment based on RAPID Artificial Intelligent (RAPID AI) Software Analysis can be used in identify stroke patients in the hospitals.

scholarly journals Epidemiological and Clinical Features of Dengue Infection in Adults in the 2017 Outbreak in Vietnam

2019 ◽  
Vol 2019 ◽  
pp. 1-6 ◽  
Author(s):  
Bui Vu Huy ◽  
Le Nguyen Minh Hoa ◽  
Dang Thi Thuy ◽  
Nguyen Van Kinh ◽  
Ta Thi Dieu Ngan ◽  
...  
Keyword(s):  
Elderly Patients ◽  
Dengue Fever ◽  
Clinical Features ◽  
Dengue Infection ◽  
Clinical Manifestations ◽  
Warning Signs ◽  
Severe Dengue ◽  
Severe Bleeding ◽  
Cross Sectional ◽  
Number Of Patients

Purpose. The clinical features and laboratory results of dengue-infected adult patients admitted to the hospital during the 2017 outbreak were analyzed in this study. Method. This is a cross-sectional study. 2922 patients aged 18 years or more with dengue fever in National Hospital for Tropical Diseases (NHTD) in the North and Hospital for Tropical Disease (HTD) in the South of Vietnam were recruited in this study. Result. Patients were admitted in the hospital around the year and concentrated from August to December, in 53/63 (84.0%) provinces in Vietnam, and patients in all ages were affected. The number of patients with dengue fever was 1675 (57.3%), dengue with warning signs 914 (31.3%), and severe dengue 333 (11.4%), respectively. Among patients with severe dengue, severe plasma leakage and dengue shock account for 238 (8.1%), severe organ impairment 73 (2.5%), and severe bleeding 22 (0.75%). The rate of mortality was 0.8%, and the outcome of dengue patients is worse in the elderly and people with underlying diseases. Conclusion. The 2017 dengue outbreak occurred in a larger scale than in the previous years in terms of time, location, and number of patients. More elderly patients were infected by dengue in this outbreak, and this may contribute to the mortality rate. Clinical manifestations of dengue patients in Southern Vietnam are more typical than the northern, but the rate of severe dengue is not different. The mortality risk and underlying conditions associated with dengue-infected elderly patients are worthy of further investigations in the future.

scholarly journals Analysis of Prelamin A Biogenesis Reveals the Nucleus to be a CaaX Processing Compartment

2008 ◽  
Vol 19 (12) ◽  
pp. 5398-5408 ◽  
Author(s):  
Jemima Barrowman ◽  
Corinne Hamblet ◽  
Carolyn M. George ◽  
Susan Michaelis
Keyword(s):  
Posttranslational Modifications ◽  
Active Sites ◽  
Intracellular Localization ◽  
Premature Aging ◽  
Lamin A ◽  
Prelamin A ◽  
Processing Enzymes ◽  
Dual Localization ◽  
Endoproteolytic Cleavage ◽  
Er Membrane

Proteins establish and maintain a distinct intracellular localization by means of targeting, retention, and retrieval signals, ensuring most proteins reside predominantly in one cellular location. The enzymes involved in the maturation of lamin A present a challenge to this paradigm. Lamin A is first synthesized as a 74-kDa precursor, prelamin A, with a C-terminal CaaX motif and undergoes a series of posttranslational modifications including CaaX processing (farnesylation, aaX cleavage and carboxylmethylation), followed by endoproteolytic cleavage by Zmpste24. Failure to cleave prelamin A results in progeria and related premature aging disorders. Evidence suggests prelamin A is imported directly into the nucleus where it is processed. Paradoxically, the processing enzymes have been shown to reside in the cytosol (farnesyltransferase), or are ER membrane proteins (Zmpste24, Rce1, and Icmt) with their active sites facing the cytosol. Here we have reexamined the cellular site of prelamin A processing, and show that the mammalian and yeast processing enzymes Zmpste24 and Icmt exhibit a dual localization to the inner nuclear membrane, as well as the ER membrane. Our findings reveal the nucleus to be a physiologically relevant location for CaaX processing, and provide insight into the biology of a protein at the center of devastating progeroid diseases.

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