Hutchinson-Gilford progeria syndrome with G608G LMNA mutation

Hutchinson-Gilford progeria syndrome (HGPS) is a rare condition originally described by Hutchinson in 1886. Death result from cardiac complications in the majority of cases and usually occurs at average age of thirteen years. A 4-yr old boy had typical clinical findings such as short stature, craniofacial disproportion, alopecia, prominent scalp veins and sclerodermatous skin. This abnormal appearance began at age of 1 yr. On serological and hormonal evaluation, all values are within normal range. He was neurologically intact with motor and mental development. An echocardiogram showed calcification of aortic and mitral valves. Hypertrophy of internal layer at internal carotid artery suggesting atherosclerosis was found by carotid doppler sonography. He is on low dose aspirin to prevent thromboembolic episodes and on regular follow up. Gene study showed typical G608G (GGC- > GGT) point mutation at exon 11 in LMNA gene. This is a rare case of Hutchinson-Gilford progeria syndrome confirmed by genetic analysis in Korea.     

C1824T mutation in the LMNA gene has no association with senile cataract

Mutations in the LMNA gene encoding lamins A/C are responsible for Hutchinson-Gilford syndrome (HGS), a disorder of premature aging. Cataract is 1 of the main manifestations. The most prevalent mutation in Hutchinson-Gilford syndrome is C1824T, which activates a cryptic splice donor site to produce an abnormal lamin A protein. The purpose of this study was to investigate a possible association of the C1824T mutation with age-related cataract. Anterior lens capsule material was collected during cataract extraction surgery from 178 patients with senile cataract during 2007-2008. DNA and mRNA were extracted and sequenced for the LMNA gene. DNA and cDNA were screened for the C1824T mutation, which was not detected. Messenger RNA (mRNA) expression was normal, with no truncation. We found that human age-related nuclear cataract is not associated with LMNA gene mutations or truncation of lamin A.     

Polymorphisms in LMNA and near a SERPINA13 gene are not associated with cognitive performance in Chinese elderly males without dementia

Aging is associated with cognitive deterioration. A recent study showed two polymorphisms (rs505058 in LMNA and rs11622883 near a SERPINA13 gene), identified in a genome-wide association study of late-onset Alzheimer's disease, to be associated with cognitive function (Mini Mental State Examination) in a UK elderly population. This study replicated these findings in Chinese elderly males without dementia. A total of 358 elderly subjects were assessed by the Cognitive Abilities Screening Instruments (CASI) and the Wechsler Digit Span Task tests. Analysis of covariance was used to compare cognitive scores among genotypic groups, with age and total education years as covariates. The two polymorphisms were not associated with the global cognitive function or specific cognitive domains in the elderly without dementia. Our data argue against that these two polymorphisms may affect cognitive function in the elderly.     

A novel homozygous p.Arg527Leu LMNA mutation in two unrelated Egyptian families causes overlapping mandibuloacral dysplasia and progeria syndrome

Mandibuloacral dysplasia (MAD) is a rare disease resulting from a mutation of LMNA gene encoding lamins A and C. The most common mutation associated with this disease is a homozygous arginine 527 replacement by histidine. Three female patients originating from two unrelated families from Northeast Egypt were examined. Their growth was retarded; they had microcephaly, widened cranial sutures, prominent eyes and cheeks, micrognathia, dental crowding, hypoplastic mandible, acro-osteolysis of distal phalanges, and joint contractures. In addition, they presented some progeroid features, such as pinched nose, premature loss of teeth, loss of hair, scleroderma-like skin atrophy, spine rigidity, and waddling gait. The clinical presentation of the disease varied between the patient originating from Family 1 and patients from Family 2, suggesting that unknown, possibly epigenetic factors, modify the course of the disease. The first symptoms of the disease appeared at the age of 2.5 (a girl from Family 1), 5, and 3 years (girls from Family 2). All patients had the same, novel homozygous c.1580G>T LMNA mutation, resulting in the replacement of arginine 527 by leucine. Computational predictions of such substitution effects suggested that it might alter protein stability and increase the tendency for protein aggregation, and as a result, might influence its interaction with other proteins. In addition, restriction fragment-length polymorphism analysis performed in 178 unrelated individuals showed that up to 1.12% of inhabitants of Northeast Egypt might be heterozygous carriers of this mutation, suggesting the presence of a founder effect in this area.     

Laminopathies: multisystem dystrophy syndromes

Laminopathies are a heterogeneous group of genetic disorders due to abnormalities in type A lamins and can manifest varied clinical features affecting many organs including the skeletal and cardiac muscle, adipose tissue, nervous system, cutaneous tissue, and bone. Mutations in the gene encoding lamins A and C (LMNA) cause primary laminopathies, including various types of lipodystrophies, muscular dystrophies and progeroid syndromes, mandibuloacral dysplasia, dilated cardiomyopathies, and restrictive dermopathy. The secondary laminopathies are due to mutations in ZMPSTE24 gene which encodes for a zinc metalloproteinase involved in processing of prelamin A into mature lamin A and cause mandibuloacral dysplasia and restrictive dermopathy. Skin fibroblast cells from many patients with laminopathies show a range of abnormal nuclear morphology including bleb formation, honeycombing, and presence of multi-lobulated nuclei. The mechanisms by which mutations in LMNA gene cause multisystem dystrophy are an active area of current investigation. Further studies are needed to understand the underlying mechanisms of marked pleiotropy in laminopathies.     

Mild variable Noonan syndrome in a family with a novel PTPN11 mutation

Noonan syndrome (OMIM 163950) is a common genetic condition with variable clinical expression and genetic heterogeneity. About half of the cases can be accounted to activating mutations in the PTPN11 gene encoding SHP-2. We report on a family with mild, variable expression of Noonan syndrome in five individuals. Clinical manifestations included short stature, craniofacial anomalies and thorax deformity, but none of the affected family members had a heart defect. Sequencing of the entire coding region of PTPN11 revealed a novel mutation c.1226G-->C in exon 11 predicting the amino acid exchange G409A. This mutation is not located in the previously known mutation clusters. Our observation and the recent report of a mutation affecting a neighbouring residue (T411M) in a family with a variable phenotype suggest that mutations in this particular region of SHP-2 may have effects on the protein that differ from those of the classical mutations.     

A homozygous ZMPSTE24 null mutation in combination with a heterozygous mutation in the LMNA gene causes Hutchinson-Gilford progeria syndrome (HGPS): insights into the pathophysiology of HGPS

Hutchinson-Gilford progeria syndrome (HGPS) is a rare premature aging disorder normally caused by a spontaneous heterozygous mutation in the LMNA gene that codes for the nuclear lamina protein lamin A. Several enzymes are involved in the processing of its precursor, prelamin A, to the mature lamin A. A functional knockout of one of the enzymes involved in prelamin A processing, the zinc metalloprotease ZMPSTE24, causes an even more severe disorder with early neonatal death described as restrictive dermatopathy (RD). This work describes a HGPS patient with a combined defect of a homozygous loss-of-function mutation in the ZMPSTE24 gene and a heterozygous mutation in the LMNA gene that results in a C-terminal elongation of the final lamin A. Whereas the loss of function mutation of ZMPSTE24 normally results in lethal RD, the truncation of LMNA seems to be a salvage alteration alleviating the clinical picture to the HGPS phenotype. The mutations of our patient indicate that farnesylated prelamin A is the deleterious agent leading to the HGPS phenotype, which gives further insights into the pathophysiology of the disorder.     

Periaxin mutation in Japanese patients with Charcot-Marie-Tooth disease

Periaxin (PRX) plays an important role in the myelination of the peripheral nerve and consequently in the pathogenesis of Charcot-Marie-Tooth disease (CMT). To date, nine nonsense or frameshift PRX mutations have been reported in eight families with CMT. The patients with PRX mutations appeared to show characteristic clinical features with early onset but slow or no progression, a common result of mutations that lead to missing a C-terminal acidic domain. Here, we report a Japanese CMT patient with these characteristic clinical features, who was a compound heterozygote for PRX R1070X and L132FsX153 mutations. We previously reported that three Japanese isolated families also had the homozygous R1070X mutation. To examine the potential founder effect of the R1070X mutation in the Japanese population, we performed haplotype analysis and found that each R1070X allele lay on a different haplotype background in these four families. Therefore, the high frequency of the R1070X mutation among the Japanese population is not likely the consequence of a founder effect, but probably a result of a mutation hot spot.     

A TP53-truncating germline mutation (E287X) in a family with characteristics of both hereditary diffuse gastric cancer and Li-Fraumeni syndrome

Mutations in CDH1, which encodes E-cadherin, have been associated with hereditary diffuse gastric cancer (HDGC) in Western populations but have not been shown to play a major role in Asians. Recently, a patient with familial gastric cancer (FGC) was shown to harbor a germline mutation in the TP53 gene, which encodes p53 and has been previously associated with Li-Fraumeni Syndrome (LFS). To determine whether mutations in TP53 are associated with FGC in Asians, we screened the entire coding region of TP53 in probands from 23 Korean FGC families. We identified a nonsense (E287X) TP53 germline mutation in a family whose history is compatible with both HDGC and LFS. Two members of this family (SNU-G2) were afflicted with brain tumors, seven with gastric cancers, two with sarcomas, and one with both gastric cancer and a sarcoma. The E287X TP53 mutation segregated with the cancer phenotype in the family members from whom DNA samples were available. To our knowledge, this is the first report of a large family with both HDGC and LFS. Our results suggest that TP53 mutational screening in FGC families should be interpreted with caution because additional TP53 mutation-carrying HDGC families may also show LFS-related phenotypes.     

Improved bronchodilation with levalbuterol compared with racemic albuterol in patients with asthma

Background: Racemic albuterol is an equal mixture of (R)-albuterol (levalbuterol), which is responsible for the bronchodilator effect, and (S)-albuterol, which provides no benefit and may be detrimental. Objective: We sought to compare 2 doses of a single enantiomer, levalbuterol (0.63 mg and 1.25 mg), and equivalent amounts of levalbuterol administered as racemic albuterol with placebo in patients with moderate-to-severe asthma. Methods: This was a randomized, double-blind, parallel-group trial. Three hundred sixty-two patients 12 years of age or older were treated with study drug administered by means of nebulization 3 times daily for 28 days. The primary endpoint was peak change in FEV₁ after 4 weeks. Results: The change in peak FEV₁ response to the first dose in the combined levalbuterol group was significantly greater compared with the combined racemic albuterol group (0.92 and 0.82 L, respectively; P = .03), with similar but nonsignificant results after 4 weeks (0.84 and 0.74 L, respectively). Improvement in FEV₁ was similar for levalbuterol 0.63 mg and racemic albuterol 2.5 mg and greatest for levalbuterol 1.25 mg. Racemic albuterol 1.25 mg demonstrated the weakest bronchodilator effect, particularly after chronic dosing. The greatest increase in FEV₁ was seen after levalbuterol 1.25 mg, especially in subjects with severe asthma. All active treatments were well tolerated, and β-adrenergic side effects after administration of levalbuterol 0.63 mg were reduced relative to levalbuterol 1.25 mg or racemic albuterol 2.5 mg. At week 4, the predose FEV₁ value was greatest in patients who received levalbuterol or placebo when compared with those who received racemic albuterol. The difference was more evident and was statistically significant in patients who were not receiving inhaled corticosteroids. Conclusion: Levalbuterol appears to provide a better therapeutic index than the standard dose of racemic albuterol. These results support the concept that (S)-albuterol may have detrimental effects on pulmonary function. (J Allergy Clin Immunol 1998;102:943-52.)     

Clinical and molecular characterization of 40 patients with Noonan syndrome

Noonan syndrome (NS, OMIM 163950) is an autosomal dominant disorder, with a prevalence at birth of 1:1000–1:2500 live births, characterized by short stature, facial and skeletal dysmorphisms, cardiovascular defects and haematological anomalies. Missense mutations of PTPN11 gene account for approximately 50% of NS cases, while molecular lesions of other genes of the RAS/MAPK pathway – KRAS, SOS1 and RAF1 – play a minor role in the molecular pathogenesis of the disease. Forty patients were enrolled in the study with a PTPN11 mutation detection rate of 31.5%, including a novel missense mutation, Phe285Ile, in a familial case with high intrafamilial phenotypic variability. All patients negative for PTPN11 mutations were further screened for mutations of the KRAS, SOS1, and RAF1 genes, revealing a Thr266Lys substitution in SOS1 in a single patient, a newborn with a subtle phenotype, characterized by facial dysmorphisms and a mild pulmonic stenosis.     

A familial case of Keratitis-Ichthyosis-Deafness (KID) syndrome with the GJB2 mutation G45E

Keratitis-Ichthyosis-Deafness (KID) syndrome (OMIM 148210) is a congenital ectodermal defect. KID consists of an atypical ichthyosiform erythroderma associated with congenital sensorineural deafness. A rare form of the KID syndrome is a fatal course in the first year of life due to severe skin lesion infections and septicaemia. KID appears to be genetically heterogeneous and may be caused by mutations in connexin 26 or connexin 30 genes. GJB2 mutations in the connexin 26 gene are the main cause of the disease. Most of the cases caused by GJB2 mutations are sporadic, but dominant transmission has also been described. To date, the rare lethal form of the disease has been only observed in two Caucasian sporadic patients with the GJB2 mutation, with the p.Gly45Glu (G45E) arising de novo. We have reported an African family with dizygotic twins suffering from a lethal form of KID. The dizygosity of the twins was confirmed by microsatellite markers. The two patients were heterozygous for the G45E mutation of GJB2, whereas the mutation was not detected in the two parents. The unusual transmission of the disease observed in this family could be explained by the occurrence of a somatic or more probably a germinal mosaic in one of the parents.     

Quality of life and health status after prophylactic salpingo-oophorectomy in women who carry a BRCA mutation: A review

Prophylactic salpingo-oophorectomy is recommended to women who carry a BRCA1 or BRCA2 mutation at age 35 or after childbearing is complete. This procedure is the mainstay of ovarian and fallopian tube cancer prevention in these women. Therefore an understanding of the short and long-term impact of the surgery is essential. Salpingo-oophorectomy, particularly when done prior to natural menopause, may impact on several aspects of quality of life and health. The health benefits of this surgery (cancer prevention) should outweigh the costs of the procedure in terms of quality of life and long term health. In this review, the impact of this surgery on quality of life and health in women who carry a BRCA mutation is discussed. Preliminary studies have focused on short-term effects, such as quality of life. In the short term, overall quality of life appears to be similar before and after surgery, however vasomotor symptoms related to surgical menopause and changes in sexual functioning are common. HRT appears to mitigate some but not all of these symptoms. Women report high levels of satisfaction with their decision to have the surgery despite the impact of prophylactic salpingo-oophorectomy. Studies of the long term health and quality of life after salpingo-oophorectomy in women who carry a BRCA mutation have not yet been published.     

Analysis of FOXF1 and the FOX gene cluster in patients with VACTERL association

VACTERL association, a relatively common condition with an incidence of approximately 1 in 20,000 -35,000 births, is a non-random association of birth defects that includes vertebral defects (V), anal atresia (A), cardiac defects (C), tracheo-esophageal fistula (TE), renal anomalies (R) and limb malformations (L). Although the?etiology is unknown in the majority of patients, there is evidence that it is causally heterogeneous. Several studies have shown evidence for inheritance in VACTERL, implying a role for genetic loci. Recently, patients with component features of VACTERL and a lethal developmental pulmonary disorder, alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV), were found to harbor deletions or mutations affecting FOXF1 and the FOX gene cluster on chromosome 16q24. We investigated this gene through direct sequencing and high-density SNP microarray in 12 patients with VACTERL association but without ACD/MPV. Our mutational analysis of FOXF1 showed normal sequences and no genomic imbalances affecting the FOX?gene cluster on chromosome 16q24 in the studied patients. Possible explanations for these results include the etiologic and clinical heterogeneity of VACTERL association, the possibility that mutations affecting this gene may occur only in more severely affected individuals, and insufficient study sample size.     

Diminished IL-10 production in subjects with allergy after infection with influenza A virus

BACKGROUND: Recent studies have documented a link between respiratory viral infections and the expression of asthma and other allergic disorders. Results from other studies have suggested that diminished production of IL-10, an anti-inflammatory cytokine, may contribute to the pathophysiologic features of these diseases. OBJECTIVE: The objective of this study was to determine whether diminished IL-10 production and TH2 cytokine skewing occur in allergic, as compared with nonallergic, subjects after experimental infection with the influenza A virus. METHODS: PBMCs were isolated from 11 subjects with allergy and 14 subjects with no allergy before and after influenza A infection and stimulated with either mitogen (PHA) or antigen (influenza A). Supernatants were assayed for IL-10, IL-4, and IFN-gamma by ELISA. RESULTS: PBMC IL-10 production was significantly diminished in subjects with allergy, as compared with subjects with no allergy, after experimental infection with influenza A virus. However, significant TH2 skewing and enhanced airway symptoms were not observed in these same subjects. CONCLUSIONS: These data provide further support that subjects with allergy have an intrinsic inability to upregulate IL-10 production in response to inflammatory stimuli and extend this observation to include respiratory viral infections. Future studies in this area could lead to a better understanding of the pathogenesis of asthma and other allergic disorders     

Gelatin-induced T-cell activation in children with nonanaphylactic-type reactions to vaccines containing gelatin

Background: Many cases of anaphylactic or nonanaphylactic reactions have been reported to measles-mumps-rubella vaccine or its component vaccines that contain gelatin as a stabilizer. Increased levels of specific IgE antibodies to gelatin have been reported in children with anaphylactic reactions. However, IgE is not increased in cases of nonanaphylactic reaction, and the mechanisms of the reaction are still controversial. Objective: The study was aimed to elucidate the relationship between nonanaphylactic reaction and gelatin. Methods: We investigated in vitro induction of activated memory helper T cells (CD4⁺ CD25⁺ CD45RO⁺ cells) in response to gelatin in children with nonanaphylactic reactions to vaccines containing gelatin. Results: In patients with delayed-type sensitivity to gelatin confirmed with a positive skin test response, CD4⁺ CD25⁺ CD45RO⁺ cells were significantly more strongly induced in culture containing gelatin than in control cultures. However, there was no significant difference between cultures with gelatin and those with control solvent in patients without reactions after vaccination. Of 76 patients with nonanaphylactic reactions after immunization with vaccine containing gelatin, 61 had an increased lymphocyte stimulation index to gelatin versus control children. Conclusion: These results suggest the possibility that nonanaphylactic reactions to gelatin-containing vaccine in Japan might be mediated by delayed hypersensitivity reactions against gelatin. (J Allergy Clin Immunol 1998;102:1028-32.)     

Evidence for association of lipopolysaccharide with Pseudomonas fluorescens strain MF0 porin OprF

Lipopolysaccharide (LPS) was found to be associated with the major outer membrane protein OprF of the psychrotrophic bacterium Pseudomonas fluorescens MF0, using two OprF purification procedures. OprF, purified under mild conditions, presented two types of association with LPS: tight (tLPS) and slight (sLPS), both of type R. LPS protected OprF from heat modification and trypsin degradation and facilitated the reincorporation of purified OprF into an artificial lipid bilayer without affecting its pore-forming activity. The size of the OprF channel depended on cell growth temperature, as did the extent of LPS phosphorylation: we suggest that LPS may be involved in modifications of OprF pore formation.     

Comparison of the effects of terfenadine with fexofenadine on nasal provocation tests with allergen

BACKGROUND: Fexofenadine, the hydrochloride salt of terfenadine active metabolite, is a nonsedative, noncardiotoxic antihistamine derivative for the treatment of allergic rhinitis. OBJECTIVE: We sought to compare the effects of terfenadine and fexofenadine on nasal provocation tests with allergen. METHODS: A preliminary provocation test (screening phase) was performed in 25 patients with a history of seasonal allergic rhinitis to grass pollen to determine the combined nasal reaction threshold, which was defined as 2 of the 3 following criteria: (1) at least a 40% decrease in peak nasal inspiratory flow and/or a 30% decrease in minimal cross-sectional area as measured by acoustic rhinometry, nasal secretions of 0.5 g, and 5 to 10 sneezes per minute. Patients were then included into a double-blind, randomized, 2-way crossover study to receive terfenadine or fexofenadine 120 mg 2 hours before provocation. Rhinorrhea, sneezing, peak nasal flow, and minimal nasal cross-sectional area, as well as symptom scores for nasal congestion and itchiness, were recorded at each allergen concentration up to the reaction threshold. The whole study was performed out of allergy season. RESULTS: Fexofenadine was as potent as terfenadine in limiting pruritus and nasal congestion. Rhinorrhea and sneezing were better controlled by fexofenadine than by terfenadine. Overall, the allergen concentration necessary to reach the combined reaction threshold was increased after treatment with both drugs. Comparison between screening and each treatment phase indicated that the shift in allergen concentration to reach the reaction threshold was significantly greater after fexofenadine than after terfenadine (P =. 033). CONCLUSION: After oral administration, fexofenadine provided better protection than terfenadine against the immediate allergic reaction.