Recent eLetters
Displaying 1-10 letters out of 80 published
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Circumscribing the clinical severity of Rubinstein-Taybi syndrome by CBP modulated genome expression
Submit responseThe respective article was well read by us. We agree with the precious scientific findings by the authors but at the same time we would like to recall the two very basic fundamental functions of CBP, which involve CBP as a bridging molecule and a cofactor (Montmini et al., 1986) for CREB modulated gene expression and histone acetyltransferase activity of CBP on CREB modulated gene expression (Lu et al., 2003) specifically and on histone acetylation in general.
This study specifically targeted lymphoid cell lines from patients with Rubinstein-Taybi syndrome but it has provided a new horizon towards defining some crucial event as the respective authors have tried to correlate the general post-transcriptional events (via histone acetylation level) with the transcriptional events (by CBP and p300 as a co- activators/cofactors). The study has given the overall status of the histone acetylation level and mutations within the CBP gene but yet unable to describe the role of these mutations in CBP specifically to any specific genes/motifs within the whole genome or in the CRE elements in the promoter region of different genes, which could play a vital role in circumscribing the clinical severity of the disease as has been in seen in a report from Sarmila et al., 2004; which stated the role in overexpressing the SMN genes associated with Spinal Muscular Atrophy. The disease shared quite similar clinical features with Rubinstein-Taybi syndrome with a vast heterogeneity.
The transcription factors are reported to be phosphorylated by Protein Kinase K (PKA) which is dependent on increase level of cAMP. CREB has been reported to be the best linked between PKA activation and gene transcription (Montmini et al., 1986). Authors also studied p300 which has been reported to interact with many transcription factors, reflecting the role of p300 and CBP as co-activators more generally in signal integration (Goodman et al., 2000).
Deficit in histone acetylation in cell lines in this study can be correlated to the defect in histone acetyltransferase activity of CBP in general on the whole genome but the specific effect through the invitro CREB acetylation must be considered by the respective authors by atleast the linkage analysis of the CREB induced genes in the described nine patients in this study. We assume, by doing so, the role of CREB or CRE modulated disease severity could be ruled out. We have done the same for Spinal Muscular Atrophy (data not published yet).
Similarly, the use of histone deacetylases (HDACi)followed by the the acetylation status is too general for the entire genome. For sure, HDACi will recover the "acetyltransferase activity" of CBP but the effect of HDACi on the coactivation function of the CBP is not well explained. Any of the histone deacetylases, will increase the whole genome expression but defining the specific HDACi molecule for a specific gene is the need for decreasing and circumscribing the clinical severity of Rubinstein-Taybi syndrome. Some studies have been reported explaining the effect of HDACi in SMA which make use of several molecules (Sumner et al., 2006 and Brichta et al., 2003, Andreassi et al., 2004).
There is a need to explore the specific genes for their epigentic control and effect in Rubinstein-Taybi syndrome therefore, further studies are needed to confirm the effect of these mutation and histone acetylation; towards defining specific genes in circumscribing the clinical severity of Rubinstein-Taybi syndrome and to develop a strategy for gene therapy.
References:
1. Montminy MR, Bilezikjian LM, (1987). Binding of a nuclear protein to the cyclic-AMP response element of the somatostatin gene. Nature. 15;328(6126):175-8.
2. Lu Q, Hutchins AE, Doyle CM, Lundblad JR, Kwok RP, (2003). Acetylation of cAMP-responsive element-binding protein (CREB) by CREB- binding protein enhances CREB-dependent transcription. J Biol Chem. 2;278(18):15727-34.
3. Sarmila Majumder, Saradhadevi Varadharaj, Kalpana Ghoshal, Umrao Monani, Arthur H. M. Burghes, Samson T. Jacob, (2004). Identification of a Novel Cyclic AMP-response Element (CRE-II) and the Role of CREB-1 in the cAMP-induced Expression of the Survival Motor Neuron (SMN) Gene. The journal of biological chemistry: 279, 15: 14803-1481.
4.Goodman RH, Smolik S, (2000). CBP/p300 in cell growth, transformation, and development. Genes Dev. 1;14(13):1553-77.
5. Sumner CJ, (2006). Therapeutics development for spinal muscular atrophy. NeuroRx: 3:235-245.
6. Brichta L, Hofmann Y, Hahnen E, Siebzehnrubl FA, Raschke H, Blumcke I, Eyupoglu IY, Wirth B, (2003). Valproic acid increases the SMN2 protein level: a well-known drug as a potential therapy for spinal muscula
Conflict of Interest:
None declared
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POLG p.G268A and p.G517V are not pathogenic mutations
Submit responseIn their recently published paper describing mutations in mitochondrial DNA polymerase gamma, Tang et al.(1) propose that the POLG p.G268A (c.803G>C) and p.G517V (c.1550G>T) variants which have previously been reported as pathogenic mutations should be considered as unclassified variants that may represent rare neutral polymorphisms or polymorphic modifiers.
We have also identified these variants in our own cohort of 627 patients that were referred with a suspected disorder of mitochondrial DNA maintenance. We detected p.G268A in 9 individuals (allele frequency 0.72%) of ages from 3 months to 63 years. Symptoms were variable ranging from severe early onset mitochondrial DNA depletion syndrome to milder late onset neuropathy/ataxia/ophthalmoplegia. In all 9 cases the variant occurred as a heterozygous change with no other pathogenic POLG mutation, suggesting that p.G268A is not a recessive mutation. Parental samples were available in 3 cases, and for each of these we found the variant in an unaffected parent, suggesting that p.G268A is very unlikely to be a dominant mutation. Furthermore, one of the 9 index cases was later found to be compound heterozygous for pathogenic mutations in another gene associated with mtDNA maintenance disorders, DGUOK. In another case the proband had a similarly affected sibling who did not have p.G268A.
Similarly, we have identified p.G517V 8 times (allele frequency 0.64%), always as a heterozygous change with no other pathogenic POLG mutation. The age of the individuals ranged from 1-81 yrs and the phenotype varied from infantile epilepsy/failure to thrive to adult onset ophthalmoplegia/ataxia/myopathy. The unaffected parent of 1 of these individuals was also heterozygous for p.G517V. A second affected individual was later found to have pathogenic mutations in RRM2B.
Furthermore, the allele frequencies of p.G268A and p.G517V in our patient cohort are remarkably similar to those found in a large control population of European origin (2700 alleles) by the NHLBI exome sequencing project (2); 0.59% and 0.86% respectively.
Therefore, our data, taken together with that for Tang et al. and the NHLBI exome sequencing project, confirm that POLG p.G268A and p.G517V are not pathogenic and are highly likely to represent neutral polymorphisms.
References. (1) Tang S, Wang J, Lee NC, Milone M, Halberg MC, Schmitt ES, Craigen WJ, Zhang W, Wong LJ. Mitochondrial DNA polymerase gamma mutations: an ever expanding molecular and clinical spectrum. J Med Genet 2011;48:669-681. (2) https://esp.gs.washington.edu/drupal/
Conflict of Interest:
None declared
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The C-G single nucleotide polymorphism at -20 of the Connective Tissue Growth Factor (CTGF) gene is not present in a European Caucasoid population of patients with type 1 diabetes and nephropathy
Submit responseRe: Genetic variant in the promoter of connective tissue growth factor gene confers susceptibility to nephropathy in type 1 diabetes. Wang et al., J Med Genet 2010; 47:391-397. Doi:10,1136/jmg.2009.073098
It was with great interest that we read the recent study by Wang et al. on a novel C/G single nucleotide polymorphism (SNP) at position -20 in the promoter of the connective tissue growth factor (CTGF) gene confers susceptibility to diabetic nephropathy in patients with type 1 diabetes (T1D).[1] Based on these findings we studied this SNP in our cohort of T1D to determine its association with the development of diabetic nephropathy. This SNP was genotyped in 932 European Caucasoid subjects and failed to detect the polymorphism.
Connective tissue growth factor (CTGF) is a secreted protein with a molecular weight at 36-38 kDa and plays an important role in the balance of degradation and synthesis of extracellular matrix although its physiological functions are not limited to this.[2] Several studies have demonstrated that CTGF plays a fundamental role in the histopathological changes seen in diabetic nephropathy. It has been demonstrated that low levels of glomerular CTGF are found in normal human glomeruli, but both mRNA and protein levels of CTGF increase during the early stages of diabetic nephropathy and continue to increase with disease progressionand these increases also correlate with the degree of albuminuria.[3]
The CTGF gene is located on Chromosome 6q23 and has 5 exons. Several SNPs have been identified in the promoter, introns, exons and 3'UTR regions of the gene.[1,4-6] Some of these SNPs have been studied and shown to be associated with various conditions including systemic sclerosis and cardiovascular diseases.[5-6] Addition, Wang et al. report has described a novel C/G SNP at position -20 in the promoter of the CTGF gene that is associated with nephropathy in T1D.[1] In this report, 862 subjects from the DCCT/EDIC cohort of T1D were genotyped. The frequencies of the CC, CG and GG genotypes were 62.76% (541/862), 31.90% (275/862) and 5.34% (46/862) in this cohort respectively. The frequency of GG genotype in patients with microalbuminuia (albumin excretion rate (AER) >40mg/24h) was significantly higher than patients with AER <40mg/24h, p<0.0001. The GG genotype was also shown to have greater transcriptional activity than that of the CG and CC genotypes.
A total of 739 Caucasoid patients with T1D (Female: 402; Male: 347) and with or without microvascular complications and 193 normal ethnically matched controls (Female: 101; Male: 92) were recruited in our study. Patients with T1D had an average age of 30.83 years (range: 1-76 years) and the average age of onset was 16.86 years (range: <1-52 years) with an average duration of T1D at 13.98 years (range: 0-55 years). The study was approved by the Local Research Ethical Committee and informed consent was obtained from all subjects. All patients have T1D as defined by The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus.[7] Normal controls were obtained from cord blood samples following normal healthy obstetric delivery in Derriford Hospital, Plymouth.
Genomic DNA was prepared from peripheral and cord blood samples using the Nucleon II extraction kit (Scotlab, Lanarkshire, UK) following the manufacture's instruction. DNA samples were sent in 96-well plates to KBioscioences together with the SNP information published in Wang's study.[1] The sequence which covers the location of the SNP in bracket: GTATAAAAGC[C/G]TCGGGCCGCC has been checked and confirmed with the published sequence of the CTGF gene.[4,8] Genotyping for this SNP was performed using KASPar assays which are a proprietary in-house system (KBiosciences, Herts, UK). Unexpectedly, our results showed there was no SNP at the position -20 of the CTGF gene in our entire population; all subjects had the CC genotype.
We tried to understand why there were discrepancies between our findings and those of Wang et al.[1] Wang's study is the only publication regarding this SNP. There are a number of possible reasons for the discrepancy. Firstly, with respect of the ethnicity, our studied population was 100% Caucasian, Wang's subjects from the DCCT/EDIC cohort of T1D contained 96-97% of Caucasian.[9] The genetic backgrounds might be different even within Caucasian populations between different geographic locations.[5,10] but we would expect that the differences in the genetic backgrounds would cause the differences in the frequency of each genotype rather than no genetic variants at the position -20 of the CTGF gene. Secondly, sample size could be an issue, according to Wang's results: the frequencies of GG and GC were 5.34% and 31.90% respectively in their population, we should be able to detect about 39 subjects with GG and 235 subjects with GC genotypes out of our 739 subjects with T1D. Therefore, it is unlikely that our sample size was too small to allow the detection of the minor genotypes GG or GC. Thirdly, genotyping techniques may give rise to false positives or negatives. We used a highly reputable commercial genotyping facility-KBiosciences. Furthermore, our samples have been extensively genotyped including another SNP (rs9399005) in the CTGF gene that were typed in parallel to this one (Our unpublished data, 2011). Wang's study used PCR in their-own laboratory and confirmed this SNP by bi -directional sequencing. Sequences were detected on a Megabase N500 sequencer and results were analysed with sequencer software (Gene Codes Corporation, Ann Arbour, Michigan, USA). Consequently, it is unlikely that technical issues could explain the discrepancy between the sets of results. Finally, we don't think that the disparate results in this SNP between the two groups are due to the gender, age, duration of diabetes or age at onset of diabetes of patients either as the CTGF gene is not located in the X or Y chromosomes and the age, duration of diabetes and age at onset of diabetes of patients in both groups were similar. In conclusion, the reason for this discrepancy is unclear but is probably a reflection of the heterogeneity of populations. Therefore, further studies are needed to confirm this SNP from different groups or independent populations.
References: 1. Wang B, Cater RE, Jaffa MA, et al. Genetic variant in the promoter of connective tissue growth factor gene confers susceptibility to nephropathy in type 1 diabetes. J Med Genet 2010;47:391-397. 2. Mason RM. Connective tissue growth factor (CCN2), a pathogenic factor in diabetic nephropathy. What does it do? How does it do it? J Cell Commun Signal 2009;3:95-104. 3. Wahab NA, Schaefer L, Weston BS, et al. Glomerular expression of thrombospondin-1, transforming growth factor beta and connective tissue growth factor at different stages of diabetic nephropathy and their interdependent roles in mesangial response to diabetic stimuli. Diabetologia 2005;48:2650-2660. 4. Blom IE, van Diji AJ, de Weger RA, et al. Identification of human ccn2 (connective tissue growth factor) promoter polymorphisms. J Clin Pathol Mol Pathol 2001;54:192-196. 5. Granel B, Agriro L, Hachulla E, et al. Association between a CTGF gene polymorphism and system sclerosis in a French population. J Rheumatol 2010;37:351-358. 6. Cozzolino M, Biondi ML, Banfi E, et al. CCN2 (CTGF) gene polymorphism is a novel prognostic risk factor for cardiovascular outcomes in hemodialysis patients. Blood Purif 2010;30:272-276. 7. The Expert Committee on the diagnosis and classification of diabetes mellitus. Report of the Expert Committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 2003;26:S5-S20. 8. Homo sapiens chromosome 6, GRCh37.p2 primary reference assembly. Retrieved on 23rd June 2011 from http://www.ncbi.nlm.nih.gov 9. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Eng J Med 1993;329:977-986. 10. Rueda B, Simeon C, Hesselstrand R, et al. A large multicenter analysis of CTGF-945 promoter polymorphism does not confirm association with systemic sclerosis susceptibility or phenotype. Ann Rheum Dis 2009;68:1618 -1620.
Conflict of Interest:
None declared
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Does c.892G>A missense point mutation (Gly298Arg) in MFN2 cause CMT-2A?
Submit responseIt was with great interest that I read Casasnovas et al article "Phenotypic Spectrum of MFN2 Mutations in the Spanish Population". The authors mention the Gly298Arg mutation in one of their families, with 2 affected individuals, and state that this has previously been described. They refer to Lawson's 2005 article (Ref#10, Lawson VH, Graham BV, Flanigan KM. Clinical and electrophysiologic features of CMT2A with mutations in the mitofusin 2 gene. Neurology 2005;65:197) as having described this mutation previously.
However, upon careful review of Lawson's article, I only found mention of this mutation as a SNP found by the Utah researchers in 3% of their control chromosomes.
Would the authors please comment on what evidence they have that this is a disease causing mutation, or is this a benign polymorphism? As the authors mention, this point mutation is in a highly conserved region of the dynamin like GTPase region of mitofusin 2, and results in a non- synonymous amino acid change, therefore one would suspect it as disease causing.
Conflict of Interest:
None declared
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E-Cadherin (CDH1) exon deletion in lobular breast carcinoma
Submit responseIt was with great interest that we read the recent article by Schrader et al. on the low frequency of CDH1 mutations in early-onset and familial lobular breast cancer (1). As detailed by Schrader et al., the cancer syndrome hereditary diffuse gastric cancer (HDGC), in addition to a high risk of diffuse gastric cancer (DGC), is associated with an increased risk of lobular breast carcinoma, a specific histological subtype of the disease (2,3). Germline mutations in CDH1, encoding E-cadherin have been identified as the underlying cause of HGDC in 30-50% of families (4). We have identified a deletion of exon 16 occurring in an individual with lobular breast cancer with an associated family history of gastric cancer. In addition, several groups have reported infrequent CDH1 inactivating mutations in sporadic and familial cases of lobular breast carcinoma that are not associated with HGDC (5-8).
An increased incidence of breast cancer has also been reported in families with Saethre-Chotzen syndrome (SCS) (9), an autosomal dominant craniosynostosis syndrome, which is characterised by premature fusion of coronal sutures and limb abnormalities. SCS is caused by mutations in the basic helix-loop-helix transcription factor TWIST1. Interestingly, TWIST1 over-expression has been associated with breast cancer progression and metastasis through loss of E-cadherin mediated cell-cell adhesion (10).
As part of our continuing study on factors contributing to the risk of breast cancer, we have recently undertaken a similar study to investigate the contribution of variants in CDH1 and TWIST1 to lobular breast cancer in a familial setting. We selected 104 unrelated individuals with lobular breast cancer, all with a family history of breast cancer fulfilling NICE criteria for BRCA1 and BRCA2 screening (>20% risk of mutation) (11). Sequence analysis and multiplex ligation-dependent probe amplification (MLPA) of BRCA1 and BRCA2 identified no mutations in this group. The age at first presentation of the probands ranged from 28-68 years and 14 patients had bilateral breast cancer. All 104 were screened for germline mutations in the coding regions of CDH1 and TWIST1 and 86 were successfully analysed for large deletions/amplifications in CDH1 using MLPA.
Like Schrader et al., we found no truncating point mutations in CDH1 however, a heterozygous deletion of CDH1 exons 1 and 2 was observed in one patient. Three of her sisters were also affected with lobular disease, two with invasive breast cancer. In one of these, with lobular carcinoma in situ, DNA was available for testing and confirmed the presence of the mutation. The four sisters were aged 50, 49, 51 and 53 years at diagnosis of lobular breast cancer, the proband eventually dying from primary pancreatic cancer aged 60 years. There was no history of gastric cancer in up to third degree relatives in the family. Oliveira et al. previously reported deletion of CDH1 exons 1 and 2 segregating in three families with familial gastric cancer (4), one of which was associated with lobular breast cancer. However, our finding is the first report of a CDH1 deletion in the context of lobular breast cancer without a history of gastric cancer.
A novel non-synonymous change in exon 5 of CDH1, c.670C>T, p.R224C, was identified in one patient. DNA was unavailable from an affected family member to test for segregation. The variant was not identified in a panel of 180 ethnically matched healthy controls. However, in-silico analysis (Polyphen) predicted this missense change to be benign and the residue is not conserved across species. Therefore, it is inconclusive if this variant predisposes to breast cancer in this family.
A novel synonymous change c.2451G>A in CDH1 exon 16 was observed in two patients and four patients had the intronic variant c.532-18C>T which has not been described in SNP databases. There is no evidence to support pathogenicity for these variants.
No mutations were identified in TWIST1.
In agreement with Schrader et al., we conclude that germline mutations in CDH1 are not common in familial lobular breast cancer. Although large single or multiple exon deletions can be occasionally identified in association with a highly penetrant phenotype for lobular breast cancer. We cannot however rule out the possibility that hypermethylation of promoter and regulatory regions of both CDH1 and TWIST1 contribute to the altered expression of these genes frequently observed in breast tumours. Additional studies are needed to provide more insight into the aetiology of lobular breast carcinoma and to identify further causal variants.
Acknowledgements. This work was funded through support of the NIHR Manchester Biomedical Research Centre and Central Manchester Foundation Trust Research Grant.
References. 1. Schrader KA, Masciari S, Boyd N, Salamanca C, Senz J, Saunders DN, Yorida E, Maines-Bandiera S, Kaurah P, Tung N, Robson ME, Ryan PD, Olopade OI, Domchek SM, Ford J, Isaacs C, Brown P, Balmana J, Razzak AR, Miron P, Coffey K, Terry MB, John EM, Andrulis IL, Knight JA, O'Malley FP, Daly M, Bender P; kConFab, Moore R, Southey MC, Hopper JL, Garber JE, Huntsman DG. Germline mutations in CDH1 are infrequent in women with early-onset or familial lobular breast cancers. J Med Genet 2011;48:64-8. 2. Keller G, Vogelsang H, Becker I. Diffuse type gastric and lobular breast carcinoma in familial gastric cancer patient with an E-Cadherin germline mutation. Am J Pathol 1999;155:337-42. 3. Brooks-Wilson AR, Kaurah P, Suriano G, Leach S, Senz J, Grehan N, Butterfield YS, Jeyes J, Schinas J, Bacani J, Kelsey M, Ferreira P, MacGillivray B, MacLeod P, Micek M, Ford J, Foulkes W, Australie K, Greenberg C, LaPointe M, Gilpin C, Nikkel S, Gilchrist D, Hughes R, Jackson CE, Monaghan KG, Oliveira MJ, Seruca R, Gallinger S, Caldas C, Huntsman D. Germline E-Cadherin mutations in hereditary diffuse gastric cancer: assessment of 42 families and review of genetic screening criteria. J Med Genet 2004;41:508-17. 4. Oliveira C, Senz J, Kaurah P, Pinheiro H, Sanges R, Haegert A, Corso G, Schouten J, Fitzgerald R, Vogelsang H, Keller G, Dwerryhouse S, Grimmer D, Chin SF, Yang HK, Jackson CE, Seruca R, Roviello F, Stupka E, Caldas C, Huntsman D. Germline CDH1 deletions in hereditary diffuse gastric cancer families. Hum Mol Genet 2009;18:1545-1555. 5. Berx G., Cleton-Jansen AM, Strumane K, de Leeuw WJ, Nollet F, van Roy F, Cornelisse C. E-Cadherin is inactivated in a majority of invasive human lobular breast cancers by truncation mutations throughout its extracellular domain. Oncogene 1996; 13:1919-25. 6. Vos CB, Cleton-Jansen AM, Berx G, de Leeuw WJ, ter Haar NT, van Roy F, Cornelisse CJ, Peterse JL, van de Vijver MJ. E-cadherin inactivation in lobular carcinoma in situ of the breast: an early event in tumorigenesis. Br J Cancer 1997;76:1131-1133. 7. Masciari S, Larsson N, Senz J, Boyd N, Kaurah P, Kandel MJ, Harris LN, Pinheiro HC, Troussard A, Miron P, Tung N, Oliveira C, Collins L, Schnitt S, Garber JE, Huntsman D. Germline E-Cadherin mutations in familial lobular breast cancer. J Med Genet 2007;44:726-731. 8. Salahshor S, Haixin L, Hou H, Kristensen VN, Loman N, Sj?berg-Margolin S, Borg A, B?rresen-Dale AL, Vorechovsky I, Lindblom A. Low frequency of E -cadherin alterations in familial breast cancer. Breast Cancer Res 2001;3:199-207. 9. Sahlin P, Windh P, Lauritzen C, Emanuelsson M, Gr?nberg H, Stenman G. Women with Saethre-Chotzen syndrome are at increased risk of breast cancer. Genes Chr Can 2007;46:656-660. 10. Yang J, Mani SA, Donaher JL, Ramaswamy S, Itzykson RA, Come C, Savagner P, Gitelman I, Richardson A, Weinberg RA. Twist, a master regulator of morphogenesis, plays an essential role in tumour metastasis. Cell 2004;117:927-939. 11. NICE clinical guideline 41. Familial breast cancer. The classification and care of women at risk of familial breast cancer in primary, secondary and tertiary care. 2006.
Conflict of Interest:
None declared
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Re:Comments on the revised Ghent nosology for Marfan syndrome
Submit responseWe would like to thank Dr. Hennekam for his comments but would like to reply to several points made by him. We agree with Dr. Hennekam that there is a good correlation between the current nosology and the FBN1 mutation uptake, but an important goal for the new nosology is to make it simpler and more easily applicable (which is not always true for the current one). There is also an important focus on the cardiovascular aspect of the disease which remains the most important for the life expectancy.
Dr. Hennekam suggests that the five major changes in the revised nosology have severe shortcomings. However, we believe there are many more reasons mentioned in the paper that played a role in the revision. Since physicians associate the diagnosis of "Marfan syndrome", above all else, with risk for aortic aneurysm/dissection, it can be detrimental to diagnose MFS in patients without tangible evidence of such risk. Avoidable consequences associated with misdiagnosis of MFS include: restriction of career aspirations or access to insurance benefits; additional financial burden associated with frequent medical care; anxiety or situational depression; unfounded marital or reproductive decisions; loss of health benefits or psychosocial stigmatization associated with exercise restriction, a particularly important issue during childhood. The challenge is to balance such concerns with the paramount need to maintain good health through proper counseling and application of sound anticipatory medical practices. Toward this objective, it is also important to avoid the diagnosis of MFS when clinical or molecular observations could reveal alternative (and often more severe) diagnoses that mandate specialized counseling or management protocols.
We agree that the focus of the current nosology is on the cardiovascular and the ocular complications, which from a medical perspective are still the most objective and have the greatest medical implications. As such it is logical to start from those two symptoms. We agree with Dr Hennekam that according to the patient survey the skeletal features may be subjectively more important but we believe this very important for the management aspect but not so much for the diagnostic decision making process. Individual skeletal findings do not bear great sensitivity but as a whole they are indeed important. As such, we did not abandon the skeletal findings but these are put more in the context of all systemic findings and the more important skeletal findings do get a greater weight in this systemic score. Other major criteria that have not been validated such as dural ectasia do get lower weight. For eg do we really want a patient with skeletal findings and dural ectasia and striae be called MFS ? We believe there is a major difference between clinical characteristics to make a diagnosis and on the other side characteristics that are important in the clinical management. Skeletal features in themselves rarely allow to make a MFS diagnosis.
We agree that there will always be patients with TGFBR1/2 mutations that resemble Marfan syndrome but we prefer to distinguish two categories based on the gene (FBN1 versus TGFBR1/2) because of the different medical implications. Again this is a choice made from a practical viewpoint to create a clear situation even though we recognize that also within the TGFBR1/2 patients there is a spectrum of disease.
We agree that there is poor genotype (FBN1)-phenotype correlation and this also reflected in the current nosology. For eg. we do stress that certain FBN1 mutations do not have cardiovascular implications and that ectopia lentis syndrome is possible with FBN1 mutations. For eg we also abandon the use of neonatal MFS; this represents the severe end of a phenotypic spectrum. With the current nosology, it is very important to distinguish TGFBR1/2 mutants because they have a more severe natural history. A nosology should also be made for the great majority of patients, not for the exceptions and with the current technology an FBN1 mutation is found in close to 95%
The combination of aortic root dilation and ectopia lentis is very specific; there is no other diagnosis than Marfan syndrome. In the current literature there is no consensus on the definition and most optimal technique to determine dural ectasia. Until there is better data on the specificity of dural ectasia, we have opted to include it in the systemic score. We had hours of discussion with ophthalmologists on the methods and cut-offs that could be used. We believe the majority of the ophthalmologist do no not measure axial globe length or corneal flattening. Although we agree that these might be interesting to study the different ocular findings for their specificity. Again there are no good data in the literature about sensitivity and specificity of the ocular findings. The pulmonary artery dilation, again has no standard measurement method or cut-off; moreover the clinical relevance of this finding is very low.
The key point is that physicians should not only look for the features specific for Marfan syndrome but also for other relevant differential diagnostics; this is specifically true for Loeys-Dietz syndrome, Shprintzen-Goldberg syndrome and vascular Ehlers-Danlos syndrome. There are criteria for vascular Ehlers-Danlos syndrome (although they also need better validation) and for Loeys-Dietz syndrome it is too early in the discovery to define good criteria, but we will continue to work on that.
There is many other points that are made in the introduction of the paper; eg children, psychosocial burden,... that also call for changes not only in the five sections that are now quoted by Dr Hennekam. We also do now define specific diagnostic categories for children and define alternative diagnoses such as MASS, MVPS (mitral valve prolapse) and ELS (ectopia lentis syndrome) in individuals older than 20 years.
Prof Dr Bart Loeys Prof Dr Harry Dietz Prof Dr Anne De Paepe
Conflict of Interest:
None declared
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Prophylactic mastectomy or surveillance?
Submit responseBancroft et al. describe the successful establishment of a novel specialist clinic for BRCA1/2 mutation carriers. (1) The authors should be applauded for the introduction of this specialized, multi-disciplinary clinic. However, although their study provides elaborate data on numbers of patients followed in this clinic, it remains unclear what the information provision and guidance for decision-making in the multi- disciplinary team consisted of. This is of special importance with respect to the counselling of BRCA1/2 carriers whether or not to undergo prophylactic mastectomy. In the article of Bancroft the effect of prophylactic mastectomy is emphasized. In contrast with surveillance for ovarian cancer that appeared to be ineffective, either annual mammography plus MRI screening or prophylactic mastectomy seem to offer comparable results with respect to survival (2); in our opinion there is no need to direct patients towards a decision for prophylactic mastectomy. Of note, although the rate of false-positive MRI results in this population is high, the impact of a false-positive MRI on the choice for prophylactic mastectomy is limited and is determined by the woman's preference before the establishment of a BRCA mutation. (3) In our multidisciplinary clinic for BRCA1/2 carriers, which we started in 1999, 27% had an initial preference for prophylactic mastectomy. After a median observation period of 2 years, 30% had undergone prophylactic mastectomy. (4) We believe that a careful counselling of the pros and cons of prophylactic mastectomy and an open discussion on real and perceived risk reduction by prophylactic mastectomy is crucial. For carriers of a BRCA1/2 mutation and their family members such counselling may be the surplus value of a specialized multidisciplinary clinic.
References 1. Bancroft EK, Locke I, Ardern-Jones A et al. The carrier clinic: an evaluation of a novel clinic dedicated to the follow-up of BRCA1 and BRCA2 carriers--implications for oncogenetics practice. J Med Genet. 2010;47:486 -491. 2. Kurian AW, Sigal BM, Plevritis SK. Survival analysis of cancer risk reduction strategies for BRCA1/2 mutation carriers. J Clin Oncol. 2010;28:222-231. 3. Hoogerbrugge N, Kamm YJ, Bult P et al. The impact of a false-positive MRI on the choice for mastectomy in BRCA mutation carriers is limited. Ann Oncol. 2008;19:655-659. 4. Landsbergen KM, Prins JB, Kamm YJ et al. Female BRCA mutation carriers with a preference for prophylactic mastectomy are more likely to participate an educational-support group and to proceed with the preferred intervention within 2 years. Fam Cancer. 2010;9:213-220.
Conflict of Interest:
None declared
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Comments on the revised Ghent nosology for Marfan syndrome
Submit responseThe Ghent criteria as proposed in 1996 are world-wide well accepted to define the diagnostic criteria for Marfan syndrome. The criteria are easy to use and work extremely well, shown by finding causative FBN1 Mutations in 97% of cases. Indeed this specificity of diagnostic criteria is amongst the highest reported in any syndromic entity. A large group of superb Marfan specialists have now suggested a revision of these criteria (1). Unfortunately the suggested five major changes in the revision have severe shortcomings:
1. More weight to aortic root aneurysm/dissection and ectopia lentis. Marfan syndrome is a systemic entity, in which many body parts are involved. There is no ratio to increase some of these manifestations (aorta; eye) or decrease others (skeleton). None has a complete sensitivity, none is 100% specific. The authors may argue that the eye and cardiovascular manifestations have the most significant implications. However, the use of new management strategies may well change this in the near future. More importantly, medical implications should not be of importance in establishing diagnostic criteria: sensitivity and specificity should be leading here. In this respect it is useful mentioning that the specificity of aortic root aneurysm/dissection is likely to be lower than the specificity of dural ectasia. One may also consider what individuals having Marfan syndrome themselves consider as the most important manifestations. Indeed, in a questionnaire study of 857 European Marfan patients it was found that not the vascular or visual problems were the most important issues for the patients themselves but this was their body build (2). In fact from a patient perspective this argues to tag more importance to the skeletal findings than any other manifestation.
2. More prominent role of FNB1 and TGFB1/2 testing. The genotype- phenotype correlation of Marfan syndrome with FBN1 mutations is weak. There are patients with a FBN1 mutation who do not have Marfan syndrome and there are patients who have all manifestations of Marfan syndrome who do not have a (detectable) FBN1 or TGFB1/2 mutation. As has been shown in many other entities it may still be that Marfan syndrome will be genetically heterogeneous. Therefore it is doubtful whether it is wise to put more emphasis on any molecular results than was already done in the existing Ghent criteria.
3. Removal or downgrading of less specific manifestations. Dural ectasia is downgraded as it may be ..sensitive but is not specific.. . However, as stated above it may well be that it is more specific than enlargement of the aortic root or ectopia lentis, and it is easily and reliably determinable (3, 4). Increased globe length and corneal flattening are removed as ..they have an unclear specificity and are not routinely measured by ophthalmologists.. . No one doubts these eye manifestations form part of the multisystemic manifestations of Marfan syndrome. It seems more logical to perform studies reliably determining the specificity of global length and corneal flattening in Marfan syndrome, and to instruct ophthalmologist to perform these (not difficult and cheap) investigations than to remove the manifestations from the criteria. Pulmonic artery dilatation is removed as ..it is not specific to this diagnosis. In addition complications ... occur rarely.. . Beyond doubt pulmonic manifestations are however a manifestation of the vascular system in Marfan syndrome and therefore can be useful. In addition, whether or not a manifestation provides complications is not influencing its usefulness as a diagnostic criterion. Surely there are still subjective qualifiers in the present proposal (such as mitral valve prolaps or pectus carinatum) but this remains inescapable in describing the human phenotype.
4. Differentiation from other connective tissue disorders. This is very valuable. However, the diagnostic criteria of one entity should not be influenced by diagnostic criteria of other entities. The similarity of Marfan syndrome to entities such as Loeys-Dietz syndrome and Shprintzen- Goldberg syndrome would simply urge for reliable diagnostic criteria of each of these entities, as comparing the criteria with those in Marfan syndrome would help best in allowing such differentiation.
5. Providing context-specific recommendations for patient counselling and follow-up. This is an excellent point and surely needs attention. However in itself such recommendations are no reason to change the diagnostic criteria, and can easily be published separately.
I conclude that the reasoning to change the existing diagnostic criteria contains significant flaws, and suggest keeping using the existing Ghent criteria. The points mentioned by the authors do not ask for adaptation of the Ghent criteria: they ask for amendments regarding entities from which Marfan syndrome should be differentiated by defining these entities better; they ask for separate recommendations for counselling and follow-up. Specific attention to the age dependent nature of some manifestations can be added too, as this is now added only for the aortic root enlargement. Suggestions for additional studies of specific manifestations can be made or the studies can be initiated by the authors themselves.
The present Ghent criteria function extremely well and are well incorporated in the care for Marfan patients: with limited amendments, the criteria can remain unchanged and even function better.
References 1. Loeys B, Harry C Dietz, Braverman AC, Callewaert BL, De Backer J, Devereux RB, Hilhorst-Hofstee Y, Jondeau G, Faivre L, Milewicz DM, Pyeritz RE, Sponseller PD, Wordsworth P, De Paepe AM. The revised Ghent nosology for the Marfan syndrome. J Med Genet 2010;47:476-485. 2. De Bie S, De Paepe A, Delvaux I, Davies S, Hennekam RC. Marfan syndrome in Europe. Community Genet 2004;7:216-225. 3. Lundby R, Rand-Hendriksen S, Hald JK, Lilleas FG, Pripp AH, Skaar S, Paus B, Geiran O, Smith HJ. Dural ectasia in Marfan syndrome: a case control study. AJNR 2009;30:1534-1540. 4. Sznajder M, Krug P, Taylor M, Moura B, Leparc JM, Boileau C, Jondeau G, Chevallier B, Pelage JP, Stheneur C. Spinal imaging contributes to the diagnosis of Marfan syndrome. Joint Bone Spine 2010 May 7. [Epub ahead of print]
Conflict of Interest:
None declared
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Reply to: The revised Ghent nosology for the Marfan Syndrome
Submit responseTo the editor
In the July issue, Loeys and colleagues present new diagnostic criteria for Marfan Syndrome (MFS) in their manuscript "The revised Ghent nosology for the Marfan Syndrome"[1]. After publication of these Revised Ghent Marfan criteria, a manuscript was published which in part supports their opinions[2]. After complimenting Loeys et.al. with the result of their multidisciplinary effort, we would like to comment on two issues:
First, the authors allocate more importance to genetic criteria for making a diagnosis of MFS and much less importance to the clinical feature "dural ectasia", compared to the 1996 "Revised diagnostic criteria for Marfan Syndrome". In our opinion this is a prudent decision, as in clinical practice a group of patients emerged after 1996, who had one major criterium for the diagnosis of Marfan Syndrome (usually aortic dilatation) as well as dural ectasia. Combined with even the slightest involvement of other organ systems (usually the skeletal system), patients in this group fulfilled the former diagnostic criteria for MFS[3], while in our hospitals most of these cases are non-familial and without FBN1 or TGFBR1/2 mutation. Although dural ectasia was once seen as an important and discriminating feature of MFS[4], different measurement methods of dural ectasia have been the subject of debate[5], and a recent study corroborated the role of dural ectasia as a non-specific marker for connective tissue disease[2]. In the now presented Revised Ghent criteria, cases with dural ectasia need substantial more other symptomatology to fulfil the criteria for Marfan Syndrome, which is in line with one of the aims of the paper, preventing overdiagnosis of Marfan Syndrome.
Second, a maybe minor point, is that the authors propose to label the term "potential Marfan Syndrome" to young individuals in whom a FBN1 mutation is identified, but in whom "aortic measurements are still below Z=3". This seems contradictory with the rest of their manuscript, as the fulfilment of criteria needed for an unequivocal diagnosis of Marfan Syndrome, does not depend on the aortic root diameter alone, but on other developing symptoms as well. Furthermore, the term "potential" means "possible"[6] and as such is confusing in this context, as the penetrance of FBN1 mutations/Marfan Syndrome is 100% at adult age. Terminology like "latent MFS" or "subclinical MFS" seems more appropriate, but in our opinion there is no need to make things more complicated then they already are: In our experience, children with a (pathogenic) FBN1 mutation but with no or only minimal clinical symptoms, are labelled by their families and doctors as having "MFS" or "carrier of MFS", without problems or confusion.
Reference List
(1) Loeys BL, Dietz HC, Braverman AC, Callewaert BL, De BJ, Devereux RB, Hilhorst-Hofstee Y, Jondeau G, Faivre L, Milewicz DM, Pyeritz RE, Sponseller PD, Wordsworth P, De Paepe AM. The revised Ghent nosology for the Marfan syndrome. J Med Genet 2010 Jul;47(7):476-85.
(2) Sheikzadeh S, Rybczynski M, Habermann CR, Bernhardt AMJ, Arslan- Kirchner M, Keyser B, Kaemerrer H, Mir TS, Staebler A, Oezdal N, Robinson PN, Berger J, Meinertz T, von Kodolitsch Y. Dural ectasia in individuals with Marfan-like features but exclusion of mutations in the genes FBN1, TGFBR1 and TGFBR2. Clin Genet 2010 Jun 23;doi:10.1111/j.1399- 0004.2010.0194.x.
(3) De PA, Devereux RB, Dietz HC, Hennekam RC, Pyeritz RE. Revised diagnostic criteria for the Marfan syndrome. Am J Med Genet 1996 Apr 24;62(4):417-26.
(4) Fattori R, Nienaber CA, Descovich B, Ambrosetto P, Reggiani LB, Pepe G, Kaufmann U, Negrini E, von KY, Gensini GF. Importance of dural ectasia in phenotypic assessment of Marfan's syndrome. Lancet 1999 Sep 11;354(9182):910-3.
(5) Weigang E, Ghanem N, Chang XC, Richter H, Frydrychowicz A, Szabo G, Dudeck O, Knirsch W, von SP, Langer M, Beyersdorf F. Evaluation of three different measurement methods for dural ectasia in Marfan syndrome. Clin Radiol 2006 Nov;61(11):971-8.
(6) Internet Communication, 03-08-2010. http://dictionary.reference.com/browse/potential
Conflict of Interest:
None declared
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A response to "SOD1, ANG, VAPB, TARDBP, and FUS mutations in familial amyotrophic lateral: genotype - phenotype correlations"
Submit responseDr. Constantin Polychronakos, Editor Journal of Medical Genetics Dear Dr. Polychronakos We read with great interest the recent publication from your journal entitled "SOD1, ANG, VAPB, TARDBP, and FUS mutations in familial amyotrophic lateral: genotype - phenotype correlations" Millecamps S., Salachas F., Cazeneuve C., et al. J Med Genet published online June 24, 2010 doi: 10.1136/jmg.2010.077180. This manuscript brings relevant information about the mutation frequencies and genotype-phenotype data regarding the main genes responsible for the familial forms of ALS (FALS). Additionally, as well pointed by the authors, this study is the first large scale evaluation of FALS in the French population. However, we would like to call the authors attention for two important aspects: 1) According to the authors "...The P56S carrier was of Japanese descent, and represents the first non-Brazilian patient carrying this mutation...". The ALS8 form was first mapped at 20q13 in a large Brazilian family in 2004, which was published in the Journal of Medical Genetics (Nishimura et al., 2004A). Later in the same year, the c.166C-T / p.Pro56Ser mutation in the VAPB gene was identified in this and six other families (Nishimura et al., 2004B) as responsible for this disorder. Additionally, microsatellites analyses around VAPB showed that these families share a common haplotype. It suggests a founder effect estimated to have occurred about 500 years ago, concomitant with Brazilian colonization by Portugal (Nishimura et al., 2005). Recently, in collaboration with our group, Funke et al. (2010) identified a German ALS8 patient, with no family record of Brazilian or Portuguese ancestry, carrying the c.166C-T mutation in VAPB, which showed that ALS8 is no more restricted to Brazil. Therefore, this German patient comprises the first case of an ALS8 patient out of Brazil and this should be corrected in Millecamps et al., MS. 2) The German patient, identified by Funke et al. (2010), carries an haplotype which is different from the one found in the Brazilian ALS8 families. This suggests that the c.166C-T (P56S) mutation is not due to the same founder and that, probably, it happened at least in two independent events. Millecamps et al., (2010) claims that "...The finding of a P56S VAPB mutation in a patient of Japanese origin presumably reflects the Portuguese trading connection with the Far East and Brazil in the mid 16th century..." suggesting that the Japanese and the Brazilian families could share the same genomic region. However, they do not show such haplotype analysis or present any historical evidence for this supposition. We believe that such information is relevant for the researchers in the ALS field and for this reason an erratum should be considered in order to ensure the best information to the readers of the Journal of Medical Genetics . We appreciate your attention Sincerely Miguel Mitne-Neto PhD Candidate Human Genome Research Center University of Sao Paulo References Mayana Zatz Professor of Genetics Director- Human Genome Research Center University of Sao Paulo President-Brazilian Muscular Dystrophy Association [A] Nishimura A.L., Mitne-Neto M., Silva H.C.A., Oliveira J.R.M., Vainzof M., Zatz M. (2004) "A novel locus for late onset amyotrophic lateral sclerosis/motor neurone disease variant at 20q13" J Med Genet. 41, 315-320 [B] Nishimura A.L., Mitne-Neto M., Silva H.C., Richieri-Costa A., Middleton S., Cascio D., Kok F., Oliveira J.R., Gillingwater T., Webb J., Skehel P., Zatz M. (2004). A mutation in the vesicle- trafficking protein VAPB causes late-onset spinal muscular atrophy and amyotrophic lateral sclerosis. Am J Hum Genet 75, 822-31 Nishimura A.L., Al-Chalabi A., Zatz M. (2005). A common founder for amyotrophic lateral sclerosis type 8 (ALS8) in the Brazilian population. Hum Genet 118, 499- 500 Funke A.D., Esser M., Kruttgen A., Weis J., Mitne-Neto M., Lazar M., Nishimura A.L., Sperfeld A.D., Trillenberg P., Senderek J., Krasnianski M., Zatz M., Zierz S., Deschauer M. (2010) The p.P56S mutation in the VAPB gene is not due to a single founder: the first European case. Clin Genet 77, 302-303 Millecamps S., Salachas F., Cazeneuve C., et al. "SOD1, ANG, VAPB, TARDBP, and FUS mutations in familial amyotrophic lateral: genotype - phenotype correlations" (2010) J Med Genet published online June 24, 2010 doi: 10.1136/jmg.2010.077180.
Conflict of Interest:
None declared
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