Non-familial Cases Research Articles

It May Take More Than a Shot: Alternatives to Immunotherapy for Alzheimer's Disease

In 1999, the field of Alzheimer's disease (AD) therapeutics was turned on its head by reports that active immunization against amyloid β (Aβ) could reduce accumulation of Aβ plaques in brains of transgenic mice engineered to model AD pathology. These studies were rapidly followed by preclinical studies from multiple laboratories demonstrating efficacy of passive immunization with Aβ specific antibodies and in some cases, amelioration of cognitive deficits seen in AD mouse models. Such findings launched intensive and continuing efforts to develop Aβ immunotherapy as a safe and effective treatment for AD. In this issue of Biological Psychiatry, Sarazin et al. (1) summarize the current status of immunotherapy for Alzheimer's disease. They highlight the challenging side effects observed in the original active Aβ immunization trial and provide a summary of the disappointing results achieved in recent phase III trials of passive Aβ immunotherapy. Concerns that these trials failed because intervention occurred too late in the disease course have spurred new trial designs targeting asymptomatic familial AD carriers. As the authors point out, all such studies are entirely predicated on the amyloid hypothesis. Notwithstanding the applicability of this hypothesis, and therefore therapy, to nonfamilial cases of AD, this review points out a number of challenges related to designing preventative immunotherapy trials for sporadic AD and the classification of at-risk subjects. Because of these challenges, from a cynical point of view, the most informative outcome of immunotherapy trials in familial AD would be failure.

Genetics of idiopathic generalized epilepsy: An overview

Idiopathic generalized epilepsy (IGE) is a common type of epilepsy. Strong support for a genetic role in IGE comes from twin and family studies. Several subtypes of IGE have been reported but families often have members affected with different subtypes. Major advances have been made in the understanding of genetic basis of monogenic inherited epilepsies. However, most IGEs are complex genetic diseases and some susceptible IGE genes are shared across subtypes that determine subtypes in specific combinations. The high throughput technologies like deoxyribonucleic acid microarrays and sequencing technologies have the potential to identify causative genes or loci in non-familial cases.

Non‐familial cases of intellectual disability could be linked to de novo genetic mutations

Non‐familial cases of intellectual disability could be linked to de novo genetic mutations

Germline mutations of AIP gene in somatotropinomas resistant to somatostatin analogues

Most cases of familial isolated pituitary adenomas with mutated aryl hydrocarbon receptor-interacting protein (AIP:HGNC:358) gene develop somatotropinomas. They are characterised by an aggressive clinical phenotype including early age at diagnosis, large tumours and frequent invasiveness. There is little information on AIP gene mutations' prevalence in isolated somatotropinomas characterised by poor response to somatostatin analogue treatment. The aim of this study was to investigate the prevalence of AIP mutations in non-familial cases of somatotropinomas with poor response to conventional treatment. Fifty patients with acromegaly (22 males/28 females, age 51±18 years) and 60 controls were included in this study performed at eight University Hospitals in Spain. None had family history of pituitary adenomas or other endocrine tumors. All patients failed to respond to conventional treatment including surgery and somatostatin analogues. Some patients received adjuvant radiotherapy and most cases required pegvisomant (PEG) treatment for normalisation of IGF1. AIP analysis was performed in DNA extracted from peripheral leucocytes, using standardised PCR protocol in which the coding regions of exons 1, 2, 3, 4, 5 and 6 were amplified. Possible deletions/duplications were studied using multiplex ligation-dependent probe amplification. SEQUENCE CHANGES OF POTENTIAL DIFFERENT SIGNIFICANCE THAT COULD BE CONSIDERED AS MUTATIONS OR VARIATIONS OF UNKNOWN SIGNIFICANCE (VUS) OF THE AIP GENE WERE FOUND IN FOUR PATIENTS (8%). IN TWO CASES, TWO DIFFERENT MUTATIONS PREVIOUSLY DESCRIBED WERE FOUND: p.Arg9Gln and p.Phe269Phe. Two other VUS were also found: c.787+24C>T in intron 5 and c.100-18C>T in intron 1. Age at diagnosis ranged from 21 to 50 years old, and in all patients, the tumor was a macroadenoma depicting IGF1 normalisation under PEG treatment. AIP germline mutations show a low, but non-negligible, prevalence in non-familial acromegaly patients with tumors resistant to treatment with somatostatin analogues.

PRRT2 is mutated in familial and non-familial benign infantile seizures

BackgroundMutations of protein-rich transmembrane protein 2 (PRRT2) were recently associated to benign familial infantile seizures (BFIS) (MIM 605751) and paroxysmal kinesigenic dyskinesias (PKD) (MIM12800). AimsTo report mutations of PRRT2 in BFIS, infantile convulsions and choreoathetosis (ICCA), and in sporadic cases affected by benign infantile epilepsy (BIE). MethodsA mutational screening of PRRT2 was performed in 5 families, and in 7 sporadic cases affected by BIE. All clinical and neurophysiological details were reviewed. ResultsThirty-three members among 5 families were collected. Fifteen individuals had infantile seizures and one had infantile seizures followed by paroxysmal kinesigenic dyskinesia (PKD). We found the c.649_650InsC PRRT2 mutation in all tested patients (13 out of 15). Age at onset ranged from 3.5 to 10 months. Focal seizures, with or without secondary generalization, occurred mainly in cluster. One patient at the age of 11 years presented with PKD successfully treated with carbamazepine. All patients had a normal cognitive development.Two out of 7 non-familial cases (28.5%) carried a de novo PRRT2 mutation: the c.649_650InsC mutation in one with clustered seizures at the age of 5 months and an unreported c.718C-T p.R240X mutation in the other who, after cluster focal seizures at the age of 5 months, experienced absences at the age of 5 years. ConclusionOur findings emphasize that PRRT2 mutations might be responsible of both BFIS and ICCA, but might be causative also for sporadic cases of benign infantile seizures. The phenotypic spectrum comprises BFIS, ICCA, and PKD.

Insight in glioma susceptibility through an analysis of 6p22.3, 12p13.33-12.1, 17q22-23.2 and 18q23 SNP genotypes in familial and non-familial glioma.

The risk of glioma has consistently been shown to be increased twofold in relatives of patients with primary brain tumors (PBT). A recent genome-wide linkage study of glioma families provided evidence for a disease locus on 17q12-21.32, with the possibility of four additional risk loci at 6p22.3, 12p13.33-12.1, 17q22-23.2, and 18q23. To identify the underlying genetic variants responsible for the linkage signals, we compared the genotype frequencies of 5,122 SNPs mapping to these five regions in 88 glioma cases with and 1,100 cases without a family history of PBT (discovery study). An additional series of 84 familial and 903 non-familial cases were used to replicate associations. In the discovery study, 12 SNPs showed significant associations with family history of PBT (P < 0.001). In the replication study, two of the 12 SNPs were confirmed: 12p13.33-12.1 PRMT8 rs17780102 (P = 0.031) and 17q12-21.32 SPOP rs650461 (P = 0.025). In the combined analysis of discovery and replication studies, the strongest associations were attained at four SNPs: 12p13.33-12.1 PRMT8 rs17780102 (P = 0.0001), SOX5 rs7305773 (P = 0.0001) and STKY1 rs2418087 (P = 0.0003), and 17q12-21.32 SPOP rs6504618 (P = 0.0006). Further, a significant gene-dosage effect was found for increased risk of family history of PBT with these four SNPs in the combined data set (P(trend) <1.0 × 10(-8)). The results support the linkage finding that some loci in the 12p13.33-12.1 and 17q12-q21.32 may contribute to gliomagenesis and suggest potential target genes underscoring linkage signals.

Are children born after infertility treatment at increased risk of retinoblastoma?

Retinoblastoma (RB) is the most frequent eye tumour in children, with an incidence of 1 in 15-20,000 births. It accounts for 11% of all cancers in the first year of life. Except for the hereditary forms, its causes are not well-known. Studies have recently suggested an increased risk of RB among children born after IVF, but the relevant literature is sparse. We assessed the association between infertility treatment, subfertility and RB. We included all children living in France diagnosed with RB between 1 January 2000 and 31 December 2006 at the Institut Curie, the national reference centre for RB diagnosis and treatment. We used multiple logistic regression to compare them with a national sample of births in France in 1998 and 2003 (n = 28 170). The study included 244 non-familial RB cases. The risk of RB increased with maternal age [adjusted odds ratio (adj OR) = 2.07, 95% confidence interval (CI) 1.33-3.22 at 35-39 years compared with younger than 25 years and adj OR = 2.42, 95% CI 1.22-4.81 at 40 years or older], but the associations with IVF (adj OR = 1.37, 95% CI 0.64-2.95) and ovarian stimulation or intrauterine insemination (adj OR = 1.35, 95% CI 0.77-2.38) were not statistically significant after adjustment for maternal age and tobacco use. Among women who had no infertility treatment, the risk of RB was significantly increased when time to pregnancy exceeded 24 months (adj OR = 2.02, 95% CI 1.17-3.48) compared with time to pregnancy ≤ 24 months. Our study did not observe a significantly increased risk of RB associated with infertility treatment, in particular with IVF. But we did find an increased risk for women for whom time to pregnancy exceeded 24 months.

Morphologic patterns associated with BRCA1 and BRCA2 genotype in ovarian carcinoma

This study was undertaken with the hypothesis that certain common morphologic features of ovarian carcinomas are predictably associated with BRCA1 and BRCA2 deficiencies. We selected 43 high-grade serous carcinomas diagnosed at Memorial Sloan-Kettering Cancer Center that were studied as part of The Cancer Genome Atlas pilot project. In addition to 12 randomly selected nonfamilial BRCA-unassociated cases, all 31 Memorial Sloan-Kettering Cancer Center cases with BRCA1 or BRCA2 abnormality were included (n=43). Slides were examined to assess tumor architecture, mitotic index, tumor-infiltrating lymphocytes (TILs), nuclear pleomorphism, necrosis, and involvement of fallopian tube epithelium. Comparing BRCA1-associated cases (BRCA1 germline mutation, n=4, BRCA1 somatic mutation, n=6, BRCA1 promoter methylation, n=13) with unassociated cases (n=12) identified statistically significant differences in morphology. BRCA1-associated high-grade serous carcinomas had more frequent Solid, pseudoEndometrioid, and Transitional cell carcinoma-like morphology (SET features) (P=0.0045), higher mitotic indexes (P=0.012), more TILs (P=0.034), and either geographic or comedo necrosis (P=0.034). BRCA2-associated cases (germline mutation, n=4 and somatic mutation, n=4) tended to show SET features, but they were relatively deficient in TILs and necrosis. Two algorithms incorporating tumor architecture, necrosis, and either mitotic indexes or TILs separated cases that showed 2 of 3 features (BRCA1 associated) from those with 0 of 3 features (BRCA unassociated; P=0.0016 and P=0.0033). A test set comprising 9 BRCA1 germline mutants and 14 high-grade serous carcinoma controls lacking BRCA1 and BRCA2 germline mutation was used to validate the algorithms, with specific emphasis on the ability to detect cases with BRCA1 germline mutation. Best results were obtained with the algorithm that incorporated SET features, necrosis, and mitotic index (P=0.0072; sensitivity of 1.0 (95% CI, 0.66–1.0); specificity of 0.57 (95% CI, 0.29–0.82); positive predictive value of 0.60 (95% CI, 0.32–0.84) and a negative predictive value of 1.0 (95% CI, 0.63–1.0)). These preliminary data indicate potential strong associations between morphology and genotype in high-grade serous carcinomas.

Analysis of Short Stature Cases Referred for Genetic Evaluation

To retrospectively analyze the profile of patients who presented with chief complaint of short stature to Medical Genetics OPD of SGPGIMS, Lucknow, India. Medical Genetics OPD records were searched for cases presenting with short stature, from January 2008 through December 2010. Short stature was defined as height less than -2 SD from mean for the corresponding age and sex for the Indian population. The workup done for the cases was analyzed, following which they were placed in one of the etiological categories of short stature. A total of 137 cases were analyzed. The number of female and male patients was 92 and 45 respectively. The evaluation done in majority of cases included anthropometry, calculation of mid-parental height, medical history, routine biochemistry and hematology, bone age assessment, thyroid function tests, antiendomysial antibody testing, karyotyping and other appropriate investigations as required. The percentages of cases in the various diagnostic categories were- skeletal dysplasia (32.1 %), turner syndrome (16.7%), endocrine deficiencies (8%), genetic syndromes (7.3%), chronic diseases (5.8%). Twenty one (15.3%) cases grouped as idiopathic short stature consisted of 9 familial and 12 non-familial cases. Twenty (14.6%) cases were found to be incompletely evaluated. Skeletal dysplasias and turner syndrome accounted for majority of cases of short stature. Cause remains unidentified in 15.3% cases and these idiopathic cases need further workup especially for the molecular defects in the pituitary GH-IGF1 axis. A detailed evaluation and good follow up of cases of short stature is required.

Variation in Age at Cancer Diagnosis in Familial versus Nonfamilial Barrett's Esophagus

Genetic influences may be discerned in families that have multiple affected members and may manifest as an earlier age of cancer diagnosis. In this study, we determine whether cancers develop at an earlier age in multiplex Familial Barrett's Esophagus (FBE) kindreds, defined by 3 or more members affected by Barrett's esophagus (BE) or esophageal adenocarcinoma (EAC). Information on BE/EAC risk factors and family history was collected from probands at eight tertiary care academic hospitals. Age of cancer diagnosis and other risk factors were compared between nonfamilial (no affected relatives), duplex (two affected relatives), and multiplex (three or more affected relatives) FBE kindreds. The study included 830 nonfamilial, 274 duplex, and 41 multiplex FBE kindreds with 274, 133, and 43 EAC and 566, 288, and 103 BE cases, respectively. Multivariable mixed models adjusting for familial correlations showed that multiplex kindreds were associated with a younger age of cancer diagnosis (P = 0.0186). Median age of cancer diagnosis was significantly younger in multiplex compared with duplex and nonfamilial kindreds (57 vs. 62 vs. 63 years, respectively, P = 0.0448). Mean body mass index was significantly lower in multiplex kindreds (P = 0.0033), as was smoking (P < 0.0001), and reported regurgitation (P = 0.0014). Members of multiplex FBE kindreds develop EAC at an earlier age compared with nonfamilial EAC cases. Multiplex kindreds do not have a higher proportion of common risk factors for EAC, suggesting that this aggregation might be related to a genetic factor. These findings indicate that efforts to identify susceptibility genes for BE and EAC will need to focus on multiplex kindreds.

The papulopustular lesion/arthritis cluster of Behcet's syndrome also clusters in families

We have previously reported distinct symptom clusters among our patients with Behçet's syndrome (BS). The presence of such clusters suggests that more than one pathogenetic mechanism might be operative in BS. Increases in the frequency of certain clusters in familial BS cases, if present, would further support this notion. To test this hypothesis, we compared the frequency of symptom clusters between familial (group F) and non-familial (group NF) cases of BS. We identified 380 BS patients who had reported a first-degree relative by reviewing 6031 patient charts. We were able to contact 186 (Group F). From the same initial pool, 500 patients were randomly selected. Of those, patients who did not report a family history of BS and who had attended our clinic during the previous 3 months made up group NF (n = 221). Both groups were questioned about their symptoms within the previous 3 months. Data were analysed using factor analysis, cluster analysis and χ2 tests. The make-up of the symptom clusters were very similar for the factor and the cluster analyses. The frequency of papulopustular lesions and joint involvement cluster was significantly higher in group F (39.2 vs. 21.5%, P < 0.001). Furthermore, the same cluster was shared in 5/17 related pairs from group F and in only 5/110 unrelated pairs from group NF [29 vs. 4.5%, P = 0.004; risk ratio (RR) = 6.47, 95% CI 2.15, 18.89]. The papulopustular lesions and arthritis cluster in BS appears to cluster in familial BS as well. This further supports the notion that the pathogenesis of BS may entail several distinct mechanisms resulting in separate phenotype clusters.

From genetics to genomics of epilepsy.

The introduction of DNA microarrays and DNA sequencing technologies in medical genetics and diagnostics has been a challenge that has significantly transformed medical practice and patient management. Because of the great advancements in molecular genetics and the development of simple laboratory technology to identify the mutations in the causative genes, also the diagnostic approach to epilepsy has significantly changed. However, the clinical use of molecular cytogenetics and high-throughput DNA sequencing technologies, which are able to test an entire genome for genetic variants that are associated with the disease, is preparing a further revolution in the near future. Molecular Karyotype and Next-Generation Sequencing have the potential to identify causative genes or loci also in sporadic or non-familial epilepsy cases and may well represent the transition from a genetic to a genomic approach to epilepsy.

Genetic Basis of Prune Belly Syndrome: Screening for HNF1β Gene

Although the cause of prune belly syndrome is unknown, familial evidence suggests a genetic component. Recently 2 nonfamilial cases of prune belly syndrome with chromosome 17q12 deletions encompassing the HNF1β gene have made this a candidate gene for prune belly syndrome. To date, there has been no large-scale screening of patients with prune belly syndrome for HNF1β mutations. We assessed the role of HNF1β in prune belly syndrome by screening for genomic mutations with functional characterization of any detected mutations. We studied patients with prune belly syndrome who were prospectively enrolled in our Pediatric Genitourinary DNA Repository since 2001. DNA from patient samples was amplified by polymerase chain reaction, sequenced for coding and splice regions of the HNF1β gene, and compared to control databases. We performed functional assay testing of the ability of mutant HNF1β to activate a luciferase construct with an HNF1β DNA binding site. From 32 prune belly syndrome probands (30 males, 2 females) HNF1β sequencing detected a missense mutation (V61G) in 1 child with prune belly syndrome. Absent in control databases, V61G was previously reported in 2 patients without prune belly syndrome who had congenital genitourinary anomalies. Functional testing showed similar luciferase activity compared to wild-type HNF1β, suggesting the V61G substitution does not disturb HNF1β function. One genomic HNF1β mutation was detected in 3% of patients with prune belly syndrome but found to be functionally normal. Thus, functionally significant HNF1β mutations are uncommon in prune belly syndrome, despite case reports of HNF1β deletions. Further genetic study is necessary, as identification of the genetic basis of prune belly syndrome may ultimately lead to prevention and improved treatments for this rare but severe syndrome.

Growth Hormone (GH-1) Gene Deletions in Children with Isolated Growth Hormone Deficiency (IGHD)

To detect growth hormone GH-1 gene deletions (6.7 kb, 7.6 kb, 7 kb) in familial/nonfamilial isolated growth hormone deficiency (IGHD) and note their clinical and investigative profile. Thirty (M16,F14) prepubertal IGHD patients aged 0.25 to 14 y, from 25 families were screened. Duration of growth failure, relevant history, clinical phenotype, and height SDS were recorded. Peak GH response to Clonidine (0.15 mg/m(2)), IGF-1, IGFBP-3 and pituitary/target gland hormones were studied. Genomic DNA of patients and family was analysed by PCR and DNA fragments were visualized on agarose gel electrophoresis. This series was divided into deletion +ve, Group I (n=12,40%) inclusive of six familial/six nonfamilial patients, and deletion -ve Group II (n=18,60%), 5 familial/13 nonfamilial cases; in total 11/30 were familial. Onset of growth failure was earlier in Group I (p<0.001) mean 1.1 vs 4.7 y. Mean height SDS was -7 vs. -4.5 in Groups I/II (p<0.01), age at presentation 5.1 vs 8.6 y. Overhanging forehead, prominent eyes, hypoplastic facies characterized Group I with FBS <50 mg/dl in 50% and very low peak GH <0.04 vs 2.04 ng/ml (p<0.001) in Group II. In both groups IGF-1 and IGFBP3 were low, other hormones were normal and MRI showed hypoplastic adenohypophysis. 40% had GH-1 gene deletion (6.7 kb deletion in 83%, 7.6 kb and a compound heterozygote in 8% each). In this series of 30 IGHD patients, frequency of GH-1 gene deletions (12/30) was 40%, and 54% among familial patients, and 31% with height SDS>-4. 83% had 6.7 kb deletion. Height SDS>-4, clinical phenotype, peak GH<1 ng/ml and hypoglycemia characterised IGHD Type IA.

A case report of motor neuron disease in a patient showing significant level of DDTs, HCHs and organophosphate metabolites in hair as well as levels of hexane and toluene in blood

Motor neuron disease is a devastating neurodegenerative condition, with the majority of sporadic, non-familial cases being of unknown etiology. Several epidemiological studies have suggested that occupational exposure to chemicals may be associated with disease pathogenesis. We report the case of a patient developing progressive motor neuron disease, who was chronically exposed to pesticides and organic solvents. The patient presented with leg spasticity and developed gradually clinical signs suggestive of amyotrophic lateral sclerosis, which was supported by the neurophysiologic and radiological findings. Our report is an evidence based case of combined exposure to organochlorine (DDTs), organophosphate pesticides (OPs) and organic solvents as confirmed by laboratory analysis in samples of blood and hair confirming systematic exposure. The concentration of non-specific dialkylphosphates metabolites (DAPs) of OPs in hair (dimethyphopshate (DMP) 1289.4 pg/mg and diethylphosphate (DEP) 709.4 pg/mg) and of DDTs (opDDE 484.0 pg/mg, ppDDE 526.6 pg/mg, opDDD 448.4 pg/mg, ppDDD + opDDT 259.9 pg/mg and ppDDT 573.7 pg/mg) were considerably significant. Toluene and n-hexane were also detected in blood on admission at hospital and quantified (1.23 and 0.87 μg/l, respectively), while 3 months after hospitalization blood testing was found negative for toluene and n-hexane and hair analysis was provided decrease levels of HCHs, DDTs and DAPs.

Frequency and clinical genetics of familial dilated cardiomyopathy in Cape Town: implications for the evaluation of patients with unexplained cardiomyopathy.

Studies from Europe and North America suggest that 20 - 50% of patients with dilated cardiomyopathy (DCM) may have familial disease. There is little information on the frequency and clinical genetics of familial DCM in Africa. To determine the frequency and probable mode of inheritance of familial DCM in patients referred for investigation of the cause of DCM at a tertiary centre in Cape Town. We conducted a retrospective analysis of consecutive patients diagnosed with DCM between 1 February 1996 and 31 December 2009 to determine the frequency of familial disease. Of 109 unrelated patients with DCM, 29 (26.6%) had familial disease. Their mean age of onset of cardiomyopathy (28.01 (standard deviation (SD) 15.33) years) was significantly younger than that for non-familial cases (39.1 (SD 12.6) years) (p=0.001). Male predominance (N=21, 72.4%) and racial distribution (15 (48.3%) coloured patients, 10 (34.5%) black Africans, 4 (13.8%) white individuals, and 1 (3.4%) of Indian descent) of familial DCM probands were similar to the non-familial cases. Of the 29 patients with familial DCM, 2 (7%) had at least one relative diagnosed with peripartum cardiomyopathy. Pedigree analysis of the 29 families was consistent with autosomal dominant inheritance in 72.4%, autosomal recessive inheritance in 17.2% and X-linked recessive inheritance in 10.4%. Familial DCM affects at least a quarter of African patients with DCM, presents at a young age, is associated with peripartum cardiomyopathy, and follows an autosomal dominant pattern of inheritance in the majority of families. Family screening for familial DCM is indicated in all cases of unexplained DCM, including patients with peripartum cardiomyopathy.

The Predisposing Pathology and Clinical Characteristics in the Scottish Retinal Detachment Study

To describe the predisposing pathology and clinical features of all incident cases of rhegmatogenous retinal detachment (RRD) recruited in Scotland during a 2-year period. Prospective surveillance study of incident cases of RRD. All incident cases of RRD recruited as part of the Scottish Retinal Detachment Study. During a 2-year period, we coordinated a comprehensive system in which every case of primary RRD presenting to 1 of 6 vitreoretinal surgical sites in Scotland was examined and approached for study inclusion. Rhegmatogenous retinal detachment incidence, predisposing features, and clinical characteristics. A total of 1202 cases were recruited. Detailed clinical information was available on 1130 (94%) of cases. By causative break, the proportions of RRD were horseshoe tear (HST) associated with posterior vitreous detachment (PVD) in 86.2%, giant retinal tear (GRT) and PVD in 1.3%, non-PVD round hole (RH) in 4.9%, retinal dialysis in 5.9%, and retinoschisis RRD in 1.6%. One in 10 cases reported significant ocular trauma. One in 5 cases were pseudophakic. Round hole RRD more frequently presented with multiple retinal breaks compared with HST RRD (67.8% vs. 48.7%; P = 0.003). In PVD-associated RRD, 56.1% (95% confidence interval [CI], 53.8-58.3) of breaks were identified in the superotemporal retina. In non-PVD RRD, 54.6% (95% CI, 47.9-61.1) of breaks were inferotemporal, followed by superotemporal in 34.9% (95% CI, 28.7-41.5). Lattice degeneration was present in 18.7% of affected eyes and more common in RH RRD (35.7%) than in HST RRD (19.3%) (P = 0.003). Seven percent reported an affected first-degree relative, and these cases were significantly more myopic than nonfamilial cases. More than 85% of RRD cases are associated with PVD and related tractional tears. Non-PVD RH RRD occurred in younger and more myopic individuals. The majority of cases are caused by more than 1 retinal break, and the macula is affected in more than 50% at presentation. Ocular trauma, previous cataract surgery, family history, and lattice degeneration are important predisposing features.

Recurrent and founder mutations in the Netherlands: cardiac Troponin I (TNNI3) gene mutations as a cause of severe forms of hypertrophic and restrictive cardiomyopathy

BackgroundAbout 2-7% of familial cardiomyopathy cases are caused by a mutation in the gene encoding cardiac troponin I (TNNI3). The related clinical phenotype is usually severe with early onset. Here we report on all currently known mutations in the Dutch population and compared these with those described in literature.MethodsTheTNNI3 gene was screened for mutations in all coding exons and flanking intronic sequences in a large cohort of cardiomyopathy patients. All Dutch index cases carrying a TNNI3 mutation that are described in this study underwent extensive cardiological evaluation and were listed by their postal codes.ResultsIn 30 families, 14 different mutations were identified. Three TNNI3 mutations were found relatively frequently in both familial and non-familial cases of hypertrophic cardiomyopathy (HCM) or restrictive cardiomyopathy (RCM). Haplotype analysis showed that p.Arg145Trp and p.Ser166Phe are founder mutations in the Netherlands, while p.Glu209Ala is not. The majority of Dutch TNNI3 mutations were associated with a HCM phenotype. Mean age at diagnosis was 36.5 years. Mutations causing RCM occurred less frequently, but were identified in very young children with a poor prognosis.ConclusionIn line with previously published data, we found TNNI3 mutations to be rare and associated with early onset and severe clinical presentation.

Familial Barrett’s Esophagus: Clues to Genetic Risks for Esophageal Adenocarcinoma

Esophageal adenocarcinoma is a particularly deadly neoplasm, and the incidence of it has been rising at an alarming rate in recent decades in Western countries [1, 2]. Barrett’s esophagus has been recognized as a precursor lesion for cancer, and screening and subsequent surveillance or other intervention for this lesion is an attractive proposition. Despite the rising incidence, the cancer still remains relatively uncommon. Therefore, selecting highrisk patients for screening, surveillance, or intervention is important in order to make the practice economically reasonable. Risk factors have been established for the cancer and for Barrett’s esophagus, including male gender, white race, older age, symptoms of gastroesophageal reflux, obesity, tobacco use, and absence of infection with Helicobacter pylori. However, most of these factors are highly prevalent in Western societies, so more specific risk factors would improve the efficiency of clinical practice. The association with white race might be because of environmental differences among races, but also suggests that genetic factors play an important role. Obviously, humans are not evolving rapidly enough to explain the rising incidence of esophageal adenocarcinoma, which is certainly because of relatively recent changes in environment or behavior. However, those changes in environment and behavior may interact with genetic factors, such that only genetically predisposed individuals develop the cancer in the modern setting of obesity and low prevalence of Helicobacter pylori. Indeed, a family history of esophageal adenocarcinoma or Barrett’s esophagus has been associated with the presence of both of those diagnoses [3]. A number of case reports of individual families suggest an autosomal dominant pattern of inheritance with incomplete penetrance [4–6]. Familial effects on the risk of esophageal adenocarcinoma may act via the promotion of other known risk factors (such as obesity or gastroesophageal reflux), via the promotion of Barrett’s esophagus among those with the recognized risk factors, via the promotion of neoplastic transformation within Barrett’s esophagus, or combinations of these loci of effects. In this issue of Digestive Diseases and Sciences, Ash and colleagues have begun to address these effects by studying their cohort of patients with Barrett’s esophagus [7]. Records of nearly 1,000 patients with Barrett’s esophagus were abstracted regarding their family history of either Barrett’s esophagus or esophageal cancer, and those with a positive history were interviewed for details. Nearly 6% of patients with Barrett’s esophagus were found to have a positive family history. The investigators then compared these familial cases of Barrett’s esophagus with the non-familial cases, seeking differences in demographics or clinical characteristics. Of note, they found no difference in gender, race, smoking history, presence of Helicobacter pylori, hiatal hernia, or length of Barrett’s esophagus. The investigators did find that familial cases were younger, and less likely to harbor neoplasia; however, they attribute these differences to referral bias, because patients with neoplasia are frequently referred to their center from outside practices, and patients with familial Barrett’s esophagus without neoplasia may be more likely to be referred to them than other non-neoplastic Barrett’s esophagus patients. The younger age of the familial Barrett’s J. H. Rubenstein (&) Veterans Affairs Center for Clinical Management Research, VA Medical Centre, 111-D, 2215 Fuller Road, Ann Arbor, MI 48105, USA e-mail: jhr@med.umich.edu

PEHO Syndrome: A Study of Five Argentinian Patients

We describe two familial and three nonfamilial cases from Argentina, examined between February 1, 1990-July 31, 2008, who met the diagnostic criteria of progressive encephalopathy, peripheral edema, hypsarrhythmia, and optic atrophy syndrome. All five children were products of normal gestation, although one was premature. Birth was uneventful in all patients. Two patients were twin brothers. During their first neurologic examination, between ages 2-6 months, patients presented with facial dysmorphia, poor visual contact, and generalized hypotonia with poor head control. Microcephaly and swelling of the dorsum of the hands and feet were evident. Hypsarrhythmia was observed in all patients (associated with epileptic spasms in four). Optic atrophy was evident in four cases. Magnetic resonance imaging indicated progressive cerebellum and brainstem atrophy in all cases. Toxoplasmosis, others, rubella, cytomegalovirus, herpes (TORCH), neurometabolic investigations, and karyotype studies produced normal results in all patients. Progressive encephalopathy, peripheral edema, hypsarrhythmia, and optic atrophy syndrome should be considered in infants with neonatal hypotonia, early onset of seizures (especially epileptic spasms), hypsarrhythmia, early loss of visual fixation, profound psychomotor retardation, typical dysmorphy, and progressive cerebellar and brainstem atrophy without a clear etiology. Autosomal recessive inheritance is suspected. Early diagnosis is important for adequate genetic counseling.