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author:("smiths, Sarah")
1.  A genetic study of Wilson’s disease in the United Kingdom 
Brain  2013;136(5):1476-1487.
Previous studies have failed to identify mutations in the Wilson’s disease gene ATP7B in a significant number of clinically diagnosed cases. This has led to concerns about genetic heterogeneity for this condition but also suggested the presence of unusual mutational mechanisms. We now present our findings in 181 patients from the United Kingdom with clinically and biochemically confirmed Wilson’s disease. A total of 116 different ATP7B mutations were detected, 32 of which are novel. The overall mutation detection frequency was 98%. The likelihood of mutations in genes other than ATP7B causing a Wilson’s disease phenotype is therefore very low. We report the first cases with Wilson’s disease due to segmental uniparental isodisomy as well as three patients with three ATP7B mutations and three families with Wilson’s disease in two consecutive generations. We determined the genetic prevalence of Wilson’s disease in the United Kingdom by sequencing the entire coding region and adjacent splice sites of ATP7B in 1000 control subjects. The frequency of all single nucleotide variants with in silico evidence of pathogenicity (Class 1 variant) was 0.056 or 0.040 if only those single nucleotide variants that had previously been reported as mutations in patients with Wilson’s disease were included in the analysis (Class 2 variant). The frequency of heterozygote, putative or definite disease-associated ATP7B mutations was therefore considerably higher than the previously reported occurrence of 1:90 (or 0.011) for heterozygote ATP7B mutation carriers in the general population (P < 2.2 × 10-16 for Class 1 variants or P < 5 × 10-11 for Class 2 variants only). Subsequent exclusion of four Class 2 variants without additional in silico evidence of pathogenicity led to a further reduction of the mutation frequency to 0.024. Using this most conservative approach, the calculated frequency of individuals predicted to carry two mutant pathogenic ATP7B alleles is 1:7026 and thus still considerably higher than the typically reported prevalence of Wilson’s disease of 1:30 000 (P = 0.00093). Our study provides strong evidence for monogenic inheritance of Wilson’s disease. It also has major implications for ATP7B analysis in clinical practice, namely the need to consider unusual genetic mechanisms such as uniparental disomy or the possible presence of three ATP7B mutations. The marked discrepancy between the genetic prevalence and the number of clinically diagnosed cases of Wilson’s disease may be due to both reduced penetrance of ATP7B mutations and failure to diagnose patients with this eminently treatable disorder.
doi:10.1093/brain/awt035
PMCID: PMC3634195  PMID: 23518715
Wilson’s disease; ATP7B; genetic prevalence
2.  Progesterone vs placebo therapy for women with epilepsy 
Neurology  2012;78(24):1959-1966.
Objective:
To assess progesterone treatment of intractable seizures in women with partial epilepsy.
Methods:
This randomized, double-blind, placebo-controlled, phase III, multicenter, clinical trial compared the efficacy and safety of adjunctive cyclic natural progesterone therapy vs placebo treatment of intractable seizures in 294 subjects randomized 2:1 to progesterone or placebo, stratified by catamenial and noncatamenial status. It compared treatments on proportions of ≥50% responders and changes in seizure frequency from 3 baseline to 3 treated menstrual cycles.
Results:
There was no significant difference in proportions of responders between progesterone and placebo in the catamenial and noncatamenial strata. Prespecified secondary analysis showed that the level of perimenstrual seizure exacerbation (C1 level) was a significant predictor of responders for progesterone but not placebo. With increasing C1 levels, responders increased from 21% to 57% with progesterone vs 19% to 20% with placebo. Reductions in seizure frequency correlated with increasing C1 levels for progesterone but not placebo, progressing from 26% to 71% for progesterone vs 25% to 26% for placebo. A prespecified clinically important separation between progesterone and placebo responders (37.8% vs 11.1%; p = 0.037) was realized among 21.4% of women who had C1 level ≥3.
Conclusion:
There was no difference in the primary outcome of ≥50% responder rates between progesterone vs placebo for catamenial or noncatamenial groups. Post hoc findings suggest that the level of perimenstrual seizure exacerbation is a significant predictor of responder rate with progesterone and that progesterone may provide clinically important benefit for a subset of women with perimenstrually exacerbated seizures.
Classification of evidence:
This study provides Class III evidence that cyclic progesterone is ineffective in women with intractable partial epilepsy. Post hoc analysis identified a subset of women with higher levels of perimenstrual seizure exacerbation that were responsive to treatment.
doi:10.1212/WNL.0b013e318259e1f9
PMCID: PMC3369508  PMID: 22649214
3.  Brittle cornea syndrome: recognition, molecular diagnosis and management 
Brittle cornea syndrome (BCS) is an autosomal recessive disorder characterised by extreme corneal thinning and fragility. Corneal rupture can therefore occur either spontaneously or following minimal trauma in affected patients. Two genes, ZNF469 and PRDM5, have now been identified, in which causative pathogenic mutations collectively account for the condition in nearly all patients with BCS ascertained to date. Therefore, effective molecular diagnosis is now available for affected patients, and those at risk of being heterozygous carriers for BCS. We have previously identified mutations in ZNF469 in 14 families (in addition to 6 reported by others in the literature), and in PRDM5 in 8 families (with 1 further family now published by others). Clinical features include extreme corneal thinning with rupture, high myopia, blue sclerae, deafness of mixed aetiology with hypercompliant tympanic membranes, and variable skeletal manifestations. Corneal rupture may be the presenting feature of BCS, and it is possible that this may be incorrectly attributed to non-accidental injury. Mainstays of management include the prevention of ocular rupture by provision of protective polycarbonate spectacles, careful monitoring of visual and auditory function, and assessment for skeletal complications such as developmental dysplasia of the hip. Effective management depends upon appropriate identification of affected individuals, which may be challenging given the phenotypic overlap of BCS with other connective tissue disorders.
doi:10.1186/1750-1172-8-68
PMCID: PMC3659006  PMID: 23642083
Brittle cornea syndrome; Corneal rupture; Blue sclera; ZNF469; PRDM5
4.  Medical students’ reactions to an experience-based learning model of clinical education 
An experience-based learning (ExBL) model proposes: Medical students learn in workplaces by ‘supported participation’; affects are an important dimension of support; many learning outcomes are affective; supported participation influences students’ professional identity development. The purpose of the study was to check how the model, which is the product of a series of earlier research studies, aligned with students’ experiences, akin to the ‘member checking’ stage of a qualitative research project. In three group discussions, a researcher explained ExBL to 19 junior clinical students, who discussed how it corresponded with their experiences of clinical learning and were given a written précis of it to take away. One to 3 weeks later, they wrote 500-word reflective pieces relating to their subsequent experiences with ExBL. Four researchers conducted a qualitative analysis. Having found many instances of responses ‘resonating’ to the model, the authors systematically identified and coded respondents’ ‘resonances’ to define how they aligned with their experiences. 120 resonances were identified. Seventy (58 %) were positive experiences and 50 (42 %) negative ones. Salient experiences were triggered by the learning environment in 115 instances (96 %) and by learners themselves in 5 instances (4 %), consistent with a strong effect of environment on learning processes. Affective support was apparent in 129 of 203 statements (64 %) of resonances and 118 learning outcomes (58 %) were also affective. ExBL aligns with medical students’ experiences of clinical learning. Subject to further research, these findings suggest ExBL could be used to support the preparation of faculty and students for workplace learning.
doi:10.1007/s40037-013-0061-4
PMCID: PMC3656171  PMID: 23670698
Clerkship education; Experience based learning; Qualitative analysis
5.  Medical students’ reactions to an experience-based learning model of clinical education 
An experience-based learning (ExBL) model proposes: Medical students learn in workplaces by ‘supported participation’; affects are an important dimension of support; many learning outcomes are affective; supported participation influences students’ professional identity development. The purpose of the study was to check how the model, which is the product of a series of earlier research studies, aligned with students’ experiences, akin to the ‘member checking’ stage of a qualitative research project. In three group discussions, a researcher explained ExBL to 19 junior clinical students, who discussed how it corresponded with their experiences of clinical learning and were given a written précis of it to take away. One to 3 weeks later, they wrote 500-word reflective pieces relating to their subsequent experiences with ExBL. Four researchers conducted a qualitative analysis. Having found many instances of responses ‘resonating’ to the model, the authors systematically identified and coded respondents’ ‘resonances’ to define how they aligned with their experiences. 120 resonances were identified. Seventy (58 %) were positive experiences and 50 (42 %) negative ones. Salient experiences were triggered by the learning environment in 115 instances (96 %) and by learners themselves in 5 instances (4 %), consistent with a strong effect of environment on learning processes. Affective support was apparent in 129 of 203 statements (64 %) of resonances and 118 learning outcomes (58 %) were also affective. ExBL aligns with medical students’ experiences of clinical learning. Subject to further research, these findings suggest ExBL could be used to support the preparation of faculty and students for workplace learning.
doi:10.1007/s40037-013-0061-4
PMCID: PMC3656171  PMID: 23670698
Clerkship education; Experience based learning; Qualitative analysis
6.  Shwachman-Diamond syndrome: a complex case demonstrating the potential for misdiagnosis as asphyxiating thoracic dystrophy (Jeune syndrome) 
BMC Pediatrics  2012;12:48.
Background
The differential diagnosis of a neonate or fetus presenting with a bell-shaped or long narrow thorax includes a wide range of bony dysplasia syndromes. Where this is accompanied by respiratory distress, asphyxiating thoracic dystrophy (ATD, Jeune syndrome) is an important potential diagnosis. Shwachman-Diamond syndrome (SDS) is widely recognised as a cause of exocrine pancreatic dysfunction, short stature and bone marrow failure. It is not so well appreciated that rib and/or thoracic cage abnormalities occur in 30–50% of patients and that, in severe cases, these abnormalities may lead to thoracic dystrophy and respiratory failure in the newborn. There are, however, at least three previous case reports of children who were initially diagnosed with ATD who were subsequently shown to have SDS.
Case presentation
This report details the case history of a patient misdiagnosed as having ATD as a neonate following the neonatal asphyxial death of her brother. She subsequently developed progressive pancytopenia but was only diagnosed with SDS at 11 years of age after referral for haematopoietic stem cell transplantation for bone marrow failure accompanied by trilineage dysplasia and clonal cytogenetic abnormalities on bone marrow examination. Subsequent testing revealed the presence of fat globules in stools, reduced faecal chymotrypsin, fat-soluble vitamin deficiency, metaphyseal dysplasia on skeletal survey and heterozygous mutations of the SBDS gene.
Conclusion
This report highlights the potential for diagnostic confusion between ATD and SDS. It is important to include SDS in the differential diagnosis of newborns with thoracic dystrophy and to seek expert clinical and radiological assessment of such children.
doi:10.1186/1471-2431-12-48
PMCID: PMC3457858  PMID: 22554078
Shwachman-Diamond syndrome; Asphyxiating thoracic dystrophy; Jeune syndrome; Differential diagnosis; Haematopoietic stem cell transplantation; Isochromosome 7q; Pancreatic insufficiency; Neonatal respiratory distress
7.  Bohring–Opitz (Oberklaid–Danks) syndrome: clinical study, review of the literature, and discussion of possible pathogenesis 
Bohring–Opitz syndrome (BOS) is a rare congenital disorder of unknown etiology diagnosed on the basis of distinctive clinical features. We suggest diagnostic criteria for this condition, describe ten previously unreported patients, and update the natural history of four previously reported patients. This is the largest series reported to date, providing a unique opportunity to document the key clinical features and course through childhood. Investigations undertaken to try and elucidate the underlying pathogenesis of BOS using array comparative genomic hybridization and tandem mass spectrometry of cholesterol precursors did not show any pathogenic changes responsible.
doi:10.1038/ejhg.2010.234
PMCID: PMC3083618  PMID: 21368916
Bohring–Opitz; Oberklaid–Danks; cholesterol biosynthesis; array CGH; trigonocephaly
8.  Autism, language and communication in children with sex chromosome trisomies 
Archives of disease in childhood  2010;96(10):954-959.
Purpose
Sex chromosome trisomies (SCTs) are found on amniocentesis in 2.3–3.7 per 1000 same-sex births, yet there is a limited database on which to base a prognosis. Autism has been described in postnatally diagnosed cases of Klinefelter syndrome (XXY karyotype), but the prevalence in non-referred samples, and in other trisomies, is unclear. The authors recruited the largest sample including all three SCTs to be reported to date, including children identified on prenatal screening, to clarify this issue.
Design
Parents of children with a SCT were recruited either via prenatal screening or via a parental support group, to give a sample of 58 XXX, 19 XXY and 58 XYY cases. Parents were interviewed using the Vineland Adaptive Behavior Scales and completed questionnaires about the communicative development of children with SCTs and their siblings (42 brothers and 26 sisters).
Results
Rates of language and communication problems were high in all three trisomies. Diagnoses of autism spectrum disorder (ASD) were found in 2/19 cases of XXY (11%) and 11/58 XYY (19%). After excluding those with an ASD diagnosis, communicative profiles indicative of mild autistic features were common, although there was wide individual variation.
Conclusions
Autistic features have not previously been remarked upon in studies of non-referred samples with SCTs, yet the rate is substantially above population levels in this sample, even when attention is restricted to early-identified cases. The authors hypothesise that X-linked and Y-linked neuroligins may play a significant role in the aetiology of communication impairments and ASD.
doi:10.1136/adc.2009.179747
PMCID: PMC3182523  PMID: 20656736
10.  Stickler syndrome caused by COL2A1 mutations: genotype–phenotype correlation in a series of 100 patients 
Stickler syndrome is an autosomal dominant connective tissue disorder caused by mutations in different collagen genes. The aim of our study was to define more precisely the phenotype and genotype of Stickler syndrome type 1 by investigating a large series of patients with a heterozygous mutation in COL2A1. In 188 probands with the clinical diagnosis of Stickler syndrome, the COL2A1 gene was analyzed by either a mutation scanning technique or bidirectional fluorescent DNA sequencing. The effect of splice site alterations was investigated by analyzing mRNA. Multiplex ligation-dependent amplification analysis was used for the detection of intragenic deletions. We identified 77 different COL2A1 mutations in 100 affected individuals. Analysis of the splice site mutations showed unusual RNA isoforms, most of which contained a premature stop codon. Vitreous anomalies and retinal detachments were found more frequently in patients with a COL2A1 mutation compared with the mutation-negative group (P<0.01). Overall, 20 of 23 sporadic patients with a COL2A1 mutation had either a cleft palate or retinal detachment with vitreous anomalies. The presence of vitreous anomalies, retinal tears or detachments, cleft palate and a positive family history were shown to be good indicators for a COL2A1 defect. In conclusion, we confirm that Stickler syndrome type 1 is predominantly caused by loss-of-function mutations in the COL2A1 gene as >90% of the mutations were predicted to result in nonsense-mediated decay. On the basis of binary regression analysis, we developed a scoring system that may be useful when evaluating patients with Stickler syndrome.
doi:10.1038/ejhg.2010.23
PMCID: PMC2987380  PMID: 20179744
COL2A1; Stickler syndrome; genotype–phenotype correlation; type II collagenopathies; splice site mutation
11.  Liver Enzymes Elevation and Immune Reconstitution Among Treatment-Naïve HIV-Infected Patients Instituting Antiretroviral Therapy 
Objectives
Because liver enzymes elevation (LEE) complicates antiretroviral (ARV) therapy, and because the strongest risk factor for ARV-related LEE is HBV/HCV coinfection, it is speculated that ARV-related LEE may be a form of immune reconstitution disease. This study summarizes the relation between immune reconstitution, ARV-induced LEE, and HBV/HCV coinfection.
Methods
Medical records of ARV-naïve HIV-infected patients initiating ARV were reviewed for hepatitis coinfection, LEE (grade ≥2 AST/ALT) and changes in CD4 T-cell counts over time in an urban HIV clinic. Risk factors for LEE were statistically evaluated, and changes in CD4 T-cell counts were estimated by a mixed-effects linear model.
Results
Predictors of LEE included HBV/HCV coinfection (OR = 6.44) and stavudine use (OR = 2.33). Nelfinavir use was protective (OR = 0.45). The mean rate of change in CD4 T-cell counts was higher in HBV/HCV coinfected subjects who developed LEE (99 cells/μL per month) compared with non-coinfected subjects who did not develop LEE (59 cells/μL per month, P = 0.03), non-coinfected subjects who developed LEE (36 cells/μL per month, P = 0.01), and coinfected subjects who did not develop LEE, 38% higher (62 cells/μL per month; P = 0.11)
Conclusions
A more robust immune restoration was observed among HBV/HCV coinfected subjects who developed liver enzyme elevation after antiretroviral initiation compared with other groups. This finding suggests that ARV-related liver enzyme elevation may be related in part to immune reconstitution, as measured by changes in CD4 T-cell counts.
doi:10.1097/MAJ.0b013e31811ec780
PMCID: PMC3075308  PMID: 18004087
Hepatotoxicity; Liver enzymes elevation; Antiretroviral drugs; Immune reconstitution; HIV/AIDS
12.  Schimke immunoosseous dysplasia: defining skeletal features 
European Journal of Pediatrics  2009;169(7):801-811.
Schimke immunoosseous dysplasia (SIOD) is an autosomal recessive multisystem disorder characterized by prominent spondyloepiphyseal dysplasia, T cell deficiency, and focal segmental glomerulosclerosis. Biallelic mutations in swi/snf-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1 (SMARCAL1) are the only identified cause of SIOD, but approximately half of patients referred for molecular studies do not have detectable mutations in SMARCAL1. We hypothesized that skeletal features distinguish between those with or without SMARCAL1 mutations. Therefore, we analyzed the skeletal radiographs of 22 patients with and 11 without detectable SMARCAL1 mutations. We found that patients with SMARCAL1 mutations have a spondyloepiphyseal dysplasia (SED) essentially limited to the spine, pelvis, capital femoral epiphyses, and possibly the sella turcica, whereas the hands and other long bones are basically normal. Additionally, we found that several of the adolescent and young adult patients developed osteoporosis and coxarthrosis. Of the 11 patients without detectable SMARCAL1 mutations, seven had a SED indistinguishable from patients with SMARCAL1 mutations. We conclude therefore that SED is a feature of patients with SMARCAL1 mutations and that skeletal features do not distinguish who of those with SED have SMARCAL1 mutations.
Electronic supplementary material
The online version of this article (doi:10.1007/s00431-009-1115-9) contains supplementary material, which is available to authorized users.
doi:10.1007/s00431-009-1115-9
PMCID: PMC2876264  PMID: 20013129
Genocopy; Immunodeficiency; Proteinuria; Skeletal dysplasia; Locus heterogeneity; Schimke immunoosseous dysplasia
13.  Exome sequencing identifies DYNC2H1 mutations as a common cause of asphyxiating thoracic dystrophy (Jeune syndrome) without major polydactyly, renal or retinal involvement 
Journal of Medical Genetics  2013;50(5):309-323.
Background
Jeune asphyxiating thoracic dystrophy (JATD) is a rare, often lethal, recessively inherited chondrodysplasia characterised by shortened ribs and long bones, sometimes accompanied by polydactyly, and renal, liver and retinal disease. Mutations in intraflagellar transport (IFT) genes cause JATD, including the IFT dynein-2 motor subunit gene DYNC2H1. Genetic heterogeneity and the large DYNC2H1 gene size have hindered JATD genetic diagnosis.
Aims and methods
To determine the contribution to JATD we screened DYNC2H1 in 71 JATD patients JATD patients combining SNP mapping, Sanger sequencing and exome sequencing.
Results and conclusions
We detected 34 DYNC2H1 mutations in 29/71 (41%) patients from 19/57 families (33%), showing it as a major cause of JATD especially in Northern European patients. This included 13 early protein termination mutations (nonsense/frameshift, deletion, splice site) but no patients carried these in combination, suggesting the human phenotype is at least partly hypomorphic. In addition, 21 missense mutations were distributed across DYNC2H1 and these showed some clustering to functional domains, especially the ATP motor domain. DYNC2H1 patients largely lacked significant extra-skeletal involvement, demonstrating an important genotype–phenotype correlation in JATD. Significant variability exists in the course and severity of the thoracic phenotype, both between affected siblings with identical DYNC2H1 alleles and among individuals with different alleles, which suggests the DYNC2H1 phenotype might be subject to modifier alleles, non-genetic or epigenetic factors. Assessment of fibroblasts from patients showed accumulation of anterograde IFT proteins in the ciliary tips, confirming defects similar to patients with other retrograde IFT machinery mutations, which may be of undervalued potential for diagnostic purposes.
doi:10.1136/jmedgenet-2012-101284
PMCID: PMC3627132  PMID: 23456818
Clinical Genetics; Molecular Genetics; Developmental; Diagnostics; Genetic Screening/Counselling

Results 1-13 (13)