A case of true hermaphroditism reveals an unusual mechanism of twinning

Traditionally twins are classified as dizygous or fraternal and monozygous or identical (Hall Twinning, 362, 2003 and 735-743). We report a rare case of 46,XX/46,XY twins: Twin A presented with ambiguous genitalia and Twin B was a phenotypically normal male. These twins demonstrate a third, previously unreported mechanism for twinning. The twins underwent initial investigation with 17-hydroxyprogesterone and testosterone levels, pelvic ultrasound and diagnostic laparoscopy. Cytogenetic analysis was performed on peripheral blood cells and skin fibroblasts. Histological examination and Fluorescence in situ hybridization studies on touch imprints were performed on gonadal biopsies. DNA analysis using more than 6,000 DNA markers was performed on skin fibroblast samples from the twins and on peripheral blood samples from both parents. Twin A was determined to be a true hermaphrodite and Twin B an apparently normal male. Both twins had a 46,XX/46,XY chromosome complement in peripheral lymphocytes, skin fibroblasts, and gonadal biopsies. The proportion of XX to XY cells varied between the twins and the tissues evaluated. Most significantly the twins shared 100% of maternal alleles and approximately 50% of paternal alleles in DNA analysis of skin fibroblasts. The twins are chimeric and share a single genetic contribution from their mother but have two genetic contributions from their father thus supporting the existence of a third, previously unreported type of twinning.

Familial isolated hyperparathyroidism is linked to a 1.7 Mb region on chromosome 2p13.3-14

BACKGROUND: Familial isolated hyperparathyroidism (FIHP) is an autosomal dominantly inherited form of primary hyperparathyroidism. Although comprising only about 1% of cases of primary hyperparathyroidism, identification and functional analysis of a causative gene for FIHP is likely to advance our understanding of parathyroid physiology and pathophysiology. METHODS: A genome-wide screen of DNA from seven pedigrees with FIHP was undertaken in order to identify a region of genetic linkage with the disorder. RESULTS: Multipoint linkage analysis identified a region of suggestive linkage (LOD score 2.68) on chromosome 2. Fine mapping with the addition of three other families revealed significant linkage adjacent to D2S2368 (maximum multipoint LOD score 3.43). Recombination events defined a 1.7 Mb region of linkage between D2S2368 and D2S358 in nine pedigrees. Sequencing of the two most likely candidate genes in this region, however, did not identify a gene for FIHP. CONCLUSIONS: We conclude that a causative gene for FIHP lies within this interval on chromosome 2. This is a major step towards eventual precise identification of a gene for FIHP, likely to be a key component in the genetic regulation of calcium homeostasis.

Trait components provide tools to dissect the genetic susceptibility of migraine

The commonly used "end diagnosis" phenotype that is adopted in linkage and association studies of complex traits is likely to represent an oversimplified model of the genetic background of a disease. This is also likely to be the case for common types of migraine, for which no convincingly associated genetic variants have been reported. In headache disorders, most genetic studies have used end diagnoses of the International Headache Society (IHS) classification as phenotypes. Here, we introduce an alternative strategy; we use trait components--individual clinical symptoms of migraine--to determine affection status in genomewide linkage analyses of migraine-affected families. We identified linkage between several traits and markers on chromosome 4q24 (highest LOD score under locus heterogeneity [HLOD] 4.52), a locus we previously reported to be linked to the end diagnosis migraine with aura. The pulsation trait identified a novel locus on 17p13 (HLOD 4.65). Additionally, a trait combination phenotype (IHS full criteria) revealed a locus on 18q12 (HLOD 3.29), and the age at onset trait revealed a locus on 4q28 (HLOD 2.99). Furthermore, suggestive or nearly suggestive evidence of linkage to four additional loci was observed with the traits phonophobia (10q22) and aggravation by physical exercise (12q21, 15q14, and Xp21), and, interestingly, these loci have been linked to migraine in previous studies. Our findings suggest that the use of symptom components of migraine instead of the end diagnosis provides a useful tool in stratifying the sample for genetic studies.

Genomewide linkage study in 1,176 affected sister pair families identifies a significant susceptibility locus for endometriosis on chromosome 10q26

Endometriosis is a common gynecological disease that affects up to 10% of women in their reproductive years. It causes pelvic pain, severe dysmenorrhea, and subfertility. The disease is defined as the presence of tissue resembling endometrium in sites outside the uterus. Its cause remains uncertain despite >50 years of hypothesis-driven research, and thus the therapeutic options are limited. Disease predisposition is inherited as a complex genetic trait, which provides an alternative route to understanding the disease. We seek to identify susceptibility loci, using a positional-cloning approach that starts with linkage analysis to identify genomic regions likely to harbor these genes. We conducted a linkage study of 1,176 families (931 from an Australian group and 245 from a U.K. group), each with at least two members--mainly affected sister pairs--with surgically diagnosed disease. We have identified a region of significant linkage on chromosome 10q26 (maximum LOD score [MLS] of 3.09; genomewide P = .047) and another region of suggestive linkage on chromosome 20p13 (MLS = 2.09). Minor peaks (with MLS > 1.0) were found on chromosomes 2, 6, 7, 8, 12, 14, 15, and 17. This is the first report of linkage to a major locus for endometriosis. The findings will facilitate discovery of novel positional genetic variants that influence the risk of developing this debilitating disease. Greater understanding of the aberrant cellular and molecular mechanisms involved in the etiology and pathophysiology of endometriosis should lead to better diagnostic methods and targeted treatments.

GENEHUNTER: your 'one-stop shop' for statistical genetic analysis?

The past decade has brought a proliferation of statistical genetic (linkage) analysis techniques, incorporating new methodology and/or improvement of existing methodology in gene mapping, specifically targeted towards the localization of genes underlying complex disorders. Most of these techniques have been implemented in user-friendly programs and made freely available to the genetics community. Although certain packages may be more 'popular' than others, a common question asked by genetic researchers is 'which program is best for me?'. To help researchers answer this question, the following software review aims to summarize the main advantages and disadvantages of the popular GENEHUNTER package.

A genomewide screen for autism susceptibility loci

We report the analysis of 335 microsatellite markers genotyped in 110 multiplex families with autism. All families include at least two "affected" siblings, at least one of whom has autism; the remaining affected sibs carry diagnoses of either Asperger syndrome or pervasive developmental disorder. Affected sib-pair analysis yielded multipoint maximum LOD scores (MLS) that reach the accepted threshold for suggestive linkage on chromosomes 5, X, and 19. Nominal evidence for linkage (point-wise P<.05) was obtained on chromosomes 2, 3, 4, 8, 10, 11, 12, 15, 16, 18, and 20, and secondary loci were found on chromosomes 5 and 19. Analysis of families sharing alleles at the putative X chromosomal linked locus and one or more other putative linked loci produced an MLS of 3.56 for the DXS470-D19S174 marker combination. In an effort to increase power to detect linkage, scan statistics were used to evaluate the significance of peak LOD scores based on statistical evidence at adjacent marker loci. This analysis yielded impressive evidence for linkage to autism and autism-spectrum disorders with significant genomewide P values <.05 for markers on chromosomes 5 and 8 and with suggestive linkage evidence for a marker on chromosome 19.

Evidence for an X-linked genetic component in familial typical migraine

Migraine is a common complex disorder that shows strong familial aggregation. There is a general increased prevalence of migraine in females compared with males, with recent studies indicating that migraine affects 18% of females compared with 6% of males. This preponderance of females among migraine sufferers coupled with evidence of an increased risk of migraine in first degree relatives of male probands but not in relatives of female probands suggests the possibility of an X-linked dominant gene. We report here the localization of a typical migraine susceptibility locus to the X chromosome. Of three large multigenerational migraine pedigrees two families showed significant excess allele sharing to Xq markers (P = 0.031 and P = 0.012). Overall analysis of data from all three pedigrees gave significant evidence in support of linkage and heterogeneity (HLOD = 3.1). These findings provide conclusive evidence that familial typical migraine is a heterogeneous disorder. We suggest that the localization of a migraine susceptibility locus to the X chromosome could in part explain the increased risk of migraine in relatives of male probands and may be involved in the increased female prevalence of this disorder.

Patient preferences for receiving remote communication support for lifestyle physical activity behaviour change: The perspective of patients with musculoskeletal disorders from three hospital services

This study examined patients’ preference ratings for receiving support via remote communication to increase their lifestyle physical activity. Methods People with musculoskeletal disorders ( n=221 of 296 eligible) accessing one of three clinics provided preference ratings for “how much” they wanted to receive physical activity support via five potential communication modalities. The five ratings were generated on a horizontal analogue rating scale (0 represented “not at all”; 10 represented “very much”). Results Most (n=155, 70%) desired referral to a physical activity promoting intervention. “Print and post” communications had the highest median preference rating (7/10), followed by email and telephone (both 5/10), text messaging (1/10), and private Internet-based social network messages (0/10). Desire to be referred was associated with higher preference for printed materials (coefficient = 2.739, p<0.001), telephone calls (coefficient = 3.000, p<0.001), and email (coefficient = 2.059, p=0.02). Older age was associated with lower preference for email (coefficient = −0.100, p<0.001), texting (coefficient = −0.096, p<0.001), and social network messages (coefficient = −0.065, p<0.001). Conclusion Patients desiring support to be physically active indicated preferences for interventions with communication via print, email, or telephone calls.

Multi-morbidity, obesity and quality of life among physically inactive Australians accessing physiotherapy clinics for musculoskeletal disorders

The benefits of physical activity are established and numerous, including improved musculoskeletal health and reduced risk of cardiovascular disease, diabetes, some cancers, and a range of other chronic conditions. While sedentary lifestyles are becoming increasingly prevalent among populations internationally, people with musculoskeletal disorders may face additional challenges to undertaking exercise and physically activities. Unfortunately, interventions in ambulatory hospital clinics for people with musculoskeletal disorders primarily focus on their presenting musculoskeletal complaint with cursory attention given to lifestyle risk factors; including physical inactivity.

Consensus statement on the role of Accredited Exercise Physiologists within the treatment of mental disorders: A guide for mental health professionals

- Objective The aim is to identify the role and scope of Accredited Exercise Physiologist (AEP) services in the mental health sector and to provide insight as to how AEPs can contribute to the multidisciplinary mental health team. - Methods A modified Delphi approach was utilised. Thirteen AEPs with experience in mental health contributed to the iterative development of a national consensus statement. Six mental health professionals with expertise in psychiatry, mental health nursing, general practice and mental health research participated in the review process. Reviewers were provided with a template to systematically provide feedback on the language, content, structure and relevance to their professional group. - Results This consensus statement outlines how AEPs can contribute to the multidisciplinary mental health team, the aims and scope of AEP-led interventions in mental health services and examples of such interventions, the range of physical and mental health outcomes possible through AEP-led interventions and common referral pathways to community AEP services. - Outcome AEPs can play a key role in the treatment of individuals experiencing mental illness. The diversity of AEP interventions allows for a holistic approach to care, enhancing both physical and mental health outcomes.

Next-generation sequencing: A frameshift in skeletal dysplasia gene discovery

In the last decade, huge breakthroughs in genetics - driven by new technology and different statistical approaches - have resulted in a plethora of new disease genes identified for both common and rare diseases. Massive parallel sequencing, commonly known as next-generation sequencing, is the latest advance in genetics, and has already facilitated the discovery of the molecular cause of many monogenic disorders. This article describes this new technology and reviews how this approach has been used successfully in patients with skeletal dysplasias. Moreover, this article illustrates how the study of rare diseases can inform understanding and therapeutic developments for common diseases such as osteoporosis. © International Osteoporosis Foundation and National Osteoporosis Foundation 2013.

Serum bilirubin concentration is modified by UGT1A1 Haplotypes and influences risk of type-2 diabetes in the Norfolk Island Genetic Isolate

Background Located in the Pacific Ocean between Australia and New Zealand, the unique population isolate of Norfolk Island has been shown to exhibit increased prevalence of metabolic disorders (type-2 diabetes, cardiovascular disease) compared to mainland Australia. We investigated this well-established genetic isolate, utilising its unique genomic structure to increase the ability to detect related genetic markers. A pedigree-based genome-wide association study of 16 routinely collected blood-based clinical traits in 382 Norfolk Island individuals was performed. Results A striking association peak was located at chromosome 2q37.1 for both total bilirubin and direct bilirubin, with 29 SNPs reaching statistical significance (P < 1.84 × 10−7). Strong linkage disequilibrium was observed across a 200 kb region spanning the UDP-glucuronosyltransferase family, including UGT1A1, an enzyme known to metabolise bilirubin. Given the epidemiological literature suggesting negative association between CVD-risk and serum bilirubin we further explored potential associations using stepwise multivariate regression, revealing significant association between direct bilirubin concentration and type-2 diabetes risk. In the Norfolk Island cohort increased direct bilirubin was associated with a 28 % reduction in type-2 diabetes risk (OR: 0.72, 95 % CI: 0.57-0.91, P = 0.005). When adjusted for genotypic effects the overall model was validated, with the adjusted model predicting a 30 % reduction in type-2 diabetes risk with increasing direct bilirubin concentrations (OR: 0.70, 95 % CI: 0.53-0.89, P = 0.0001). Conclusions In summary, a pedigree-based GWAS of blood-based clinical traits in the Norfolk Island population has identified variants within the UDPGT family directly associated with serum bilirubin levels, which is in turn implicated with reduced risk of developing type-2 diabetes within this population.

Migraine and glutamate: Modulators of glutamatergic signalling as potential treatments of neuropsychiatric disorders

Migraine is a complex neurological disorder with a well-documented genetic basis. Migraine is a product of allelic variation in genes of neurological, vascular and hormonal origin interacting with environmental triggers. Presentation can include attacks of head pain with symptoms of nausea, emesis, photophobia, phonophobia, and occasionally, visual sensory disturbances, known as aura. Migraine pain is difficult to ignore, associated with a deep sense of malaise and manifests as a throbbing, pulsatile headache, localized to one side of the head that intensifies with physical activity and that can last from 4-72 hours. Migraine is diagnosed according to criteria developed by the International Headache Society (IHS) and is subdivided into two main types based on the occurrence of aura symptoms that may be present in the early stages of the headache: migraine with aura (MA) and migraine without aura (MO). The majority (about 70%) of migraineurs are diagnosed with the MO subtype whilst the remaining 30% experience MA accompanied by neurological symptoms that manifest as fully reversible, visual, sensory and/or dysphasic speech disturbances in conjunction with their headache. Glutamate is the primary excitatory neurotransmitter in the central nervous system (CNS) and over-excitation of glutamate receptors is regarded as a contributing factor, through various mechanisms, to the pathology of migraine. In this chapter we present an overview of the pathophysiology and co-morbidity of migraine with other psychiatric disorders and discuss the role of the glutamatergic system in migraine, its molecular components as potential drug targets, in addition to the current treatments and progress of modulators of glutamatergic signaling.

Review of Diagnostic Screening Instruments for Alcohol and Other Drug Use and Other Psychiatric Disorders

In recent years there has been a growing recognition that many people with drug or alcohol problems are also experiencing a range of other psychiatric and psychological problems. The presence of concurrent psychiatric or psychological problems is likely to impact on the success of treatment services. These problems vary greatly, from undetected major psychiatric illnesses that meet internationally accepted diagnostic criteria such as those outlined in the Diagnostic and Statistical Manual (DSM-IV) of the American Psychiatric Association (1994), to less defined feelings of low mood and anxiety that do not meet diagnostic criteria but nevertheless impact on an individual’s sense of wellbeing and affect their quality of life. Similarly, the presence of a substance misuse problem among those suffering from a major psychiatric illness, often goes undetected. For example, the use of illicit drugs such as cannabis and amphetamine is higher among those individuals suffering from schizophrenia (Hall, 1992) and the misuse of alcohol in people suffering from schizophrenia is well documented (e.g., Gorelick et al., 1990; Searles et al., 1990; Soyka et al., 1993). High rates of alcohol misuse have also been reported in a number of groups including women presenting for treatment with a primary eating disorder (Holderness, Brooks Gunn, & Warren, 1994), individuals suffering from post-traumatic stress disorder (Seidel, Gusman and Aubueg, 1994), and those suffering from anxiety and depression. Despite considerable evidence of high levels of co-morbidity, drug and alcohol treatment agencies and mainstream psychiatric services often fail to identify and respond to concurrent psychiatric or drug and alcohol problems, respectively. The original review was conducted as a first step in providing clinicians with information on screening and diagnostic instruments that may be used to assess previously unidentified co-morbidity. The current revision was conducted to extend the original review by updating psychometric findings on measures in the original review, and incorporating other frequently used measures that were not previously included. The current revision has included information regarding special populations, specifically Indigenous Australians, older persons and adolescents. The objectives were to: ● update the original review of AOD and psychiatric screening/diagnostic instruments, ● recommend when these instruments should be used, by whom and how they should be interpreted, ● identify limitations and provide recommendations for further research, ● refer the reader to pertinent Internet sites for further information and/or purchasing of assessment instruments.