27 years of prenatal diagnosis for Huntington disease in the United Kingdom.

PURPOSE: There is little long-term, population-based data on uptake of prenatal diagnosis for Huntington disease (HD), a late-onset autosomal dominant neurodegenerative disorder, and the effect of the availability of preimplantation genetic diagnosis (PGD) on families' decisions about conventional prenatal diagnosis is not known. We report trends in prenatal diagnosis and preimplantation diagnosis for HD in the United Kingdom since services commenced. METHODS: Long-term UK-wide prospective case record-based service evaluation in 23 UK Regional Genetic Centres 1988-2015, and four UK PGD centers 2002-2015. RESULTS: From 1988 to 2015, 479 prenatal diagnoses were performed in the UK for HD. An exclusion approach was used in 150 (31%). The annual rate of HD prenatal diagnosis has remained around 18 (3.5/million) over 27 years, despite a steady increase in the use of PGD for HD since 2002. CONCLUSION: Although increasing number of couples are choosing either direct or exclusion PGD to prevent HD in their offspring, both direct and exclusion prenatal diagnosis remain important options in a health system where both PGD and prenatal diagnosis are state funded. At-risk couples should be informed of all options available to them, preferably prepregnancy.

Mutations in XPR1 cause primary familial brain calcification associated with altered phosphate export.

Primary familial brain calcification (PFBC) is a neurological disease characterized by calcium phosphate deposits in the basal ganglia and other brain regions and has thus far been associated with SLC20A2, PDGFB or PDGFRB mutations. We identified in multiple families with PFBC mutations in XPR1, a gene encoding a retroviral receptor with phosphate export function. These mutations alter phosphate export, implicating XPR1 and phosphate homeostasis in PFBC.

Nosocomial pulmonary tuberculosis contact investigation in a neonatal intensive care unit.

The diagnosis of smear-positive pulmonary tuberculosis in a medical officer working in a metropolitan Australian neonatal intensive care unit led to a contact investigation involving 125 neonates, 165 relatives, and 122 healthcare workers with varying degrees of exposure. There was no evidence of nosocomial tuberculosis transmission from the index case.

How do partners find out about the risk of Huntington's disease in couple relationships?

Whilst a growing body of work has explored family communication about Huntington's disease and how at-risk individuals learn about their risk, the experience of telling a partner and partners' experiences of finding out about this potentially devastating hereditary illness have received little attention. This study describes the experiences of partners in finding out about Huntington's disease and any impact on couple's relationships/marriages. We undertook a thematic analysis of qualitative interviews which explored the dynamics of partners' marriages after predictive testing and partners' views of genetic counseling. A main theme from partners' accounts was how they found out about their spouse's risk of Huntington's disease and the impact this had on marital relations. The analysis revealed four types of disclosure experiences: (1) marital secrets; (2) alerting, but not telling; (3) knowing and seeing; (4) marital ignorance. Our findings demonstrate that partners' experiences of (non)disclosure about the risk of HD within marriages is an important factor which contributes to couples' coping or marital problems. Exploring how spouses found out about their partner's risk of HD will illuminate issues about a couple's past and future patterns of communication and their coping strategies. A practical and ethical implication is the extent to which genetic counselors should inform partners about the course and nature of Huntington's disease when a partner is the support person for the individual being tested.

Mutations in SLC20A2 are a major cause of familial idiopathic basal ganglia calcification.

Familial idiopathic basal ganglia calcification (IBGC) or Fahr's disease is a rare neurodegenerative disorder characterized by calcium deposits in the basal ganglia and other brain regions, which is associated with neuropsychiatric and motor symptoms. Familial IBGC is genetically heterogeneous and typically transmitted in an autosomal dominant fashion. We performed a mutational analysis of SLC20A2, the first gene found to cause IBGC, to assess its genetic contribution to familial IBGC. We recruited 218 subjects from 29 IBGC-affected families of varied ancestry and collected medical history, neurological exam, and head CT scans to characterize each patient's disease status. We screened our patient cohort for mutations in SLC20A2. Twelve novel (nonsense, deletions, missense, and splice site) potentially pathogenic variants, one synonymous variant, and one previously reported mutation were identified in 13 families. Variants predicted to be deleterious cosegregated with disease in five families. Three families showed nonsegregation with clinical disease of such variants, but retrospective review of clinical and neuroimaging data strongly suggested previous misclassification. Overall, mutations in SLC20A2 account for as many as 41% of our familial IBGC cases. Our screen in a large series expands the catalog of SLC20A2 mutations identified to date and demonstrates that mutations in SLC20A2 are a major cause of familial IBGC. Non-perfect segregation patterns of predicted deleterious variants highlight the challenges of phenotypic assessment in this condition with highly variable clinical presentation.

Factor analysis of behavioural symptoms in Huntington's disease.

A principal-components factor analysis was performed on behavioural data obtained from the European Huntington's Disease Network REGISTRY study. 1690 valid assessments using the United Huntington's Disease Rating Scale Behavioural Rating Scale were included in the analysis. This large data set confirmed previous reports of distinct behavioural patterns within Huntington's disease comprising a depressive factor, a dysexecutive factor, an irritability factor and a psychosis factor.

Discriminant analysis of Beck Depression Inventory and Hamilton Rating Scale for Depression in Huntington's disease.

Depression is common in Huntington's disease, but standard rating scales have doubtful validity in this population. Using data from the European Huntington's Disease REGISTRY study, the authors examined the discriminant value of items on the Beck Depression Inventory (N=843) and the Hamilton Rating Scale for Depression (N=768). Good discriminators of depression, apart from "depressed mood," were "guilt," "loss of interest," and "suicidality." Items that discriminated poorly were "weight loss," "sleep disturbance," "loss of appetite," "psychomotor retardation," "agitation," and "irritability." These findings highlight the limited usefulness of these scales within the area of Huntington's disease.

Challenges assessing clinical endpoints in early Huntington disease.

The basic aim of this study was to evaluate the current accepted standard clinical endpoint for the earliest-studied HD participants likely to be recruited into clinical trials. As the advent of genetic testing for HD, it is possible to identify gene carriers before the diagnosis of disease, which opens up the possibility of clinical trials of disease-modifying treatments in clinically asymptomatic persons. Current accepted standard clinical endpoints were examined as part of a multinational, 32-site, longitudinal, observational study of 786 research participants currently in the HD prodrome (gene-positive but not clinically diagnosed). Clinical signs and symptoms were used to prospectively predict functional loss as assessed by current accepted standard endpoints over 8 years of follow-up. Functional capacity measures were not sensitive for HD in the prodrome; over 88% scored at ceiling. Prospective evaluation revealed that the first functional loss was in their accustomed work. In a survival analysis, motor, cognitive, and psychiatric measures were all predictors of job change. To our knowledge, this is the first prospective study ever conducted on the emergence of functional loss secondary to brain disease. We conclude that future clinical trials designed for very early disease will require the development of new and more sensitive measures of real-life function.

How young people find out about their family history of Huntington's disease.

Family communication about adult-onset hereditary illness can be problematic, leaving some relatives inadequately informed or ignorant of their risk. Although studies have explored the barriers and facilitators in family communication about genetic risk, questions remain about when, what, how and indeed whether to tell relatives. The process of disclosure is also dependent upon the way in which genetic information is realized and understood by recipients, but research here is limited. Our paper explores young people's experiences of finding out about a family history of the hereditary disorder Huntington's disease (HD). In-depth interviews explored how and when young people found out, their reactions to different communication styles and any impact on family relations. We recruited young people through the North of Scotland regional genetics clinic and the Scottish Huntington's Association (SHA). Thirty-three young people (aged 9-28) were interviewed. A qualitative analysis was undertaken which revealed four types of disclosure experiences: (1) having always been told, (2) gradually told, (3) HD was kept a secret, or (4) HD as a new diagnosis. In particular, the timing and style of disclosure from relatives, and one's stage of awareness, were fundamental in structuring participants' accounts. This article focuses on questions of when, how and indeed whether to tell children, and sits within a broader set of research and practice issues about what professionals and families (should) tell children about parental illness and genetic risk.

Mycophenolate mofetil embryopathy may be dose and timing dependent.

Mycophenolate mofetil (MMF) is an immunosuppressive agent that has now been recognized as teratogenic in humans. A pattern of malformations from in utero exposure to MMF has recently been described, and includes cleft lip and palate, microtia and atresia of the external auditory canal. We present a nulliparous mother who had taken MMF for recurrent erythema multiforme for the first 5 weeks of her pregnancy, and developed a spontaneous miscarriage during the seventh week of pregnancy. For her second pregnancy, she took MMF on her own accord for four days in the seventh week after her last menstrual period. The newborn had bilateral microtia, absence of the external auditory canals, and right iris and chorioretinal coloboma, consistent with the pattern recognized as part of the MMF embryopathy phenotype. As the newborn was not exposed to other immunosuppressive agents in utero, we believe that the phenotype described to be the result of the teratogenic effect of MMF. The spontaneous miscarriage in the first pregnancy may be due to the higher dose and longer duration of MMF exposure. The second pregnancy, with MMF exposure of 4 days, proceeded to term with the resultant phenotype. We conclude that the effect and severity of the embryopathy may be dependent on the dose, timing, and duration of MMF exposure. The manufacturer and the United States Food and Drug Administration have now disseminated information regarding the teratogenic risk of MMF. Women should be fully counseled and advised about contraception during the course of treatment with MMF.

Recurrence of tuberculosis at a Sydney chest clinic between 1994 and 2006: reactivation or reinfection?

OBJECTIVE: To estimate the incidence of recurrence of culture-positive tuberculosis (TB) and the relative contributions of reinfection and reactivation (based on DNA fingerprinting). DESIGN, SETTING AND PARTICIPANTS: Retrospective analysis of all culture-positive TB notifications between 1994 and 2006 from Liverpool Chest Clinic in the south-west of Sydney. Patients with more than one notification of culture-positive TB during this period were identified. Genotyping of Mycobacterium tuberculosis was used to determine whether recurrence was due to reinfection or reactivation. MAIN OUTCOME MEASURES: Estimation of the incidence of recurrence of culture-positive TB (cases per 100 000 person-years of follow-up), and the proportions of reinfection and reactivation. RESULTS: Three cases of recurrent culture-positive disease were identified (incidence of recurrence: 57.7 per 100 000 person-years of follow-up). All three patients were treated with directly observed therapy. Two of these patients had evidence of reinfection with different strains; both were natives of a country with a high incidence of TB and had returned to that country after the initial episode. The other patient had evidence of reactivation of the initial strain, indicating secondary failure of treatment. This patient had poor adherence to treatment. CONCLUSIONS: Our observations suggest there is a very low rate of reactivation of tuberculosis. The low incidence of recurrence due to reinfection reflects the low incidence of tuberculosis in Australia. When reinfection does occur, this probably has been sustained during residence in a country with a high incidence of tuberculosis.

Late stage care in Huntington's disease.

Huntington's disease (HD) is a relentlessly progressive neurodegenerative disease, which is presently incurable. Despite the hope for future therapies that exists for the families, they meantime are aware that there is little that their clinicians can do to delay either onset or progression of the disease. There are unique issues to address in a disorder where patients are aware in advance that their ability to communicate, as well as their cognitive capacity, will become impaired. Most affected individuals have experience of the disease in its late stages because of their parent's and other family member's illness. Many have their own ideas and anxieties about how their own care ought to proceed. There are no published guidelines for management of this stage of disease, although all clinicians involved in the care of HD will have their own experiences to share. This paper describes one method for such management, which includes discussion about placement for care advance directives for feeding and treatment.

Genetic professionals' reports of nondisclosure of genetic risk information within families.

Patients attending genetic clinics are often the main gatekeepers of information for other family members. There has been much debate about the circumstances under which professionals may have an obligation, or may be permitted, to pass on personal genetic information about their clients but without their consent to other family members. We report findings from the first prospective study investigating the frequency with which genetics professionals become concerned about the failure of clients to pass on such information to their relatives. In all, 12 UK and two Australian regional genetic services reported such cases over 12 months, including details of actions taken by professionals in response to the clients' failure to disclose information. A total of 65 cases of non-disclosure were reported, representing <1% of the genetic clinic consultations in the collaborating centres during the study period. These included 39 cases of the failure of parents not passing full information to their adult offspring, 22 cases where siblings or other relatives were not given information and four cases where information was withheld from partners -- including former and prospective partners. Professionals reported clients' reasons for withholding information as complex, more often citing concern and the desire to shield relatives from distress rather than poor family relationships. In most cases, the professionals took further steps to persuade their clients to make a disclosure but in no instance did the professional force a disclosure without the client's consent.

Family communication about genetic risk: the little that is known.

Although family communication is important in clinical genetics only a small number of studies have specifically explored the passing on of genetic knowledge to family members. In addition, many of these present exploratory or tentative findings based upon small sample sizes, or data collected only a short time after testing. Nevertheless, if health professionals are to develop effective strategies to help patients' deal with communication issues, we need to know more about what actually happens in families. The aim of this commentary is to identify factors which appear to influence whether patients share information about genetic risk with relatives who are unaware of that risk, with whom they share it and how they go about it. The paper draws upon evidence and thinking from the disciplines of psychology (including family therapy), sociology, medicine and genetic counselling. It is presented under the following headings: disease factors, individual factors, family factors and sociocultural factors. It concludes by highlighting a number of key issues which are relevant for health professionals.

Effective monosomy or trisomy of chromosome band 2q37.3 due to the unbalanced segregation of a 2;11 translocation.

We report a seven generation family in which a 2;11 chromosome translocation is segregating. Both unbalanced segregants have been found in the family, and cytogenetic analysis demonstrates that this results in effective monosomy or trisomy for chromosome band 2q37.3. Those family members who are monosomic exhibit a variable phenotype with a number of features associated with an Albright's Hereditary Osteodystrophy-like phenotype (AHO-like) whilst those who are trisomic have a phenotypic spectrum ranging from mild facial anomalies and growth retardation to apparent normality. The latter group of patients represent the first reported patients with pure trisomy for chromosome band 2q37.3.

Homozygosity for CAG mutation in Huntington disease is associated with a more severe clinical course.

Huntington disease is caused by a dominantly transmitted CAG repeat expansion mutation that is believed to confer a toxic gain of function on the mutant protein. Huntington disease patients with two mutant alleles are very rare. In other poly(CAG) diseases such as the dominant ataxias, inheritance of two mutant alleles causes a phenotype more severe than in heterozygotes. In this multicentre study, we sought differences in the disease features between eight homozygotes and 75 heterozygotes for the Huntington disease mutation. We identified subjects homozygous for the Huntington disease mutation by DNA testing and compared their clinical features (age at onset, symptom presentation, disease severity and disease progression) with those of a group of heterozygotes, who were assessed longitudinally. The age at onset of symptoms in the homozygote cases was within the range expected for heterozygotes with the same CAG repeat lengths, whereas homozygotes had a more severe clinical course. The observation of a more rapid decline in motor, cognitive and behavioural symptoms in homozygotes was consistent with the extent of neurodegeneration as available at imaging in three patients, and at the post-mortem neuropathological report in one case. Our analysis suggests that although homozygosity for the Huntington disease mutation does not lower the age at onset of symptoms, it affects the phenotype and the rate of disease progression. These data, once confirmed in a larger series of patients, point to the possibility that the mechanisms underlying age at onset and disease progression in Huntington disease may differ.

New challenges for gamete donation programmes: changes in guidelines are needed.

In the UK, the Human Fertilisation and Embryology Act 1990 prevents children born as a result of donor-assisted conception from gaining access to identifying information about their genetic origins. There is growing concern that current screening protocols regarding gamete donation are ill-suited, especially in relation to genetic disease. There are no guidelines addressing the issues of confidentiality that might arise if a disease emerges after insemination and establishment of pregnancy. Donors may become aware that they are at risk of a familial condition after they have donated gametes or recipients of donated gametes may become aware of a genetic illness in the resulting child. At present, there is no agreed method for allowing this information to be given to the donor or other recipients of gametes from that person. We suggest that these issues should be raised with donors, and appropriate counselling and predictive tests offered to them. Changes in regulations regarding gamete donation should be considered that accommodate recent and possible future developments in genetics. Furthermore, consideration should be given to the storage of samples of DNA from donors for the future provision of genetic information.

Prenatal testing for Huntington's disease: a European collaborative study.

This European study involving seven genetic centres from six countries - Aberdeen, Cardiff (UK), Leiden (Netherlands), Leuven (Belgium), Paris (France), Rome (Italy), Athens (Greece) has gathered information on prenatal testing by direct mutation analysis and exclusion testing for Huntington's disease (HD) from the six European countries during the period 1993-1998. Data describing the parent belonging to the HD family was collected; this included their sex and age as well as their risk of developing HD. Information about previous pregnancies, the rank of the pregnancy being tested and its outcome was also gathered. In addition the number of previous prenatal tests for HD was recorded. Three hundred and five results were recorded by the participating countries between 1993 and 1998. The largest groups came from the UK (157) and the Netherlands (90). The mean age for the parent from the HD family was 30.8 years. In half of the tests the prospective parent was an asymptomatic gene carrier, 42% remained at risk, and 6% of the prospective parents were already showing clinical features of HD. 65% of tests performed used mutation analysis.