The pathogenetic basis for a disease continuum in early- and late-onset ataxia-dystonia supports a unified genetic diagnostic approach.

INTRODUCTION: Genetically inherited ataxic disorders are classified by their age of disease presentation into early- and late-onset ataxia (EOA and LOA, presenting before or after the 25th year-of-life). In both disease groups, comorbid dystonia co-occurs frequently. Despite overlapping genes and pathogenetic features, EOA, LOA and dystonia are considered as different genetic entities with a separate diagnostic approach. This often leads to diagnostic delay. So far, the possibility of a disease continuum between EOA, LOA and mixed ataxia-dystonia has not been explored in silico. In the present study, we analyzed the pathogenetic mechanisms underlying EOA, LOA and mixed ataxia-dystonia. METHODS: We analyzed the association of 267 ataxia genes with comorbid dystonia and anatomical MRI lesions in literature. We compared anatomical damage, biological pathways, and temporal cerebellar gene expression between EOA, LOA and mixed ataxia-dystonia. RESULTS: The majority (≈65%) of ataxia genes were associated with comorbid dystonia in literature. Both EOA and LOA gene groups with comorbid dystonia were significantly associated with lesions in the cortico-basal-ganglia-pontocerebellar network. EOA, LOA and mixed ataxia-dystonia gene groups were enriched for biological pathways related to nervous system development, neural signaling and cellular processes. All genes revealed similar cerebellar gene expression levels before and after 25 years of age and during cerebellar development. CONCLUSION: In EOA, LOA and mixed ataxia-dystonia gene groups, our findings show similar anatomical damage, underlying biological pathways and temporal cerebellar gene expression patterns. These findings may suggest the existence of a disease continuum, supporting the diagnostic use of a unified genetic approach.

De novo variants in CDK13 associated with syndromic ID/DD: Molecular and clinical delineation of 15 individuals and a further review.

De novo variants in the gene encoding cyclin-dependent kinase 13 (CDK13) have been associated with congenital heart defects and intellectual disability (ID). Here, we present the clinical assessment of 15 individuals and report novel de novo missense variants within the kinase domain of CDK13. Furthermore, we describe 2 nonsense variants and a recurrent frame-shift variant. We demonstrate the synthesis of 2 aberrant CDK13 transcripts in lymphoblastoid cells from an individual with a splice-site variant. Clinical characteristics of the individuals include mild to severe ID, developmental delay, behavioral problems, (neonatal) hypotonia and a variety of facial dysmorphism. Congenital heart defects were present in 2 individuals of the current cohort, but in at least 42% of all known individuals. An overview of all published cases is provided and does not demonstrate an obvious genotype-phenotype correlation, although 2 individuals harboring a stop codons at the end of the kinase domain might have a milder phenotype. Overall, there seems not to be a clinically recognizable facial appearance. The variability in the phenotypes impedes an à vue diagnosis of this syndrome and therefore genome-wide or gene-panel driven genetic testing is needed. Based on this overview, we provide suggestions for clinical work-up and management of this recently described ID syndrome.

Two Novel Mutations in the SLC25A4 Gene in a Patient with Mitochondrial Myopathy.

In a 28-year-old male with a mild mitochondrial myopathy manifesting as exercise intolerance and early signs of cardiomyopathy without muscle weakness or ophthalmoplegia, we identified two novel mutations in the SLC25A4 gene: c.707G>C in exon 3 (p.(R236P)) and c.116_137del in exon 2 (p.(Q39Lfs*14)). Serum lactate levels at rest were elevated (12.7 mM). Both the patient's father and brother were heterozygous carriers of the c.707G>C mutation and were asymptomatic. The second mutation causes a 22 bp deletion leading to a frame shift likely giving rise to a premature stop codon and nonsense-mediated decay (NMD). The segregation of the mutations could not be tested directly as the mother had died before. However, indirect evidence from NMD experiments showed that the two mutations were situated on two different alleles in the patient. This case is unique compared to other previously reported patients with either progressive external ophthalmoplegia (PEO) or clear hypertrophic cardiomyopathy with exercise intolerance and/or muscle weakness carrying recessive mutations leading to a complete absence of the SLC25A4 protein. Most likely in our patient, although severely reduced, SLC25A4 is still partially present and functional.

Economic analysis of chromosome testing in couples with recurrent miscarriage to prevent handicapped offspring.

STUDY QUESTION: Which strategy is least expensive to prevent the birth of a handicapped child in couples with recurrent miscarriage (RM); parental chromosome analysis followed by amniocentesis in case of carrier status of one of the parents, or amniocentesis in all ongoing pregnancies without the knowledge of parental carrier status? SUMMARY ANSWER: For virtually all couples with RM amniocentesis in all ongoing pregnancies without the knowledge of parental carrier status is less expensive in preventing the birth of a handicapped child than parental chromosome analysis followed by amniocentesis in case of carrier status of one of the parents. WHAT IS KNOWN ALREADY: One of the causes of RM is a balanced chromosome abnormality in one of the partners. If one of the partners is carrier of a balanced structural chromosomal abnormality, the risk of offspring with an unbalanced structural chromosome abnormality is increased. Like all couples, couples with RM also have an age-dependent risk for fetal aneuploidy, of which trisomy 21 is most common. STUDY DESIGN, SIZE, DURATION: Model-based economic analysis to compare costs and effects of two strategies in couples with RM to prevent the birth of a handicapped child in case of ongoing pregnancy. PARTICIPANTS/MATERIALS, SETTING, METHODS: Comparison of two strategies in women with RM: strategy (I) parental chromosome analysis followed by amniocentesis in pregnancy in case of carrier status of one of the parents and strategy (II) amniocentesis in all ongoing pregnancies without the knowledge of carrier status. No testing was the reference strategy. Data on probabilities and costs were derived from the literature. Incremental costs and effects were calculated [incremental cost-effectiveness ratio (ICER)]. Effectiveness was expressed as the number of prevented births of handicapped child equivalents compared with no testing. In these calculations, the birth of a handicapped child was valued 10 times worse than the loss of a viable pregnancy due to amniocentesis. MAIN RESULTS AND THE ROLE OF CHANCE: Depending on the risk for carrier status, the ICER for Strategy I (parental chromosome analysis followed by amniocentesis in case of carrier status of one of the parents) varied between € 226,000 and € 6,556,000 per prevented handicapped child equivalent. For Strategy II (amniocentesis in all ongoing pregnancies without the knowledge of carrier status), the ICER varied between € 2000 and € 233 000 per prevented handicapped child equivalent. Strategy I was less expensive than Strategy II only for a small subgroup of couples with maternal age <23 years, three or more previous miscarriages and a family history of RM. LIMITATIONS, REASONS FOR CAUTION: Our analysis is not a plea for amniocentesis in all women with RM. Individual risk assessment with serum markers and nuchal translucency is probably more effective at lower cost. WIDER IMPLICATIONS OF THE FINDINGS: This analysis can be used by clinicians to explain the chances of adverse pregnancy outcome in couples with RM, as well as by policy makers in health-care economics. Future guidelines on RM might be more restrictive from the perspective of the limited health-care resources that we have available.

Knowledge and perceived risks in couples undergoing genetic testing after recurrent miscarriage or for poor semen quality.

Couples with recurrent miscarriage (RM) and men with poor semen quality may undergo genetic testing as part of the diagnostic work-up. This study explored their knowledge and perception of genetic testing, evaluated psychological wellbeing and identified associated variables. A prospective questionnaire study was conducted in seven clinical genetics centres and referring gynaecological departments in couples with RM or poor semen quality. Questionnaires were completed before disclosure of genetic test results. Main outcome measures were knowledge, perceived risk, anxiety and depression. Of 439 participants, 256 were not aware genetic testing was part of the diagnostic work-up. One-third (36% RM, 33% poor semen quality) indicated they had not received information about the genetic test from their doctor. Perceived risk of receiving an abnormal genetic test result was higher than objective risk. Anxiety was highly correlated with perceived risk. Women with RM were more anxious than women in the poor semen quality group or men (P<0.01). These couples undergoing genetic testing have a suboptimal understanding of the nature of testing, overestimate the risks of receiving an abnormal result and some show high levels of anxiety. The results of this study can be used to improve patient counselling before genetic testing.

The psychological impact of testing for thrombophilia: a systematic review.

BACKGROUND: Nowadays, large numbers of patients are tested for thrombophilia, even though the benefits of this strategy remain unclear. A potential disadvantage of this predominantly genetic testing is the psychological impact, including fear, depression and worry. OBJECTIVES: To systematically review studies that determined the nature and extent of the psychological impact of testing for thrombophilia. PATIENTS/METHODS: We searched the MEDLINE data base (1966-2008), the EMBASE data base (1985-2008) and the PsychInfo data base (1806-2008) for relevant trials, without language restrictions. Bibliographies of relevant articles were scanned for additional articles. We reviewed all relevant studies that focused on the psychological impact of testing for thrombophilia. Only full papers of studies that included 15 patients or more were considered eligible for this review. Two reviewers independently extracted data and assessed quality. RESULTS: Six studies fulfilled the eligibility criteria. As these studies varied appreciably in methodology, the pooling of data was not possible. Studies of psychological impact of genetic testing for thrombophilia report few negative results, although most assessments were limited to short-term follow-up, or lacked methodological accuracy. CONCLUSIONS: No valid conclusions can be drawn about the psychological impact of genetic testing in patients based on the current available literature. Given the large number of patients that are being exposed to testing for thrombophilia, and the uncertain benefits, there is an urgent need for more uniformity in the measurement of the psychological impact of thrombophilia testing.

Endocrine intervention during irradiation does not prevent damage to the thyroid gland.

Radiation to the head-neck region may damage the thyroid gland, leading to hypothyroidism or thyroid carcinoma. Outcomes of radiation protection by lowering plasma thyroid-stimulating hormone (TSH) have thus far been ambiguous. Our aim was to evaluate the radioprotective effect of inhibiting the thyroid gland's activity during x-radiation. For this purpose, of 80 5-week old Wistar rats, 64 received cervical irradiation with 15 Gy (single dose). During irradiation, endocrine intervention was done, using thyroxine (T(4)), T(4) plus iodine, or iodine alone compared to placebo. During the endocrine interventions and follow-up, TSH and T(4) concentrations were measured periodically. Histologic examination of thyroid, pituitary gland, or the hypothalamus and any suspect lymph nodes, lungs, and liver was performed after 6 and 54 weeks. It was found that during the endocrine intervention, plasma levels of TSH were lower in rats given T(4) and higher in rats given iodine. After 6 and 54 weeks, no significant reduction in hypothyroidism or thyroid carcinoma was found between the different groups of rats given any endocrine intervention or no intervention. In conclusion, the administration of T(4), iodine or the combination during x-irradiation does not protect against radiation-induced thyroid damage.

The effect of cervical X-irradiation on activity index of thyrocytes and plasma TSH: a pre-clinical model for radiation-induced thyroid damage.

Because radiotherapy in the head and neck region is necessary in the treatment of childhood cancer, possibilities to prevent damage to the thyroid gland must be explored. We developed a model in which radiation-induced effects can be investigated in a way that these effects can be quantified, using thyroid dysmorphology and plasma TSH. Thirty-five Wistar rats, 5 weeks old, were X-irradiated on the cervical region, with a single dose varying from 0 to 20 Gy. After 6 weeks, TSH, T4 and T3 were determined, and thyroid glands were processed for histological examination by two independent pathologists. A histological classification scale was developed, using follicular size, colloid density and cell height of thyrocytes to measure hyperplasia and hypertrophy. By the sum of these scores, a cell-activity index was calculated, which was related to plasma TSH concentration. Numbers of PAS-positive droplets and epithelial desquamation were also counted. Inter-observer reliability was assessed. Good to very good reliability was found for scores of follicular size, colloid density and cell height. Significant increase of cell-activity index was found after 10, 15 and 20 Gy. The plasma TSH concentration was positively correlated to the cell-activity index, increasing with radiation-doses up to 15 Gy. The number of desquamated cells was significantly increased after radiation doses >10 Gy, with moderate reliability. In conclusion, this model using cell-activity index of thyrocytes together with plasma thyrotropin concentrations and desquamation of cells can be used for interpretation and future (pre-clinical) studies of prevention of radiation-induced thyroid damage.