Genetic counselling for at-risk family members with hereditary transthyretin amyloidosis: data from a single-centre study.

BACKGROUND: Hereditary transthyretin-related amyloidosis is an autosomal dominant disorder. Recently, disease-modifying therapies (DMTs) have been developed. For at-risk individuals, genetic analysis aids in the early administration of medical care; however, few studies have evaluated the current status of genetic counselling and management of presymptomatic carriers of amyloidogenic variants. METHODS: We retrospectively evaluated the medical records of 202 consecutive participants. RESULTS: A total of 103 clients who received genetic counselling for predictive testing were at-risk, and 83 underwent predictive testing. Genetic testing results were positive in 33 patients, 11 of whom had confirmed amyloid deposition and were administered DMTs. For presymptomatic V30M (p.V50M) carriers, 32.0 ± 2.4 years (median ± standard error) was the age when amyloid deposition was first identified (95% confidence interval 27.4-36.6). Serum transthyretin (TTR) levels decreased serially with an estimated slope of -1.2 mg/dL/year. CONCLUSIONS: Our study suggests the clinical utility of management using a combination of predictive testing and monitoring methods. Psychosocial support should be considered with collaboration between geneticists/genetic counsellors and psychologists. For a more optimised protocol for monitoring and designing future interventional trials in presymptomatic carriers, prospective cohort studies are necessary to clarify the natural history, particularly in the early stages of the disease.

Clinical utility of urinary mulberry bodies/cells testing in the diagnosis of Fabry disease.

Introduction: Variants in the galactosidase alpha (GLA) gene cause Fabry disease (FD), an X-linked lysosomal storage disorder caused by α-galactosidase A (α-GAL) deficiency. Recently, disease-modifying therapies have been developed, and simple diagnostic biomarkers for FD are required to initiate these therapies in the early stages of the disease. Detection of urinary mulberry bodies and cells (MBs/MCs) is beneficial for diagnosing FD. However, few studies have evaluated the diagnostic accuracy of urinary MBs/MCs in FD. Herein, we retrospectively evaluated the diagnostic ability of urinary MBs/MCs for FD. Methods: We analyzed the medical records of 189 consecutive patients (125 males and 64 females) who underwent MBs/MCs testing. Out of these, two female patients had already been diagnosed with FD at the time of testing, and the remaining 187 patients were suspected of having FD and underwent both GLA gene sequencing and/or α-GalA enzymatic testing. Results: Genetic testing did not confirm the diagnosis in 50 females (26.5%); hence, they were excluded from the evaluation. Two patients were previously diagnosed with FD, and sixteen were newly diagnosed. Among these 18 patients, 15, including two who had already developed HCM at diagnosis, remained undiagnosed until targeted genetic screening of at-risk family members of patients with FD was performed. The accuracy of urinary MBs/MCs testing exhibited a sensitivity of 0.944, specificity of 1, positive predictive value of 1, and negative predictive value of 0.992. Conclusions: MBs/MCs testing is highly accurate in diagnosing FD and should be considered during the initial evaluation prior to genetic testing, particularly in female patients.

Overproduction and selective abortion of ovules based on the order of fertilization revisited.

Given that seeds fertilized by slowly growing pollen are of low quality genetically, we theoretically reanalyzed the hypothesis that plants selectively abort ovules fertilized later to enhance the mean quality of resulting seeds. We assumed that both superior and inferior pollen exist, the superior pollen growing faster to fertilize ovules, resulting in seeds of higher quality than those of ovules fertilized by inferior pollen. We developed two models to determine the conditions under which selective abortion is favored. In the first model, ovules in one flower are fertilized by pollen grains that arrive at different times, with each visit bringing both fast- and slow-growing pollen. In the second model, ovules in two flowers are fertilized by all pollen grains that arrive at the same time. In the first model, we found that selective abortion based on the order of fertilization is never advantageous irrespective of the duration of the time lag between the two visits. Rather, random abortion is possibly favored. In the second model, although selective abortion based on the order of fertilization can be advantageous, the parameter region favoring it is rather restricted. This is because overproduction can be advantageous only if the quantity of the superior pollen is not limited in one flower but is limited in the other flower. In addition, the degree of overproduction was very low, implying that the merit of overproduction (increase in the number of superior seeds) is low compared to the cost of overproducing ovules. These results suggest that selective abortion of ovules based on the order of fertilization is not as advantageous as previously considered.