Estimating the relative frequency of leukodystrophies and recommendations for carrier screening in the era of next-generation sequencing.

Leukodystrophies are a heterogeneous group of heritable disorders characterized by abnormal brain white matter signal on magnetic resonance imaging (MRI) and primary involvement of the cellular components of myelin. Previous estimates suggest the incidence of leukodystrophies as a whole to be 1 in 7,000 individuals, however the frequency of specific diagnoses relative to others has not been described. Next generation sequencing approaches offer the opportunity to redefine our understanding of the relative frequency of different leukodystrophies. We assessed the relative frequency of all 30 leukodystrophies (associated with 55 genes) in more than 49,000 exomes. We identified a relatively high frequency of disorders previously thought of as very rare, including Aicardi Goutières Syndrome, TUBB4A-related leukodystrophy, Peroxisomal biogenesis disorders, POLR3-related Leukodystrophy, Vanishing White Matter, and Pelizaeus-Merzbacher Disease. Despite the relative frequency of these conditions, carrier-screening laboratories regularly test only 20 of the 55 leukodystrophy-related genes, and do not test at all, or test only one or a few, genes for some of the higher frequency disorders. Relative frequency of leukodystrophies previously considered very rare suggests these disorders may benefit from expanded carrier screening.

Unusual teeth in unusual places: Criteria for identifying teratomatous dental elements in archeological contexts.

OBJECTIVE: This paper describes the dental elements (i.e., teeth and incomplete tooth-like structures) formed by mature cystic teratomas and provide some diagnostic criteria to aid in their paleopathological identification and analysis. MATERIALS: Hard tissue structures from 13 clinically-derived mature cystic teratomas excised between 2003 and 2007. All are from female patients (N = 13) between the ages of 17 and 56. METHODS: A dental and osteological inventory identified number of teeth and tooth types present in each specimen. RESULTS: Of the 13 specimens, nine contained dental elements. The number per teratoma ranged from one to seven. A wide variety of tooth types were present in the teratomas with some teeth independent of, and others embedded within, bony matrices. CONCLUSIONS: While some teratoma teeth exhibit distinguishable types and laterality, the majority will exhibit some degree of abnormality in size, form, developmental completion, or association with other irregular bony elements. SIGNIFICANCE: Give the modern clinical prevalence and yet relatively few paleopathological cases reported, it is likely that mature teratomas are under-identified in the archeological record. The diagnostic criteria presented in this paper can aid paleopathologists in their identification and analysis of these neoplasms. LIMITATIONS: Precise paleopathological identification of teratoma elements can be difficult; particularly when they are no longer constrained or contextualized by unmineralized neoplastic borders. As such, there is a risk that such remnants may be mistaken for fetal parts or disassociated elements. SUGGESTIONS FOR FURTHER RESEARCH: Application of these criteria, paired with careful excavation techniques, is advised.

Predicting metacarpal length using paired ratios with bilateral X-ray films.

INTRODUCTION: When the metacarpal bones sustain severe osseous injury requiring reconstruction, functional recovery relies on the precise distribution of tension throughout full range of motion. While the small scale of hand structures compounds the effects of altering normal anatomy, literature lacks consensus recommendations for the acceptable degree of length alteration and/or appropriate methods of length estimation in reconstructive procedures. Length asymmetry has been reported in human metacarpal bones; however, studies assessing this phenomenon in living subjects with attention to functional implications or length prediction are lacking. METHODS: Hand X-rays were obtained for 34 patients aged 25-80 without history of metacarpal trauma, joint degeneration, or pathologic bone metabolism. A scaled bivariate model predicted metacarpal length using an ipsilateral paired metacarpal and matching contralateral ratio: Estimate_Dx_R = Median_Dy_R * (Median_Dx_L/Median_Dy_L). A second set of predictions used the contralateral metacarpal as a control. Pearson correlation coefficients, paired t-tests, and chi-square tests evaluated the symmetry between bilateral metacarpal lengths and paired metacarpal ratios as well as the accuracy of each predictive method. RESULTS: The contralateral control and target metacarpal differed significantly in digits 1, 2, 3, and 5. No significant difference in matched metacarpal ratios of the right and left hands was found. For all digits except 5D, bivariate model predictions generated were more strongly correlated with actual target length. Chi-square tests did not detect a significant difference in predictive value of the two models. CONCLUSION: The scaled bivariate model we describe may be useful and economic in generating accurate length estimates of metacarpals for reconstructive procedures.

The Impact of Fabry Disease on Reproductive Fitness.

Fabry disease (FD) is a pan-ethnic, X-linked, progressive lysosomal storage disorder caused by pathogenic mutations in the GLA gene. Published case reports and abstracts suggest that decreased reproductive fitness may occur in males with FD. In order to understand the impact of FD on reproductive fitness and increase the accuracy of reproductive genetic counseling, this study examines a large, multi-centered population of individuals with FD to determine if males have reduced reproductive fitness. Study data were collected on 376 patients through two, gender-specific surveys distributed across the United States and Canada. The number of biological live-born children among individuals with FD was compared to statistics from the general population. Information was also collected on reduced sperm count, depression, pain, use of assisted reproductive technology, and reproductive choice. On average, females affected by FD had more biological live-born children (1.8) than males affected by FD (1.1). However, males affected by FD had an increased mean number of biological children (1.1) compared to the mean number of biological children fathered by men in the United States (0.9). Sixteen of the 134 males with FD reported oligospermia, which suggests that an infertility work up may be indicated for males having difficulty impregnating their partners. In our large multicenter sample, males and females with FD do not exhibit reduced reproductive fitness; on average they have more biological children than the general population in the United States. This information should assist clinicians in providing accurate reproductive genetic counseling and treatment for individuals with FD.

Pace alteration and estimation of time intervals.

This experiment examined the effects on participants' estimates of interval duration of altering the pace of auditory stimuli contained within "filled" intervals. Because most previous studies on the filled interval effect have utilized visual displays, auditory stimuli were used to assess whether the effect would be present. In addition, previous studies compared two intervals, one of which was filled and the other unfilled. In the present study, both intervals were filled with tones at one of three rates (or "paces"): slow, medium, or fast. 25 participants (20 women) ages 18 to 29 years (M = 20.4, SD = 2.3) were recruited from psychology courses and programs. Participants first heard a "training" interval filled with tones at one of the three paces and then attempted to reproduce the duration of that training interval in the "test" interval. The pace of stimuli in each pair of training and test intervals was varied so participants received all possible combinations of paces of auditory stimuli during the training and test trial sets. Analysis showed that, when training pace was fast and test pace was medium or slow, participants' estimates were longer than the actual test interval durations. Conversely, when training pace was slow and test pace was medium or fast, participants' estimates were shorter than actual test interval durations. In addition, when judging shorter intervals, participants estimated more time had passed than actually had, while they estimated that less time had passed than actually had for longer intervals, thus providing support for Vierordt's law.