Background Urea cycle disorders are caused by dysfunction in any of the six enzymes and two transport proteins involved in urea biosynthesis. Our study focuses on Ornithine Transcarbamylase deficiency (OTCD), an X-linked disorder that results in a dysfunctional mitochondrial enzyme, which prevents the synthesis of citrulline from carbamoyl phosphate and ornithine. This enzyme deficiency can lead to hyperammonemic episodes and severe cerebral edema. The objective of this study was to use a cognitive battery to expose the cognitive deficits in asymptomatic carriers of OTCD. Materials and Methods In total, 81 participants were recruited as part of a larger urea cycle disorder imaging consortium study. There were 25 symptomatic participants (18 female, 7 male, 25.6 years ± 12.72 years), 20 asymptomatic participants (20 female, 0 male, 37.6 years ± 15.19 years), and 36 healthy control participants (21 female, 15 male, 29.8 years ± 13.39 years). All participants gave informed consent to participate and were then given neurocognitive batteries with standard scores and T scores recorded. Results When stratified by symptomatic participant, asymptomatic carrier, and control, the results showed significant differences in measures of executive function (e.g. CTMT and Stroop) and motor ability (Purdue Assembly) between all groups tested. Simple attention, academic measures, language and non-verbal motor abilities showed no significant differences between asymptomatic carriers and control participants, however, there were significant differences between symptomatic and control participant performance in these measures. Conclusions In our study, asymptomatic carriers of OTCD showed no significant differences in cognitive function compared to control participants until they were cognitively challenged with fine motor tasks, measures of executive function, and measures of cognitive flexibility. This suggests that cognitive dysfunction is best measurable in asymptomatic carriers after they are cognitively challenged.

49, XXXXY is a rare aneuploidy and variant of Klinefelter syndrome, occurring in 1 per 80,000-100,000 live births. We present a cohort of 40 affected males, focusing on musculoskeletal problems. Subjects were participants in an annual 49er family support group meeting. Children were examined in a multidisciplinary clinic by a pediatric neurologist and geneticist, a pediatric orthopedist, a neurodevelopmentalist, and two physical therapists. The patient data were collected from this clinic from 2004 to 2012. All patients were required to have karyotypes that confirmed the presence of XXXXY. There was a high prevalence of musculoskeletal disorders, particularly hypotonia (34 patients [85%]), radioulnar synostosis (30 [75%]), pes planus (26 [65%]), asymmetric hip rotation (27 [67.5%]), and clinodactyly (24 [60%]). Other, less common lower-extremity disorders, included, 5 patients (12.5%) with unilateral club foot, 5 boys (12.5%) with pes cavus, 10 patients (25%) genu valgum and 2 children with genu varus (5%). To our knowledge, this is the first large cohort of boys with 49, XXXXY that focuses on musculoskeletal disorders. There was an increased incidence of hypotonia, clubfoot, avascular necrosis of the femoral head, radioulnar synostosis, and pes planus compared to the normative population. Boys with 49, XXXXY would benefit from multidisciplinary evaluations, particularly from pediatric orthopedists, physical therapists, neurologists, and geneticists for appropriate medical care.

Genome-wide association studies have identified thousands of variants that are associated with numerous phenotypes. One such variant, rs13266634, a nonsynonymous single nucleotide polymorphism in the solute carrier family 30 (zinc transporter) member eight gene, is associated with a 53% increase in the risk of developing type 2 diabetes (T2D). We hypothesized that individuals with the protective allele against T2D would show a positive response to short-term and long-term resistance exercise. Two cohorts of young adults—the Eccentric Muscle Damage (EMD; n = 156) cohort and the Functional Single Nucleotide Polymorphisms Associated with Muscle Size and Strength Study (FAMuSS; n = 874)—were tested for association of the rs13266634 variant with measures of skeletal muscle response to resistance exercise. Our results were sexually dimorphic in both cohorts. Men in the EMD study with two copies of the protective allele showed less post-exercise bout strength loss, less soreness, and lower creatine kinase values. In addition, men in the FAMuSS, homozygous for the protective allele, showed higher pre-exercise strength and larger arm skeletal muscle volume, but did not show a significant difference in skeletal muscle hypertrophy or strength with resistance training.

Background and PurposeOrnithine transcarbamylase deficiency (OTCD) is an X-chromosome linked urea cycle disorder (UCD) that causes hyperammonemic episodes leading to white matter injury and impairments in executive functioning, working memory, and motor planning. This study aims to investigate differences in functional connectivity of two resting-state networks—default mode and set-maintenance—between OTCD patients and healthy controls.MethodsSixteen patients with partial OTCD and twenty-two control participants underwent a resting-state scan using 3T fMRI. Combining independent component analysis (ICA) and region-of-interest (ROI) analyses, we identified the nodes that comprised each network in each group, and assessed internodal connectivity.ResultsGroup comparisons revealed reduced functional connectivity in the default mode network (DMN) of OTCD patients, particularly between the anterior cingulate cortex/medial prefrontal cortex (ACC/mPFC) node and bilateral inferior parietal lobule (IPL), as well as between the ACC/mPFC node and the posterior cingulate cortex (PCC) node. Patients also showed reduced connectivity in the set-maintenance network, especially between right anterior insula/frontal operculum (aI/fO) node and bilateral superior frontal gyrus (SFG), as well as between the right aI/fO and ACC and between the ACC and right SFG.ConclusionInternodal functional connectivity in the DMN and set-maintenance network is reduced in patients with partial OTCD compared to controls, most likely due to hyperammonemia-related white matter damage. Because several of the affected areas are involved in executive functioning, it is postulated that this reduced connectivity is an underlying cause of the deficits OTCD patients display in this cognitive domain.