Purpose To evaluate the safety and efficacy of N-acetylmannosamine (ManNAc) in GNE myopathy, a genetic muscle disease caused by deficiency of the rate-limiting enzyme in N-acetylneuraminic acid (Neu5Ac) biosynthesis. Methods We conducted an open-label, phase 2, single-center (NIH, USA) study to evaluate oral ManNAc in 12 patients with GNE myopathy (ClinicalTrials.gov NCT02346461). Primary endpoints were safety and biochemical efficacy as determined by change in plasma Neu5Ac and sarcolemmal sialylation. Clinical efficacy was evaluated using secondary outcome measures as part of study extensions, and a disease progression model (GNE-DPM) was tested as an efficacy analysis method. Results Most drug-related adverse events were gastrointestinal, and there were no serious adverse events. Increased plasma Neu5Ac (+2,159 nmol/L, p < 0.0001) and sarcolemmal sialylation (p = 0.0090) were observed at day 90 compared to baseline. A slower rate of decline was observed for upper extremity strength (p = 0.0139), lower extremity strength (p = 0.0006), and the Adult Myopathy Assessment Tool (p = 0.0453), compared to natural history. Decreased disease progression was estimated at 12 (γ = 0.61 [95% CI: 0.09, 1.27]) and 18 months (γ = 0.55 [95% CI: 0.12, 1.02]) using the GNE-DPM. Conclusion ManNAc showed long-term safety, biochemical efficacy consistent with the intended mechanism of action, and preliminary evidence clinical efficacy in patients with GNE myopathy.

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XYY syndrome is characterized by a variable neurodevelopmental phenotype, with features including developmental delays, cognitive impairments, and an increased risk for mental health conditions. There are two recent developments that have primarily motivated this review. The first is the increased use of non-invasive prenatal screening (NIPS), which will likely result in more individuals being diagnosed with XYY prenatally. As such, health care providers (HCPs) both within genetics and outside of the specialty are more likely to encounter this diagnosis in the future. The second is advances in the understanding of the phenotypic variability of XYY through biobank and deep phenotyping efforts. As the phenotypic spectrum of XYY syndrome continues to expand, families will face greater uncertainty when receiving this diagnosis. Given both of these developments, HCPs will need to have up-to-date and accurate information about XYY to better counsel families. Furthermore, the ability to employ effective counseling techniques, such as anticipatory guidance, will aid in supporting and guiding families through the diagnostic journey. This review aims to provide insight on the neurodevelopmental and psychosocial aspects of XYY syndrome by discussing current research and borrowing from the relevant psychosocial literature of other genetic conditions. In this way, we hope to equip HCPs with the ultimate goal of improving the care and support provided to individuals with XYY and their families.