Translational Science of Rare Diseases

Urea cycle disorders (UCD) result from either direct deficiency of a urea cycle enzyme or improper transport of urea cycle intermediates between cellular compartments. The urea cycle is the primary metabolic mechanism by which the body detoxifies waste nitrogen that otherwise accumulates as ammonia. Given this critical role, individuals with a UCD can present with severe hyperammonemia that may prove fatal. Furthermore, the care and management of those with a UCD is challenging and is hampered by our limited ability to prospectively predict the severity of disease in individuals based upon biochemical or molecular results. Similarly, treatment paradigms for UCD, while resulting in improvement in symptomatology are far from curative. Recent preclinical and clinical research has focused on both developing reliable predictors of severity and at advancing therapies and treatments that move closer to a cure. We present here an overview of this emerging work, targeting both areas of research, to provide a review of the state of investigation with regard to UCD.

Danon disease is a rare, X-linked genetic disorder. We report a case of a 17-year-old male with learning difficulties who presented due to advanced heart failure and the subsequent discovery of this highly penetrant but variable disease among a family unit. Cascade screening was offered to all siblings and parents that demonstrated great phenotypic heterogeneity among family members, most pronounced among female siblings. We highlight the importance of genetic testing to ultimately clinch the diagnosis of Danon disease, but how cost and reimbursement remain a major barrier in ensuring genetic testing is performed more routinely in South-East Asia, and more efforts are needed to improve this. Our case also highlights the utility of echocardiographic strain imaging in detecting subclinical disease as part of the cascade screening process. In view of the myriads of presentations, a high index of suspicion, thorough multi-systemic evaluation at baseline and robust follow-up care following genetic testing and cascade screening are all pivotal in the diagnosis and care of the condition.