Translational Science of Rare Diseases

Organic acidemias or acidurias (OAs) are a group of metabolic disorders which result in organic acids detected in the urine (or plasma). They include the systemic OAs, the cerebral OAs, and the ketogenic/ketolytic OAs. In general, all types of OA can be treated using a similar conceptual organization. The goals of therapy (acute and chronic) include reversal/prevention of catabolism, limitation of non-tolerated precursors, scavenging of toxic intermediates, replacement of the deficient product, use of cofactors when able and treatment of complications using standard methods. In the future, this framework will also include replacement of dysfunctional enzyme with a functional one. Here we review how this conceptional framework applies to the systemic OAs (propionic acidemia, methylmalonic aciduria without homocystinuria, and isovaleric acidemia), the cerebral OA (glutaric aciduria 1) and the ketogenic/ketolytic OA (HMG-CoA lyase deficiency). We review the current recommendations and use examples of how to use this conceptional framework.

Lysosomal Storage Disorders (LSDs) comprise a group of disorders causing defects at the organelle and sub-organelle level with a wide range of pathophysiologies and clinical consequences. Signs and symptoms of LSDs involve multiple organ systems. The main pathological mechanism of most LSDs was previously thought to be cytotoxic effects of a specific storage substance secondary to functional impairment or insufficient lysosomal enzymes. Other pathophysiologic mechanisms of LSDs have been discovered such as dysfunction of cell signaling, disturbance of cell homeostasis, inflammatory process and dysfunction of autophagy. The goal of treatment is to balance equilibrium of the enzyme and the accumulated substance. Replacing deficient enzyme through exogenous enzyme replacement therapy (ERT) or stem cell transplantation has been the main method of treatment for several years. The ability of ERT to alleviate neurologic symptoms is limited owing to the inability of the exogenous enzyme to cross the blood-brain barrier. The benefit of stem cell transplantation on neurologic symptoms has been demonstrated for Hurler syndrome, but it is not clear for most LSDs. Other strategies, such as gene therapy, have been under development to overcome this limitation and provide a better outcome. Early treatment or pre-symptomatic treatment could also slow disease progression and improve prognosis. The scope of this article is to review current and new therapeutic strategies as well as disease non-specific management.

Taken as a group, genetic disorders affect a significant proportion of the population. Historically thought of as pediatric disorders, inborn errors of metabolism (IEM) are becoming increasingly relevant to the adult clinical provider; given the improvements in screening, diagnosis and management, an increasing number of children with IEM’s are able to transition adulthood. Currently available data suggests that adult-medicine clinical providers are ill-prepared to appropriately care for this population. Although practical management and transition guidelines exist for a minority of disorders, there is a significant lack of guidance for the great majority of conditions. Based on our review of the relevant literature, we set out to provide practical recommendations to assist in the transition from adolescence to adulthood, with an emphasis on patients with an inborn error of metabolism.

Like many rural states and developing countries, Mississippi lacks sufficient clinical genetics services to meet the needs and demands of patients with rare disorders in the post-genomic age. The essential responsibilities of the Medical Geneticist and Genetic Counselor are to establish a genetic diagnosis in a patient with a suspected genetically-determined disorder, to provide evidence-based genetic counseling and to directly provide or link the patient to treatment and other necessary resources. In Mississippi we have used both telemedicine (asynchronous and synchronous) and other alternative delivery arrangements to augment statewide capacity. Here we provide a narrative of our experience and a potentially generalizable model for other health systems with a clinical genetics service shortfall.

Undiagnosed and rare conditions are collectively common and affect millions of people worldwide. The NIH Undiagnosed Diseases Program (UDP) strives to achieve both a comprehensive diagnosis and a better understanding of the mechanisms of disease for many of these individuals. Through the careful review of records, a well-orchestrated inpatient evaluation, genomic sequencing and testing, and with the use of emerging strategies such as matchmaking programs, the UDP succeeds nearly 30 percent of the time for these highly selective cases. Although the UDP process is built on a unique set of resources, case examples demonstrate steps genetic professionals can take, in both clinical and research settings, to arrive at a diagnosis for their most challenging cases.

The majority of children in hospice care do not have cancer, but many have rare diseases. Thus, it is essential that rare disease specialists have a functioning knowledge of the palliative care system and its role in meeting the unique needs of pediatric patients with genetic disorders or inborn errors of metabolism. Creating a team of providers that both understands the natural history of the specific rare disease and truly understands the principles of palliative care leads to optimal outcomes for patients. Here, we discuss the importance of genetic counseling and describe the basic tenants of palliative care. By approaching this topic from a rare disease perspective, we discuss the unique features of improving quality of life for patients and families. In addition, we discuss the role of self-care in preventing care provider burnout of families and medical providers. The thoughtful approach to palliation in rare diseases is essential to optimize the experience for all participants in a patient’s shortened life.

 Individually rare but collectively common, inborn errors of metabolism (IEMs) are genetic disorders of metabolic pathways that result in multisystem dysfunction and may reduce lifespan if untreated. The IEM patient population requires collaborative care from primary care providers such as pediatricians/general practitioners, specialists, metabolic geneticists, dietitians and genetic counselors. Ideally, a patient and his or her family would have regular access to a comprehensive care team, however, some patients may require their primary care provider to manage some aspects of their IEM-related care. There have been many advances in the diagnosis and treatment of IEMs especially since the initiation of newborn screening in the United States for phenylketonuria (PKU) in the 1960s. These advancements have resulted in individuals with IEMs living into adulthood and having children of their own, creating an aging patient population and subsequent needs across this increased lifespan. Genetic counseling is a key component in the care and education of patients with IEMs at the time of the initial diagnosis and beyond. We highlight many genetic counseling concepts and issues that need to be addressed and reassessed over the lifespan of a patient with an IEM. This review is intended to support the patient’s primary care provider in recognizing these concepts and issues to reinforce for patients with IEMs in the medical home and the importance of referring for genetic counseling.