Ornithine transcarbamylase deficiency (OTCD) is the most common inherited disorder of the urea cycle and, in general, is transmitted as an X-linked recessive trait. Defects in the OTC gene cause an impairment in ureagenesis, resulting in hyperammonemia, which is a direct cause of brain damage and death. Patients with late-onset OTCD can develop symptoms from infancy to later childhood, adolescence or adulthood. Clinical manifestations of adults with OTCD vary in acuity. Clinical symptoms can be aggravated by metabolic stressors or the presence of a catabolic state, or due to increased demands upon the urea. A prompt diagnosis and relevant biochemical and genetic investigations allow the rapid introduction of the right treatment and prevent long-term complications and mortality. This narrative review outlines challenges in diagnosing and managing patients with late-onset OTCD.

Clinical findings of hepatomegaly and splenomegaly, the abnormal enlargement of the liver and spleen, respectively, should prompt a broad differential diagnosis that includes metabolic, congestive, neoplastic, infectious, toxic, and inflammatory conditions. Among the metabolic diseases, lysosomal storage diseases (LSDs) are a group of rare and ultrarare conditions with a collective incidence of 1 in 5000 live births. LSDs are caused by genetic variants affecting the lysosomal enzymes, transporters, or integral membrane proteins. As a result, abnormal metabolites accumulate in the organelle, leading to dysfunction. Therapeutic advances, including early diagnosis and disease-targeted management, have improved the life expectancy and quality of life of people affected by certain LSDs. To access these new interventions, LSDs must be considered in patients presenting with hepatomegaly and splenomegaly throughout the lifespan. This review article navigates the diagnostic approach for individuals with hepatosplenomegaly particularly focusing on LSDs. We provide hints in the history, physical exam, laboratories, and imaging that may identify LSDs. Additionally, we discuss molecular testing, arguably the preferred confirmatory test (over biopsy), accompanied by enzymatic testing when feasible.

Inherited metabolic diseases (IMDs) are rare heterogenous genetic conditions. Advanced technology and novel therapeutic developments have led to the improved life expectancy of patients with IMDs. Long-term, they require close surveillance from specialist adult metabolic providers. Healthcare transition (HCT) is the planned, purposeful process of preparing adolescents for adult-centered medical care and has been recognized globally as a necessary component of care for IMDs. Two recent surveys outlined barriers to the HCT in the US and the UK. The limited knowledge of IMDs among adult physicians was one of the barriers. Some work on specialty curriculum has started and aims to improve the structured training and awareness of rare diseases. Other barriers included social and legal aspects of adulthood, social, vocational and educational support for young adults, care fragmentation and insurance coverage. Although various HCT tools are available, they cannot always be standardized for IMDs. Despite the remarkable differences in the healthcare systems and physicians’ training, collaboration among metabolic centers is possible. International rare disease alliance may enhance the patients’ management via guidelines development and standardized training for adult metabolic providers.

The onset of the COVID-19 pandemic caused significant changes in healthcare delivery. Telemedicine rapidly and unexpectedly became the primary vehicle for ambulatory management. As newborn screen (NBS) referrals require varying levels of acuity, whether telemedicine could be used as a safe and effective medium to return these results were unknown. We sent an online survey to metabolism providers internationally to investigate triage differences of abnormal NBS results during the COVID-19 pandemic. The survey compared personal practice for the periods of March–June 2019 and March–June 2020. Responses were received from 44 providers practicing in 8 countries. Nearly all (93%) practiced in areas of widespread SARS-COV-2 community transmission during spring 2020. There was a significant expansion of telemedicine use for NBS referrals at the onset of the COVID-19 pandemic (OR: 12, 95% CI: 3.66–39.3, p < 0.0001). Telehealth primarily replaced in-person ambulatory metabolism visits. The increased frequency of virtual care was similar across NBS analytes. Providers found telehealth for NBS referral equally efficacious to in-person care. Institutional patient surveys showed no difference in satisfaction with provider communication, provider empathy, or appointment logistics. Our survey was limited by unprecedented disruption in healthcare delivery, necessitating further validation of telegenetics for NBS in the post-pandemic era. Nevertheless, our findings demonstrate that telemedicine is potentially a viable and practical tool for triaging abnormal NBS results.

Background: Reproductive planning is an emerging concern for women with inherited metabolic disease (IMD). Anticipatory guidance on contraception is necessary to prevent unintended pregnancies in this population. Few resources exist to aid informed decision-making on contraceptive choice. A retrospective case–control study was performed to examine trends in reproductive planning for adolescent and adult women seen at the Children’s Hospital of Philadelphia (CHOP). Literature review on contraception and IMD was performed to assess global use. Results: In a cohort of 221 reproductive-aged female IMD patients, 29.4% reported routine contraceptive use. Anticipatory guidance on contraception was provided by metabolic physicians to 36.8% of patients during the study period. Contraception discussion was more likely to occur in women older than 21 years, who lived independently and were followed by gynecology. Women who received contraception counseling from their metabolic physician were 40-fold more likely to use regular contraception. Use of combined hormonal contraceptives was most commonly reported, but contraception choice varied by age and IMD. Conclusion: Metabolic physicians are ideally suited to provide guidance on contraception to women with IMD. Reproductive planning should be addressed routinely using shared decision-making. Contraceptives should be selected for their efficacy, effects on metabolism, and likelihood of patient adherence.