Neurological symptoms

Clinical evidence suggests a wide range and severity of neurological symptoms in adults and adolescents with late-onset OTCD (Table 1), primarily characterized by acute changes accompanying HAEs. Clinical studies have reported mild-to-severe signs of neurological impairment, including decreased level of consciousness, coma, drowsiness/lethargy, abnormal motor function (e.g., slurred speech, impaired fine motor skills), seizures, and altered mental status (including irritability) (Fig. 1). Patients may also present with psychiatric manifestations (e.g., atypical aggression, unusual behavior) during HAEs (Table 1). These symptoms are generally in accordance with neurological symptoms described by other review articles (Simpson et al. 2003, Helman et al. 2014, Waisbren et al. 2019, Seker Yilmaz et al. 2022).

Table 1 Studies reporting neurological symptoms in patients with late-onset OTCDFig. 1

Clinical evidence suggests a wide range and severity of neurological symptoms and cognitive impairment with late-onset ornithine transcarbamylase deficiency

Neurological symptoms may be intermittent and may completely resolve between HAEs; however, these symptoms can progress, and the disease can become fatal if untreated (e.g., encephalopathy). Interestingly, Toquet et al. (2021) found that almost all patients with late-onset OTCD (91%, 21/23) experienced neurological symptoms during their first HAE (e.g., coma, lethargy, confusion) (Toquet et al. 2021), highlighting the importance of recognizing their association with late-onset OTCD (and subsequent diagnosis), as timely treatment may mitigate long-term cognitive impacts of late-onset OTCD and even prevent death. Of note, some patients in this study had medical history of neurological symptoms before their first identified HAE (e.g., seizures, confusion), indicating neurological symptoms can precede a recognized HAE, and may be attributed to a previously unidentified HAE that did not result in death.

Cognitive symptoms

Clinical evidence has also suggested a wide range and severity of cognitive symptoms in adults and adolescents with late-onset OTCD (Table 1), which may appear acutely or as subacute changes in everyday functioning. Although early studies reported that almost all patients had normal cognitive development and intelligence (Gyato et al. 2004, Keskinen et al. 2008), many studies included here reported intellectual disability, cognitive impairment, or psychiatric disorders (Fig. 1). This agrees with other studies that have noted subacute symptoms of late-onset OTCD, including behavioral disorders and intellectual difficulties (National Organization for Rare Disorders 2017, Ibrahim et al. 2023).

Neurocognitive batteries and behavioral testing, such as use of Stroop Task and Behavior Rating Inventory of Executive Functioning, have also highlighted deficits in executive functioning and motor ability, not only in adult patients with diagnosed late-onset OTCD, but also in heterozygous females who were previously considered “asymptomatic” (Sprouse et al. 2014, Sen et al. 2024). A Urea Cycle Disorders Consortium (UCDC) study found intelligence was impaired across five cognitive domains (intelligence, executive functioning, memory, visuomotor integration, and visual perception) in patients with diagnosed late-onset OTCD with history of HAEs (Buerger et al. 2019).

Symptom onset with HAEs

Neurological symptoms are often dependent on duration and severity of HAEs (Helman et al. 2014), which in many cases are triggered by physiological stressors such as changes in diet (e.g. increased protein intake, rapid weight loss, starvation, fasting), use of steroids or chemotherapy, infections or illness, surgery, and pregnancy (e.g. childbirth, postpartum period) (Table 2). Altered mental status and encephalopathy are among the most common initial symptoms of late-onset OTCD associated with HAEs (Seker Yilmaz et al. 2022). However, these neurological symptoms in adolescents and adults may not be recognized as associated with an HAE during an emergency presentation, resulting in diagnostic delays (Ibrahim et al. 2023).

Table 2 Case studies of neurological symptom onset in late-onset OTCDAge of symptom onset

Age of onset of symptoms in late-onset OTCD varies from young children to older adults (summarized in Table 1), with adults typically experiencing difficulties associated with physiological stressors, such as pregnancy, prolonged illness or fasting, or treatment with steroids. Multiple case studies report that age at onset was often later than anticipated in adults, due to prolonged diagnostic delay after failing to recognize earlier symptoms of HAEs and neurocognitive changes (Table 2). Tuchman et al. (2008) reported a median 5-year delay in diagnosis from onset of first symptoms suggestive of UCD for patients aged 0–37 years from the United States UCDC (Tuchman et al. 2008).

Diagnosis

Delays in diagnosis can lead to a significant burden, poorer outcomes, and potentially death in patients with late-onset OTCD. For example, Abbot et al. (2022) reported the case of a 64-year-old female, whose ongoing neurological symptoms of lethargy and confusion were mistaken for symptoms of age-related cognitive decline (Abbott et al. 2022). In another case, a 43-year-old female (whose 22-month-old son died due to severe HAEs) was not evaluated for late-onset OTCD until developing HAEs with neurological symptoms (Pizzi et al. 2019). This highlights the critical importance of genetic testing and comprehensive family counseling after an affected child is diagnosed, including careful review of maternal symptoms, illnesses, and dietary practices.

Early diagnosis is critical in management of neurological symptoms of late-onset OTCD and prevention of morbidity and mortality; Rüegger et al. (2014) found in patients with UCDs, including late-onset OTCD, 46% were affected by cognitive impairment if diagnostic delay (from first symptoms) was < 1 year, but 75% were affected if diagnostic delay was > 1 year (Rüegger et al. 2014). As most patients with UCDs are diagnosed after symptom onset (60%), as opposed to high-risk family screening (25%), newborn screening (9%), or prenatal testing (4%) (Posset et al. 2019), early recognition of late-onset OTCD symptoms is critical.

Role of neuroimaging and electroencephalography

Neuroimaging has been used to assess functional outcomes in patients with late-onset OTCD, especially with onset during adolescence or adulthood (clinical evidence outlined in Table 3). In these studies, a range of neuroimaging and neuromonitoring modalities, including electroencephalography (EEG), computed tomography, structural magnetic resonance imaging (MRI), functional MRI, functional near-infrared spectroscopy, and proton magnetic resonance spectroscopy (1H-MRS) have been used to evaluate patients with late-onset OTCD. EEG was able to detect abnormalities in brain waves correlating with ammonia levels and subclinical seizures in UCDs (Chanvanichtrakool et al. 2024), and neuroimaging identified differences in prefrontal connectivity, efficiency, microstructure, and brain metabolism in patients with late-onset OTCD (Table 3). Many of these changes were associated with executive functioning, suggesting patients with late-onset OTCD may experience challenges with daily skills, such as planning, focusing, memory, initiation, and multitasking. Importantly, prefrontal cortex, executive functioning, and working memory may be impacted in patients with late-onset OTCD who are considered “asymptomatic” (Gropman 2010, Gropman et al. 2013a, Anderson et al. 2020, Sen et al. 2022).

Table 3 Neuroimaging in patients with late-onset OTCDPhysicians’ perspectivesIdentifying patients with late-onset OTCD: acute presentation

It is essential to identify patients with late-onset OTCD as quickly as possible. Serum ammonia testing should immediately be completed in cases where patients present with acute neurological changes or behavioral disturbances of unknown origin (e.g., confusion, memory deficits, brain fog, lethargy, aggression, increased anxiety, hallucinations, and vision changes), especially when accompanied by severe headache, vomiting, and/or decreased alertness, health care providers (HCPs). If ammonia levels are elevated, providers are encouraged to seek expert advice from a medical/biochemical geneticist to assess possible late-onset OTCD or other UCDs/metabolic disorders, even with the presence of known liver dysfunction since this can also be seen in untreated UCDs (Ben-Ari et al. 2010). Carefully reviewing the patient’s history for potential stressors, such as dietary alterations (e.g., protein loading), illness (especially leading to decreased oral intake/fasting), use of steroids or chemotherapy, surgery, or recent pregnancy (especially ≤ 3 days after delivery, when excess protein is being reabsorbed), is essential. In some cases, individuals may self-restrict protein (e.g., vegetarian diet) because of non-specific effects of high protein intake, such as headache, nausea, or general malaise. Reviewing clinical history is important in identifying any signs of potential prior HAEs or liver dysfunction in patients with cognitive symptoms, as this may further suggest a potential late-onset OTCD diagnosis.

Identifying patients with late-onset OTCD: challenges

In patients presenting later in life with previously undiagnosed OTCD, any earlier symptoms may have been unrecognized secondary to the wide range of variability in presentation and severity, even among affected males, and may differ from typical clinical presentations in textbook cases. For example, males presenting with acute change in behavior or cognition may have late-onset OTCD, but this may be overlooked as a possibility if they had not presented with symptoms as a neonate, since many providers may assume that males always present with severe OTCD. As a result, these mental status changes may be inaccurately attributed to hepatic encephalopathy due to presumed alcoholism or other substance abuse. Unfortunately, this mistake has led to fatal diagnostic delays (personal communication, National Urea Cycle Disorders Foundation). Assessing any additional symptoms suggestive of an HAE may be particularly useful when subacute changes in everyday functioning are also reported. For example, adolescents may present with new-onset learning difficulties in school; recognizing this as a subacute neurocognitive symptom of potential late-onset OTCD may be aided by further consideration of the patient’s clinical and family history.

Given it is often overlooked as a possible diagnosis, patients with late-onset OTCD often present with clinical symptoms similar to more common neurodegenerative and neurodevelopmental disorders. Overall, we encourage physicians to, at earliest signs of unexplained neurocognitive symptoms (with or without HAE onset), review clinical and family history and immediately test ammonia levels, and thus include OTCD in their differential diagnoses. Even in patients without previous history of HAEs, liver dysfunction, or any family members with history of OTCD/HAEs, those presenting with verified unexplained neurocognitive alterations and/or elevated ammonia levels should consult with a medical/biochemical geneticist for further evaluation of possible late-onset OTCD or other UCDs/metabolic disorders. A normal ammonia level by itself should not exclude continuing to pursue additional testing in the setting of a suggestive clinical presentation.

Management of late-onset OTCD

Further, timely diagnosis of adults and adolescents with late-onset OTCD allows for initiation of appropriate treatment and intervention in times of physiological stress that may prevent further HAEs, neurological injury, or death. Long-term management may include a low-protein diet (low protein medical food and specialized low nitrogen amino acid–containing formula), nitrogen-scavenging medications, or liver transplantation. Treatments currently in development, such as adeno-associated virus–based gene therapies (Baruteau et al. 2021) and gene-editing technologies, or messenger RNA administration (Prieve et al. 2018), may offer physicians, patients, and their families additional treatment options.

Biomarkers and molecular testing for late-onset OTCD

More patients are being diagnosed with late-onset OTCD later in life, in adolescence and adulthood. This may be due to more awareness of UCDs among HCPs, widely available rapid testing of ammonia levels and plasma amino acids, and use of next-generation genetic panels, whole exome/genome sequencing, and expanded carrier screening (the latter are being more routinely offered to women who are pregnant or preparing for pregnancy).

Plasma ammonia levels correlate with risk of HAEs (Lee et al. 2015), and Kido et al. (2021) demonstrated blood ammonia level of ≥ 360 µmol/L was a significant indicator of poor neurodevelopmental outcomes (Kido et al. 2021a), although plasma ammonia levels above 100 µmol/L can result in symptoms (Lichter-Konecki et al. 2022). Plasma glutamine levels may also be high (> 800 µmol/L) (Lichter-Konecki et al. 2022), although they are a weaker predictor of HAEs (Lee et al. 2015); however, Sen et al. (2020) demonstrated brain glutamine levels (detected using 1H-MRS) may remain elevated even after blood levels normalize (Sen et al. 2020). A single normal ammonia or glutamine level may not definitively rule out a potential diagnosis, and in the event of high clinical suspicion, testing should ideally be repeated during periods of time when behavioral or cognitive symptoms are or have been recently present and/or combined with molecular testing of the genes associated with UCDs.

Finally, 1H-MRS may be used where possible to monitor brain metabolism (Gropman et al. 2008a, Gropman et al. 2008b). Neuroimaging data are useful for detection of CNS injury; however, they are not sufficient to describe the full effects of cognitive symptoms in affected patients and families (including behavioral outcomes and quality of life [QoL] implications). Although baseline functional assessments may be helpful in predicting behavioral outcomes in patients with subacute or chronic symptoms of potential late-onset OTCD, we suggest ammonia levels be included as key biomarkers in the immediate diagnostic work-up for patients presenting with symptoms of potential late-onset OTCD, in addition to molecular testing to assess pathogenic variants in OTC (and other genes associated with HAEs) via sequencing that includes detection of deletions or duplications.

Burden of late-onset OTCD

Diagnosis of a genetically inherited disease such as late-onset OTCD has major implications for other family members, and adequate genetic and psychological counseling is essential. The overall burden of late-onset OTCD may include death of affected family members due to complications of the disease and awareness that multiple family members have been and can be affected by OTCD (Keskinen et al. 2008, Bijvoet et al. 2016, Toquet et al. 2021, Baker et al. 2022). Late-onset OTCD may also have an impact on daily functioning at school, work, and in family life (Waisbren et al. 2019, Kido et al. 2021b). There is also a financial burden imposed by late-onset OTCD (e.g., gaps in insurance coverage, out-of-pocket costs) (Baker et al. 2022).

Given the total burden of late-onset OTCD, social support systems (e.g., financial support and reimbursement) and counseling for patients and families affected by OTCD are imperative (Kido et al. 2021b). Societies, such as the National Urea Cycle Disorders Foundation (National Urea Cycle Disorders Foundation) and Connecting Families Urea Cycle Disorders Foundation (Connecting Families UCD Foundation 2025), aim to raise awareness about UCDs, including access to diagnosis and treatment, and can provide support to affected families.

Impact of late-onset OTCD

Cognitive changes in late-onset OTCD may impact education and career options. Some studies have reported negative impacts of late-onset OTCD on school, work, social life, and mental health, including in individuals previously considered “asymptomatic” (Waisbren et al. 2019, Kido et al. 2021b). These negative impacts are thought to be related to underrecognized behavioral, emotional, and intellectual difficulties in patients with late-onset OTCD (Jamiolkowski et al. 2016) (Tables 1, 2 and 3). Finally, patients with late-onset OTCD, their caregivers, and their families often experience negative impacts on QoL and mental health (Enns et al. 2019), stemming from death of affected family members, effects on daily life, constant treatment demands (e.g., expensive medications, maintaining protein-restricted diet), and managing the severe and unpredictable symptoms of late-onset OTCD. Consideration of the overall burden of late-onset OTCD is key to developing effective management strategies and improving patient outcomes.

Late-onset OTCD education

Education of frontline HCPs who may be first to assess patients presenting with late-onset OTCD symptoms later in life is vital, ensuring providers recognize symptoms suggestive of late-onset OTCD and associated HAEs. Informed and collaborative interprofessional teams, including clinical providers, nurses, pharmacists, and dieticians, can dramatically impact patient outcomes. As symptoms may be overlooked in patients with late-onset OTCD, particularly in males, and in patients with subacute cognitive changes that may present without an HAE, education to bring awareness of the importance of ammonia testing in these patients is potentially lifesaving.

Furthermore, families planning pregnancies should be provided with additional support, as newborns and mothers are particularly at risk of severe HAEs. Lack of routine genetic screening for late-onset OTCD imposes an additional burden (Enns et al. 2019, Stepien et al. 2019, Stepien et al. 2024). “Asymptomatic” carrier females of OTC pathogenic variants should be monitored closely during pregnancy and especially in the postpartum period for acute symptom onset. Education of HCPs in signs and symptoms of HAEs with close neurologic monitoring and low threshold for ammonia monitoring is particularly important for carriers of OTC pathogenic variants who were previously considered “asymptomatic” but may show acute and subacute neurological and cognitive symptoms of late-onset OTCD during times of physiological stress (Sprouse et al. 2014, Sen et al. 2024).

Overall, HCP education may allow for easier recognition of HAE symptoms, prompt ammonia testing, and early consultation with medical/biochemical geneticists, who can initiate prompt assessment, testing, diagnosis, and treatment, potentially resulting in reduced morbidity and mortality of late-onset OTCD.