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New research shows female OTC carriers (heterozygous females) face more symptoms, risks than expected

Images of study authors Jirair Bedoyan and Andrea Gropman

Ornithine transcarbamylase (OTC) deficiency is a rare genetic disorder that allows ammonia to build up in the blood, causing brain damage, coma, or death if left untreated. It is thought to occur in approximately 1 in 14,000 individuals born in the United States.

OTC deficiency is the most common of the eight urea cycle disorders (UCDs) and the only one that is X-linked, or the result of a mutation on the X chromosome. 

While it almost always leads to symptoms in males, symptoms among females can vary widely.It has long been thought that 80% of female OTC carriers do not face symptoms or are “asymptomatic.” As a result, they are not typically treated or monitored, and little research has been done on their long-term health risks.

A new study from the Urea Cycle Disorders Consortium (UCDC), NUCDF’s research partner, shows that female OTC carriers face both symptoms and health risks at higher levels than previously thought. Study authors say that they should be monitored to reduce risks and possibly treated to address symptoms that may have gone unrecognized.

The new study—the largest of female OTC carriers to date—examined data from the UCDC’s longitudinal study and also built on prior brain imaging studies led by Andrea Gropman, M.D., of Children’s National Hospital.

The paper includes a case study of an apparently healthy and academically high achieving woman who suddenly began displaying confusion and protein aversion at age 35 following the birth of her daughter. At that time, doctors diagnosed her with a psychiatric condition.

Four years later, her daughter was diagnosed with OTC deficiency. The mother was tested and found to carry the same OTC gene change as her daughter. Once diagnosed, the mother began treatment and her symptoms improved.

An expanded history uncovered other female relatives in the family with psychiatric diagnoses such as bipolar disorder, dementia, and “erratic” behavior. They had never been tested for the same OTC gene change.

This story—not uncommon in the UCD community—highlights the risks of OTC deficiency to female carriers, the difficulties with diagnosis, and the need for consensus around both risks and treatment protocols.

“We believe that many of these individuals are not truly asymptomatic,” says lead study author Jirair K. Bedoyan, M.D., Ph.D., of the University of Pittsburgh. “Chronically elevated ammonia levels can cause more subtle problems. Stress, surgery, intercurrent illnesses, or metabolic decompensation may tip them over into a hyperammonemia crisis. Their symptoms can change over time. We need better ways to monitor and manage these risks.”

Health records review uncovers risks, common symptoms

The study team analyzed data from 302 female OTC carriers. Of those studied, 143 were symptomatic at baseline, 22 were initially asymptomatic but later developed symptoms, and 111 were asymptomatic throughout the study period. The status of 26 individuals was either missing or unknown.

Five subjects who were initially asymptomatic went on to develop elevated ammonia levels, with two requiring hospital admission and nitrogen scavenger therapy.

“We found that the risk of ‘asymptomatic’ female OTC carriers developing hyperammonemia at some point in their lifetime is at least 4%,” says Dr. Bedoyan. “But, because there is incomplete information among the cohort investigated using data from the UCDC longitudinal study, we believe that risk could be as high as 15%.”

The records also showed that female OTC carriers from both the symptomatic and asymptomatic groups suffered from mild to severe neuropsychiatric conditions such as mood disorders and sleep problems and could have mild cognitive impairment. Subjects began displaying neuropsychiatric or behavioral symptoms at the median age of 17 years. The high ammonia levels appeared at the median age of 50 years.

In all, 38% of the asymptomatic patients and 33% of the patients who were initially asymptomatic but developed symptoms later suffered from mild to severe psychiatric symptoms. Behavioral symptoms commonly reported among the combined groups include sleep problems, mood problems, easy distractibility, short attention, food refusal, impulsivity, and hyperactivity, with a few exhibiting temper tantrums, self-injurious and aggressive attributes.

“Sleep problems and mood disorder are more common among female OTC carriers than in the general female population of similar age range. Some behavioral symptoms appeared at levels closer to those noted in the elderly,” says Dr. Bedoyan. “Are female OTC carriers exhibiting some form of mild cognitive impairment similar but likely distinct from what is seen among the elderly? More studies are needed on this.”

The study also confirmed that a majority of female OTC carriers are not currently restricting their dietary protein intake. “What are the risks of that?” asks Dr. Bedoyan. Again, he says, more research is needed.

Neuroimaging insights

To examine the brain impacts of being a female OTC carrier, the mother and daughter highlighted in the case study underwent multimodal imaging studies with Dr. Gropman. Their results were compared to those of other female OTC carriers in the longitudinal study and to typical unaffected controls to better understand changes and impacts over time.

The studies found structural changes and alterations in cognitive function for the study subjects and in the broader study population for both symptomatic and asymptomatic female OTC carriers.

“We found that areas of the brain are quite sensitive to even mild elevations in ammonia and glutamine, even in the absence of a severe hyperammonemia crisis,” says Dr. Bedoyan. “Dr. Gropman’s brain imaging studies document changes in brain neural function among female OTC carriers.”

Two prior brain imaging studies (here and here) had compared female OTC carriers with age-matched controls. They found that OTC carriers had higher glutamine levels and lower levels of both choline and myoinositol in their brains, identifying those as potential brain injury indicators (biomarkers) for the first time. In the hyperammonemic brain, glutamine acts as a storage depot for ammonia; myoinositol acts as an osmotic buffer to try to decrease the brain swelling caused by the increased ammonia/glutamine; choline is a component in the covering of the white matter tracts in brain areas that underlie skills like working memory and reaction speed.

Another study found evidence of executive dysfunction—problems with a group of mental skills including working memory, flexible thinking, and self-control that allow individuals to learn, work, and manage daily life—in carriers who had been labeled asymptomatic. Previous research also associated lower myoinositol levels in the brain’s frontal and posterior white matter with decreased non-verbal intelligence.

“We can’t forget that early work which found abnormalities on the cognitive studies and brain imaging among female OTC carriers,” says Dr. Gropman. “Many NUCDF families participated in those studies. Their contributions were the key to better understanding the impacts and underlying mechanisms affecting this group and led us to launch this study.”

Dr. Bedoyan says that this research supports further investigation of these biomarkers. “Subtle findings early on—behavioral and/or biochemical—may hint at who might be at risk for hyperammonemia later, or be at risk for mild cognitive impairment, or exhibit some non-verbal intelligence limitation,” he says.

Implications for doctors, patients

Dr. Bedoyan emphasizes that asymptomatic female OTC carriers should not be dismissed by physicians and lost to follow-up care.

“If you are a female OTC carrier, you and your loved ones should be aware: if you have behavioral symptoms, don’t dismiss them,” he says. “Talk to your doctor about possibly modifying your diet to restrict protein. Consider more frequently assessing your cognitive function. Consider enrolling in the UCDC longitudinal study to both advance the research and remain informed of future studies.”

Dr. Bedoyan says his goal is not to frighten patients, but rather to make them aware of the risks so they can elect to take protective measures such as closer monitoring, changing their dietary and/or exercise regimen, or adding low-dose supplements or nitrogen scavenger medication. He wants female OTC carriers to manage their risks just like the risks of cardiovascular disease are measured, monitored, and managed.

The researchers say that evidence-based care guidelines and a clinical risk score calculator are needed to help guide physicians and help patients reduce symptoms and improve long-term quality of life. They are planning another study to follow a group of female carriers over time. The hope is to use machine learning (ML) to develop an algorithm that can assign weight factors to various parameters like glutamine elevation, low myoinositol, and sleep disturbances to help identify those at risk.

Terminology around the condition is even beginning to change. Female OTC carriers are increasingly being called “heterozygous OTC females”—indicating they have inherited one copy of a gene with OTC-related changes—to more adequately convey their status and the risks they face.

Dr. Bedoyan offers several takeaways for both doctors and patients:

  • Sleep studies may be useful for asymptomatic female OTC carriers—they are easy to do and can be repeated over time.
  • Ongoing neuropsychiatric evaluations should also be offered.
  • Some protein restriction should be discussed.
  • Low dose nitrogen scavenger therapy or mild supplementation with either L-citrulline or L-arginine should be discussed.
  • Neuroimaging modalities (fNIRs and 1H MRS) should be considered part of the diagnostic toolbox for asymptomatic female OTC carriers to tease out potential pathology in such patients and follow changes over time.

“We also need to educate doctors that carrier status involves risk that should be monitored and perhaps treated,” says Dr. Bedoyan. “Families can be the best advocates. We need to repeat the truth so many times that it becomes like second nature.”


Citation: Sen K, Izem R, Long Y, Jiang J, Konczal LL, McCarter RJ; Members of the Urea Cycle Disorders Consortium (UCDC); Gropman AL, Bedoyan JK. Are asymptomatic carriers of OTC deficiency always asymptomatic? A multicentric retrospective study of risk using the UCDC longitudinal study database. Mol Genet Genomic Med. 2024 Apr;12(4):e2443. doi: 10.1002/mgg3.2443. PMID: 38634223; PMCID: PMC11024633.


The Urea Cycle Disorders Consortium (UCDC) is part of the Rare Diseases Clinical Research Network (RDCRN). It is funded by the NIH under grant number U54HD061221 as a collaboration between by the National Center for Advancing Translational Sciences (NCATS), the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) 


For further reading

Gropman AL, Seltzer RR, Yudkoff M, Sawyer A, VanMeter J, Fricke ST. 1H MRS allows brain phenotype differentiation in sisters with late onset ornithine transcarbamylase deficiency (OTCD) and discordant clinical presentations. Mol Genet Metab. 2008 May;94(1):52-60. doi: 10.1016/j.ymgme.2007.12.008. Epub 2008 Feb 11. PMID: 18262815; PMCID: PMC2486377.

Gropman AL, Fricke ST, Seltzer RR, Hailu A, Adeyemo A, Sawyer A, van Meter J, Gaillard WD, McCarter R, Tuchman M, Batshaw M; Urea Cycle Disorders Consortium. 1H MRS identifies symptomatic and asymptomatic subjects with partial ornithine transcarbamylase deficiency. Mol Genet Metab. 2008 Sep-Oct;95(1-2):21-30. doi: 10.1016/j.ymgme.2008.06.003. Epub 2008 Jul 26. PMID: 18662894; PMCID: PMC3724938.

Gropman A. Brain imaging in urea cycle disorders. Mol Genet Metab. 2010;100 Suppl 1(Suppl 1):S20-30. doi: 10.1016/j.ymgme.2010.01.017. Epub 2010 Feb 13. PMID: 20207564; PMCID: PMC3258295.

Sprouse C, King J, Helman G, Pacheco-Colón I, Shattuck K, Breeden A, Seltzer R, VanMeter JW, Gropman AL. Investigating neurological deficits in carriers and affected patients with ornithine transcarbamylase deficiency. Mol Genet Metab. 2014 Sep-Oct;113(1-2):136-41. doi: 10.1016/j.ymgme.2014.05.007. Epub 2014 May 20. PMID: 24881970; PMCID: PMC4458385.

Gropman AL, Gertz B, Shattuck K, Kahn IL, Seltzer R, Krivitsky L, Van Meter J. Diffusion tensor imaging detects areas of abnormal white matter microstructure in patients with partial ornithine transcarbamylase deficiency. AJNR Am J Neuroradiol. 2010 Oct;31(9):1719-23. doi: 10.3174/ajnr.A2122. Epub 2010 May 20. PMID: 20488904; PMCID: PMC3758695.

Pacheco-Colón I, Washington SD, Sprouse C, Helman G, Gropman AL, VanMeter JW. Reduced Functional Connectivity of Default Mode and Set-Maintenance Networks in Ornithine Transcarbamylase Deficiency. PLoS One. 2015 Jun 11;10(6):e0129595. doi: 10.1371/journal.pone.0129595. PMID: 26067829; PMCID: PMC4466251.

Anderson A, Gropman A, Le Mons C, Stratakis C, Gandjbakhche A. Evaluation of neurocognitive function of prefrontal cortex in ornithine transcarbamylase deficiency. Mol Genet Metab. 2020 Mar;129(3):207-212. doi: 10.1016/j.ymgme.2019.12.014. Epub 2020 Jan 10. PMID: 31952925; PMCID: PMC7416502.


Hear from Dr. Bedoyan on the study: