Altered mental status: a common complaint that led to a rare diagnosis - Ornithine Transcarbamylase Deficiency

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1 Altered mental status: a common complaint that led to a rare diagnosis - Ornithine Transcarbamylase Deficiency Joshua J. White, OMS3 Charles C. Finch, D.O., FACOEP Arizona College Of Osteopathic Medicine Outline Introduction Case Presentation: Timeline of events, history and physical exam Discussion: Overview of Ornithine Transcarbamylase (OTC) Deficiency What can we learn from this case? Osteopathic Approach Take away points for health care providers Questions

2 Introduction: Altered Mental Status Invitation: 1. Throughout my presentation, compare what you would do to what was done. 2. Based on physical exam findings and lab results, what would your differential diagnosis include? 3. What can you do in the future to improve your evaluation of patients with altered mental status? When a patients clinical presentation and labs don t fit the more common diagnosis, what is next in your workup? HPI 7 year old Caucasian male presents to a small community hospital Emergency Department with several episodes of vomiting and increased confusion. Per his father, he had a 2-day history of flu-like symptoms to include vomiting. Earlier in the day patient became confused, and was not responding appropriately to simple commands. This prompted father to bring him to the Emergency Department for evaluation. There is no history of any diarrhea or rashes. Father reports multiple episodes of non-bloody vomiting throughout the day.

3 HPI Con t PMH: seasonal allergies, and periods of intermittent vomiting usually initiated of times of increased hunger. PSH: None FH: No relevant family history reported SH: Father admits to other family members with similar symptoms of vomiting and runny nose. Allergies: NKDA Medications: Flonase 50 mcg/inh nasal spray. Immunizations are up to date Physical Exam Vitals: Temperature ( C) RR BP SpO2 on RA HR /59 98% 96 General: Patient is well developed, sleeping and arousable although appears to be slow to respond and confused. CV: Regular rate and rhythm. No murmurs, rubs, clicks or gallops. Respiratory: Clear to auscultation bilaterally in all fields. Chest expansion is equal bilaterally. No retractions or obvious respiratory distress. Abdomen: Soft, mild tenderness in the right lower quadrant with guarding present and no rebound. No distension appreciated and no other areas of focal tenderness. No organomegaly, masses or CVA tenderness. Neurologic: Awake, slow to respond and not acting appropriate during questioning. No focal deficits. Muscle strength is 5/5 in both upper and lower extremities. Sensation and reflexes are intact bilaterally. Meningitis is not suspected.

IV Fluids and Labs Abdominal Ultrasound due to concern for appendicitis Timeline: workup decisions Labs showed a leukocytosis, and mild elevation in liver transaminases Patient became more confused,

4 IV Fluids and Labs Abdominal Ultrasound due to concern for appendicitis Timeline: workup decisions Labs showed a leukocytosis, and mild elevation in liver transaminases Patient became more confused, and a Lumbar Puncture was ordered. Head and abdominal CT, chest x-ray to look for cause of leukocytosis Arranged for life flight transfer to a pediatric hospital for further specialty care Lab Results Heme WBC: 20.2 K/mcL Complete Differential Neutrophil Absolute: 17.9 K/mcL Chemistries AST: 99 unit/l ALT 145 unit/l Total Bilirubin: 1.5 mg/dl UA: negative Respiratory panel: Negative Including: Influenza, RSV, Adenovirus, B. pertussis, Mycoplasma pneumoniae, C. Pneumoniae, Coronavirus, Human Metapneumovirus, parainfluenza.

5 En route to the Hospital En Route Erratic breathing Dilated Pupils Clonus Due to patient s worsening clinical presentation of encephalopathy: Intubated for airway protection Mannitol bolus Ammonia level was checked Hospital Course Given an ammonia level was checked and found to be severely elevated at 381 (15-45 µ/dl). Treatment: Aggressive IV fluid hydration was continued to prevent further catabolism. The patient was given an ammonul IV bolus (sodium phenylacetate + sodium benzoate) to treat his hyperammonemia. Nephrology was consulted, and dialysis was started due to the hyperammonemia. The diagnosis of OTC deficiency was initially suspected based on his clinical presentation and hyperammonemia, and confirmed through genetic testing and liver biopsy. The patient s mental status did not improve despite aggressive therapy. An EEG was performed and results were significant for global encephalopathy. Given evidence of brain death, the parents withdrew life support and patient was pronounced dead.

6 What Is Ornithine Transcarbamylase (OTC) Deficiency? Discussion Ornithine Transcarbamylase is a mitochondrial enzyme responsible for the 2 nd step of the urea cycle, where ornithine and carbamoyl phosphate are turned into citrulline Ornithine Transcarbamylase (OTC)

7 Urea Cycle Disorders Elevated levels of Ammonia in the brain: Usually presents first with: Vomiting, altered mental status, and poor feeding. Can progress to: coma, seizures, encephalopathy.

can present at any time from infancy through adulthood. The prevalence of OTC deficiency is estimated to be at a range of 1/14,000 to 1/80,000.

8 Patient Presentation OTC Deficiency is an x-linked recessive disorder and patients present with either a full or partial deficiency. Patients who have OTC deficiency are males with full deficiency of the enzyme and present with symptoms shortly after birth, or males and/or females with a partial deficiency who can present at any time from infancy through adulthood. The prevalence of OTC deficiency is estimated to be at a range of 1/14,000 to 1/80,000. Epidemiology Mortality rates in the past have been as high as 50%. Recent estimates of mortality note a rate of 24% for neonatal presentation, and 11% for those affected after the neonatal period. This improvement is due to early diagnosis and improved treatment

9 Diagnosis Laboratory findings of elevated plasma ammonia levels with a normal glucose and anion gap suggests OTC deficiency. The diagnosis for neonatal onset (full deficiency) OTC deficiency is made by finding elevated glutamine, low/absent citrulline, and elevated urinary orotic acid levels. Late onset (partial deficiency) requires genetic testing and/or liver biopsy to confirm the diagnosis. Treatment Treatment for OTC deficiency is mainly focused on treating hyperammonemia. It includes a pharmacological intervention that targets ammonia elimination, which is typically a combination of intravenous sodium phenylacetate and sodium benzoate. A nutritional supplementation is also given with the amino acids L- citrulline or L-arginine; and a low-protein diet is maintained to avoid further catabolism. Patients presenting with severely elevated levels require dialysis to filter nitrogen from the blood. The only definitive treatment for OTC deficiency is liver transplantation. Prompt recognition and treatment is key for the best clinical outcome.

10 Ammonia Level Early diagnosis and treatment is crucial to successful outcomes of patients that present with OTC deficiency. In patients who present with altered levels of consciousness, clinicians should consider checking an ammonia level, as the consideration of OTC deficiency is a concern. If elevated, nitrogen scavenger therapy should be initiated immediately to prevent further complications. Family History/Genetic Counseling Since OTC deficiency is known to be x-linked recessive, prenatal testing can be done through chorionic villus sampling or amniotic fluid cell analysis. Newborn screening is limited, as it provides low specificity and limited benefit. Genetic testing is recommended to help families identify patients at risk, and to assist families with the preparation and early treatment OTC deficiency.

11 Osteopathic Approach Treating the patient as a whole This patient had a history of intermittent idiopathic vomiting for the past 2 years, how does that fit into this clinical picture? His vomiting in periods of increased hunger was likely due to ammonia buildup triggered by increased catabolism. The deficiency manifested itself in subtle ways for 2 years prior to the acute event. What would it take to have been caught earlier? What can we learn from this case? 1. If a patient presents with an altered mental status that cannot be explained by anything else, consider checking an ammonia level. 2. For patients with OTC deficiency or other genetic disorders, encourage genetic counseling, family education and potentially prenatal screening. 3. When the clinical and laboratory findings are not matching up to the most common presentations, think about the more rare life threatening diseases for your differential diagnosis.

12 Acknowledgements I would like to acknowledge Dr. Charles Finch for his mentorship and for his help writing and editing this case. I also acknowledge Dr. Ryan Stolworthy of Rocky Mountain Specialists for allowing access to this case. I would also like to thank the Arizona Osteopathic Medical Association for this opportunity to get involved with research and to spread knowledge gained with the rest of the medical community. References 1. Ah Mew N, Simpson KL, Gropman AL, et al. Urea Cycle Disorders Overview Apr 29 (Updated 2017 Jun 22). In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; Available from: 2. Arranz, J.A., Riudor, E., Marco-Marín, C. et al. J Inherit Metab Dis 200) 30: Baby s First Test. Ornithine Transcarbamylase deficiency. Accessed on 1/ Batshaw ML, Tuchman M, et al. A longitudinal study of urea cycle disorders, Molecular Genetics and Metabolism. Volume 113, Issues 1 2, 2014, Pages , ISSN Brassier A, Gobin S, et al. Long-term outcomes in Ornithine Transcarbamylase deficiency: a series of 90 patients. Orphanet J Rare Dis May 10; 10: Caldovic L, Abdikarim I, et al. Genotype-Phenotype Correlations in Ornithine Transcarbamylase Deficiency: A Mutation Update. J Genet Genomics May 20;42(5): Dalal A, Morry A, et al. Adult-onset ornithine transcarbamylase (OTC) deficiency unmasked by the Atkins diet. Journal of Hepatology. Volume 52, Issue 2, 2010, Pages , ISSN Galal NM, Fouad HM, Saied A, Dabnon M. Hyperammonemia in the pediatric emergency setting Dec 26(12): Häberle J, Boddaert N, Burlina A, et al. Suggested guidelines for the diagnosis and management of urea cycle disorders. Orphanet Journal of Rare Diseases. 2012; 7: Häberle, J. and Koch, H. G. Genetic approach to prenatal diagnosis in urea cycle defects. Prenat. Diagn., 2004, 24: doi: /pd Häberle J., Rubio V. Hyperammonemias and Related Disorders. In: Blau N., Duran M., Gibson K., Dionisi Vici C. (eds) Physician's Guide to the Diagnosis, Treatment, and Follow- Up of Inherited Metabolic Diseases. Springer, Berlin, Heidelber Pp Helman G, Pacheco-Colón I, Gropman AL. The urea cycle disorders. Semin Neurol Jul;34(3): Laemmle A, Keogh A, et al. Frequency and Pathophysiology of Acute Liver Failure in Ornithine Transcarbamylase Deficiency (OTCD) April 12, Lee, Brendan. Urea cycle disorders: Clinical features and diagnosis Urea cycle disorders: Clinical Features and diagnosis. Updated Sep 20, Smith VS, Mikesell D, Stoker JA. The Use of lactulose syrup for the control of hyperammonemia in Reye's syndrome: report of a case. The Journal of the American Osteopathic Association. October 1978, Vol. 78, Spence JE, Maddalena A, et al. Prenatal diagnosis and heterozygote detection by DNA analysis in ornithine transcarbamylase deficiency, The Journal of Pediatrics, Volume 114, Issue 4, Part 1,1989, Pp , ISSN Summar M. Ornithine Transcarbamylase Deficiency. National Organization for Rare Disorders. Accessed Jan 6,

13 Questions?

UREA CYCLE DISORDERS - The What, Why, How and When

UREA CYCLE DISORDERS - The What, Why, How and When George A. Diaz, MD, PhD Program for Inherited Metabolic Diseases Department of Genetics and Genomic Sciences Department of Pediatrics Icahn School of