A previously healthy 27-year-old man was brought to hospital after been found late at night confused, agitated and talking incoherently. He represented 12 days later with focal seizures, progressing to anarthria and encephalopathy. MR scan of brain showed diffuse cerebral oedema and his plasma ammonia was >2000 µmol/L (12–55 µmol/L). He developed refractory status epilepticus and subsequently died. Genetic analysis identified an ornithine transcarbamylase (OTC) gene mutation on the X chromosome. We discuss this atypical presentation of OTC deficiency as a rare but treatable cause of hyperammonaemic encephalopathy.
- metabolic disease
- clinical neurology
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Urea cycle disorders are inborn errors of metabolism that can present for the first time in adulthood in otherwise healthy individuals.1 2 The first presentation may be acute life-threatening encephalopathy, seizures or neuropsychiatric disorder.1–3 Ornithine transcarbamylase (OTC) deficiency (OMIM) number 300461) is an X-linked disorder and the most common inherited defect of the urea cycle with an estimated prevalence of 1:35 000 births.4 It typically presents with severe hyperammonaemic encephalopathy during infancy in hemizygous men. Late-onset OTC deficiency accounts for 11% of cases,4 with onset reported up to the seventh decade of life.5
A 27-year-old male doctoral student with no previous medical history was found late at night confused, verbalising incoherently and walking aimlessly in his home. He was combative when approached by family members. This state of altered consciousness persisted for 3 hours until he was restrained and brought to hospital. On arrival, he was disorientated, agitated and unable to follow commands. There was no meningism or focal neurological signs. He was sedated with haloperidol (2 mg intramuscularly) and lorazepam (2 mg intravenously). His Glasgow coma scale (GCS) score dropped to 9/15 and he was transferred to the high-dependency unit for monitoring. He was initially treated empirically for bacterial meningitis and viral encephalitis with intravenous ceftriaxone (2 g two times per day) and intravenous acyclovir (15 mg/kg three times a day). The following morning, he was alert and conversant with no memory of events.
Neurological examination was normal. Routine laboratory investigations, arterial blood gas, MR scan of brain and cerebrospinal fluid (CSF) studies were normal. Electroencephalogram (EEG) (figure 1) showed subtle bilateral posterior theta slowing and intermittent bilateral anterior temporal slowing, possibly representing a postictal state. We provisionally diagnosed complex partial seizures with a prolonged postictal state and started levetiracetam (250 mg two times per day). We discharged him with a plan for repeat EEG in 2 weeks.
The patient represented 12 days later with two witnessed focal-onset seizures. There was a prodrome of slurred speech, paraesthesia and weakness of the left arm, evolving into generalised tonic-clonic convulsions lasting 30–40 s. Two further seizures occurred with a persistent marked expressive speech disturbance interictally. There was profound difficulty with phonation rendering him essentially non-verbal; however, he retained the ability to communicate coherently via texting on his phone. An EEG (figure 2) performed to exclude focal status epilepticus, showed mild bilateral theta slowing posteriorly, but with no epileptiform discharges or lateralised disturbance of cerebral function.
Neurological examination identified anarthria, yet with intact comprehension and coherent communication through writing or texting. There was marked difficulty with phonation, particularly with vowels. His speech was limited to making soft ‘ah’ sounds. Tongue protrusion and depression were normal, but tongue elevation was poor. Swallow reflexes were preserved, and he could manipulate a food bolus; other reflexive buccofacial movements such as coughing and yawning were intact. Corneal, gag and jaw reflexes were preserved. The remaining neurological examinations were normal. A repeated MR scan of brain was normal.
We treated him empirically with intravenous methylprednisolone (1 g/day for 3 days) for suspected autoimmune encephalitis. The seizures were controlled on an increased dose of levetiracetam (1 g two times per day). On the sixth day, he became globally bradykinetic with increased tone in upper limbs, remained unable to verbalise, but still communicated coherently via text message. A second course of intravenous methylprednisolone was started on day 9 of admission. On the 12th day of admission, he deteriorated further with more pronounced bradykinesia, increased tone and deafferentation of the left upper limb. Autoimmune encephalitis panel was reported negative (including anti-NMDA, anti-CASPR2, anti-LGI1, anti-GAD, anti-GABAb and anti-AMPA). On day 13, he became increasingly drowsy and agitated. Shortly thereafter, there was markedly clinical deteriorated with a precipitous drop in GCS score to 5/15, necessitating intubation and ventilation. A repeat MR scan of brain (figure 3) the next day showed diffuse cerebral oedema with widespread cortical diffusion restriction with partial sparing of the perirolandic and occipital cortices. This radiographic pattern was highly suspicious for a hyperammonaemic encephalopathy. Plasma ammonia was >2000 µmol/L (12–55 µmol/L), suggesting a urea cycle disorder. He subsequently developed super-refractory status epilepticus, persisting despite loading doses of six antiseizure medications followed by appropriate maintenance dose (levetiracetam 2 g two times per day, phenytoin 300 mg once per day, lacosamide 200 mg two times per day, valproate 1 g two times per day, phenobarbital 15 mg/kg, midazolam 0.2 mg/kg, propofol 2 mg/kg). Unfortunately, after 6 hours of convulsive seizures, CT angiography showed absent cerebral blood flow. Ventilatory support was stopped and the patient died. Postmortem metabolic studies showed mildly elevated serum glutamine (789 µmol/L) and markedly elevated urinary orotic acid (31 531 µmol/L) and uric acid (20 287 µmol/L). Genetic analysis identified an OTC gene mutation (c.118C>T; p.Arg40Cys), causative for OTC deficiency.
This report illustrates the diagnostic challenge of late-onset OTC deficiency. This is a rare cause of hyperammonaemic encephalopathy, but is treatable if the diagnosis is made early. Several other cases of fatal adult-onset OTC deficiency have been reported (see online supplemental table 1).3 5–8
A challenging aspect of this case was the focal speech disturbance preceding the development of subtle extrapyramidal features and ultimately a rapidly progressing encephalopathy. The nature of the speech disturbance is best described as an apraxia of speech given the retention of reflexive non-volitional movements such as chewing, swallowing and coughing. This clinical presentation bears some similarity to the Foix-Chavany-Marie opercular syndrome, characterised by severe anarthria, loss of voluntary muscular functions of the face and tongue, with preserved reflex and autonomic function. Mastication and swallowing are usually impaired in this syndrome, whereas this patient’s reflexive actions remained intact.9 Foix-Chavany-Marie opercular syndrome is an atypical form of pseudobulbar palsy usually caused by bilateral opercular dysfunction. Opercular syndromes may develop as a rare ictal manifestation in epilepsia partialis continua and symptomatic focal status epilepticus.10 In one reported case, surface EEG found no evidence of cortical epileptic activity.11
We diagnosed a urea cycle disorder based on significantly elevated plasma ammonia concentration, which had been measured due to the characteristic MRI findings often seen in hyperammonaemic encephalopathy. These include bilateral symmetrical cortical high T2 signal in the frontal, insular, cingulate and parietal cortex with conspicuous sparing of the perirolandic and occipital cortices, often with diffusion restriction and corresponding low apparent diffusion coefficient (ADC) signal consistent with cytotoxic oedema.12 The hyperammonaemic state can have many effects on central nervous system function, but the proposed primary mechanism of neuronal dysfunction is glutamate accumulation and excitotoxicity.13 It is not understood why frontal, insular and cingulate regions are more metabolically vulnerable to elevated ammonia concentrations. However, this susceptibility to hyperammonaemic glutamatergic excitotoxicity in the opercular regions bilaterally may explain this presentation mimicking an atypical opercular syndrome, before ammonia concentrations reached a critical threshold causing a global cerebral dysfunction and encephalopathy.
This patient had a hemizygous pathogenic variant in the OTC gene (c.118C>T; p.Arg40Cys), causing OTC deficiency. This variant leads to an amino acid exchange of arginine with cysteine at a highly conserved residue in the OTC gene. The same variant was described in a patient who died at the age of 18 years after one previous crisis when aged 14 years.14 Other pathogenic missense variants have been described affecting the p.Arg40 amino acid residue indicating its functional importance.6 Over 230 pathogenic OTC mutations have been identified.7 Molecular analysis of the tertiary structure of OTC suggests that mutations affecting amino acids at the interior active site of the enzyme are associated with total loss of function and neonatal onset of disease. While mutations affecting surface residues of the enzyme are associated with partial loss of function, thus giving later-onset and milder clinical phenotypes as in this patient.15 OTC deficiency has partially dominant X-linked inheritance with some women developing a much milder phenotype. De novo mutations occur at high frequency in women, while men predominantly inherit the mutation from their mother; therefore, once identified familial genetic screening is important.16 The proband’s mother has so far declined testing and the lone male sibling has tested negative for the pathogenic variant.
In late-onset OTC deficiency presenting in acute metabolic crisis, there is often an identifiable precipitant that triggers metabolic decompensation. The precipitant can be increased dietary protein load or physiological stress such as infection, excessive exertion, surgery or pregnancy.3 Glucocorticoids enhance protein turnover promoting a general catabolic state and corticosteroid therapy may occasionally trigger hyperammonaemic crisis in OTC deficiency.17 In this patient’s case, a heavy academic workload combined with demanding athletic commitments may have contributed to metabolic decompensation. Importantly, no change in diet or protein load was reported. Empirical administration of corticosteroids throughout the course of treatment may have exacerbated hyperammonaemic crisis.
This case highlights that late-onset metabolic disorders should be considered within the differential for progressive seizure disorders, especially if investigations for autoimmune encephalitides are negative. Early diagnosis is critical for effective treatment and to prevent long-term complications of hyperammonaemia.18 Testing plasma ammonia should be considered in patients with transient episodes of altered consciousness or seizures, even when there is no evidence of renal or hepatic dysfunction.19 Late-onset OTC deficiency may mimic autoimmune encephalitis and patients may have more focal symptoms, such as an atypical opercular syndrome in this case.
Ornithine transcarbamylase deficiency is a rare but treatable cause of hyperammonaemic encephalopathy and can present in adulthood.
Early stages of hyperammonaemic crisis can mimic more focal pathologies; certain areas such as the operculum appear uniquely vulnerable to glutamatergic excitotoxicity.
Plasma ammonia should be checked in all patients with relapsing encephalopathy, seizures or focal symptoms in the absence of a structural lesion, and when considering empirical corticosteroids for suspected autoimmune encephalitis.
Corticosteroid therapy can both trigger the onset and potentially exacerbate hyperammonaemic crisis in patients with undiagnosed urea cycle disorder.
Häberle J, Burlina A, Chakrapani A, et al. Suggested guidelines for the diagnosis and management of urea cycle disorders: First revision. J Inherit Metab Dis. 2019. doi:10.1002/jimd.12100
Meijer R, Vivekananda U, Balestrini S, et al. Ammonia: What adult neurologists need to know. Pract Neurol. 2021. doi:10.1136/practneurol-2020–0 02 654
Patient consent for publication
This study does not involve human participants.
Contributors ED conceived of and drafted the manuscript. JMG, CG, MWA, PB, ET and EC reviewed, revised and edited the manuscript.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Provenance and peer review Not commissioned. Externally peer reviewed by Elaine Murphy, London, UK.
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