Acute Fulminant Encephalopathy in an Adult due to Ornithine Transcarbamylase Deficiency

Dear Sir,

A 55-year-old gentleman with a history of a single episode seizure during his adolescent years, presented with non-specific symptoms of paresthesia of extremities and diffuse headache since a month. He was started on vitamin B complex tablets and low-dose pregabalin for the same. One week before the presentation, he also developed subtle memory impairment and altered behavior with aggressive traits. He was admitted to a local hospital and was given a haloperidol injection following which he developed drowsiness that persisted through the day and was referred to our institution for further management.

In the emergency, the patient was unresponsive and was not localized to painful stimuli, but had preserved brainstem reflexes. There was no history of prior alcohol use or recreational drug use, consumption of pesticides, or other unknown substances. He was admitted for further evaluation of encephalopathy and the initial differentials included a subacute progressive encephalopathy, possibly of a metabolic autoimmune or infectious etiology. Initial magnetic resonance imaging (MRI) of the brain with contrast did not show any abnormality. His laboratory tests showed hyperammonemia (168 mmol/L), but the liver function tests (serum glutamic-oxaloacetic transaminase (SGOT) 42 IU/L, serum glutamic pyruvic transaminase (SGPT) 37 IU/L) and ultrasound abdomen showed normal findings.

His ambulatory electroencephalogram (EEG) showed a moderate degree of generalized slowing [Supplementary Figure 1 ^{(146.1KB, tif)} ]. He was started with anti-hepatic coma measures including lactulose retention enema with antibiotics metronidazole and rifaximin despite normal liver function tests with gastroenterology opinion aiming reduction in gut ammonia production. He was put on a protein-restricted diet. A cerebrospinal fluid (CSF) analysis was done which showed normal findings for routine CSF, culture, viral polymerase chain reaction (PCR), and autoimmune encephalitis panel. Blood cultures were negative. His viral markers including hepatitis B total core antigen, surface antigen, and hepatitis C were negative. In the subsequent 12 h, there was an exponential rise in ammonia levels (457 mmol/L) despite the best hepatic coma measures.

Hemodialysis was initiated on the third day and three sessions were given on consecutive days. However, sensorium remained poor and there was a relentless rise in the ammonia levels (997.1 mmol/L). At this stage, his liver function tests showed mild elevation with SGOT 99.4 and SGPT 53.5 IU/L, respectively. He developed hemodynamic instability and the following computed tomography (CT) of the brain imaging showed diffuse cerebral edema. He developed herniation and succumbed within the next 24 h. The rapid progression of encephalopathy with hyperammonemia in the absence of a decompensated liver disease suggested a possible metabolic pathway disorder. His plasma amino acid level estimates by high-performance liquid chromatography (HPLC) revealed mildly elevated glutamate and low citrulline levels [Supplementary Table 1] along with significantly elevated urinary orotic acid [Supplementary Table 2], suggestive of a proximal urea cycle defect. Genetic testing could not be done for the patient due to his early death. The patient's relatives were counseled regarding the need for genetic counseling and testing. His daughter was detected to have heterozygous c.848G >T (P.Gly283val) mutation in exon 8 of the ornithine transcarbamylase (OTC) gene but was asymptomatic at the time of testing.

Supplementary Table 1.

Serum levels of amino acids by HPLC

Test	Plasma mmol/L	Reference range Umol/L
Aspartic Acid	26	34-94
Glutamic acid	21	17-69
Asparagine	17	28-65
Serine	35	92-196
Glutamine	907	457-857
Histidine	84	68-108
Glycine	274	166-330
Threonine	62	102-246
Citrulline	5	19-52
Alanine	172	242-594
Arginine	10	1-81
Tyrosine	25	35-107
Cystine	26	36-58
Valine	81	155-343
Methionine	34	13-60
Tryptophan	9	10-140
Phenylalanine	41	34-86
Iso-leucine	47	34-106
Ornithine	18	47-195
Leucine	72	86-206
Lysine	365	116-276
Hydroxy proline	-	0-53
Proline	158	58-324
Total amino acids	2489	3000-5000
Total BCAA	200	<600
Gly/BCAA	1.37
Ala/BCAA	0.85
Gly/Total	9%	<10%
Ala/Total	6%	<10%

BCAA: Branched chain amino acids

Supplementary Table 2.

Urine orotic acid and creatinine

	Amino acids	Value	Reference
1	Urinary orotic acid	2,264.4 Umol/L	Reference 0.5-3.3
2	Oroditine	ND
3	Urinary creatinine	5.74 mmol/L	4-17 mmol/L
4	Ratio of urinary orotic acid/creatinine	394.4 Umol/mmol Cr	0–30 Umol/mmol

This is a case of subacute progressive encephalopathy due to high ammonia in adults in a patient with no pre-existing liver disease. The causes of this type of rapid encephalopathy due to liver injury include viral infection, medications like valproate, steroids, and chemotherapy. But extremely high levels of ammonia without obvious other causes lead to suspicion of urea cycle disorders (UCDs). They are rare inborn errors of metabolism, due to mutations resulting in the deficiency of one of the six enzymes in the urea cycle. Out of these, ornithine transcarbamylase deficiency (OTCD) is one of the most common enzyme defects worldwide with an incidence of 1 per 42,000 live births.[1] The disorder commonly presents in neonates and children but rarely, in adults as well. All of them are autosomal recessive, except OTCD, which has an X-linked pattern of inheritance [Table 1]. The defective gene lies on the short arm of the X chromosome on band Xp21.12. As OTCD has an X-linked pattern of inheritance, males are more severely affected, but 15% of the female carriers can also be affected.[2,3] In adults, it can present with rapid and fatal hyperammonemia.[4]

Table 1.

Genetic mutations in different urea cycle disorders

Urea Cycle Disorder	Gene	Inheritance	Plasma amino acids	Urine organic acids
1-Carbamyl phosphate synthetase I deficiency	CPS 1	AR	↓Arginine↓Citrulline	↓/Normal urine orotic acid
2-Ornithine transcarbamylase	OTC	X-linked	↓Arginine↓Citrulline	↑Urine orotic acid
3-Arginosuccinic acid synthase deficiency or citrullinemia type I	ASS	AR	↑Arginine↑Citrulline
4-Arginosuccinic acid lyase deficiency or arginosuccinic aciduria	ASL	AR	↑Arginine↑Citrulline
5-Arginase deficiency	ARG1	AR	↑↑Arginine
N-acetyl glutamate synthase deficiency	NAGS	AR	↓Arginine↓Citrulline	↓/Normal urine orotic acid

Except for a single episode of seizure during his adolescent years, our case remained asymptomatic till he was 55 years of age. None of his family members except his single daughter who is apparently healthy but genetic mutation positive. The trigger which caused hyperammonemia is not clear, which could be minor infections or medications or Atkins diet or weight loss.

Urea cycle deficits present with a variable clinical spectrum across age groups depending on the residual urea cycle activity in the liver.[5] Older children and adults present with hyperammonemia and episodic encephalopathy under stress conditions like infection, anesthesia, certain drugs, diet, or pregnancy. Other features may include recurrent vomiting, seizures, protein avoidance, behavioral changes, ataxia, progressive spasticity, and mental retardation. Compared to children, an adult will present with more psychiatric symptoms including hallucinations, and disorientation.[6] If there is a minor deficiency of an enzyme of the urea cycle, the symptoms may present later in life, as was in our case.

The core feature of hyperammonemia-induced-encephalopathy is an increase in astrocyte glutamine synthesis, and swelling of astrocytes in response to the osmotic effect of glutamine accumulation, causing raised intracranial pressure.[7]

Various therapies have been tried for the treatment of hyperammonemia in cases of UCD including the following: 1. Nitrogen scavenging therapy 2. Replacement of deficient urea cycle intermediates 3. Reduction of protein catabolism 4. Therapy for rapid reduction of plasma ammonia levels by extracorporeal techniques 5. Liver transplantation.

Alternative pathway treatment diverts nitrogen from the urea cycle to various other routes of excretion. Sodium phenylacetate combines with glutamine, producing phenylacetylglutamine. Phenylacetylglutamine is excreted by the kidneys and sodium benzoate conjugates with glycine, producing sodium hippurate, which is also excreted by the kidneys. Arginine (urea cycle intermediate) can also be administered in the patient with OTCD as low plasma arginine levels are associated with OTCD. Protein intake should be restricted for at least the first 24–48 h and the caloric requirement should be met with carbohydrates and fats during this period, especially in patients on hemodialysis, to prevent excess catabolic state. Currently, the treatment of choice for hyperammonemia due to UCDs is hemodialysis or renal replacement therapy or both as early as possible.[8,9,10,11,12] We initiated hemodialysis for our patient early during the course of the hospital stay, but despite repeated sessions of hemodialysis, the patient did not respond. Liver transplantation is the treatment option for patients having recurrent hyperammonemia and for those patients who do not respond well to pharmacological and dietary measures alone.

Plasma citrulline levels aid in distinguishing proximal from distal UCDs. Plasma citrulline is absent or in trace amounts in carbamyl phosphate synthetase 1 (CPS-1) deficiency and low or normal in late-onset OTCD, both of which are proximal UCDs. In the distal UCDs, like arginine succinic acid synthetase deficiency, plasma citrulline levels are significantly elevated (ten-fold), and in argininosuccinic acid lyase deficiency, there is a moderate elevation of plasma citrulline levels accompanied by elevation of argininosuccinic acid in plasma and urine. Plasma arginine levels are reduced in all UCDs except for arginase deficiency (five- to seven-fold elevation). Urine orotic acid levels help to differentiate CPS-1 deficiency from OTCD as they are significantly elevated in OTCD, as in our case as well. Urinary orotic aciduria is also present in arginase deficiency and citrullinemia type. Genetic testing would give a definitive diagnosis.

CONCLUSION

The current case shows that urea cycle defects can be a cause of hyperammonemia with rapidly progressive encephalopathy in the absence of evidence for pre-existing liver disease. Early aggressive therapies with dialysis followed by liver transplantation may be an option in severe cases of OTC deficiency. Episodic high ammonia levels without obvious liver disease should prompt the clinician to think about these rare metabolic diseases.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

Supplementary Figure 1

Generalized delta slow wave intermixed with frontal triphasic sharp waves