Inborn errors of metabolism (IEM) are of concern in
India, the spectrum being wide, varied and poorly diagnosed. Population
based studies indicate tyrosinemia, maple syrup urine disease and
phenylketonuria to be the commonest inborn errors of amino acid
metabolism among newborns in India(1). Amino acid disorders seen in a
tertiary care hospital would be more varied, as they would include sick
children. We report 2 cases of citrullinemia with hyperammonemia which
represent the disruption of different metabolic pathways.
Case reports
Patient 1. A neonate presented at 20 hours
of age with poor feeding and respiratory distress. He was born to
consanguineous parents and two previous siblings had died in the
neonatal period with similar complaints. There was no history of birth
asphyxia or any risk factors for sepsis. The blood counts, blood sugar,
electrolytes and chest X-ray were normal and blood culture was
sterile. On examination he was in severe respiratory distress with weak
peripheral pulses and a capillary refill time >4 seconds. Arterial blood
gas revealed severe metabolic acidosis with an anion gap of 35. Serum
urea was 37 mg%, plasma ammonia 294 µg/dL (normal 20-80 µg/dL) and serum
lactate 4.5 mM (normal 0.3-1.3mM). Urine was negative for reducing
substances and ketones. Amino acid profiles determined by high
performance liquid chromatography, revealed raised levels of citrulline
(440 moles/L), proline (410 moles/L) and lysine (680 moles/L). He was
resuscitated with normal saline, provided ionotropic support and
metabolic acidosis corrected with intravenous sodium bicarbonate. He was
also started on therapeutic doses of vitamin B12, pyridoxine, riboflavin
and thiamine. The neonate improved and was started on nasogastric feeds
on the third hospital day. He deteriorated 4 days later with the same
manifestations and died on the 8th day of life.
Patient 2. A 15-year-old boy presented
with a history of episodic vomiting associated with subacute
encephalopathy from the age of one year. There were 2-3 months of
asymptomatic periods between the episodes. He was born of
non-consanguineous parents at full term and had a normal perinatal
period with no evidence of birth asphyxia. His developmental history was
normal. During hospital stay he had 2 episodes of convulsive seizures.
In view of his clinical history he was investigated for an IEM.
Investigations revealed high blood ammonia (288 µg/dL), markedly
elevated levels of citrulline (2200 µmoles/l, normal 1-55 µmoles/l),
normal ornithine (35 µmoles/l) and low blood urea (12 mg/dL). The
urinary orotic acid was elevated (26 mg/g creatinine, normal < 20
mg/g creatinine). He was treated with anti-convulsants and sodium
benzoate (250 mg / kg body weight /day), advised a restricted protein
diet and continues to do well a year later.
Discussion
Hyperammonemia accompanied by citrullinemia can occur
either from a disruption of energy metabolism due to an absence of
pyruvate carboxylase or from a defect of the urea cycle.
Pyruvate carboxylase deficiency (EC 6.4.1.1.) (McKusick
266150) is characterized by lactic acidemia from a lack of
gluconeogenesis and the Cori Cycle as well as by low aspartate and the
accumulation of the urea cycle intermediate, citrulline. This elevated
level of citrulline results in an increase of the other urea cycle
intermediates arginine and ornithine. The deficiency also features
elevated levels of blood proline, alanine and lysine, from an increased
availability of pyruvate. Elevated alanine also reflects the associated
hyperammonemia. Although pyruvate and orotic acid levels were not
determined and moderately elevated citrulline may suggest a
argininosuccinate lyase deficiency in Patient 1, the metabolic profile
especially the severe metabolic acidosis and lactic academia do not
support a urea cycle disorder(2) but more likely a deficiency of
pyruvate carboxylase in this patient. Pyruvate carboxylase deficiency
presents in 3 clinical forms, infantile, severe neonatal and benign. A
partial deficiency of pyruvate carboxylase that is ultimately fatal
underlies the infantile form (Type A/N American form) while enzyme
activity is completely absent in the severe neonatal (Type B) form
(French (or UK) phenotype) (3-5). Low levels of the enzyme (upto 5%)
with a benign clinical course and no major metabolic upsets characterize
the benign form of the enzyme deficiency(6,7). The clinical and
biochemical profile and death of the neonate would suggest Type B
pyruvate deficiency in Patient 1.
Hyperammonemia with critically elevated levels of
citrulline indicates a deficiency of argininosuccinate synthetase (EC
6.3.4.5) in the urea cycle, the classical citrullinemia type II (CTLN2;
McKusick 603471). Citrullinemia from a urea cycle defect will also
feature low to normal levels of the other urea cycle intermediates and
an increased excretion of orotic acid from an increased availability of
carbamoyl phosphate. The hyperammonemia that accompanies a urea cycle
defect will reflect in high blood glutamine and alanine. The notable
citrullinemia and biochemical profile of patient 2 suggests a deficiency
of argininosuccinate synthetase.
Although enzymatic determinations and DNA analysis
are considered confirmatory for metabolic and genetic disorders, these
two cases of citrullinemia were delineated from their clinical,
biochemical and different amino acid profiles, into an energy disorder
of a pyruvate carboxylase deficiency and a urea cycle defect of partial
argininosuccinate synthetase deficiency. The severe citrulli-nemia of
argininosuccinate synthetase deficiency is in fact considered sufficient
confirmation for the disorder(8). In a partial deficiency of
argininosuccinate synthetase the disease presents when the system is
challenged with a protein load. Until such events, metabolism is normal
as evidenced by the episodic history of Patient 2, explaining the normal
development of this patient.
Pyruvic acidemia has been reported in a child from
India by Tibrewala, et al.(9) based on characteristic clinical
and non-enzymatic biochemical profiles. There is one report in an Indian
neonate of a urea cycle defect of argininosuccinate synthetase
deficiency by Balsekar, et al.(10) also based on clinical and
biochemical profiles. Arguably citrullinemia I, II, III, must be more
common in India than documented, the inability to investigate limiting
detection. In the context we recommend amino acid determinations in
cases of hyperammonemia suspected to underlie an IEM.
Contributors : NT and JJ managed and diagnosed
the case and helped in drafting the paper. DK carried out the laboratory
analysis and helped in drafting the paper. AO drafted the paper and will
act as guarantor for the paper.
Funding: None.
Competing interests: None stated.
