UREA CYCLE DISORDERS

Moderator: Dr. A.K Bala

Speaker: Dr. Aradhana Mishra

UREA CYCLE

 Is the principal mechanism for the clearance of

nitrogenous waste resulting from protein
turnover
 Is the sole source of endogenous production of
arginine, ornithine, and citrulline
 Urea synthesis takes place in the mitochondrial
matrix and cytosol of the liver cell.
EPIDEMIOLOGY

 Overall estimated prevalence is 1 in 35000 live

births and they are the most common genetic
cause of hyperammonemia in infants.
 CLINICAL MANIFESTATIONS OF
HYPERAMMONEMIA
symptoms and signs are mostly related
to brain dysfunction .

Neonatal period :

Asymptomatic at birth

Refusal to feed, vomiting, tachypnea,

convulsion and lethargy progressing to a
deep coma.

It can trigger increased intracranial

pressure that may be manifested by a
bulging fontanelle and dilated pupils.
Contd..

 In infants and older children acute

hyperammonemia is manifested by
vomiting and neurologic abnormalities such as
ataxia, mental confusion, agitation, irritability,
and combativeness. These manifestations may
alternate with periods of lethargy and
somnolence that ultimately progress to coma.
 DIAGNOSIS
 The main criterion for diagnosis is
hyperammonemia
 In older children and adult, the normal limit is less
than 35μmole/L, in term infants levels upto100
μmole/L and in preterm infant upto150 μmole/L may
be normal.
 Manifestations occur when blood ammonia level
>200 μmole/L.
 Serious neurologic sequelae are likely in newborns
with levels >300 μmole/L for more than 12 hr.
TREATEMENT OF ACUTE
HYPERAMMONEMIA

 The goal of therapy is to lower the

concentration of ammonia.
 This is accomplished in 2 ways:
 (a) removal of ammonia from the body in a
form other than urea and
 (b) minimizing endogenous protein
breakdown and favoring endogenous protein
synthesis by providing adequate calories and
essential amino acids
Long term therapy
 Protein restricted diet (1-2g/kg/day) with
essential amino acids
 Sodium benzoate (250-500 mg/kg/24 hr)
 Sodium phenylacetate (250-500 mg/kg/24 hr)
 Arginine (200-400 mg/kg/24 hr) or citrulline
(in patients with OTC deficiency, 200-400
mg/kg/24 hr)
 Newer compounds like phenylbutyrate and
glycerol phenylbutyrate have advantage over
phenylacetate.
Contd...
 Long-term care is best achieved by a team of
experienced professionals (pediatrician,
nutritionist, child neurologist, metabolic
geneticist)
 The patient should be on regular follow up
with Growth parameters, especially head
circumference, and nutritional indices (blood
albumin, prealbumin, pH, electrolytes, amino
acids, zinc, selenium).
 Overzealous dietary protein restriction
should be avoided.
Contd...
 Catabolic states (infections, fasting) that
may trigger hyperammonemia should be
avoided. They must be treated vigorously
if they occur.
 In all children with urea cycle defects
avoid valproic acid because this drug
elevates blood ammonia even in healthy
subjects.
 UREA CYCLE DISORDERS

Disorder Deficient Enzyme Inheritance Pattern

Carbamyl phosphate Carbamyl phosphate Autosomal recessive

synthetase deficiency synthetase

Ornithine Ornithine X-linked

transcarbamylase transcarbamylase
deficiency
Citrullinemia Argininosuccinate Autosomal recessive
synthetase

Argininosuccinic aciduria Argininosuccinate lyase Autosomal recessive

Argininemia Arginase Autosomal recessive

MASS SCREENING of newborn infants identifies patients with ASS,

ASL, and arginase deficiencies.
CARBAMYL PHOSPHATE SYNTHETASE AND
N-ACETYLGLUTAMATE SYNTHETASE
DEFICIENCIES
 produce similar clinical and biochemical
manifestations.
 presents within first few days or even hours of
life with signs and symptoms of
hyperammonemia.
 Increased intracranial pressure is frequent.
 Late forms (as late as 32 yr of age) : acute bout
of hyperammonemia (lethargy, headache,
seizures, psychosis) in a apparently normal
indivdual, may lead to coma and death .
ORNITHINE TRANSCARBAMYLASE
DEFICIENCY
 X-linked partially dominant disorder.
 MC form of all the urea cycle disorders, comprising
approximately 40% of cases.
 Clinical manifestations in a male newborn
are usually those of severe hyperammonemia
occurring in the first few days of life.
 Milder forms of the condition are commonly seen
in heterozygous females and in some affected males.
 Mild forms characteristically have episodic
manifestations which are separated by periods of
wellness.
High protein diet & catab. States
act as Triggering factor
CONTD....
 This form should be differentiated from
lysinuric protein intolerance which may
show some features of OTC deficiency, but the
former can be differentiated by increased
urinary excretion of lysine, ornithine, and
arginine and elevated blood concentrations of
citrulline.
 Confirmatory diagnosis by gene sequencing
( liver biopsy indicated )
Contd...
 Prenatal diagnosis is by analysis of DNA in
amniocytes or chorionic villous samples
 Detection of asymptomatic female carriers:

•ORAL PROTEIN LOAD TEST

•ALLOPURINOL LOADING TEST

Family history: unexplained deaths in male

newborns in the maternal lineage.
Liver transplantation is a successful t/t performed
during infancy
 ARGININOSUCCINATE SYNTHETASE
(ASS)
DEFICIENCY (CITRULLINEMIA

Citrullinemia type 1 Citrullinemia type 2

( classical ) Mitochondrial transport
ASS deficiency protein ( citrin ) deficiency

Neonatal Adult Form

Severe or Intrahepatic ( 20-40
neonatal Subacute Cholestasis years)
form or mild
(mc) form
ARGININOSUCCINATE LYASE
DEFICIENCY
(ARGININOSUCCINIC ACIDURIA)
NEONATAL FORM
Severe hyperammonemia develop in the first few days of life and
mortality is high

SUBACUTE OR LATE FORM

intellectual disability,
failure to thrive
hepatomegaly.
dry and brittle hair “trichorrhexis nodosa”.
 ARGINASE DEFICIENCY
(HYPERARGININEMIA)
 Two genetically distinct arginases in
humans.
 Cytosolic (ARG1)- found in the liver
and erythrocytes
 Mitochondrial (ARG2)- found in
kidney and brain.
 CF : A progressive spastic
diplegia with scissoring of the
lower extremities, choreoathetotic
movements, loss of developmental
milestones in a previously normal
infant.Intellectual disability is
progressive; seizures are common, but
episodes of severe hyperammonemia
are uncommon.
 Gyrate Atrophy of the Retina and
Choroid
 Caused by a deficiency of
ornithine 5-aminotransferase
 CF:
 limited to the eyes and include
night blindness, myopia, loss of
peripheral vision, and posterior
subcapsular cataracts.
 Start between 5 and 10 yr of
age and progress to complete
blindness by the 4th decade of
life.
 Atrophic lesions in the retina
resemble cerebral gyri.
HYPERAMMONEMIA-HYPERORNITHINEMIA
HOMOCITRULLINEMIA
SYNDROME

 Defect in the transport system of ornithine

from the cytosol into the mitochondria.
 Acute episodes of hyperammonemia f/b
progressive neurologic signs, such as lower limb
weakness, increased deep tendon reflexes,
spasticity, clonus, seizures and varying degrees
of psychomotor retardation may develop.
 ornithine, homocitrulline, ammonia
TRANSIENT HYPERAMMONEMIA
OF THE NEWBORN
 Usually occur in preterm with RDS.
 Plasma ammonia as high as 4,000 μmole/L.
 With treatment recovery is complete without
any sequele.