PEDBASE.org - The Pediatric Database - Detailed information of ARGININOSUCCINIC ACIDURIA

ARGININOSUCCINIC ACIDURIA

DEFINITION:

A disorder of the urea cycle characterized by the accumulation of ammonia resulting in an altered level of consciousness and/or persistent vomiting.

EPIDEMIOLOGY:

incidence: 1/70,000
age of onset:
- newborn
risk factors:
- familial - autosomal recessive
  - chrom.#: 7cen-q11.2
  - gene: argininosuccinate lyase (ASL)
- M = F

PATHOGENESIS:

1. Background

ASL is the fourth enzyme in the urea cycle
catalyzes the conversion of argininosuccinic acid (ASA) to arginine + fumeric acid

2. Genetic Defect

genetic defect -> deficiency of ASL activity -> accumulation of ammonia and argininosuccinic acid
ammonia is a neurotoxin affecting the CNS
ASA accumulates in the urine, blood, and CSF
there may be both complete and partial deficiencies of ASL activity, the latter characterized by recurrent episodes trig-gered by sudden protein loads or intercurrent infections

CLINICAL FEATURES:

1. Complete ASL Deficiency

usually normal at birth with onset of features 24-72 hours after feeding (protein load) commences:

1. Neurological Manifestations

lethargy -> coma
infantile hypotonia
neonatal seizures

2. Gastrointestinal Manifestations

persistent vomiting (+/- dehydration)
poor feeding
hepatomegaly

3. Others

hyperventilation (due to respiratory alkalosis)
hypothermia

2. Partial ASL Deficiency

onset in childhood characterized by recurrent episodes of:

1. Neurological Manifestations

lethargy -> coma
acute ataxia
hyperactivity

2. Gastrointestinal Manifestations

persistent vomiting (+/- dehydration)
hepatomegaly

other manifestations may include:
- friable hair (trichorrhexis nodosa)
- progressive mental retardation
- seizures
- failure to thrive

INVESTIGATIONS:

1. Serum

venous hyperammonemia (>500 uM [complete]; >100 uM [partial])
normal anion gap; respiratory alkalosis
amino acids
- citrulline between 100-300 uM
- elevated argininosuccinic acid, low arginine
- elevated glutamine, alanine, and lysine

2. Urine

elevated ASA

3. Diagnosis

deficiency of ASL activity in liver, erythrocytes, and cultured skin fibroblasts
prenatal
- deficiency of ASL activity in cultured chorionic villi or amniocytes

MANAGEMENT:

1. Supportive

a chronic disease with a life-long risk of episodes of hyper-ammonemia and thus must:
- provide long-term follow-up
- moniter ammonia levels
- coordinate a multidisciplinary approach:
  - Paediatrics, Neurology, Dietary, Genetics, Metabolics
- plan for acute episodes

2. Goals of Therapy

asymptomatic control of and avoidance of acute episodes
not curative

3. Diet

1. Protein Restriction

1. Exogenous

IV D10W (during an acute episode)
Mead Johnson 80056 Formula
- non-protein containing formula
- supplement with arginine

2. Endogenous

High Caloric Diet
- use to avoid or during an acute episode to mini-mize tissue catabolism and thus the breakdown of endogenous protein

4. Convert Nitrogen to an Excretable Compound

1. Sodium Benzoate

conjugate with glycine and excreted as hippuric acid

2. Sodium Phenylacetate

conjugate with glutamine and excreted as phenylacetyl-glutamine

3. Dialysis

Peritoneal or Hemodialysis

5. Prognosis

100% mortality if untreated
there is a direct correlation between the duration of hyper-ammonemic coma and morbidity (mental retardation, developmental delays, cortical atrophy)
good prognosis if disorder is treated prospectively from birth

Pediatric Database - ARGININOSUCCINIC ACIDURIA

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