Tegay - Urea Cycle Disorders

Urea Cycle

• 2 major functions

  • Removal of nitrogenous waste via incorporation of Ammonia into Urea

  • Synthesis of amino acids

    • Arginine, ornithine, citrulline

• Primarily occurs in liver in heptocytes

• All autosomal recessive except OTC

  • OTC deficiency is X-linked recessive

Ammonia

• Product of metabolism of proteins / amino acids

  • Adult <35 mmol / L

  • Neonates <100 mmol / L

• Hyperammonemia

  • Neuronal excitation = cell death and cerebral edema

    • Through increasing extracellular glutamate and overactivation of NMDA receptors

  • Seizures, coma, death

  • Brain atrophy, cognitive impairment

Urea Cycle Disorder Symptoms

• Early

  • 48 hours

    • Decreased feeding / vomitting

    • Lethargy

    • Tachypnea (Rapid breathing)

    • Seizure activity

  • Followed by

    • Encephalopathy / Coma

    • Respiratory Failure

    • Cerebral Edema and Death

• Late

  • Variable onset and severity

    • Headache, vomitting, ataxia and incoordination

    • Psychiatric / Behavioral changes

      • Delirium, psychosis, autism, ADD / ADHD, manic

    • Cognitive Impairment

      • DD / MR, Early dementia

  • Often forecased by

    • Feve, illness, trauma, fasting, post-partum, protein load

  • Still at risk for Hyperammonemic Encephalopathy

    • Even if previously asymptomatic, can be fatal

Etiology of Hyperammonemia

• Liver diseases

  • Non-genetic

    • Infection, toxin, trauma, ischemia

  • Genetic other than UCD

    • Tyrosinemia Type I

    • Organic Acidemias

    • Mitochondrial Disorders

Ornithine Transcarbamylase (OTC) Deficiency

• Most COMMON UCD

• X-linked Recessive

  • Ornithine Transcarbamylase (OTC) gene mutation

  • 3 - 4% germline mutation

• Symptoms

  • High Orotic Acid and Ammonia, low Citrulline / ASS / ARG

  • Classic

    • Asymptomatic at birth

    • 2 - 3 days old

      • Poor feeding, vomiting, lethargy, hyperventilation, seizure

    • 1-week-old

      • Lethal Hyperammonemic Encephalopathy

        • Cerebral edema, hypothermia, coma, respiratory failure, death

  • Mild

    • Episodic Hyperammonemic Symptoms

      • Mild to severe / life-threatening

    • Chronic symptoms

      • Protein avoidance, headaches, neuropsychiatric difficulty

• Diagnosed via low Citrulline, not on some newborn screenings

  • Ammonia level tests

  • Blood gas/ metabolic profile / lactic acid level tests to exclude metabolic acidosis and high anion gap

  • Plasma amino acid profile and urine organic acids

    • Typically glutamine / alanine high and citrulline / ASA / arginine low

    • Increased orotic acid on uOA and or elevated after an allopurinol load

  • Confirmed via Enzyme activity analysis which requires liver biopsy

    • Not useful for preimplantation / prenatal

  • OTC gene sequencing with 60% - 90% detection rate

• Treatment

  • Variable outcomes if treated, neuralcognitive development depends on initial hyperammonemic encephalopathy duration

  • ID / ADHD, executive deficits, brain atrophy

  • Acute treatment

    • Hemodialysis

    • Protein cessation

    • IV glucose and lipids to prevent catabolism and IV arginine

    • IV ammonia scavengers (eg. Na + Benzoate and Na + Phenylbutyrate)

  • Chronic treatment

    • Protein restriction and essential amino acid metabolic formula

    • Oral citrulline (or arginine) and ammonia scavengers

      • Na benzoate, Na phenylbuterate (Ravicti)

    • Avoid Valproic acid, fasting, fever, steroids, protein load

    • Liver transplant

Citrullinemia (ASS1) Deficiency

• Autosomal recessive

  • Arginosuccinic Acid Synthetase 1 (ASS1) gene

• Symptoms

  • High citrulline, ammonia, orotic acid

  • Low levels argininosuccinate and arginine

  • Classic

    • Asymptomatic at birth

    • 4 - 7 days

      • Progressive Hypermammonemic Encephalopathy

        • Poor feeding, vomiting, lethargy, hyperventiliation, seizures

    • 1 - 2 weeks

      • Lethal hyperammonemic Encephalopathy

        • Cerebral edema, hypothermia, coma, respiratory failure, death

  • Late-onset

    • Episodic Hyperammonemic Symptoms

      • Mild - severe / life-threatening

    • Chronic Symptoms

      • Protein avoidance, recurrent headaches, neuropsychiatric difficulty

• Diagnosed via high citrulline

  • Ammonia level test

  • Blood gas/ metabolic profile / lactic acid level tests to exclude other acidosis and other IEM

  • Plasma amino acid profile and urine organic acids where citrulline/glutamine/alanine very high, ASA/arginine, ornithine low

    • Increased orotic acid on uOA

  • ASS1 Enzyme activity in fibroblasts, liver, CVS or amniocytes, useful for prenatal / preimplanation genetics

  • ASS1 genotyping with deletion / duplication analysis has 96% detection

• Treatment

  • Variable outcomes if treated, neuralcognitive development depends on initial hyperammonemic encephalopathy severity

  • ID / ADHD, executive deficits, brain atrophy

  • Acute treatment

    • Hemodialysis / hemofiltration

    • Protein cessation

    • IV glucose and lipids to prevent catabolism and IV arginine

    • IV ammonia scavengers (eg. Na + Benzoate and Na + Phenylbutyrate)

  • Chronic treatment

    • Protein restriction and essential amino acid metabolic formula

    • Oral arginine NOT citrulline and ammonia scavengers

      • Na benzoate, Na phenylbuterate (Ravicti)

    • Avoid Valproic acid, fasting, fever, steroids, protein load

    • Liver transplant

Arginosuccinate Lyase (ASL) Deficiency

• Autosomal recessive

  • Arginosuccinate Lyase (ASL) gene

• Symptoms

  • High Citrulline and Arginosuccinate

  • Low Arginine, Hyperammonemia, and mild to NO Orotic Acid

  • Brittle hair and hypertension

  • At birth asymptomatic

  • Classic

    • 4 - 7 days

      • Progressive Hypermammonemic Encephalopathy

        • Poor feeding, vomiting, lethargy, hyperventiliation, seizures

    • 1 - 2 weeks

      • Lethal hyperammonemic Encephalopathy

        • Cerebral edema, hypothermia, coma, respiratory failure, death

  • Late-onset

    • Episodic Hyperammonemic Symptoms

      • Mild - severe / life-threatening

    • Chronic Symptoms

      • Protein avoidance, recurrent headaches, neuropsychiatric difficulty

• Diagnosed via high citrulline

  • Ammonia level test

  • Blood gas/ metabolic profile / lactic acid level tests to exclude other acidosis and other IEM

  • Plasma amino acid profile and urine organic acids where citrulline/ASA, glutamine, alanine high

  • Arginine / ornithine low

  • ASL Enzyme activity in fibroblasts, liver, RBC, CV, or amniocyte

    • Useful in prenatal / preimplanation

  • ASL genotyping with deletion / duplication analysis has 90% detection

• Treatment

  • Most have some degree of neurcognitive deficiency, ADHD, seizures, eventual liver failure

  • Acute treatment

    • Hemodialysis / hemofiltration

    • Protein cessation

    • IV glucose and lipids to prevent catabolism and IV arginine

    • IV ammonia scavengers (eg. Na + Benzoate and Na + Phenylbutyrate)

  • Chronic treatment

    • Protein restriction and essential amino acid metabolic formula

    • Oral arginine NOT citrulline and ammonia scavengers

      • Na benzoate, Na phenylbuterate (Ravicti)

    • Avoid Valproic acid, fasting, fever, steroids, protein load

    • Liver transplant

Arginase (ARG) Deficiency

• Autosomal recessive

  • Arginase (ARG1) gene

• Symptoms

  • Increased arginine, mild intermittent hyperammonemia, occasional mild orotic acid elevations

  • Asymptomatic at birth

  • After 1 - 3 years

    • Growth slows

    • Motor and cognitive development slows and regression occurs

    • Spasticity and seizures develop

  • Adulthood

    • Severe MR, microcephaly

    • Short stature

    • Severe spasticity and joint contractures

    • Lack of ambulation, bowel and bladders control

    • Low risk of hyperammonemic encephalopathy

• Diagnosed via elevated arginine

  • Ammonia level test

  • Blood gas/ metabolic profile / lactic acid level tests to exclude other acidosis and other IEM

  • Plasma amino acid profile and urine organic acids where arginine high, orotic acid minimally elevated or may be normal

  • ARG1 Enzyme activity in fetal red blood cells

    • Useful in prenatal / preimplanation but need umbilical blood sampling

  • ARG1 genotyping with deletion / duplication analysis

• Treatment

  • Improved but still increased risk for ID, short stature, join contactures, etc

  • Not typically encephalopathic

  • Chronic treatment

    • Protein restriction and essential amino acid metabolic formula

    • Oral ammonia scavengers NO oral arginine or citrulline (eg. Na + Benzoate and Na + Phenylbutyrate)

    • Avoid valproic acid, fasting, fever, steroids, protein loud

    • Liver transplant if neuro intact but poor response to treatment

NAGS and CPS1 Deficiency

• Preo-Orotic UCD, rarest

• Both Autosomal Recessive

  • N-AcetylGlutamate Synthestase (NAGS)

  • Carbamoyl Phosphate Synthetase 1 (CPS1)

  • NAGS and CPS1 genotyping and deletion / duplication analysis

• Symptoms

  • High ammonia, glutamine, alanine

  • Low citrulline, ASA, arginine

  • NO orotic acid

  • Symptoms indistingusihable from OTC/ASS1/ASL

• Diagnosed via

  • High ammonia, glutamine, alanine

  • Low citrulline, ASA, arginine

  • NO orotic acid

  • Confirmed via Enzyme Activity analysis via liver biopsy

• Treatment

  • Outcome varies, no enzyme / metabolite testing is useful

    • Acute treatment

      • Hemodialysis / hemofiltration

      • Protein cessation

      • IV glucose and lipids to prevent catabolism and IV arginine

      • IV ammonia scavengers (eg. Na + Benzoate and Na + Phenylbutyrate)

    • Chronic treatment

      • Protein restriction and essential amino acid metabolic formula

      • Oral arginine or citrulline and ammonia scavengers

        • Na benzoate, Na phenylbuterate (Ravicti)

      • Avoid Valproic acid, fasting, fever, steroids, protein load

      • Liver transplant

    • Carglumic acid for NAGS deficiency, synthetic N-acetylglutamate