Congenital hyperammonemia in children

Introduction to congenital hyperammonemia in children Congenital hyperammonemia is a disease in which the congenital metabolic abnormality of urea synthesis causes an increase in blood ammonia and causes damage to the nervous system. The principle of treatment is to correct the abnormal metabolism of children, but at the same time should ensure the nutritional needs of their growth and development. basic knowledge The proportion of illness: 0.0003% (the incidence rate of newborns is 0.0003%) Susceptible people: children Mode of infection: non-infectious Complications: respiratory alkalosis, coma

Causes of congenital hyperammonemia in children

Urea cycle (25%):

The ammonia produced by the decomposition of amino acids in the body and the ammonia absorbed by the intestinal tract are the normal components of body fluids, but the excess ammonia is neurotoxic. The main detoxification method of ammonia in the human body is to synthesize ammonia into the liver and then discharge it with urine. The metabolic pathway for the synthesis of urea is called the urea cycle. Through the urea cycle and other detoxification methods, the blood ammonia is maintained at a normal level, generally 27-82 mol/L (50-130 g/dl), and the urea cycle must have 6 The participation of enzymes:

(1) Formation of carbamyl phosphate: First, in the mitochondria, ammonia and CO2 form carbamyl groups under the action of carbamyl phosphate synthetase (CPS) and allosteric activator N-acetylglutamate. Phosphoric acid.

(2) Synthesis of citrulline: Carbamoyl phosphate is condensed with ornithine to form citrulline under the action of ornithine transcarbamoylase (OTC), and then enters the cytoplasm through the mitochondrial membrane.

(3) Formation of arginyl succinic acid: In the cytoplasm, citrulline and aspartate form arginyl succinic acid via the action of argininosuccinate synthetase (AS).

(4) Decomposed into arginine and fumaric acid: Arginyl succinate is decomposed into arginine and fumaric acid by argininosuccinase (AL).

(5) decomposition into ornithine and non-toxic urea: then, arginase (ARG) decomposes arginine into ornithine and non-toxic urea, the former is converted to citrulline, the latter by Kidney discharge.

(6) N-acetylglutamate synthetase (NAGS): N-acetylglutamate (NAG) required for urea cycle is derived from glutamic acid and acetyl-CoA via N-acetylglutamate Synthetic enzyme (N-acetylglutamate synthetase, NAGS) catalyzed.

Enzyme deficiency (10%):

When one of the enzymes in the cycle has congenital defects, the process of synthesizing urea from ammonia is disordered, and free ammonia accumulates in the body to form hyperammonemia, which is clinically characterized as severe brain dysfunction.

Causes

The enzymes in the urea cycle have genetic defects, which cause urea synthesis disorders and increased blood ammonia.

Congenital hyperammonemia prevention in children

1. Heterozygous detection: can be based on family analysis, protein load test, genetic analysis or enzyme activity check.

2. Prenatal diagnosis: Genetic analysis of amniotic cells or villi can early diagnose OTC deficiency, measure the enzyme activity of amniotic cells or villi, diagnose AL deficiency and AS deficiency; measure the special amino acid level in amniotic fluid to help diagnose.

According to the above, genetic counseling can be done and the pregnancy can be terminated if necessary.

Congenital hyperammonemia complications in children Complications, respiratory alkalosis, coma

Respiratory alkalosis, apnea, convulsions, often coma, progressive brain stem function, increased intracranial pressure, secondary infection, ataxia, behavioral abnormalities, dysplasia, mental retardation.

Symptoms of Congenital Hyperammonemia in Children Common Symptoms Respiratory Alkalosis Antifeeding Muscle Tension Hypertonic Muscle Tension Reduces Anorexia Ataxia Distinct Ambition Increased Intracranial Pressure Attack Behavior Drowsiness

The clinical manifestations of urea cycle disorders are mainly the toxicity of hyperammonemia, so the symptoms overlap with each other. The severity of clinical symptoms is parallel with the degree of enzyme deficiency. The symptoms of complete enzyme deficiency are serious. Early onset, fulminant hyperammonemia in neonatal period, normal at birth, endogenous ammonia after lactation and endogenous ammonia decomposed in the body due to lack of enzymes, can not synthesize urea, so high ammonia Hemorrhage, starting sleepiness within a few days after birth, refusal to breastfeed, vomiting, with increased blood ammonia accumulation, excessive ventilation, respiratory alkalosis, hypothermia, apnea, low or increased muscle tone, may have seizures , often caused by coma, progressive brain stem function, increased intracranial pressure, and more death in infancy.

When partial enzyme deficiency occurs, it usually starts several months after birth or later. The symptoms of hyperammonemia in childhood are mild, appear intermittent, are intolerant to protein, and eat more protein or When the infection occurs, blood ammonia is obviously elevated, paroxysmal acute vomiting, anorexia, headache, ataxia, drowsiness, confusion, even coma, some convulsions, abnormal behavior, irritability, hyperactivity or Aggressive behavior, chronic course, may have dysplasia, progressive degenerative symptoms, mental retardation, succino-succinic aciduria has special nodular freckle (trichorrhexis nodosa).

Examination of congenital hyperammonemia in children

1. Increased blood ammonia: The blood ammonia is usually 234.8 ~ 587mol / L (400 ~ 1000g / dl), the normal value is 27 ~ 82mol / L (46 ~ 139g / dl), hyperammonemia coma, blood Ammonia can be as high as 352.2 to 1526.2 mol/L (600 to 2600 g/dl).

2. Amino acid quantitative analysis: Check blood and urine amino acids to determine whether there is any increase in specificity, special attention should be paid to glutamate, glutamine, alanine, citrulline, arginine and arginyl amber Quantitative analysis to distinguish enzyme defects in the urea cycle.

3. Protein load test: When the urea cycle is disordered, it is intolerant to protein food. It can be used for protein load test for clinical diagnosis and heterozygous detection. Naturally eat breakfast, give protein 1g/kg, observe blood ammonia and blood, urine. Changes in amino acids and whey acid were measured once every 2 hours for 3 times.

4. Blood glucose measurement, blood gas analysis, organic acid in urine: Respiratory alkalosis often occurs in urea cycle disorders, organic aciduria is also often associated with hyperammonemia, but unlike urea cycle disease, due to lower blood sugar, metabolism Acidic acidosis, the discharge of specific organic acids in the urine.

5. Determination of enzyme activity: Hyperammonemia caused by lack of carbamyl phosphate synthase (CPS) activity requires percutaneous liver biopsy to measure CPS activity, and diagnosis of ornithine carbamoyltransferase (OTC) deficiency is also required. To measure the OTC activity of hepatocytes, the diagnosis of citrullinemia should be determined whether the activity of argininosuccinate synthetase (AS) is lacking. At this time, the enzyme of hepatocytes or skin fibroblasts can be used, and when aminosuccinic aciduria is used, It can measure the activity of spermatozoa lyase (AL) in hepatocytes, peripheral red blood cells and skin fibroblasts. When suspected of arginine, the activity of liver, red blood cells and leukocyte arginase should be measured.

6. Genetic analysis: OTC deficiency and CPS deficiency can be diagnosed by molecular genetic methods.

7. Prenatal diagnosis: Genetic analysis of amniotic fluid cells or villi can early diagnose OTC deficiency, measure the enzyme activity of amniotic cells or villi, diagnose AL deficiency and AS deficiency; measure the special amino acid level in amniotic fluid to help diagnose.

8. Heterozygous detection: can be based on family analysis, protein load test, genetic analysis or enzyme activity check.

Electroencephalogram examination has abnormal brain waves. Brain CT examination is performed when conditions are met. Other routine examinations include B-ultrasound and X-ray examination.

Diagnosis and diagnosis of congenital hyperammonemia in children

Clinical manifesters should first check blood ammonia and blood and urine amino acid quantitation to diagnose hyperammonemia, and then carry out other biochemical tests to identify the cause, if necessary, need to do enzyme activity determination or DNA analysis to confirm the diagnosis.

Differential diagnosis

1. Neonatal transient hyperammonemia: mainly found in premature infants, patients with extremely high blood ammonia, early symptoms, severe neurological inhibition symptoms, difficulty breathing, such as early hemodialysis, can be within 5 days Symptoms are relieved and the prognosis is good. Asymptomatic hyperammonemia can also be seen in low birth weight infants for unknown reasons.

2. Organic acidurias: often accompanied by hyperammonemia, which is characterized by normal blood amino acid quantitation, low uric acid, high specific organic acids in the urine, low blood sugar, and increased blood glycine. Metabolic acidosis.

3. Lysinuric protein intolerance: accompanied by hyperammonemia, due to the transport defects of arginine, lysine and ornithine in the renal tubules and intestinal epithelium, the above in the blood The increase of each amino acid affects the metabolic function of the urea cycle.

4. Hyperammonemia - hyperornithemia - hyperammonemia hyperonithinemia homocitrullinuria: HHH syndrome, a disorder of ornithine transport into the mitochondria.

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