Disorders of Amino Acid Metabolism

Key Concepts:

Terms in this set (32)

Phenotypic Heterogeneity
different patients with same disorder expressing the trait differently
Biochemical Heterogeneity
different patients with blocks in same pathway with different accumulation of metabolites
Molecular Heterogeneity
different patients with different mutations in same gene
Locus/Genetic Heterogeneity
different patients with different mutations in different genes
Hyperammonemia Causes
urea cycle defects, reye syndrome, transient hyperammonemia of newborn, liver disease
Carbamoyl Phosphate Synthetase I (CPSI) Deficiency Symptoms and Diagnosis
• Lesion: ammonia can't form carbamoyl phosphate
• Symptoms: Vomiting, Seizures, Death
• Diagnosis: low citrulline, no orotic acid
Ornithine Transcarbamylase (OTC) deficiency Symptoms and Diagnosis
• Lesion: carbamyl phosphate can't form citrulline
• Symptoms: Vomiting, Lethargy, Seizures, Coma, intellectual disability
• Diagnosis: Increased orotic acid, increased glutamine, decreased citrulline
• Inheritance: X-linked so males have severe neonatal ammonia intoxication and females can be asymptomatic
Citrullinemia/Argininosuccinate Synthetase (AS) Deficiency Symptoms and Diagnosis
• Lesion: citrulline cant form argininosuccinate
• Symptoms: vomiting, lethargy, seizures, coma, death, intellectual disability
• Diagnosis: Increased citrulline, decreased argininosuccinate
Argininosuccinatic aciduria/Argininosuccinate Lyase (AL) deficiency Symptoms and Diagnosis
• Lesion: argininosuccinate can't form arginine and fumarate
• Symptoms: vomiting, lethargy, seizures, coma, intellectual disability, brittle hair
• Diagnosis: increased argininosuccinic acid, increased citrulline, decreased arginine
Arginemia/Arginase deficiency Symptoms and Diagnosis
• Lesion: arginine can't form ornithine
• Symptoms: Vomiting, irritability, movement disorder
• Diagnosis: Increased arginine
Urea Cycle Defect Treatment
Protein Restricted Diet, Na Benzoate (Nitrogen Scavenger), arginine, liver transplant, dialysis, IV glucose
Phenylketonuria (PKU) Forms
-Deficiency in Phenylalanine Hydroxylase
-Deficiency in Tetrahydrobiopterin (BH4) which is cofactor for phenylalanine hydroxylase (1-2% of hyperphenylalaninemia)
-Deficiency in dihydrobiopterin reductase (quinonoid/BH2 to BH4/tetrohydrobiopterin)
-BH4 also used for tyrosine hydroxylase (tyrosine to epinephrine) and tryptophan hydroxylase (tryptophan to serotonin)
PKU Symptoms and Inheritance
• Symptoms: intellectual disability, mousy odor, light pigmentation, abnormal gait, autistic behavior, eczema, seizure
• Inheritance: Autosomal Recessive
PKU Diagnosis
Diagnosis: hyperphenylalaninemia, liver enzymes and newborn screening
PKU Treatment
Treatment: low phenylalanine diet, special food/formula, Biopterin, replacement of deficient product (tyrosine)
Maternal PKU Syndrome
-infants have symptoms as result of in utero exposure to mother's elevated Phe level
-Symptoms: microcephaly, retardation, heart disease, dysmorphism, time/dose dependent
Causes of Hypertyrosinemia
transient tyrosinemia of newborn, liver disease, inborn errors of tyrosine catabolism
Hepatorenal Tyrosinemia (Type I)
-Lesion: error in fumarylacetaoacetate hydrolase
-Inheritance: Autosomal Recessive
Hepatorenal Tyrosinemia (Type I) Symptoms
Symptoms: severe liver disease in young, growth failure in old, porphyria like symptoms
Hepatorenal Tyrosinemia (Type I) Diagnosis
Diagnosis: elevated methionine, tyrosine and phenylalanine, elevated succinylacetone
Hepatorenal Tyrosinemia (Type I) Treatment
Treatment: Nitrisinone (NTBC) inhibits pHPPD enzyme to make it like Type III hypertyrosinemia which is benign since there is no elevated succinylacetone accumulation
Oculocutaneous Tyrosinemia (Type II)
Lesion: error in transaminase
pHPPD deficiency (Type III)
error in pHPPD, clinically benign
Nonketotic Hyperglycinemia
-Lesion: mutation in gene encoding P protein component (out of P, T, H, L) account for most cases of defect in glycine cleavage system (glycine to CO2 and NH3)
Nonketotic Hyperglycinemia Symptoms
Symptoms: lethargy, seizures, apena, hypotonia, profound, intellectual disability
Nonketotic Hyperglycinemia Diagnosis
Diagnosis: increased glycine in CSF, no ketones
Nonketotic Hyperglycinemia Treatment
None
Classical Homocystinuria
-Lesion: cystathionine B-synthase deficiency (methionine/homocysteine to cystathionine to Cysteine)
Classical Homocystinuria Symptoms
Symptoms: Marfan like phenotype, osteoporosis, ectopia lentis, developmental delay
Classical Homocystinuria Diagnosis
Diagnosis: increased methionine, increased homocysteine
Classical Homocystinuria Treatment
Treatment: Betaine and Pyridoxine (B6), low methionine diet
-Betaine: forces homocysteine to reform methionine
-Pyridoxine (B6): cofactor for cystathionine B-synthase
Diagnosis of Inborn Errors of Amino Acids
Amino Acid Analysis: High Pressure Liquid Chromatography (HPLC) where ninhydrin reacts with amino acid to create Ruhemann's Purple which can be read for intensity to indicate amino acid in sample
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