Amino Acid Disorders Flashcards
What are Physiological Fucntions of Amino Acids?
Building blocks of proteins
Intermediates in metabolism
Key compounds e.g. Neurotransmitters, haem
What are clinical manifestation of Inborn Errors of Metabolsim?
- Toxic accumulation of substrates before the blocks or of intermediates from alternative metabolic pathways
- Defects in energy production or utilisation caused by a deficiency of products after the block
What are causes of Toxic Accumulation associated Inborn Errors of metabolism?
- Disorder of protein metabolism (e.g amino acidopathies, organic acidopathies, urea cycle defects)
- Disorders of carbohydrate intolerance
- Lysosomal storage disorders
What are causes of disorders of energy production, utilization associated Inborn Errors of metabolism?
- Fatty acid oxidation defects
- Disorders of carbohydrate utilization, production (i.e. Glycogen storage disorders, disorders of gluconeogenesis and glycogenolysis)
- Mitochondrial disorders
What are features of Amino Acid Disorders?
- Clinically and biochemically heterogeneous
- Age of onset variable
- Characterised by Pathological accumulation of physiological metabolites and Presence of non-physiological metabolites
What are types of Primary Amino Acids Disorders?
- Phenylketonuria
- Tyrosinaemia (I/II/III)
- Maple syrup urine disease
- Homocystinuria
- Non-ketotic hyperglycinaemia
- Hyperprolinaemia (I/II)
- Sulphite oxidase deficiency
- Urea cycle disorders (OTC deficiency, CPS deficiency, Citrullinaemia, Argininosuccinic aciduria, Argininaemia, NAG deficiency)
- Hyperornithinaemia - hyperammonaemia homocitrullinaemia (HHH)
What are some examples of Primary Renal Amino Acid disorders?
Cystinuria
- Cystine, Ornithine, Arginine, Lysine
Hartnup disease
- Neutral amino aciduria
Lysinuric protein intolerance
- Lysine, Ornithine, Arginine
Iminoglycinuria
- Proline,hydroxyproline,glycine
What are secondary causes of Aminoacidopathies?
Generalised aminoaciduria
- Fanconi syndrome
- Galactosaemia
- Tyrosinaemia type I
- Cystinosis
Increases in urine/plasma
- Glycine – immaturity, anticonvulsants
Increases in plasma
- Alanine: Lactic acidosis
- Glutamine: Hyperammonaemia
- Methoinine/Tyrosine: Liver diseases
- Isoleucine/Leucine/Valine: Ketosis
What is Phenylketonuria?
- Autosomal recessive leading deficiency of phenylalanine hydroxylase
If untreated, develop
- Severe mental retardation
- Microcephaly
- Possibly epilepsy;
- Older patients have behavioural problems,
- Some suffer from psychiatric illness
- Movement disorders with extrapyramidal signs
How is Phenyketonuria screened?
- Increased blood phenylalanine levels
- NHS Newborn Bloodspot Screening Programme
- Phenylketone detected in the urines
What is the management of Phenylketonuria?
- Phe restricted diet
- Requiring dietetic and laboratory monitoring
- Recommendation: Clinical referral by 14 days of age and dietary treatment initiated by 21 days of age
- UK guidelines: Phe 360μmol/L up to 5 yrs, 480μmol/L 5-10 yr; <700μmol/L thereafter
How is Phenylketonuria monitored through life?
- Maternal PKU syndrome: fetal anomalies including cardiac and skeletal defect, microcephaly, developmental delay and low birthweight if exposed to high level of phe in-utero
- Require strict dietary control pre-conception
What is Tyrosinaemia Type 1?
- Deficiency of enzyme fumarylacetoacetate hydrolase leading to accumulation of toxic compound succinylacetone
- Presents during infancy or during first year
What are symptoms of Tyrosinaemia Type 1?
- Liver failure: Jaundice, Increased transaminases, Pronounced coagulopathy (increased prothrombin time + thrombocytopenia), Alpha fetoprotein; Renal tubulopathy – hypophosphataemic ricket
- Porphyria like neurologic crisis due to SuAc inhibiting porphobilinogen synthase in erythrocytes
What are complications of Tyrosinaemia Type 1?
Hepatic carcinoma
How is the diagnosis of Tyrosinaemia Type 1 made?
Biochemical and Haematological
Specialised metabolic tests:
- Increased tyrosine (+ methionine) in plasma amino acids
- Succinylacetone (pathognomonic!) on urine organic acids or on DBS
Mutation analysis: Rarely required for diagnosis but useful for prenatal testing
How is Tyrosinaemia Type 1 treated?
- NTBC (2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione)
- Inhibitionof4-hydroxyphenylpyruvatedehydrogenase
- Liver transplant
What are Urea Cycle Defects?
- Enzyme defects in this pathway all contribute to hyperammonaemia
- Causes Orotic aciduria
- All autosomal recessive except for OTC which is X-linked
What is the Urea Cycle?
- Urea cycle occurs primarily in the liver for removal of excess nitrogen
- Converts toxic ammonia and other nitrogenous compound into urea (non-toxic) which is excreted in urine
What are features of Ornithine transcarbamylase deficiency?
- X-linked
- Present first few days of life with lethargy, anorexia, respiratory alkalosis, vomiting, irritability, seizure
- Male hemizygotes usually present in infancy, neonatal presentation is catastrophic
- Female carriers often asymptomatic however may have symptoms in childhood e.g. after excessive protein intake, or metabolic stress e.g. fasting or severe illness; severe hyperammonaemia causing brain damage
- Patient with this condition may appear to be faddy eaters
