Inherited metabolic disorders Flashcards
Common characteristics of inherited metabolic disorders
- Often under-diagnosed
- Normal at birth
- Nature of mutation(varies)
- Symptomatic later
- Exacerbated by diet or illness
- Mimics sepsis, without known risk factors
Type of inheritance for most inherited metabolic disorders
- Autosomal recessive
Management principles of inherited metabolic disorders
- Special diets (excluded or enriched)
- Peritoneal or haemodialysis
- Administer deficient metabolite
- Administer deficient enzyme
- Administer cofactor or coenzyme
- Activate alternate pathways
- Bone marrow or liver transplant
- Prenatal screening for future pregnancies
Amino acids - disorders
Transport Disorders -
Dibasic Amino acids (Cystinuria)
Neutral Amino acids (Hartnup Disease)
Metabolism -
Phenylalanine / Tyrosine
Urea Cycle Defects -
Cystinuria
- Defective cystine transporter
- Cystine in urine –> crystallises to form stones
Management of cystinuria
- Symptomatic treatment
- Prevent stone formation - water intake, alkalisation
- Lithotripsy, chelation
Phenylketonuria
Normal at birth Gradually Neuropsychological problems Micreocephaly, Low IQ Seizures, Tremors Impaired myelination Blonde hair Musty odour
Phenylketonuria genetics
- Autosomal recessive disorder
- Characterised by mutations in the gene for the hepatic enzyme phenylalanine hydroxylase(PAH)
Phenylketonuria pathophysiology
When Phe cannot be metabolized by the body, a typical diet that would be healthy for people without PKU causes abnormally high levels of Phe to accumulate in the blood, which is toxic to the brain.
If left untreated, complications of PKU include severe intellectual disability, brain function abnormalities, microcephaly, mood disorders, irregular motor functioning, and behavioral problems such as attention deficit hyperactivity disorder, as well as physical symptoms such as a “musty” odor, eczema, and unusually light skin and hair coloration
What is tetrahydrobiopterin
Co-factor for PAH
A deficiency in tetrahydrobiopterin can cause severe neurological issues related to a toxic buildup of L-phenylalanine
Phenylketonuria management
- Diet
- L-dopa, 5-HT, BH4
- Foetus can be affected too
Urea cycle defects
- Glutamine, glutamic acid, aspartic acid, glycine
- Soon after birth; if untreated, fatal – lethargy, poor feeding, seziures, coma, death
- High ammonia - ammonia intoxication
Management of UCD
- Reduction of dietary protein intake
- Removal of excess toxic products - levulose (ammonia)
- Removal of excess precursors (Na benzoate - glycine, Na phenylbutyrate - glutamate)
- Replacement of intermediates in urea synthesis(citrulline, arginine, forces available enzymes to maximal activity)
- Liver transplant
How does administration of levulose help with management of UCD
- Administration of levulose reduces ammonia through its action of acidifying the colon
- Bacteria metabolize levulose to acidic byproducts which then promotes excretion of ammonia in the faeces as ammonium ions, NH4+.
Antibiotics can be administered to kill intestinal ammonia producing bacteria.
Sodium benzoate and sodium phenylbutyrate can be administered to covalently bind glycine (forming hippurate) and glutamine (forming phenylacetylglutamine), respectively. These latter compounds, which contain the ammonia nitrogen, are excreted in the faeces
Effects of arginine or citrulline on urea production
Dietary supplementation with arginine or citrulline can increase the rate of urea production
