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
GSD1
Glucose 6 phosphatase deficiency
- Key enzyme in gluconeogenesis
Clinical features of GSD1
Hypoglycaemia, lactic acidosis, lipidaemia, hepatomegaly, uricaemia
Neutropenia, bruising, renal disease
GSD1 management
Continuous feeds or corn starch (slow absorption)
Limit other sugars – fructose, galactose, sucrose, maltose
Inhibit uric acid production – Allopurinol
High cholesterol – Statins
Liver transplant
Galactosemia
GAL1PUT deficiency
Galactose 1 Phosphate Uridyl Transferase
Prolonged jaundice, cataracts, poor wt gain, hepatomegaly
No screening in UK
Galactose free diet (milk free), Soy milk
MCAD deficiency
Completely ‘normal’ when well
Hypoglycaemia when unwell or fasting
Unable to mobilise fatty acids & ketones when low glucose
Reduced total carnitine, reduced free carnitine/acyl carnitine ratio
Management of MCAD deficiency
Avoid fasting (unable to eat)
Slow release carbohydrates eg starch (provide glucose overnight)
Supplement Carnitine
Riboflavin - benefits some patients with electron transport chain deficiency
Medic-Alert Bracelet
Lysosomes
Spherical vesicles containing >50 hydrolytic enzymes
Breaks down all kinds of biomolecules
Phagocytosis, endocytosis, autophagy
Stomach of the cell; Suicide bags or sacs; Recycling unit
Mucopolysacccharidoses
Mucopolysaccharidoses are a group of metabolic disorders caused by the absence or malfunctioning of lysosomal enzymes needed to break down molecules called glycosaminoglycans (GAGs).
Features of mucopolysaccharidoses
Coarse facies, mental retardation, short stature, contractures, dysostosis multiplexa
Hurler, Hunter, Sanfilippo,
Symptomatic treatment
Lipid storage disorders
Gangliosidosis Tay Sachs Gaucher Niemann-Pick Mucolipidoses Lipofuscinosis
General features of lysosomal storage disorders
Neuro-regression Seizures Hepato-splenomegaly Hematologic Skeletal Cherry Red Spot
Mitochondrial disorders
Inherited by maternal mitochondrial DNA
Respiratory chain defects (Energy production)
Presentation of mitochondrial disorders
Brain, Eye, heart, muscle problems
Leigh’s Disease – subacute necrotising encephalomyelopathy
Symptomatic treatment
Death in early life
Pronuclear transfer
Mitochondrial replacement therapy (MRT, sometimes called mitochondrial donation) is the replacement of mitochondria in one or more cells to prevent or ameliorate disease.
What are peroxisomes
Peroxisomes contain at least 50 different enzymes, which are involved in a variety of biochemical pathways in different types of cells. Peroxisomes originally were defined as organelles that carry out oxidation reactions leading to the production of hydrogen peroxide.
Because hydrogen peroxide is harmful to the cell, peroxisomes also contain the enzyme catalase, which decomposes hydrogen peroxide either by converting it to water or by using it to oxidize another organic compound
Examples of peroxisomal disorders
Zellwegers, Refsum, Adrenoleucodystrophy etc
What happens in peroxisomal disorders
Accumulation of VLCFA in adrenal glands and peripheral nerves
- Import/export defects
Management of peroxisomal disorders
- Diet, bone marrow transplantation
