Subcellular Organisation + Inborn Errors Flashcards
Floppy baby distress
Severe respiratory distress
Continued presence of developmental isoforms of cytochrome c oxidase (complex IV) in neonates
Recovery occurs after several months in a high-O2 environment
Gout
Membrane of lysosome disprupted –> contents released –> intracellular components digestion –> lysis –> crystals of Uris acid are phagocytosed
Lysosomal storage disease
Missing lysosomal enzyme –> build-up of substrate
Build-up of indigestible matter –> enlarged lysosomes –> interfere with normal cell functions
1. Lysosomal acid lipase (LAL) deficiency –> characterised by impaired cholesterol metabolism
2. Cholesterol ester storage disease –> low LAL activity ( hypercholesterolaemia, hepatomegaly, early onset severe atherosclerosis
3. Wolman’s disease: no detectable LAL activity –> usually fatal by 1
Peroxisome biogenesis disorders (PBDs)
Insufficiencies in peroxisomal enzymes
Liver, brain, kidney, skeletal
Symptoms: low plasmalogens, high levels of very long chain fatty acids and build up of bile-acid precursors
Zellwegers syndrome –> most severe floppy baby
Failure to traffic enzymes properly –> non-functional peroxisomal, usually fatal by 6 months
Hypotonia, hypothesia, seizure, tall forehead
Gross cortical neuronal migration defect, dilated ventricles (atrophy of surrounding tissue) cystic degradation
Hepatomegaly, jaundice, fibrosis, cholestasis
Myoclonic epilepsy with ragged red fibres (MERFF)
95% mitochondria threshold
Ptosis, muscle wastage
Histological stain –> red deposits –> aggregates of abnormal mitochondria –> progress disease as there is a cellular response to proliferate mitochondria despite structural abnormality
Phenylketonuria
Defect in phenylalanine hydroxylase
Normal when born, but excess substrate accumulates to impact neurological function
Can’t make protein, neurotransmitters, melanin pigment from the lacking tyrosine
Maternal PKU –> mother must go back on diet for conception and pregnancy
Glycogen storage disease 1 (glucose-6-phosphates deficiency)
Histology: full of glycogen deposits in liver
Short stature, distended abdomen, moon face, hypoglycaemia
Hypoglycaemia after overnight fast
Fail to mobilise glycogen
Treat with oral glucose replacement
Hyperlipodaemia
Increased production of NADPH, NADH, acetyl CoA and glycerol from oxidation of glucose
Stimulation of hepatic fatty acid and triglyceride synthesis, and suppression of fatty acid synthesis
Increased plasma triglyceride in VLDL, increased LDL from liver, balance of lipid metabolism disturbed
GLUT1 deficiency
Intractable seizures, unresponsive to anticonvulsants, often worse on fasting, microcephalic (slow brain growth compared to head size), delayed development
CSF glucose very below normal but blood glucose is normal
GLUT1 on astrocytes and capillaries –> environment of neurones
Diseases halves the usually high affinity/capacity transporter –> can’t maintains physiological function
Use ketogenic diet as tho starved
Very long chain acyl CoA dehydrogenase deficiency
Lethargy, hypotonia, following upper respiratory infection
Hypoglycaemia and abnormal liver function and concentric hypertrophy
Accumulation of long chain fatty acids
Treat with medium chain triglyceride - C8/10, coconut, easily digested, use as fuel, no shuttle for uptake in mitochondria, octanoyl CoA synthase and beta oxidation
Muscle cramps, exercise intolerance, acute muscle cell destruction
Gaucher disease
Lysosomal enzyme defect –> massive accumulation of undigested material in spleen and liver –> hepatosplenomegaly
Episodic bone crisis, lung + neurological
Acid B-glucosidase –> glucocerebroside (glycosphingolipid) liver spleen bone marrow
Replace enzyme but have to modify glycosylation pattern to be endocytosed by lysosome
Leber hereditary optic neuropathy
Onset usually in adulthood: early–> mid-life
Causes blindness
Mutation in DNA for NADH-Q reductase (complex 1) mitochondrial disease
