DM Disorders Flashcards
Type 0 GSD
Enzyme deficiency: Glycogen Synthase
Rare, early death
Von Gierke disease
Type I GSD
Enzyme Deficiency: Glucose 6-phosphatase in liver & kidney cortex. Last step of Gluconeogenesis & Glycogenolysis.
Clinical: Massive enlargement of liver due to build-up of glycogen (normal structure). Severe fasting hypoglycemia. Lactic acidosis. Hyperuricemia, Hyperlipidemia.
Pompe Disease
Type II GSD
Enzyme deficiency: Lysosomal a(1-4) glucosidase (acid maltase) in heart, muscle, liver.
Clinical: Enlarged heart & liver due to lysosomal glycogen accumulation. Lysosomes can rupture. Myopathy, hypotonia, weakness. Early onset- early death. Late onset- breathing problems & myopathy.
Cori Disease
Type III GSD, aka Forbes Disease aka limit dextrinosis
Enzyme deficiency: debranching enzyme (4:4 transferase)
Clinical: Enlarged liver & heart. Muscle weakness and hypotonia. Mild hypoglycemia. Muscular dystrophy.
Andersen Disease
Type IV GSD aka familial cirrhosis
Enzyme deficiency: glycogen branching enzyme (4:6 transferase)
Clinical: Autoimmune attack against abnormally long & unbranched glycogen. Hepatic scarring & enlargement. Muscle weakness, cardyomyopathy.
McArdle Disease
Type V GSD
Enzyme deficiency: Muscle phosphorylase (hepatic isozyme unaffected).
Clinical: child is tired & unmotivated. Rhabdomyolysis, myoglobinemia, myoglobinuria after forced exercise. Muscle cramps & lowered lactate in blood.
Hers Disease
Type VI GSD
Enzyme deficiency: Hepatic phosphorylase (muscle isozyme is normal)
Clinical: Hepatomegaly, growth retardation, mild fasting hypoglycemia.
Tauri Disease
Type VII GSD
Enzyme deficiency: PFK-1 in muscle and RBCs (hepatic isozyme is normal).
Clinical: Similar to McArdle but with hemolysis.
Hurler Syndrome
Lysosomal Storage Disorder- Mucopolysaccharidosis
Enzyme Deficiency: Iduronidase
Accumulating Substrates: Heparan Sulfate, Dermatan Sulfate
Clinical: Corneal clouding, course facial features, short stature, developmental delay, hepatosplenomegaly, poor joint mobility. Treat with enzyme replacement.
Hunter Syndrome
Lysosomal Storage Disorder- Mucopolysaccharidosis
Enzyme Deficiency: Iduronase Sulfatase. X-linked
Accumulating Substrates: Heparan Sulfate, Dermatan Sulfate
Clinical: Similar to Hurler Syndrome but no corneal clouding. Typically less severe and with variable expressivity.
Tay-Sachs disease
Lysosomal Storage Disorder- Sphingolipidosis
Enzyme Deficiency: B-hexoaminidase
Accumulating Substrate: Ganglioside
Clinical: Early development normal, followed by delay, followed by regression of developmental milestones. Death by age 6. Onion-shell inclusions in lysosomes, cherry-red spot.
Gaucher
Lysosomal Storage Disorder- Sphingolipidosis
Enzyme Deficiency: B-glucosidase
Accumulating substrate: Glucosyl ceramide
Clinical: Presents later in life, osteoporosis, hepatosplenomegaly. “Crumpled tissue paper” appearance of cytoplasm.
Fabry
Lysosomal Storage Disorder- Sphingolipidosis
Enzyme deficiency: Alpha-Galactosidase. X-linked
Accumulating substrate: Globoside
Clinical: Accumulation of globoside in skin, blood vessels, kidneys, and nerves. “Bath trunk” rash, heart attacks, renal damage, and peripheral neuropathy.
Niemann-Pick
Lysosomal Storage Disorder- Sphingolipidosis
Enzyme Deficiency: Sphingomyelinase
Accumulating substrate: Sphingomyelin
Clinical: Similar to Tay-Sachs, but different substrate accumulates. “Foamy-cell” appearance due to sphingomyelin accumulation.
Metachromatic Leukodystrophy
Lysosomal Storage Disorder- Sphingolipidosis
Enzyme Deficiency: Aryl sulfatase A
Accumulating Substrate: Sulfatide
Clinical: Sulfatide accumulates in neurons. Progressive paralysis and demyelination.
Menke’s Syndrome
Inherited defect in dietary copper absorption
X-linked
Clinical: Early age of presentation. Twisty grayish kinky hair due to Tyrosinase dysfunction (melanin synthesis). Aneurysm and neuro dysfunction due to low lysyl oxidase activity.
Wilson Disease
Inherited defect in copper coupling and decoupling from ceruloplasmin.
Enzyme Deficiency: Copper Transporting ATP-ase (ATP-7B gene). Autosomal Recessive
Clinical: Toxic levels of copper in liver- cirrhosis. Kayser-Fleischer rings in cornea and neurological symptoms due to free copper in blood accumulating in eyes and basal ganglia. Low ceruloplasmin levels.
Hereditary Hemochromatosis
Inherited defect in sensing blood iron levels to adjust intestinal absorption.
Enzyme affected: HFE (HFE gene, senses blood iron levels and adjusts dietary iron absorption). Most common allele: C282Y. Allelic heterogeneity & compound heterozygotes.
Delayed age of onset- females are symptomatic later than males. Abnormally high iron absorption from diet. Accumulation in liver, pancreas, skin. Hepatomegaly (cirrhosis), diabetes (b-cell damage), bronze skin.
Leber’s Hereditary Optic Neuropathy
Hereditary Mitochondrial Disease
Defect in Complex 1 of ETC
Degeneration of retinal ganglia cells, atrophy of optic nerve, typically manifests between ages 25 to 35 and leads to blindness.
Deafness induced by aminoglycoside antibiotics
Hereditary defect in mitochondrially encoded rRNA.
Predisposition to aminoglycoside toxicity causing deafness days to weeks after administration.
Kearns-Sayer
Hereditary mitochondrial disease.
Deletion within mitochondrial DNA. Leads to weakness of skeletal muscle, cardiac problems, paralysis of eye muscle, ataxia, retinal degeneration, diabetes and dementia.
MELAS
Most common mitochondrial disease.
Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis, and Stroke-like episodes.
Strokes, myopathy, muscle twitching, dementia, deafness. Lactic acid accumulation toxic to brain.
Commonly due to mutation in mitochondrial tRNA.
MERRF
Hereditary mitochondrial disease.
Myoclonic Epipelpsy, Ragged Red Fibers
Most common mutation in tRNA. Myoclonus followed by seizures, ataxia, muscle weakness, worsening eyesight and hearing loss. Histologically muscle fibers look “ragged” due to overproliferation of defective mitochondria.
