DM Disorders

Question 1

Type 0 GSD

Answer 1

Enzyme deficiency: Glycogen Synthase

Rare, early death

Question 2

Von Gierke disease

Answer 2

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.

Question 3

Pompe Disease

Answer 3

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.

Question 4

Cori Disease

Answer 4

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.

Question 5

Andersen Disease

Answer 5

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.

Question 6

McArdle Disease

Answer 6

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.

Question 7

Hers Disease

Answer 7

Type VI GSD

Enzyme deficiency: Hepatic phosphorylase (muscle isozyme is normal)

Clinical: Hepatomegaly, growth retardation, mild fasting hypoglycemia.

Question 8

Tauri Disease

Answer 8

Type VII GSD

Enzyme deficiency: PFK-1 in muscle and RBCs (hepatic isozyme is normal).

Clinical: Similar to McArdle but with hemolysis.

Question 9

Hurler Syndrome

Answer 9

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.

Question 10

Hunter Syndrome

Answer 10

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.

Question 11

Tay-Sachs disease

Answer 11

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.

Question 12

Gaucher

Answer 12

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.

Question 13

Fabry

Answer 13

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.

Question 14

Niemann-Pick

Answer 14

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.

Question 15

Metachromatic Leukodystrophy

Answer 15

Lysosomal Storage Disorder- Sphingolipidosis

Enzyme Deficiency: Aryl sulfatase A

Accumulating Substrate: Sulfatide

Clinical: Sulfatide accumulates in neurons. Progressive paralysis and demyelination.

Question 16

Menke’s Syndrome

Answer 16

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.

Question 17

Wilson Disease

Answer 17

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.

Question 18

Hereditary Hemochromatosis

Answer 18

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.

Question 19

Leber’s Hereditary Optic Neuropathy

Answer 19

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.

Question 20

Deafness induced by aminoglycoside antibiotics

Answer 20

Hereditary defect in mitochondrially encoded rRNA.

Predisposition to aminoglycoside toxicity causing deafness days to weeks after administration.

Question 21

Kearns-Sayer

Answer 21

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.

Question 22

MELAS

Answer 22

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.

Question 23

MERRF

Answer 23

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.