Energy Metabolism

Question 1

Type 1 (Classic) Galactosemia

Answer 1

Autosomal recessive deficiency of galactose 1-phosphate uridly transferase

• Early cataracts (due to accumulation of galactitol in the lens, causing osmotic damage)
• Vomiting/diarrhea following lactose ingestion
• Lethargy
• Liver damage, hyperbilirubinemia
• Mental retardation

Question 2

Type II Galactosemia

Answer 2

Autosomal recessive deficiency of galactokinase

• Early cataracts (galactose accumulates, converts to galactitol via aldose reductase, and galactitol becomes trapped in lens, causing osmotic damage)

Question 3

Essential fructosuria

Answer 3

Autosomal recessive deficiency of fructokinase

Benign disorder characterized by fructosuria

Question 4

Hereditary fructose intolerance

Answer 4

Autosomal recessive deficiency of aldolase B, which normally cleaves frustose 1-P into DHAP and glyceraldehyde. Causes fructose 1-P to accumulate in the liver and kidney.

• Lethargy, vomiting
• Liver damage, hyperbilirubinemia
• Hypoglycemia
• Hyperuricemia
• Renal proximal tubule defect (Fanconi syndrome)
• NO cataracts (characteristic of galactosemia)

Question 5

Inhibitors of oxidative phosphorylation

Answer 5

NADH dehydrogenase complex 1 (inhibited by barbiturates and rotenone [insecticide] )

Coenzyme Q (inhibited by doxorubicin)

Cytochrome a/a3 (inhibited by cyanide and CO)

ATP synthase (inhibited by oligomycin)

Question 6

von Gierke disease (type 1 glycogen storage disease)

Answer 6

Autosomal recessive deficiency of glucose-6-phosphatase

• Severe fasting hypoglycemia
• Lactic acidosis
• Hepatomegaly (protruding abdomen with emaciated extremities)
• Hyperlipidemia (skin xanthomas)
• Hyperuricemia (decreased P_i leads to increased AMP, which is degraded to urice acid)
• Short-stature and doll-like facies

Tx: frequent oral glucose; avoidance of fructose/galactose

Question 7

Pompe disease (type II glycogen storage disease)

Answer 7

Autosomal recessive deficiency of lysosomal alpha-1,4-glucosidase (acid maltase)

• Cardiomegaly (“pompe trashes the pump”)
• Muscle weakness
• Glycogen-like inclusion bodies
• Death by 2 years

Question 8

Cori disease (type III glycogen storage disease)

Answer 8

Autosomal recessive deficiency of debranching enzyme (alpha-1,6-glucosidase)

• Milder form of von Gierke (mild hypoglycemia, hepatomegaly, no lactic acidosis)
• Glycogen with short outer branches

Question 9

Anderson disease (type IV glycogen storage disease)

Answer 9

Deficiency of branching enzyme

• Infantile hypotonia
• Cirrhosis
• Death by 2 years

Question 10

McArdle disease (type V glycogen storage disease)

Answer 10

Autosomal recessive deficiency of muscle glycogen phosphorylase (“McArdle = Muscle”)

• Increased glycogen in muscle
• Muscle cramps and weakness with exercise
• Myoglobinuria
• Arrhythmia from electrolyte disturbances

Question 11

Hers disease (type VI glycogen storage disease)

Answer 11

Autosomal recessive deficiency of hepatic glycogen phosphorylase

• Increased glycogen in liver
• Mild fasting hypoglycemia
• Hepatomegaly/cirrhosis

Question 12

Type I familial dyslipidemia (hyperchylomicronemia)

Answer 12

Autosomal recessive deficiency of lipoprotein lipase or apoC-II, resulting in excess TG in blood and its deposition in several tissues

• Pancreatitis
• Hepatosplenomegaly
• Eruptive/pruiritic xanthomas
• NO increased risk of atherosclerosis

Question 13

Type IIa familial dyslipidemia (familial hypercholesterolemia)

Answer 13

Autosomal dominant deficiency or absence of LDL receptors, resulting in elevated LDL and icnreased risk for atherosclerosis and coronary artery disease.

• Xanthomas of Achilles tendon
• SQ tuberous xanthomas over eblows
• Xanthelasma (lipid in eyelid)
• Corneal arcus

Absence of LDL often causes MI before age 20

Question 14

Abetalipoproteinemia

Answer 14

Low to absent serium apoB-100 and apoB-48, resulting in very low serum TGs and cholesterol.

Fat accumulates in intestinal enterocytes and in hepatocytes. Essential fatty acids and fat-soluble vitamins are not well absorbed.

• Steatorrhea
• Cerebellar ataxia
• Pigmentary degeneration in the retina
• Acanthocytes (thorny erythrocytes)

Question 15

Type IV familial hyperlipidemia (hypertriglyceridemia)

Answer 15

Autosomal dominant overproduction of VLDL in the liver. Causes pancreatitis.

Question 16

Phenylketonuria

Answer 16

Autosomal recessive deficiency of phenylalanine hydroxylase (normally converts phenylalanine to tyrosine) or decreased tetrahydrobioptern (BH₄, required cofactor)

• Infants are normal at birth but if untreated show slow development severe mental retardation, autistic symptoms, and loss of motor control
• Children may have pale skin and white-blonde hair
• Disorder of aromatic AA metabolism –> musty body odor

Maternal PKU - lack of proper diet may cause microcephaly, growth retardation, and intellectual disability in their child.

Question 17

Alkaptonuria

Answer 17

Autosomal recessive defect of homogentisate oxidase, which normally degrades homogentisic acid to maleyacetoacetate (within the degradative pathways of tyrosine to fumarate)

• Dark connective tissue
• Brown pigmented sclerae
• Urine turns black on prolonged exposure to air
• Homogentisic acid is toxic to cartilage and may cause debilitating arthralgias

Question 18

Branched-chain ketoacid dehydrogenase deficiency (maple syrup urine disease

Answer 18

Autosomal recessive deficiency of alpha-ketoacid dehydrogenase, which normall degrades branched amino acids (Isoleucine, Leucine, Valine)

• Infants are initially normal, after which they become progressively lethargic, lose weight, and have alternating episodes of hypertonia and hypotonia
• Urine smells like maple syrupt/burnt sugar

Tx: restriction of leucine, isoleucine, and valine; thiamine supplementation

Question 19

Propionyl-CoA carboxylase / Methylmalonyl-CoA mutase deficienies

Answer 19

Valine, methionine, isoleucine, threonine and odd-carbon fatty acids are all converted into propionyl-CoA, which undergoes carboxylation to methylmalonyl-CoA by propionyl-CoA carboxylase (requires biotin). Methylmalonyl-CoA is then converted to Succinyl-CoA by methylmalonyl-CoA mutase (requires Vit B12)

Deficiency of either enzyme results in neonatal ketoacidosis due to failure to metabolize ketoacids produced from these four amino acids.

• Methylmalonyl CoA mutase deficiency causes methylmalonic aciduria
• Propionyl CoA carboxylase deficiency causes accumulation of propionic acid and methyl citrate

Question 20

Homocystinuria

Answer 20

Characterized by DVTs, stroke, atherosclerosis, marfan-like habitus, mental retardation, joint contractures, and lens subluxation (ectopia lentis). Etiologies (all autosomal recessive):

• Cystathionine synthase deficiency (requires Vit B6) - usually combines homocysteine with serine to produce cystathionine
  
  • Tx: decrease methionine, increase cysteine, increase Vit B12 and folate in diet
• Homocysteine methyltransferase (methionine synthase) deficiency (requires folate, Vit B12)
  
  • Tx: increase methionine in diet

Question 21

Cystinuria

Answer 21

Autosomal recessive defect of renal PCT and intestinal amino acid transporter for Cysteine, Ornithine, Lysine, and Arginine (“COLA”)

Excess cystine in the urine can lead to precipitation of hexagonal cystine stones

Dx: Urinary cyanide-nitroprusside test

Tx: urinary alkalinization (potassium citrate, acetazolamide)

Question 22

Catecholamine synthesis

Answer 22

• Phenylalamine hydroxylase (requires BH₄) - phenylalanine to tyrosine
• Tyrosine hydroxylase (requires BH₄) - tyrosine to DOPA
  
  • Tyrosine may also be convereted to thyroxine and fumarate (via homogentistic acid))
• DOPA decarboxylase (requires Vit B6) - DOPA to dopamine
  
  • Inhibited by carbidopa (for PD)
• Tyrosinase - DOPA to melanin
• **Dopamine beta-hydroxylase **(requires Vit C, Cu^<u>+2</u>) - dopamine to norepinephrine
  
  • Dopamine is degraded to homovanillic acid
• **N-methyltransferase **(requires SAM) - norepinephrine to epinephrine
  
  • Epi and Norepi are degraded to vanillylmandelic acid

Question 23

Products of tryptophan

Answer 23

• Serotonin (via BH₄ and B₆)
• Niacin (via B₆) - NAD, NADP

Question 24

Products of arginine

Answer 24

• Creatine
• Urea
• Nitric oxide (via BH₄)

Question 25

Products of histidine

Answer 25

• Histamine (via B₆)

Question 26

Products of glutamate

Answer 26

• GABA (via B₆)
• Glutathione

Question 27

Hypoxanthine-guanine phosphoribosyltransferase (HGPRT)

Answer 27

Catalyzes conversion of hypoxanthine to inosine monophosphate and guanine to guanosine monophosphate (with addition of PRPP)

Critical enzyme in the purine salvage pathway

Lesch-Nyhan syndrome - defective purine salvage due to X-linked absence of HGPRT. Results in excess uric acid production and de novo purine synthesis; characterized by intellectual disability, self-mutilation, aggression, hyperuricemia, gout, and dystonia; tx is allopurinol and febuxostat

Question 28

Arginase deficiency

Answer 28

Arginase is an enzyme of the urea cycle that cleaves arginine to produce urea and ornithine

Deficiency of arginase leads to build-up of arginine, resulting in lower extremity spasticity and choreoathetoid movements (may mimic cerebral palsy)

Question 29

NADPH oxidase

Answer 29

Converts O₂ to O₂^- (superoxide), which is required for oxidative burst (oxygen-dependent killing by neutrophils)

Deficiency of NADPH oxidase (X-linked or AR) leads to chronic granulomatous disease (recurrent infection and granuloma formation with catalase-positive organisms; colorless Nitroblue tetrazolium test)