Year Two Review
Part 2
Eric Niederhoffer,
Ph.D.
SIU-SOM
Outline
• Pyrimidine and purine synthesis
including salvage and degradation
• Glycogen storage disorders
• Lysosomal storage disorders
• Heme synthesis and degradation
including oxygen binding/unloading of heme
• Integration of metabolism
including lipid synthesis/degradation,
glycolysis/gluconeogenesis, TCA cycle and
glycogenolysis/glycogen synthesis
Pyrimidine and Purine Synthesis
HCO3- + Gln
R5P
CPSII
RPK
CP
Asp
PRPP
Oro
UMPS
Gln
Gly
UMP
UTP
CDP
N10fTHF
CO2
Asp
dCDP
dUMP
N5,N10-mTHF
TS
dTMP
RNA
DNA
IMP
GDP
ADP
RR
dGTP
dATP
Pyrimidine and Purine Salvage
UTP
CDP
dCDP
IMP
dUMP
N5,N10-mTHF
TS
RR
GDP
dTMP
ADP
RR
dGTP
UMP
TMP
UTPT
RNA
DNA
U
T
PRPP
HGPT
A
G
adenosine
ADA
inosine
PNP
PRPP
HX
XO
APT
urate
X
XO
dATP
Pathway Disorders
Rare autosomal recessive disorders
• UMP synthase – deficiency in either orotate
•
•
•
phosphoribosyltransferase or OMP decarboxylase leads to
hereditary orotic aciduria, megaloblastic anemia appearing weeks to
months after birth that does not respond to cobalamin, folic acid, or
iron, orotic crystalluria and nephropathy, cardiac malformations,
strabismus, and recurrent infection. Urine orotic acid overexcretion.
Enzyme assay of RBC. Treatment with oral uridine.
Adenosine deaminase – (Severe combined immunodeficiency
disorder) variety of clinical phenotypes, history of infections,
diarrhea, dermatitis, and failure to thrive, ribs and vertebrae
abnormalities (defects in cartilaginous structures). Lymphopenia, B
and T cell production affected. Enzyme assay of RBC/WBC.
Treatment by bone marrow/stem cell transplantation or enzyme
replacement.
Purine nucleotide phosphorylase – (Immunodeficiency)
lymphopenia, thymic deficiency, recurrent infections, and
hypouricemia, developmental delay, ataxia, or spasticity. T cell
production affected. Enzyme assay of RBC, lymphocytes,
fibroblasts. Treatment by bone marrow/stem cell transplantation.
Adenine phosphoribosyl transferase – frequent infections,
renal colic, renal failure. Elevated urine levels of 2,8dihydroxyadenine, 8-hyroxyadenine, and adenine; serum uric acid
normal. Enzyme assay. Treated with dietary purine restriction, high
fluid intake, and avoidance of urine alkalinization, Allopurinol to
prevent oxidation of adenine.
Pathway Disorders
X-linked recessive disorder
• Hypoxanthine-guanine phosphoribosyl transferase –
(Lesch-Nyhan syndrome) usually presents at 3 to 12 months with
orange sandy urine precipitate, dystonia, intellectual disability,
self-mutilation (lips, tongue, fingers), and gout. Elevated serum
and urine uric acid levels. Enzyme assay on RBC, lymphocytes,
fibroblasts. Molecular genetics of gene. Treated supportively
with low-purine diet, allopurinol, and plenty of hydration.
Glycogen Storage Disorders
ls acid maltase
GSDII
Glycogen
transglycosylase
branching enzyme
hPP
GSDIV
GSDVI
mPP
GSDV
G1P
debranching enzyme
GSDIII
Glc
hG6Pase
GSDI
G6P
F6P
PFK-1
GSDVII
F16BP
GS
GSD0
UDP-Glc
Pathway Disorders
Rare autosomal recessive disorders
• Glycogen synthase –.(GSD type 0) fasting hypoglycemia,
•
•
•
ketosis, especially before feeding. Periodic acid-Schiff stain shows
decreased hepatic glycogen stores, muscle is normal. Treatment is
appropriate diet to avoid hypoglycemia.
Glucose-6-phosphatase – (GSD type Ia, Von Gierke) history
hypoglycemic seizures, hypotonia, hepatomegaly, xanthomas,
manifestations of gout, hypertension, renal failure, and short stature.
Fasting glucose, ischemic forearm test (negative), Enzyme assay.
Treatment by high-protein diet, uncooked corn starch.
Lysosomal acid maltase – (GSD type II, Pompe, a-1,4glucosidase); infantile - feeding and breathing difficulties, hypotonia,
cardiomegaly; adult – limb-girdle weakness, respiratory muscle
involvement. Hyperlipidemia, fasting ketonemia. Ischemic forearm
test normal. Enzyme assay of fibroblasts. Periodic acid-Schiff stain
is positive for lysosomal glycogen inclusions. Treatment by enzyme
relacement, high protein diet.
Debranching enzyme – (GSD type III, Forbes-Cori, amylo-1,6glucosidase), infantile seizures, hepatomegaly, growth retardation,
progressive muscle weakness. Ischemic forearm test positive.
Enzyme assay of fibroblasts. Periodic acid-Schiff stain is positive for
basophilic glycogen deposits in all tissues. Treatment is supportive
by corn starch, liver transplantation.
Pathway Disorders
Rare autosomal recessive disorders
•
•
•
•
Branching enzyme – (GSD type IV, Andersen,
transglucosidase) history not specific, hepatic failure, cirrhosis,
hepatosplenomegaly, failure to thrive. Prenatal PCR and DNA
analysis. Enzyme assay. Diffuse amylopectin-like deposits in the
heart, liver, muscle, spinal cord, and peripheral nerves. Treatment is
supportive with liver transplantation and diet.
Myophosphorylase – (GSD type V, McArdle) cramps, fatigue,
and pain after exercise (depends on severity of deficiency), unique
"second-wind" phenomenon. Ischemic forearm test positive.
Enzyme assay. Periodic acid-Schiff stain gives subsarcolemmal
blebs. Treatment by avoiding intense exercise, provide high protein
diet.
Hepatic phosphorylase – (GSD type VI, Hers) most common
among Mennonite religious group, also X-linked form, history of
bulging abdomen, growth retardation, and slight delay in motor
milestones, hepatomegaly. Enzyme assay on liver biopsy, RBC,
WBC; molecular genetics of gene. Glycogen-distended hepatocytes,
muscle normal. Treatment with dietary management as appropriate
for clinical presentation.
Phosphofructokinase-1 – (GSD type VII, Tarui, M form, classic)
history of exertional fatigue, nausea and vomiting, muscle cramps,
hyperuricemia, myoglobinuria following high-intensity exercise.
Ischemic forearm test positive. Enzyme assay on muscle biopsy.
Periodic acid-Schiff diastase-negative stain gives subsarcolemmal
blebs. Treatment to avoid high carbohydrate diet especially before
exercise.
Lysosomal Storage Disorders
Lipid metabolism
• Landing, Sandhoff, Tay-Sachs, Krabbe,
Gaucher, Niemann Pick (A,B), Wolman,
metachromatic leukodystrophy, Fabry
Glycoprotein metabolism
• Schindler
Mucopolysaccharide metabolism
• Hurler/Scheie, Hunter, Sanfilippo (A,B,C,D),
Morquio (A,B), Maroteaux–Lamy, Sly
Other lysosomal enzymes
• Pompe, Niemann-Pick (C)
Oligosaccharidoses
GM2 gangliosidosis variant O
(Sandhoff-Jatzkewitz disease)
b-N-Acetylhexosaminidases A&B
a-Mannosidosis
a-Mannosidase
Aspartylglycosylaminuria
4-L-Aspartylglycosylamine
amidohydrolase
5
6
Gal
GlcNAc 4
a
b
b Man
6
5
NANA
Gal
GlcNAc 4
b
a
a
NANA
3
7
2
Man
GlcNAc
GlcNAc
5
6
a
Gal
GlcNAc 4
3
b
b
8
b
a
Man GlcNAc
b
Fuc
5
6
NANA
Gal
GlcNAc 4
a
b
NANA
Typical Asn-GlcNAc OS structure
GM1 gangliosidosis
b-Galactosidase
Mucolipidosis I
(Sialidosis)
Sialidase
b-Mannosidosis
b-Mannosidase
Fucosidosis
a-Fucosidase
1
Asn
Glycosaminoglycoses
(mucopolysaccharidoses)
Sanfilippo’s A
Hunter’s
iduronate sulfatase heparan N-sulfatase
Mucolipodosis VII
b-glucuronidase
Hurler-Scheie Aldurazyme®
a-L-iduronidase (laronidase)
Sanfilippo’s C
Acetyl-CoA: a-glucosaminide
acetyltransferase
Maroteaux-Lamy
N-acetylgalactosamine sulfatase
DS
HS
2
IdUA
4
GalNAc
a
1
3
OSO3H OSO3H
2
IdUA
1
OSO3H
a
GlcN
6
OSO3H
b
GlcUA
Gal
11
b
10
OSO3H
b
GalNAc
b
OSO3H
7,9
a
GlcUA
GlcNAc
8
OSO3H
5
b
GlcNAc
8
OSO3H
9
a
Sanfilippo’s B
N-acetylglucosaminidase
Sandhoff/Tay-Sachs
b-hexosaminidase A,B,S
KS
5
4
b
Gal
b
GlcNAc
b
OSO3H
Morquio’s A
Sanfilippo’s D
N-acetylgalactose-6-sulfatase
N-acetylglucosamine-6-sulfatase
Morquio’s B
b-galactosidase
Gangliosidoses
neuraminidase
(sialidase)
NANA
NANA
b
b
b
b
Gal
GalNAc
Gal
Cer
Glu
Generalized gangliosidosis
b-galactosidase
GD1
Cer
b
Glu
NANA
b
NANA
Cer
b
Glu
b
Gal
b
GalNAc
b
Glu
b
GM2
Cer
b
Gaucher’s disease
b-glucosylceramidase
SAP-C
Cerezyme
Cer
PC
Niemann-Pick disease
sphingomyelinase
S + FA
b
Gal
GM1
b
Glu
Gal
GM3
Fabry’s disease
a-galactosidase A
SAP-B
b
b
a
Cer
Glu
Gal
Gal
Cer
b
Sandhoff’s disease
b-hexosaminidase A&B
Glu
Cer
Cer
GalNAc
NANA
Gal
b-galactosidase
SAP-B, SAP-C
b
Tay-Sachs disease
b-hexosaminidase A
GM2 activator
Sialidosis
neuraminidase
(sialidase)
SAP-B
Cer
Gal
b
Glu
b
Gal
a
Gal
b
GalNAc
Krabbe’s disease
b-galactosylceramidase
b
Cer
Gal SAP-A, SAP-C
Metachromatic leukodystrophy
arylsulfatase A
SAP-B
b
Cer
Gal
SO3H
General Physical Features
• Coarse facial features (sometimes with
macroglossia)
• Corneal clouding or related ocular
abnormalities
• Angiokeratoma
• Umbilical/inguinal hernias
• Short stature
• Developmental delays
• Joint or skeletal deformities
• Organomegaly (especially liver and
spleen)
• Muscle weakness or lack of control (ataxia,
seizures, etc.)
• Neurologic failure/decline or loss of gained
development
Heme Synthesis
mit
SCoA + Gly
5AS
PBGS
PBG
5ALA
PBGD
Heme
HMB
FC
UPGIIIS
PPIX
UPGIII
UPGIIIDC
CPGIII
CPGO
PPGO
PPGIX
Pathway Disorders
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•
•
•
PBG synthase – (5-aminolevulinic acid dehydratase) extremely
rare autosomal recessive (hepatic porphyria) neurological findings,
abdominal tenderness, neuropathy, not associated with cutaneous
photosensitivity. Elevated urine ALA, coproporphyrin III and
protoporphyrin IX, normal PBG, elevated RBC zinc protoporphyrin
but decreased (80%) PBG synthase. DNA analysis. Treatment by
avoiding precipitating factors, drugs that induce P450 induction,
provide hematin, high carbohydrate diet (glucose inhibits 5-AS).
PBG deaminase – (Acute intermittent porphyria) autosomal
dominant, abdomen pain, psychiatric symptoms (hysteria), motor
neuropathies (more commonly lower limbs), and constipation but no
skin rash. Increased urinary porphobilinogen secretion, molecular
genetic analysis. Treatment during attacks with high carbohydrate
(glucose) diet and hematin, otherwise, balanced diet.
Uroporphyrinogen III synthase – (Congenital erythropoetic
porphyria, Gunther disease) rare autosomal recessive,
photosensitivity, nail abnormalities, brown or pink teeth. Elevated
urine and RBC levels of uroporphyrin I, hemolytic anemia. Enzyme
assay, molecular genetic analysis, red porphyrin fluorescence in
intact RBC and erythroid precursor cells. Treated with absolute
avoidance of sun exposure, supportive/cosmetic care.
Uroporphyrinogen III decarboxylase – (Porphia cutana
tarda) 80% acquired/20% familial/autosomal dominant, acquired by
ethanol abuse, estrogen therapies, hemochromatosis genes,
hepatitis and human immunodeficiency viral infections,
environmental toxins, photosensitivity, tea/wine colored urine.
Carboxylated porphyrins in serum and urine. Enzyme assay of RBC,
molecular genetic analysis. Treatment with avoidance of
sunlight/environmental exposure.
Pathway Disorders
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•
•
Coproporphyrinogen oxidase – (Hereditary coproporphyria)
autosomal dominant, abdominal pain, neuropathies (motor, lower
limbs), constipation, and skin changes (photosensitivity). Excess
secretion and levels of coproporphyrins in stool and urine.
Treatment with high carbohydrate (glucose) diet and hematin.
Protoporphyrinogen oxidase – (Variegate porphyria)
autosomal dominant, photosensitivity, abdominal discomfort. Urinary
aminolevulinic acid and porphobilinogen levels are greatly elevated
during attacks, molecular genetic analysis. Treatment with
avoidance of inducing drugs, providing high carbohydrate diet,
hematin.
Ferrochelatase – (Erythropoetic protoporphyria) autosomal
dominant (X-linked, autosomal recessive), photosensitivity,
heptabiliary disease, jaundice. Elevated protoporphyrin
concentration in red blood cells, plasma, bile, and feces. Treatment
with avoidance of sun exposure, maintain balanced diet.
Heme Degradation
res
Heme
HO
BVR
BV
BR
indirect
unconjugated
pre-hepatic
albumin
albumin-BR
albumin
ligandin
hepatocyte
ligandin-BR
UDP-GT
ER
BR diglucuronide
direct
conjugated
post-hepatic
Pathway Disorders
Autosomal recessive disorders
• UDP-glucuronyl transferase – mild deficiency (Gilbert
•
syndrome) most common inherited cause of unconjugated
hyperbilirubinemia, intermittent jaundice without hemolysis or liver
disease, precipitated by dehydration, fasting, menstrual periods,
intercurrent illness, trauma, over exertion, nonspecific symptoms
such as abdominal cramps, fatigue, and malaise, mild jaundice.
Unconjugated hyperbilirubinemia (by definition [bilirubin] < 6 mg/dL,
commonly < 3 mg/dL), normal complete blood count, reticulocyte
count, and blood smear, normal liver function panel. Treatment is
reassurance and avoiding precipitating factors.
UDP-glucuronyl transferase – severe deficiency (CriglerNajjar syndrome) rare, types 1 and 2 (Arias syndrome). Type 1
almost complete deficiency associated with neonatal unconjugated
hyperbilirubinemia (17-50 mg/dL) and kernicterus, hypotonia,
deafness, oculomotor palsy, lethargy. Type 2 deficiency
unconjugated bilirubin (6-20 mg/dL), persistent jaundice at birth or
after. Elevated unconjugated bilirubin with normal liver function
panel. Phenobarbital treatment distiguished type 1 (no effect) from
type 2 (lowers serum bilirubin 25%). Treatment of bilirubin
encephalopathy with plasma exchange transfusion and long-term
phototherapy.
Integration of Metabolism
SSB
•
•
•
metabolism in brain, nervous tissue and muscle
alcohol processing and effect on metabolic pathways
vitamins in neuromuscular metabolism
ERG
• regulation of metabolism and diabetes