eric niederhoffer, ph.d. siu-som
DESCRIPTION
Year Two Review Part 2. Eric Niederhoffer, Ph.D. SIU-SOM. 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 - PowerPoint PPT PresentationTRANSCRIPT
Outline
• Pyrimidine and purine synthesisincluding salvage and degradation
• Glycogen storage disorders
• Lysosomal storage disorders
• Heme synthesis and degradationincluding oxygen binding/unloading of heme
• Integration of metabolismincluding lipid synthesis/degradation, glycolysis/gluconeogenesis, TCA cycle and glycogenolysis/glycogen synthesis
Pyrimidine and Purine SynthesisHCO3
- + Gln
CP
CPSII
Asp
Oro
R5P
PRPP
RPK
UTP
TSN5,N10-mTHF
dTMP
DNARNA
dGTP dATPRR
GDP ADP
IMP
Gln
Gly
CO2
Asp
N10fTHFUMP
UMPS
CDP
dCDP
dUMP
Pyrimidine and Purine Salvage
U TPRPP
UMP TMP
RR
UTPT
GPRPP
HGPT
A
APTX
XO
adenosine
inosineADA
HXPNP
urateXO
UTP
CDP
dCDP
dUMPTSN5,N10-mTHF
dTMP
RNA DNA
IMP
GDP ADP
dGTP dATPRR
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 2,8-dihydroxyadenine, 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
hPPGSDVI
hG6PaseGSDI
mPPGSDV
debranching enzymeGSDIII
PFK-1GSDVII
transglycosylasebranching enzyme
GSDIV
GSGSD0
Glycogen
G1P
G6PGlc
UDP-Glc
F6P
F16BP
acid maltaseGSDII
ls
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-1,4-glucosidase); 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-1,6-glucosidase), 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 DisordersRare 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
NANA Gal GlcNAcMan
Man
NANA Gal GlcNAc
NANA Gal GlcNAc
NANA Gal GlcNAcMan GlcNAc
GlcNAc GlcNAc
Fuc
Asn12
3
456
7
8
a
a
a
a
a
a
b
b
b
b
bb b b3
4
4
4
5
5
56
6
6
Typical Asn-GlcNAc OS structure
Aspartylglycosylaminuria4-L-Aspartylglycosylamine
amidohydrolase
a-Mannosidosisa-MannosidaseGM2 gangliosidosis variant O
(Sandhoff-Jatzkewitz disease)b-N-Acetylhexosaminidases A&B
GM1 gangliosidosisb-Galactosidase
Mucolipidosis I (Sialidosis)
Sialidase
b-Mannosidosisb-Mannosidase
Fucosidosisa-Fucosidase
Glycosaminoglycoses(mucopolysaccharidoses)
HS IdUA GlcN GlcUA GlcNAc
OSO3H OSO3H OSO3H
DS IdUA GalNAc GlcUA GalNAc
OSO3H OSO3H OSO3H
a aa
a
b
b b b
1
2
3
5
5
6
7,9
8
9
1
2 4
KS Gal GlcNAc Gal GlcNAc
OSO3H OSO3H OSO3Hb b b10
11
8
4b
Aldurazyme®(laronidase)
Maroteaux-LamyN-acetylgalactosamine sulfatase
Sandhoff/Tay-Sachsb-hexosaminidase A,B,S
Hunter’siduronate sulfatase
Hurler-Scheiea-L-iduronidase
Mucolipodosis VIIb-glucuronidase
Sanfilippo’s Aheparan N-sulfatase
Sanfilippo’s CAcetyl-CoA: a-glucosaminide
acetyltransferase
Sanfilippo’s DN-acetylglucosamine-6-sulfatase
Sanfilippo’s BN-acetylglucosaminidase
Morquio’s AN-acetylgalactose-6-sulfatase
Morquio’s Bb-galactosidase
Gangliosidoses
Cer PC
S + FA
Cer
neuraminidase(sialidase)
GD1Cer GalGlu
NANA
NANA
GalNAc Galbbbb
GM1Cer GalGlu
NANA
GalNAc Galbbbb
GM2Cer GalGlu
NANA
GalNAcbbb
GM3Cer GalGlu
NANA
bb
Cer GalGlubb
Cer Glub
Cer Gal GalGlu abb
Cer Galb
Cer Gal SO3Hb
Cer Gal GalGlu GalNAcabb b
Generalized gangliosidosisb-galactosidase
Tay-Sachs diseaseb-hexosaminidase A
GM2 activator
Sialidosisneuraminidase
(sialidase)SAP-B
b-galactosidaseSAP-B, SAP-C
Gaucher’s diseaseb-glucosylceramidase
SAP-C
Sandhoff’s diseaseb-hexosaminidase A&B
Fabry’s diseasea-galactosidase A
SAP-B
Niemann-Pick diseasesphingomyelinase
Metachromatic leukodystrophyarylsulfatase A
SAP-B
Krabbe’s diseaseb-galactosylceramidase
SAP-A, SAP-CCerezyme
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
mit
Heme Synthesis
SCoA + Gly
5AS
5ALAPBGPBGS
PBGD
HMB
UPGIIIS
UPGIII
UPGIIIDC
CPGIIICPGO
PPGIX
PPIX
PPGO
FC
Heme
Pathway Disorders• 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
• 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
BVRBR
indirectunconjugatedpre-hepatic
HOBVHeme
ER
hepatocyte
directconjugatedpost-hepatic
albumin
albumin-BR
ligandin
albumin
ligandin-BR
BR diglucuronide
UDP-GT
res
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 (Crigler-Najjar 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.