A 54-year-old female presents to her family
physician's office with a 2 week history of
pain and numbness in her left hand
A 7-year-old boy is brought to the physician
with a recent history of decreased activity
A 63-year-old woman is brought to the
physician for evaluation of her
“parkinsonism”
When do you suspect problems in
metabolic pathways?
Eric Niederhoffer
SIU-SOM
Metabolism in Skeletal
Muscle and Nervous Tissue
•
Metabolism in skeletal muscle
•
Pathways overview
•
Regulation in skeletal muscle
•
Ischemic forearm test
•
Metabolism in nervous tissue
•
Pathways overview
•
Clinical aspects
•
Clinical aspects
•
Clinical/laboratory findings
•
Examples of inherited metabolic disorders
•
Glycogen storage disease type VII
•
Pyruvate dehydrogenase complex deficiency
•
Maple syrup urine disease
•
Inborn errors of metabolism
•
Review questions
Metabolism in
Skeletal Muscle
•Glycolysis
•Glycogenolysis
-oxidation (ketone bodies)
•Krebs (tricarboxylic acid) cycle
•Branched-chain amino acids
•Electron transport chain
•Calcium regulation
•Key enzyme regulation
Pathways Overview
Ketone
bodies
Glucose
Glycogen
Glycolysis
Fatty acids
Glycogenolysis
G6P
Ca2+
Phosphorylase kinase a
Lactate
No O2
Branched-chain
amino acids
Ile, Leu, Val
-Oxidation
Ca2+
PDH
Acetyl-CoA
Pyruvate
Krebs
cycle
Electron
Transport
Chain
Ca2+
ICDH, aKGDH
Production of ATP
Regulation in
Skeletal Muscle
Ep
Glc
AR
Glycolysis
ATP
Citrate
AC
cAMP
PKA
ATP
G6P
Ca2+
Phosphorylase
kinase a
F6P
PFK-2
PP
Pi
IMP
AMP
PFK-1
NH4+
AMP
Pi
F16BP
Glycogen
Glycogenolysis
PEP
PDHP
Ca2+
PDHP
F26BP
PK
-Oxidation
Fatty acids
PDHK
PDH
Pyr
PDH
Acetyl-CoA
Ischemic Forearm Test
• Obtain baseline lactate and ammonia levels
• Inflate blood pressure cuff and perform repetitive rapid grip
exercise
• Once fatigued, remove cuff and obtain blood samples for lactate
and ammonia levels
• Normal result is elevated lactate and ammonia then return to
baseline in 10-15 minutes
Glucose
Glycogen
Glycolysis
Glycogenolysis
G6P
hypoxia
Lactate
Pyruvate
Adenylate kinase
2ADP
ATP
2ATP
Acetyl-CoA
NH4+
AMP
IMP
AMP deaminase
(hypoxia, low energy charge)
Metabolism in
Nervous Tissue
•Glycolysis
•Glycogenolysis (stress)
-oxidation (ketone bodies)
•Krebs (tricarboxylic acid) cycle
•Branched-chain amino acids
•Electron transport chain
Pathways Overview
Glucose
Glycogen
Glycolysis
Glycogenolysis
Lactate
(glial)
Lactate
G6P
No O2
Pyruvate
Branched-chain
amino acids
Ile, Leu, Val
Krebs
cycle
Ketone
bodies
Fatty
acids
-oxidation
Acetyl-CoA
Electron
Transport
Chain
Production of ATP
Clinical Aspects for Inborn
Errors of Metabolism in
Muscles
Toxic accumulation disorders
•Protein metabolism disorders (amino acidopathies, organic
acidopathies, urea cycle defects)
•Carbohydrate/intolerance disorders
•Lysosomal storage disorders
Energy production/utilization disorders
•Fatty acid oxidation defects
•Carbohydrate utilization, production disorders (glycogen
storage, gluconeogenesis, and glycogenolysis disorders)
•Mitochondrial disorders
•Peroxisomal disorders
•Metabolic acidosis (elevated anion gap)
•Hypoglycemia
•Hyperammonemia
Clinical Aspects for Inborn
Errors of Metabolism in
Nervous Tissue
Evidence of familial coincidence
Progressive decline in nervous functioning
Appearance and progression of unmistakable
neurologic signs
General symptoms
•State of consciousness, awareness, reaction to stimuli
•Tone of limbs, trunk (postural mechanisms)
•Certain motor automatisms
•Myotatic and cutaneous reflexes
•Spontaneous ocular movements, fixation, pursuit; visual
function
•Respiration and circulation
•Appetite
•Seizures
Clinical/Laboratory Findings
Clinical findings
AA
OA
UCD
CD
GSD
FAD
LSD
PD
MD
Episodic decompensation
X
+
++
+
X
+
-
-
X
Poor feeding, vomiting,
failure to thrive
X
+
++
+
X
X
+
+
+
Dysmorphic features
and/or skeletal or organ
malformations
X
X
-
-
X
X
+
X
X
Abnormal hair and/or
dermatitis
-
X
X
-
-
-
-
-
-
Cardiomegaly and/or
arrhythmias
-
X
-
-
X
X
+
-
X
Hepatosplenomegaly
and/or splenomegaly
X
+
+
+
+
+
+
X
X
Developmental delay +/neuroregression
+
+
+
X
X
X
++
+
+
Lethargy or coma
X
++
++
+
X
++
-
-
X
Seizures
X
X
+
X
X
X
+
+
X
Hypotonia or hypertonia
+
+
+
+
X
+
X
+
X
Ataxia
-
X
+
X
-
X
X
-
-
Abnormal odor
X
+
X
-
-
-
-
-
-
Primary metabolic
acidosis
X
++
+
+
X
+
-
-
X
Primary respiratory
alkalosis
-
-
+
-
-
-
-
-
-
Hyperammonemia
X
+
++
X
-
+
-
-
X
Hypoglycemia
X
X
-
+
X
+
-
-
X
Liver dysfunction
X
X
X
+
X
+
X
X
X
Reducing substances
X
-
-
+
-
-
-
-
-
Ketones
A
H
A
A
L/A
L
A
A
H/A
Laboratory Findings*
http://emedicine.medscape.com/article/804757-workup
Examples of Inherited
Metabolic Disorders
Pentose Phosphate
Pathway
R5P
nucleotides
Glucose
Glycogen
G6P
Glycolysis
Glycogenolysis
Glycogenesis
Tarui disease
Glycogen Storage Disease Type VII
F6P
PFK
F16BP
PDH complex deficiency
PDH
Pyruvate
Acetyl-CoA
Branched-chain
amino acids
Ile, Leu, Val
Branched-chain a-keto acids
aKMV, aKIC, aKIV
BCaKADH
Maple syrup urine disease
Branched-chain ketoaciduria
Krebs
cycle
Glycogen Storage Disease Type VII
(Tarui Disease)
Classic, infantile onset, Late onset
Exercise intolerance, fatigue, myoglobinuria
Phosphofructokinase
•Tetramer of three subunits (M, L, P)
•Muscle/heart/brain - M4; liver/kidneys - L4; erythrocytes - M4, L4, ML3,
M2L2, M3L
General symptoms of classic form
•Muscle weakness, pronounced following exercise
•Fixed limb weakness
•Muscle contractures
•Jaundice
•Joint pain
Laboratory studies
•Increased serum creatine kinase levels
•No increase in lactic acid levels after exercise
•Bilirubin levels may increase
•Increased reticulocyte count and reticulocyte distribution width
•Myoglobinuria after exercise
•Ischemic forearm test - no lactate increase with ammonia increase
Pyruvate Dehydrogenase Complex
Deficiency
Neonatal, infantile, childhood onset
Abnormal lactate buildup (mitochondrial disease)
Pyruvate dehydrogenase complex
•E1 - a (thiamine dependent) and  subunits, a2 2 tetramer
•E2 - monomer (lipoate dependent)
•E3 - dimer (riboflavin dependent) common to aKGDH and BCαKDH
•X protein - lipoate dependent
•Pyruvate dehydrogenase phosphatase
Nonspecific symptoms (especially with stress, illness, high
carbohydrate intake)
•Severe lethargy, poor feeding, tachypnea
•Key feature is gray matter degeneration with foci of necrosis and
capillary proliferation in the brainstem (Leigh syndrome)
•Infants with less than 15% PDH activity generally die
Developmental nonspecific signs
•Mental delays
•Psychomotor delays
•Growth retardation
Laboratory studies
•High blood and cerebrospinal fluid lactate and pyruvate levels
•Elevated serum and urine alanine levels
•If E2 deficient, elevated serum AAs and hyperammonemia
•If E3 deficient, elevated BCAA in serum, aKG in serum and urine
•Ischemic forearm test – lactate increases baseline
Maple Syrup Urine Disease
(Branched-Chain a-Ketoaciduria)
Classic (early) and late onset (5 clinical phenotypes; classic,
intermediate, intermittent, thiamine-responsive, and E3-deficient)
Encephalopathy and progressive neurodegeneration
Branched-chain a-ketoacid dehydrogenase complex
•E1 - a (thiamine dependent) and  subunits, a2 2 tetramer
•E2 - monomer (lipoate dependent)
•E3 - dimer (riboflavin dependent) common to aKGDH and PDH
•BCαKADH kinase
•BCαKADH phosphatase
Initial symptoms
•Poor feeding, vomiting, poor weight gain, and increasing lethargy
Neurological signs
•Alternating muscular hypotonia and hypertonia, dystonia, seizures,
encephalopathy
Laboratory studies
•Elevated BCAA in serum
•Presence of alloisoleucine in serum
•Presence of a-HIV, lactate, pyruvate, and aKG in urine
Treatment
•Restriction of BCAA
•Supplementation with thiamine
Inborn Errors of Metabolism
Carbohydrates (Glycogen storage diseases)
Amino acids (Maple syrup urine disease)
Organic acids (Alkaptonuria)
Mitochondrial function (Pyruvate dehydrogenase deficiency)
Purines and pyrimidines (Lesch-Nyhan disease)
Lipids (Familial hypercholesterolemia)
Porphyrins (Crigler-Najjar syndromes)
Metals (Hereditary hemochromatosis)
Peroxisomes (X-linked adrenoleukodystrophy)
Lysosomes (GM2 gangliosidoses - Tay Sachs disease)
Hormones (hyperthyroidism)
Blood (Sickle cell disease)
Connective tissue (Marfan syndrome)
Kidney (Alport syndrome)
Lung (a1-antitrypsin deficiency)
Skin (Albinism)
Review Questions
• How does muscle produce ATP
(carbohydrates, fatty acids, ketone
bodies, branched-chain amino acids)?
• How is skeletal muscle
phosphofructokinase-1 regulated?
• What are the key Ca2+ regulated steps?
• How does nervous tissue (neurons and
glial cells) produce ATP
(carbohydrates, fatty acids, ketone
bodies, branched-chain amino acids)?
• How do glial cells (astrocytes) assist
neurons?
• What are some key clinical features
(history, physical, laboratory test
results) associated with defects in
metabolism that affect muscles and
nervous tissue?