Inborn Errors of Metabolism

Michael Marble, MD
Professor of Clinical Pediatrics
Division of Clinical Genetics
Department of Pediatrics, LSUHSC
and Childrens Hospital

A 3 day old male is brought to the emergency room with a history of lethargy
progressing to unresponsiveness. You take an initial history which reveals
that the baby had been feeding normally for 24 hours but thereafter became
irritable and lost interest in feeding. On exam, you notice that he is
breathing fast and deep and is unresponsive. Along with other possible
diagnoses, you suspect metabolic disease.
(4) Plasma ammonia result is 1400 micromole/L (0-80). What is the most likely
diagnosis? Which tests would you send to confirm a specific metabolic disorder?
Ornithine transcarbamylase deficiency. Plasma amino acids, urine orotic acid

(2) You obtain a complete metabolic profile which shows a normal result. Urinalysis
shows elevated specific gravity but is otherwise normal. Capillary blood gas shows
respiratory alkalosis: 7.53/ pCO2 20/HCO3 nl, BE nl
(1) Which laboratory studies would you order to obtain quick evidence for or against
metabolic disease?
(3) Based on these results, what type of metabolic disease is most likely? Which test
would you order next?
Urea cycle disease; plasma ammonia
(5) You confirm that the patient has ornithine transcarbamylase deficiency. What
is the recurrence risk in the next pregnancy? Who else in the family should be
tested?
X-linked inheritance therefore 50% recurrence risk if mother is a carrier.
(6) What is the treatment?
Hemodialysis, low protein diet, arginine, phenylbutyrate
Urea Cycle Disorders
DIET
Protein NH4
+
+ HCO
3

Carbamoyl
Phosphate
Ornithine
Citrulline
Argininosuccinic
Acid
Arginine
urea(2N)
UREA
CYCLE
Asp
(N)
OTC
Urea cycle disorders:
Ornithine
transcarbamylase
deficiency (X-linked)
Carbamoyl phosphate
synthase deficiency (AR)
Citrullinemia (AR)
Argininosuccinic acidemia
(AR)
Argininemia (AR)
Hyperammonemia
without metabolic
acidosis (usually have
respiratory alkalosis)
OTC deficiency is the
most common and is X-
linked
X-linked inheritance, partially
affected female
Headaches, recurrent vomiting,
avoids meat
A 3 day old male is brought to the emergency room with a history of lethargy progressing to
unresponsiveness. You take an initial history which reveals that the baby had been feeding
normally for 24 hours but thereafter became irritable and progressively less interested in
feeding. On exam, you notice immediately that he is breathing fast and deep and is
unresponsive. Along with other possible diagnoses, you suspect metabolic disease.
(2) You obtain a blood gas, basic metabolic profile, urinalysis and plasma
ammonia which show the following:
(1) Which laboratory studies would you order to obtain quick evidence for
or against metabolic disease?
(3) Based on these results, what type of metabolic disease is most likely?
Organic acidemias (this patient has propionic acidemia)
136
10 4.8
101 26
0.7
96
UA 3+ ketones
Ammonia 646
(0-36)
Capillary blood gas:
7.11/CO2 19, HCO3 9, BE - 11
(4) How would you confirm a specific metabolic disorder
in this case?
Urine organic acids, plasma acylcarnitine profile
Isoleucine
Valine
Methionine
Cholesterol
Odd chain fatty
acids
leucine
Isovaleryl CoA HMG CoA
Acetyl CoA
Krebs
Cycle
Methylmalonyl CoA Propionyl CoA Succinyl CoA
biotin B12
Lysine
Tryptophan
Glutaryl CoA Crotonyl CoA
3MCC
Acetyl
CoA
Bicarb is used to buffer the
propionic acid, leading to
increased anion gap
methylmalonic
acidemia
propionic
acidemia
isovaleric
acidemia
glutaric
acidemia
ETS
ATP
Even chain fatty acids
Anabolic
Catabolic
ATP
Organic Acids
Organic acids are the intermediates in the catabolism
of amino acids, lipids and other compounds; specific
enzyme deficiencies lead to characteristic urine organic
acid profiles
Long chain
fatty acid
Fatty
acid
Fatty acyl-CoA
Fatty acyl-carnitine
Fatty acyl-carnitine
Fatty acyl-CoA
acetyl
CoA
ketones
Free carnitine
Plasma Cytoplasm
Mitochondrion
Krebs
Free carnitine
Detected by
acylcarnitine profile
Propionyl
CoA
propionylcarnitine
Fatty acid
oxidation
Organic acids are metabolized in the mitochondria; blocks in
their metabolism lead to elevation of specific acylcarnitines
which are identified by plasma acylcarnitine profile
CoA
Selected Organic Acidemias

Propionic

Methylmalonic

Isovaleric

Glutaric

Maple syrup
urine


biotin

B12

riboflavin

riboflavin

thiamine


Usually severe

Some respond to B12

Sweaty foot odor to urine

Macrocephaly, dystonia,

Maple syrup odor,
elevated branched chain
amino acids






Disease Cofactor Other features
Abnormal MRI
Wide anion gap
ketoacidosis
+
+
+
+
+
Glutaric Acidemia Type 1

Severe
movement
disorder
Intercurrent illnesses (usually viral)
greatly increase the risk of metabolic
encephalopathy and long term
disability; therefore preventive
measures against catabolism are
critical

The parents of organic acidemia
patients should be given emergency
protocols for management during
intercurrent illnesses
D10 + NS at 1.5
maintenance volume;
IV carnitine
Glutaric acidemia type 1
(patient with viral illness)
Urea cycle disease versus organic
acidemias
lethargy/coma
vomiting
hyperammonemia
metabolic
ketoacidosis
primary
respiratory
alkalosis
UCD
OA
+ +/-
+
+
+
+
+ +
-
-
+
You are called to the newborn nursery regarding an 8 hour old female who
is listless and not interested in feeding. The baby is severely hypotonic and
lethargic but no other obvious abnormalities are noted. Accucheck shows
normal glucose. Blood gas, complete metabolic profile, CBC, plasma
ammonia, lactate and urinalysis all show normal results. Chest X-ray
comes back normal. Along with other possibilities, you suspect a
neuromuscular disorder and consult neurology. Maintenance IVFs are
started. Pregnancy history is significant for decreased fetal movements.
While awaiting neurology consult, the baby has apnea spells and develops
myoclonic jerks. and is intubated. An EEG shows a burst suppression
pattern.
(2) How would you confirm the diagnosis?
CSF/plasma glycine ratio
(3) What is the prognosis?
Very poor, despite treatment
(1) What is the most likely diagnosis?
Nonketotic hyperglycinemia
Nonketotic hyperglycinemia
*Defect in glycine
catabolism
autosomal recessive
symptoms in first 24 hours
hypotonia/encephalopathy,
seizures, burst suppression EEG
increased CSF/plasma glycine
Tx: benzoate,
dextramethorphan
poor prognosis, diet ineffective
Glycine
NH3 + CO2
*Diagnosis based on elevated
CSF/Plasma glycine ratio
A 15 month old female, previously healthy, was brought to the emergency room after the
mother had difficulty arousing her in the morning. Over the past 2 days, the child had had
a low grade fever, cough, mild diarrhea and 3 episodes of vomiting. Due to poor appetite,
the patient did not eat very much for dinner and missed her ususal bedtime snack the night
before presentation. In the ER, she was noted to have a depressed mental status but was
partially responsive. Exam was otherwise normal. Initial lab testing showed the following:
The ER physician starts an IV and gives a bolus
of glucose to correct hypoglycemia. The
physician also gives normal saline boluses for
rehydration. Then IVFs with D5 normal saline
is started at 1.5 maintenance fluids. Followup
labs show normal serum glucose but no change
in acid-base status. The patients mental status
worsens and she becomes comatose. She is
transferred to the PICU. Plasma ammonia level is
found to be mildly elevated at 101 micromoles/L .
CBC: WBC mildly elevated
CMP shows sodium 139, Cl 104, CO2 13
BUN 28 Cre 0.6, glucose 37, mild elevation of
ALT and AST
Urinalysis negative for reducing substances
and ketones, specific gravity is elevated
Based on the above presentation and lab results, the patient most likely
has a disorder within which category of inborn error of metabolism?
Fatty acid oxidation defects (specifically MCAD in this patient)
How would you confirm a specific diagnosis?
Plasma acylcarnitine profile
Patient who presented with
hypoglycemia and altered
mental status
Diagnosis of fatty acid oxidation disorders
by acylcarnitine analysis
Long chain
fatty acid
Fatty
acid
Fatty acyl-CoA
Fatty acyl-carnitine
Fatty acyl-carnitine
Fatty acyl-CoA
MCAD
SCAD
acetyl
CoA
ketones
Free
carnitine
Plasma Cytoplasm
Mitochondrion
18 16
14 12 8 6
4
fatty acyl
CoAs
+
Fatty acyl-carnitine
(C6-C12) (C6-C12)
Detected by
acylcarnitine
analysis
MCAD
deficiency
Fatty
acids
fasting
ketones
acetyl CoA
Krebs
cycle
*key pathway for
adaptation to fasting
VLCAD LCHAD MCAD SCAD
CPT1/CPT2
+
Brain
Fatty acid oxidation
Distinguishing feature of FAOD is
hypoketotic hypoglycemia
Medium chain acyl CoA dehydrogenase
deficiency(MCAD) is most common and
has a 25% risk of death with first episode
LCHAD, VLCAD and carnitine uptake
disorder are variably associated with,
hepatomegaly, liver disease, hypertrophic
cardiomyopathy and potential
arrythmias
All are autosomal recessive

LCHAD deficiency
Hypoketotic hyoglycemia, hypotonia, failure to thrive
At
diagnosis
On
dietary
treatment
Variable Clinical presentations of
fatty acid oxidation
Hyoketotic hypoglycemia in neonatal
period
Later onset hypoketotic hypoglycemia
Sudden infant death syndrome
Hypertrophic cardiomyopathy,
arrythmias
Liver disease
Adolescent or adult onset myopathy
Acute rhabdomyolysis
Asymptomatic

Disease
Typical
presentation
Comments
Probably benign
Most common FAOD, may
be associated with SIDS
SCAD
MCAD
VLCAD
Hypoketotic
hypoglycemia
N/A
Variable: hypoketotic
hypoglycemia,
hypertrophic
cardiomyopathy,
myopathy, liver dz
Extemely variable
ranging from neonatal to
adult onset
LCHAD
Variable: hypoketotic
hypoglycemia,
hypertrophic
cardiomyopathy,
myopathy, liver dz
Extremely variable,
need low fat diet
Fatty acid oxidation disorders
Diagnosis is based on the specific
pattern of acylcarnitine elevations
Disorders of carnitine metabolism
(1) Carnitine transports long chain fatty acids into the
mitochondria
(2) Carnitine deficiency can be primary or secondary
(3) Primary carnitine deficiency is caused by abnormal
transport of carnitine itself into the cells (carnitine uptake
disorder, AKA systemic carnitine deficiency)
(4) Secondary carnitine deficiency is caused by other
metabolic disorders through the formation of carnitine
esters (acylcarnitines) by abnormal organic/fatty acids
Decreased total carnitine
Decreased free carnitine
Normal acyl/free ratio
Normal total carnitine
Normal or increased free
carnitine
Normal acyl/free ratio
Plasma:
Urine:
Primary (CUD)
Decreased/normal total
carnitine
Decreased free carnitine
Increased acyl/free ratio
Decreased/normal total
carnitine
Decreased free carnitine
Increased acyl/free ratio
Plasma:
Urine:
MCAD, organic acidemias etc
A 6 day old female who is breast fed is brought to the
emergency room due to poor feeding, vomiting and jaundice?
Initial laboratory studies show the following:
136
10 4.8
115 26
0.7
73
Total
Bilirubin 19
Direct
bilirubin 5.2
AST 987
ALT 767
Which metabolic disorder do you suspect?
galactosemia
Which other routine tests should you order?
PT, PTT, urine reducing substances
How would you confirm the diagnosis?
Enzyme assay, DNA
How would you treat this patient?
Galactose free diet
What are the acute and long term complications of this
disorder?
Liver disease, E coli sepsis, cataracts, MR, speech
delay, ovarian failure



Lactose
Galactose
glucose
Gal-1-P
galactokinase
(galactose-glucose)
Glucose-1-P
glycolysis
galactose-1-P
uridyltransferase
UDP galactose
UDP glucose
pyruvate
epimerase
(cataracts)
(classical)
(benign)
Breast
milk,
cows
milk
Glucose-6-P
Galactose Metabolism
Treatment: galactose free
diet, ophthalmology and
developmental followup
A 9 year old male is brought to the emergency room due to acute
vomiting and lethargy shortly after a birthday party. Past medical
history is significant for failure to thrive in late infancy which
resolved without determination of a diagnosis. He had had several
bouts of vomiting in the past, usually after consuming candy or soft
drinks at parties. He has had no dental cavities. Laboratory results
in the ER are as follows:
136
10 4.8
115 26
0.7
73
Total
Bilirubin 6.4
Direct
bilirubin 5.2
AST 767
ALT 987
What is the most likely metabolic diagnosis?
Hereditary fructose intolerance

A 3 month old female is found to have hepatomegaly on routine exam. She
is asymptomatic. Lab testing shows hypoglycemia, lactic acidemia,
hyperuricemia, hyperlipidemia and elevated AST and ALT.
What is the most likely diagnosis?
Glycogen storage disease

How would you confirm the diagnosis?
DNA, liver biopsy

What is the treatment?
dietary
Glycogen Storage Disease 1a
Von Gierke
disease
weakness
hepatomegaly facial features
Hypoglycemia,
lactic acidosis,
hyperuricemia,
hyperlipidemia,
neutropenia
Glycogen Storage
Disease 1b
Sibling with same disorder
Autosomal recessive
Glycogen
Glucose 1- P
Glucose 6- P
Glucose-6-
phosphatase
Glucose
Glut 2
glucose
cytoplasm
plasma
pyruvate
Lactic acidosis
gluconeogenesis
glycolysis
Pentose
phosphate
shunt
(hyperuricemia)
GSD types
1a and 1b
ER
Glycogen is a storage
form of glucose:
Liver glycogen
releases glucose into
the circulation
Muscle glycogen is
used locally
Krebs
cycle
Acetyl
CoA
Malonyl
CoA
Stimulates fatty acid
synthesis and inhibits
fatty acid breakdown
(Hyperlipidemia)
Disease
Typical
presentation
Other features
Hepatomegaly, lactic acidosis,
hyperuricemia, hyperlipidemia
Puffy cheeks, neutropenia
Von Gierke
(GSDIa)
GSDIb
Pompei
(GSD II)

Puffy
cheeks
Weakness, hypotonia,
cardiomyopathy
EKG: short PR
intervals, wide QRS
Similar to Von Gierke
but milder, normal
lactate
Muscle, including
cardiac may be
involved
Hepatomegaly, lactic acidosis,
hyperuricemia, hyperlipidemia
Debrancher
deficiency (GSD III)
McCardle disease
(GSD VI)
Only muscle
involvement
Risk of rhabdomyolysis
Brancher deficiency
(GSD IV)
Fatal liver disease
(amylopectinosis)
Other organ
involvement
Selected glycogen storage diseases
Treatment
Nocturnal NG
feedings, avoid
fasting
Nocturnal NG feedings,
avoid fasting,
neutropenia precautions

Enzyme
replacement
Similar to GSD1a
? transplant
Avoid excess
excercise
Apparently normal development for the first 6
months but begins to slow down. She was able
to sit unassisted by 1 year. She was very
socially interactive and could grasp objects.
Gradually lost her ability to sit and grasp
objects. Became less and less interactive, and
lost interest in eating and became emaciated.
She had splenomegaly. Ophthalmology exam
revealed a cherry red spot macula:
What type of disorder do you
suspect?
Lysosomal storage disease
How would you confirm a
diagnosis?
Enzyme assay
What is the differential
diagnosis of cherry red
macula?
Patient with developmental
regression
Lysosomal lipid storage
disorders associated with
cherry red macula:
Niemann-Pick A
Tay-Sachs disease
GM1 gangliosidosis
Sandhoff disease
Farber lipogranulomatosis
Sialidosis
Lysosomal storage disease: ocular
features
Mucoploysaccharides
(glycosaminoglycans)
Bone, connective
tissue, skin,
cornea,joints etc
Cell
membranes,
organelles
Bacteria,
viruses
Lysosome
Sphingolipids,
glycolipids etc
Food
particles
Glycoproteins
Acid hydrolases
The cells wrecking
crew
Glycogen
Abnormal
lysosomal storage
leads to
developmental
regression
Metachromatic
Leukodystrophy
Rapid developmental
regression starting in late
infancy
Lysosomal accumulation of
sulfatides
GM1 Gangliosidosis
Neonatal presentation: hypotonia, ascites
A 14 month old female presented with developmental delay to your clinic.
She was reportedly normal at birth but at 8 months was noted to have
mild kyphosis when sitting. She had chronic rhinorrhea. Late in infancy,
the parents noticed gradual changes in craniofacial features including
thickening of the eyebrows, large tongue, prominence of forehead. The
patient hand been pulling to stand but lost this ability and seemed to be
regressing in overall development. On exam, you notice a scaphocephalic
head shape, frontal bossing, relatively thick eyebrows, cloudy cornea and
stiff elbows.
The patient most likely has a disorder within which category of
inborn error of metabolism?
Lysosomal storage disease (mucopolysaccharidosis)
How would you confirm a specific diagnosis?
Enzyme assay, urine mucopolysaccharies (glycosaminoglycans),
skeletal survey
Mucopolysaccharidosis
Hurler Syndrome: comparison with sibs
Hurler syndrome
Mucopolysaccharidosis
Hurler syndrome alpha L-iduronidase def.
organomegaly
Sanfilipo Syndrome (MPS 3)
facial features
Sanfilipo (MPS III)
Less severe somatic
features
Developmental delay
Behavioral problems
Neurological regression
Maroteaux-Lamy (MPS VI)
Maroteaux-
Lamy syndrome
(MPS6)
Morquio (MPS IV)
Lysosomal storage disease:
laboratory diagnosis
Urine mucopolysaccharides
Urine oligosaccharide
Enzyme assay
DNA (for genetic counseling and to rule
out pseudoalleles)
Disease
Typical
presentation
Inheritance
Developmental regression,
dysosotosis multiplex, cloudy cornea,
organomegaly, cardiac valve disease
Hurler (MPS1)
Hunter (MPS2)
San Filippo
(MPS3)

Autosomal
recessive
Later onset, mild
somatic features
Mainly skeletal
involvement
Similar to Hurler but no cloudy
cornea
Morquio (MPS4)
Maroteaux-Lamy
(MPS6)
Similar to Hurler but
CNS sparing
Treatment
X-linked
Autosomal
recessive
Autosomal
recessive
Autosomal
recessive
BMT/ERT
BMT/ERT
BMT/ERT
?ERT
One year old female with failure to thrive, developmental delay and
hypotonia, MRI showed basal ganglia abnormalities. Labs show mild
elevation of lactate.
Mitochondrial genome sequencing: mutation
m.8993T>G in a subunit of ATP synthase
Mitochondrial genome
disorders
Maternal
inheritance
Heteroplasmy
Replicative
segregation
Mitochondrial genome
disorders
Myoclonic epilepsy, lactic acidosis, stroke-like
episodes (MELAS)
Myoclonic epilepsy ragged red fibers
(MERRF)
Neuropathy, ataxia, retinintis pigmentosa
(NARP)
Nonsyndromic deafness/diabetes
Kearn Sayres: sporadic giant deletions
Pearson syndrome: sporadic giant deletions
Leigh syndrome
other
PKU Adult with Mental
Retardation: born before
newborn screening era
Severe mental
retardation,
microcephaly,
behavioural
problems
Phenylalanine hydroxylase defect
Autosomal recessive
Normal infant at birth
Phe Tyr
Dietary
protein
PAH
Neurotransmitters,
melanin etc
PKU: Clinical Problems if
Untreated
mental retardation
seizures
hypopigmentation
rash
Tx: low phenylalanine diet
*Due to newborn screening, the above problems
rarely occur.
Heel stick:
Obtain at about
48 hours
If obtained too
early, false
negative
Filter paper
with blood
spots and
demographic
information
Guthrie cards
Patients with PKU: low Phe diet, frequent
monitoring of Phe, dietary counseling
Normal growth and development
Studies have shown that
NBS has virtually
eliminated mental
retardation due to PKU
Phenylketonuria
HYPERCHLOREMIC
METABOLIC ACIDOSIS
LIVER DISEASE
CATARACTS
HYPERBILIRUBINEMIA
REDUCING SUBSTANCES
Selected Presentations/Diagnostic Considerations
INFANT/CHILD WITH
SUSPECTED
METABOLIC DISEASE
KETONES NEGATIVE
ENCEPHALOPATY < 24 HRS
OLD, BURST SUPPRESSION
EEG
METABOLIC
ACIDOSIS
HYPOGLYCEMIA
INAPPROPRIATELY LOW
KETONES
RESPIRATORY ALKALOSIS
HYPERAMMONEMIA
FATTY ACID
OXIDATION
DEFECT
ORGANIC
ACIDEMIA
UREA CYCLE
DISEASE
GALACTOSEMIA
NON KETOTIC
HYPERGLYCINEMIA
HYPOGLYCEMIA
HEPATOMEGALY
GLYCOGEN
STORAGE
DISEASE (LIVER)
DEVELOPMENTAL
REGRESSION
SKELETAL DYSPLASIA
ORGANOMEGALY
VARIABLE CLOUDY CORNEA
Lysosomal storage
(MPS)
WIDE ANION GAP
METABOLIC ACIDOSIS,
KETONURIA,
HYPERAMMONEMIA
DEVELOPMENTAL
REGRESSION
ORGANOMEGALY
CHERRY RED MACULA
Lysosomal storage
(glycolpids))
WEAKNESS
RHABDOMYOLYSIS
GLYCOGEN
STORAGE
DISEASE (MUSCLE)
Or FAOD