Inborn Errors of Metabolism

1
Inborn Errors of Metabolism

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

2
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.
(1) Which laboratory studies would you order to
obtain quick evidence for or against metabolic
disease?
(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
(3) Based on these results, what type of
metabolic disease is most likely? Which test
would you order next? Urea cycle disease plasma
ammonia
(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

• 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
3
Urea Cycle Disorders
DIET

Carbamoyl Phosphate
Protein
?NH4
HCO3
Hyperammonemia without metabolic acidosis
(usually have respiratory alkalosis)
OTC
Ornithine
Citrulline
UREA CYCLE

• Urea cycle disorders
• Ornithine transcarbamylase deficiency (X-linked)
• Carbamoyl phosphate synthase deficiency (AR)
• Citrullinemia (AR)
• Argininosuccinic acidemia (AR)
• Argininemia (AR)

Asp (N)
Arginine
urea(2N)
Argininosuccinic Acid
OTC deficiency is the most common and is X-linked
4
Headaches, recurrent vomiting, avoids meat
X-linked inheritance, partially affected female
5
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.
(1) Which laboratory studies would you order to
obtain quick evidence for or against metabolic
disease?
(2) You obtain a blood gas, basic metabolic
profile, urinalysis and plasma ammonia which
show the following
136
101
26
Ammonia 646 (0-36)
Capillary blood gas 7.11/CO2 19, HCO3 9, BE - 11
96
UA 3 ketones
10
4.8
0.7
(3) Based on these results, what type of
metabolic disease is most likely? Organic
acidemias (this patient has propionic acidemia)
(4) How would you confirm a specific metabolic
disorder in this case? Urine organic acids,
plasma acylcarnitine profile
6
Organic Acids
Anabolic
Catabolic
ATP
Isoleucine Valine Methionine Cholesterol Odd
chain fatty acids
methylmalonic acidemia
propionic acidemia
biotin
B12
Methylmalonyl CoA
Propionyl CoA
Succinyl CoA
Bicarb is used to buffer the propionic acid,
leading to increased anion gap
Krebs Cycle
isovaleric acidemia
leucine
Isovaleryl CoA
HMG CoA
3MCC
Acetyl CoA
ETS
Even chain fatty acids
ATP
Lysine Tryptophan
glutaric acidemia
Acetyl CoA
Glutaryl CoA
Crotonyl CoA
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
7
Organic acids are metabolized in the
mitochondria blocks in their metabolism lead to
elevation of specific acylcarnitines which are
identified by plasma acylcarnitine profile
Long chain fatty acid
Fatty acid
Detected by acylcarnitine profile
Fatty acyl-CoA
Free carnitine
Fatty acyl-carnitine
Propionyl CoA
propionylcarnitine
Fatty acyl-carnitine
Free carnitine
acetyl CoA
Krebs
CoA
Fatty acyl-CoA
Fatty acid oxidation
ketones
Mitochondrion
Plasma
Cytoplasm
8
Selected Organic Acidemias
Wide anion gap ketoacidosis
Disease
Cofactor
Other features
Propionic Methylmalonic Isovaleric Glutaric Ma
ple 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




Abnormal MRI

9
Glutaric Acidemia Type 1
Severe movement disorder
10
Glutaric acidemia type 1
(patient with viral illness)

• 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 ¼ NS at 1.5 maintenance volume IV carnitine
11
Urea cycle disease versus organic acidemias
UCD
OA
lethargy/coma
vomiting
hyperammonemia
metabolic ketoacidosis
primary respiratory alkalosis





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-

-

12
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.
(1) What is the most likely diagnosis?
Nonketotic hyperglycinemia
(2) How would you confirm the diagnosis? CSF/plasm
a glycine ratio
(3) What is the prognosis? Very poor, despite
treatment
13
Nonketotic hyperglycinemia
Defect in glycine catabolism
Glycine
NH3 CO2

• autosomal recessive
• symptoms in first 24 hours
• hypotonia/encephalopathy, seizures, burst
  suppression EEG
• increased CSF/plasma glycine
• Tx benzoate, dextramethorphan
• poor prognosis, diet ineffective

Diagnosis based on elevated CSF/Plasma glycine
ratio
14
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
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
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 ¼ 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 .
Patient who presented with hypoglycemia and
altered mental status
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
15
Diagnosis of fatty acid oxidation disorders by
acylcarnitine analysis
Long chain fatty acid
Fatty acid
Detected by acylcarnitine analysis
MCAD deficiency
Fatty acyl-CoA
Fatty acyl-carnitine
(C6-C12)
(C6-C12)
Free carnitine
fatty acyl CoAs

Fatty acyl-carnitine
Fatty acyl-carnitine
acetyl CoA
Fatty acyl-CoA
SCAD
18
16
4
14
12
8
6
MCAD
ketones
Mitochondrion
Plasma
Cytoplasm
16
Fatty acid oxidation
Brain
CPT1/CPT2
ketones
Fatty acids
VLCAD LCHAD MCAD SCAD

acetyl CoA
fasting
key pathway for adaptation to fasting
Krebs cycle

• 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

17
LCHAD deficiency
Hypoketotic hyoglycemia, hypotonia, failure to
thrive
At diagnosis
On dietary treatment
18

• 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

19
Fatty acid oxidation disorders
Typical presentation
Disease
Comments
Probably benign
SCAD
N/A
Most common FAOD, may be associated with SIDS
Hypoketotic hypoglycemia
MCAD
VLCAD
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
Diagnosis is based on the specific pattern of
acylcarnitine elevations
20
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

Primary (CUD)
MCAD, organic acidemias etc
Decreased/normal total carnitine Decreased free
carnitine Increased acyl/free ratio
Plasma
Decreased total carnitine Decreased free
carnitine Normal acyl/free ratio
Plasma
Decreased/normal total carnitine Decreased free
carnitine Increased acyl/free ratio
Urine
Normal total carnitine Normal or increased free
carnitine Normal acyl/free ratio
Urine
21
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
Total Bilirubin 19 Direct bilirubin 5.2
AST 987 ALT 767
136
115
26
73
10
4.8
0.7
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
22
Galactose Metabolism

glucose
(cataracts)
galactokinase
Breast milk, cows milk
Galactose
Lactose
Gal-1-P
(galactose-glucose)
UDP glucose
galactose-1-P uridyltransferase
epimerase
(benign)
UDP galactose
(classical)
Glucose-1-P
Treatment galactose free diet, ophthalmology
and developmental followup
Glucose-6-P
glycolysis
pyruvate
23
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
Total Bilirubin 6.4 Direct bilirubin 5.2
AST 767 ALT 987
136
115
26
73
10
4.8
0.7
What is the most likely metabolic
diagnosis? Hereditary fructose intolerance
24
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
25
Glycogen Storage Disease 1a
Von Gierke disease
26
Glycogen Storage Disease 1b
hepatomegaly
facial features
Hypoglycemia, lactic acidosis, hyperuricemia,
hyperlipidemia, neutropenia
weakness
27
Sibling with same disorder
Autosomal recessive
28
Glycogen
Krebs cycle

• Glycogen is a storage form of glucose
• Liver glycogen releases glucose into the
  circulation
• Muscle glycogen is used locally

Lactic acidosis
Acetyl CoA
pyruvate
Glucose 1- P
Malonyl CoA
gluconeogenesis
glycolysis
Stimulates fatty acid synthesis and inhibits
fatty acid breakdown (Hyperlipidemia)
Pentose phosphate shunt (hyperuricemia)
Glucose 6- P
ER
GSD types 1a and 1b
Glucose-6-phosphatase
Glucose
cytoplasm
Glut 2
plasma
glucose
29
Selected glycogen storage diseases
Typical presentation
Disease
Other features
Treatment
Hepatomegaly, lactic acidosis, hyperuricemia,
hyperlipidemia
Von Gierke (GSDIa)
Nocturnal NG feedings, avoid fasting
Puffy cheeks
Hepatomegaly, lactic acidosis, hyperuricemia,
hyperlipidemia
Nocturnal NG feedings, avoid fasting, neutropenia
precautions
GSDIb
Puffy cheeks, neutropenia
Pompei (GSD II)
Weakness, hypotonia, cardiomyopathy
EKG short PR intervals, wide QRS
Enzyme replacement
Similar to Von Gierke but milder, normal lactate
Muscle, including cardiac may be involved
Debrancher deficiency (GSD III)
Similar to GSD1a
Brancher deficiency (GSD IV)
Fatal liver disease (amylopectinosis)
Other organ involvement
? transplant
McCardle disease (GSD VI)
Only muscle involvement
Avoid excess excercise
Risk of rhabdomyolysis
30
Patient with developmental regression
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?

31
Lysosomal storage disease ocular features

• Lysosomal lipid storage disorders associated with
  cherry red macula
• Niemann-Pick A
• Tay-Sachs disease
• GM1 gangliosidosis
• Sandhoff disease
• Farber lipogranulomatosis
• Sialidosis

32
Cell membranes, organelles
Bone, connective tissue, skin, cornea,joints etc
Sphingolipids, glycolipids etc
Mucoploysaccharides (glycosaminoglycans)
Glycoproteins
Glycogen
Bacteria, viruses
Food particles
Acid hydrolases
Lysosome
Abnormal lysosomal storage leads to developmental
regression
The cells wrecking crew
33
Metachromatic Leukodystrophy

• Rapid developmental regression starting in late
  infancy
• Lysosomal accumulation of sulfatides

34
GM1 Gangliosidosis

• Neonatal presentation hypotonia, ascites

35
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
36
Mucopolysaccharidosis

• Hurler Syndrome comparison with sibs

37
Hurler syndrome
38
Mucopolysaccharidosis

• Hurler syndrome alpha L-iduronidase def.

organomegaly
39
Sanfilipo Syndrome (MPS 3)

• facial features

• Sanfilipo (MPS III)
• Less severe somatic features
• Developmental delay
• Behavioral problems
• Neurological regression

40
Maroteaux-Lamy (MPS VI)
41
Maroteaux-Lamy syndrome (MPS6)
42
Morquio (MPS IV)
43
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44
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45
Lysosomal storage disease laboratory diagnosis

• Urine mucopolysaccharides
• Urine oligosaccharide
• Enzyme assay
• DNA (for genetic counseling and to rule out
  pseudoalleles)

46
Typical presentation
Disease
Inheritance
Treatment
Developmental regression, dysosotosis multiplex,
cloudy cornea, organomegaly, cardiac valve disease
Hurler (MPS1)
Autosomal recessive
BMT/ERT
Similar to Hurler but no cloudy cornea
X-linked
Hunter (MPS2)
BMT/ERT
Autosomal recessive
San Filippo (MPS3)
Later onset, mild somatic features
Autosomal recessive
Mainly skeletal involvement
Morquio (MPS4)
?ERT
Maroteaux-Lamy (MPS6)
Autosomal recessive
Similar to Hurler but CNS sparing
BMT/ERT
47
One year old female with failure to thrive,
developmental delay and hypotonia, MRI showed
basal ganglia abnormalities. Labs show mild
elevation of lactate.
48
Mitochondrial genome sequencing mutation
m.8993TgtG in a subunit of ATP synthase
49
Mitochondrial genome disorders

• Maternal inheritance
• Heteroplasmy
• Replicative segregation

50
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

51
PKU Adult with Mental Retardation born before
newborn screening era
PAH
Dietary protein
Phe
Tyr
Neurotransmitters, melanin etc

• Phenylalanine hydroxylase defect
• Autosomal recessive
• Normal infant at birth

Severe mental retardation, microcephaly,
behavioural problems
52
PKU Clinical Problems if Untreated

• mental retardation
• seizures
• hypopigmentation
• rash
• Tx low phenylalanine diet

Due to newborn screening, the above problems
rarely occur.
53
Guthrie cards

• Heel stick
• Obtain at about 48 hours
• If obtained too early, false negative

Filter paper with blood spots and demographic
information
54
Phenylketonuria
Patients with PKU low Phe diet, frequent
monitoring of Phe, dietary counseling

• Studies have shown that NBS has virtually
  eliminated mental retardation due to PKU

Normal growth and development
55
Selected Presentations/Diagnostic Considerations
Lysosomal storage (MPS)
GLYCOGEN STORAGE DISEASE (MUSCLE) Or FAOD
Lysosomal storage (glycolpids))
WEAKNESS RHABDOMYOLYSIS
DEVELOPMENTAL REGRESSION SKELETAL
DYSPLASIA ORGANOMEGALY VARIABLE CLOUDY CORNEA
GLYCOGEN STORAGE DISEASE (LIVER)
HYPOGLYCEMIA HEPATOMEGALY
DEVELOPMENTAL REGRESSION ORGANOMEGALY CHERRY RED
MACULA
HYPERCHLOREMIC METABOLIC ACIDOSIS LIVER
DISEASE CATARACTS HYPERBILIRUBINEMIA REDUCING
SUBSTANCES
INFANT/CHILD WITH SUSPECTED METABOLIC DISEASE
RESPIRATORY ALKALOSIS HYPERAMMONEMIA
UREA CYCLE DISEASE
GALACTOSEMIA

• METABOLIC ACIDOSIS
• HYPOGLYCEMIA
• INAPPROPRIATELY LOW KETONES

KETONES NEGATIVE ENCEPHALOPATY lt 24 HRS OLD,
BURST SUPPRESSION EEG
WIDE ANION GAP METABOLIC ACIDOSIS, KETONURIA,
HYPERAMMONEMIA
FATTY ACID OXIDATION DEFECT
ORGANIC ACIDEMIA
NON KETOTIC HYPERGLYCINEMIA