Download Inborn Errors of Metabolic Etiology

Inborn Errors of Metabolism
Michael Marble, MD
Professor of Clinical Pediatrics
Division of Clinical Genetics
Department of Pediatrics, LSUHSC
and Children’s 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.
(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
(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+
+
Hyperammonemia
without metabolic
acidosis (usually have
respiratory alkalosis)
Ornithine
•Carbamoyl phosphate
synthase deficiency (AR)
•Citrullinemia (AR)
OTC
Citrulline
UREA
Urea cycle disorders:
•Ornithine
transcarbamylase
deficiency (X-linked)
Carbamoyl
Phosphate
HCO3
Arginine
CYCLE
urea(2N)
Argininosuccinic
Acid
•Argininosuccinic acidemia
(AR)
•Argininemia (AR)
OTC deficiency is the
most common and is Xlinked
Asp
(N)
Headaches, recurrent vomiting,
avoids meat
X-linked inheritance, partially
affected female
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 96
4.8 10 0.7
Capillary blood gas:
UA 3+ ketones
7.11/CO2 19, HCO3 9, BE - 11
(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
Ammonia 646
(0-36)
Organic Acids
Anabolic
Catabolic
ATP
propionic
acidemia
Isoleucine
Valine
methylmalonic
acidemia
biotin
Propionyl CoA
Methionine
Cholesterol
B12
Methylmalonyl CoA
Succinyl CoA
Bicarb is used to buffer the
propionic acid, leading to
increased anion gap
Odd chain fatty
acids
Krebs
Cycle
isovaleric
acidemia
leucine
Isovaleryl CoA
3MCC
HMG CoA
Acetyl CoA
ETS
Even chain fatty acids
Lysine
Tryptophan
glutaric
acidemia
Glutaryl CoA
Crotonyl CoA
Acetyl
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
ATP
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
Fatty acyl-carnitine
CoA
propionylcarnitine
Free carnitine
acetyl
CoA
Fatty acyl-CoA
Fatty acid
oxidation
Mitochondrion
Plasma
Cytoplasm
ketones
Krebs
Selected Organic Acidemias
Disease
Cofactor
Other features
Wide anion gap
ketoacidosis
Propionic
biotin
Usually severe
+
Methylmalonic
B12
Some respond to B12
+
Isovaleric
riboflavin
Sweaty foot odor to urine
+
Glutaric
riboflavin
Macrocephaly, dystonia,
Abnormal MRI
+
Maple syrup
urine
thiamine
Maple syrup odor,
elevated branched chain
amino acids
+
Glutaric Acidemia Type 1
Severe
movement
disorder
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
Urea cycle disease versus organic
acidemias
UCD
OA
+
+
+
++
+
+/-
metabolic
ketoacidosis
-
+
primary
respiratory
alkalosis
+
-
lethargy/coma
vomiting
hyperammonemia
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/plasma glycine ratio
(3) What is the prognosis?
Very poor, despite treatment
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
*Diagnosis based on elevated
CSF/Plasma glycine ratio
Glycine
NH3 + CO2
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 patient’s 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
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
Fatty acyl-carnitine
Free
carnitine
+
(C6-C12)
fatty acyl
CoAs
(C6-C12)
Fatty acyl-carnitine
acetyl
CoA
Fatty acyl-CoA
SCAD
18
16 14 12
8 6
4
MCAD
Mitochondrion
Plasma
Cytoplasm
ketones
Fatty acid oxidation
Brain
CPT1/CPT2
Fatty
acids
VLCAD
LCHAD MCAD
fasting
*key pathway for
adaptation to fasting
•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
SCAD
ketones
+
acetyl CoA
Krebs
cycle
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
Fatty acid oxidation disorders
Disease
Typical
presentation
SCAD
Probably benign
MCAD
Hypoketotic
hypoglycemia
Most common FAOD, may
be associated with “SIDS”
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
Comments
N/A
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
Primary (CUD)
Plasma:
Decreased total carnitine
Decreased free carnitine
Normal acyl/free ratio
Urine:
Normal total carnitine
MCAD, organic acidemias etc
Plasma: Decreased/normal total
carnitine
Decreased free carnitine
Increased acyl/free ratio
Urine: Decreased/normal total
carnitine
Normal or increased free
carnitine
Decreased free carnitine
Normal acyl/free ratio
Increased acyl/free ratio
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
136 115 26
4.8 10 0.7
73
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
Galactose Metabolism
glucose
Breast
milk,
cow’s
milk
Lactose
(galactose-glucose)
Galactose
(cataracts)
galactokinase
epimerase
(benign)
Treatment: galactose free
diet, ophthalmology and
developmental followup
Gal-1-P
UDP glucose
galactose-1-P
uridyltransferase
UDP galactose
(classical)
Glucose-1-P
Glucose-6-P
glycolysis
pyruvate
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
136 115 26
4.8 10 0.7
73
Direct
bilirubin 5.2
What is the most likely metabolic diagnosis?
Hereditary fructose intolerance
AST 767
ALT 987
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”
Glycogen Storage
Disease 1b
facial features
weakness
hepatomegaly
Hypoglycemia,
lactic acidosis,
hyperuricemia,
hyperlipidemia,
neutropenia
Sibling with same disorder
Autosomal recessive
Glycogen
Krebs
cycle
Glycogen is a storage
form of glucose:
Lactic acidosis
•Liver glycogen
releases glucose into
the circulation
•Muscle glycogen is
used locally
Acetyl
CoA
Glucose – 1- P
pyruvate
Malonyl
CoA
gluconeogenesis
glycolysis
Pentose
phosphate
shunt
Stimulates fatty acid
synthesis and inhibits
fatty acid breakdown
(Hyperlipidemia)
Glucose – 6- P
ER
(hyperuricemia)
Glucose
cytoplasm
Glut 2
plasma
glucose
Glucose-6phosphatase
GSD types
1a and 1b
Selected glycogen storage diseases
Disease
Typical
presentation
Von Gierke
(GSDIa)
Hepatomegaly, lactic acidosis,
hyperuricemia, hyperlipidemia
GSDIb
Hepatomegaly, lactic acidosis,
hyperuricemia, hyperlipidemia
Pompei
(GSD II)
Weakness, hypotonia,
cardiomyopathy
Other features
Puffy
cheeks
Puffy cheeks, neutropenia
Treatment
Nocturnal NG
feedings, avoid
fasting
Nocturnal NG feedings,
avoid fasting,
neutropenia precautions
EKG: short PR
intervals, wide QRS
Enzyme
replacement
Debrancher
deficiency (GSD III)
Similar to Von Gierke
but milder, normal
lactate
Muscle, including
cardiac may be
involved
Similar to GSD1a
Brancher deficiency
(GSD IV)
Fatal liver disease
(amylopectinosis)
Other organ
involvement
? transplant
McCardle disease
(GSD VI)
Only muscle
involvement
Risk of rhabdomyolysis
Avoid excess
excercise
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?
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
Cell
membranes,
organelles
Bone, connective
tissue, skin,
cornea,joints etc
Mucoploysaccharides
(glycosaminoglycans)
Sphingolipids,
glycolipids etc
Glycoproteins
Glycogen
Food
particles
Acid hydrolases
Lysosome
Abnormal
lysosomal storage
leads to
developmental
regression
“The cells wrecking
crew”
Bacteria,
viruses
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)
MaroteauxLamy 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
Hurler (MPS1)
Developmental regression,
dysosotosis multiplex, cloudy cornea,
organomegaly, cardiac valve disease
Hunter (MPS2)
Similar to Hurler but no cloudy
cornea
San Filippo
(MPS3)
Later onset, mild
somatic features
Inheritance
Treatment
Autosomal
recessive
BMT/ERT
X-linked
BMT/ERT
Autosomal
recessive
Morquio (MPS4)
Mainly skeletal
involvement
Autosomal
recessive
Maroteaux-Lamy
(MPS6)
Similar to Hurler but
“CNS sparing”
Autosomal
recessive
?ERT
BMT/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
•Maternal
inheritance
•Heteroplasmy
•Replicative
segregation
Mitochondrial genome
disorders
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
PAH
Dietary
protein
Phe
Tyr
Neurotransmitters,
melanin etc
•Phenylalanine hydroxylase defect
•Autosomal recessive
•Normal infant at birth
Severe mental
retardation,
microcephaly,
behavioural
problems
PKU: Clinical Problems if
Untreated
• mental retardation
• seizures
• hypopigmentation
• rash
Tx: low phenylalanine diet
*Due to newborn screening, the above problems
rarely occur.
“Guthrie cards”
Heel stick:
•Obtain at about
48 hours
•If obtained too
early, false
negative
Filter paper
with blood
spots and
demographic
information
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
Selected Presentations/Diagnostic Considerations
Lysosomal storage
(glycolpids))
DEVELOPMENTAL
REGRESSION
ORGANOMEGALY
CHERRY RED MACULA
RESPIRATORY ALKALOSIS
HYPERAMMONEMIA
Lysosomal storage
(MPS)
DEVELOPMENTAL
REGRESSION
SKELETAL DYSPLASIA
ORGANOMEGALY
VARIABLE CLOUDY CORNEA
ORGANIC
ACIDEMIA
HYPOGLYCEMIA
HEPATOMEGALY
INFANT/CHILD WITH
SUSPECTED
METABOLIC DISEASE
GLYCOGEN
STORAGE
DISEASE (LIVER)
HYPERCHLOREMIC
METABOLIC ACIDOSIS
LIVER DISEASE
CATARACTS
HYPERBILIRUBINEMIA
REDUCING SUBSTANCES
GALACTOSEMIA
UREA CYCLE
DISEASE
WIDE ANION GAP
METABOLIC ACIDOSIS,
KETONURIA,
HYPERAMMONEMIA
WEAKNESS
RHABDOMYOLYSIS
GLYCOGEN
STORAGE
DISEASE (MUSCLE)
Or FAOD
KETONES NEGATIVE
ENCEPHALOPATY < 24 HRS
OLD, BURST SUPPRESSION
EEG
NON KETOTIC
HYPERGLYCINEMIA
METABOLIC
ACIDOSIS
HYPOGLYCEMIA
INAPPROPRIATELY LOW
KETONES
FATTY ACID
OXIDATION
DEFECT