Inborn Errors of Metabolism - PowerPoint PPT Presentation

Loading...

PPT – Inborn Errors of Metabolism PowerPoint presentation | free to download - id: 45e4bc-YjhkM



Loading


The Adobe Flash plugin is needed to view this content

Get the plugin now

View by Category
About This Presentation
Title:

Inborn Errors of Metabolism

Description:

... 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 ... – PowerPoint PPT presentation

Number of Views:716
Avg rating:3.0/5.0
Slides: 52
Provided by: ValuedGate746
Category:

less

Write a Comment
User Comments (0)
Transcript and Presenter's Notes

Title: Inborn Errors of Metabolism


1
Inborn Errors of Metabolism
  • Michael Marble, MD
  • Associate 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 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 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? Plasma amino acids
  • You confirm that the patient has OTC 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.

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
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
(4) How would you confirm a specific metabolic
disorder in this case? Urine organic acids,
plasma acylcarnitine profile
6
Organic Acidemias
Organic acids are intermediates in the catabolic
pathways to break down amino acids, lipids and
other compounds to acetyl CoA and succinyl CoA
which are entry points into the Kreb cycle
Isoleucine Valine Methionine Cholesterol Odd
chain fatty acids
biotin
B12
Methylmalonyl CoA
Propionyl CoA
Succinyl CoA
Krebs Cycle
leucine
Isovaleryl CoA
HMG CoA
3MCC
Acetyl CoA
Lysine Tryptophan
Acetyl CoA
Glutaryl CoA
Crotonyl CoA
Urine organic acid analysis will show elevation
of organic acids proximal to the enzymatic block
the resulting pattern is interpreted by the
metabolic laboratory
7
Acylcarnitine analysis for organic acidemias
organic acidemias cause elevations of specific
acylcarnitines
Long chain fatty acid
Fatty acid
Detected by acylcarnitine profile
Fatty acyl-CoA
Free carnitine
Fatty acyl-carnitine
CPT1
Propionyl CoA
propionylcarnitine
Fatty acyl-carnitine
Free carnitine
acetyl CoA
Krebs
Fatty acyl-CoA
Fatty acid oxidation
ketones
Mitochondrion
Plasma
Cytoplasm
8
Selected Organic Acidemias
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
Urea cycle disease versus organic acidemias
UCD
OA
lethargy/coma
vomiting
hyperammonemia
metabolic ketoacidosis
primary respiratory alkalosis





/-

-

-

11
You are called to the newborn nursery regarding
an 8 hour old female infant who is listless and
not interested in feeding. On exam, 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 is performed and 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
12
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
13
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. Initial lab testing showed the
following
CBC WBC mildly elevated CMP shows sodium 144, 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
How would you confirm a specific
diagnosis? Plasma acylcarnitine profile
14
Diagnosis of fatty acid oxidation disorders by
acylcarnitine analysis
Long chain fatty acid
Fatty acid
Detected by acylcarnitine analysis
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
15
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
  • MCAD deficiency 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

16
LCHAD deficiency
Hypoketotic hyoglycemia, hypotonia, failure to
thrive
At diagnosis
On dietary treatment
17
  • 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

18
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
19
Diagnosis of fatty acid oxidation disorders by
acylcarnitine analysis
Long chain fatty acid
Fatty acid
Detected by acylcarnitine analysis
Fatty acyl-CoA
Fatty acyl-carnitine
CPT1
(C6-C12)
(C6-C12)
CPT2
CACT
FC
fatty acyl CoAs

Fatty acyl-carnitine
Fatty acyl-carnitine
acetyl CoA
Fatty acyl-CoA
MCAD
SCAD
LCHAD
VLCAD
16
4
14
12
10
ketones
Mitochondrion
Plasma
Cytoplasm
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 causes 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
An infant with apparently normal development for
the first 6 months begins to slow down. She was
able to sit unassisted by 1 year. She was very
socially interactive and could grasp objects.
After one year she gradually lost her ability to
sit and she could no longer grasp objects. She
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
  • GM1 gangliosidosis
  • Tay-Sachs disease
  • 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 a history of 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 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
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 (MPS VI)
42
Morquio (MPS IV)
43
(No Transcript)
44
(No Transcript)
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
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
48
PKU Clinical Problems if Untreated
  • mental retardation
  • seizures
  • hypopigmentation
  • rash
  • Tx low phenylalanine diet

Due to newborn screening, the above problems
rarely occur.
49
Guthrie cards
  • Heel stick
  • Obtain at about 48 hours
  • If obtained too early, false negative

Filter paper with blood spots and demographic
information
50
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
51
Selected Presentations/Diagnostic Considerations
Lysosomal storage (MPS)
GLYCOGEN STORAGE DISEASE (MUSCLE)
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
About PowerShow.com