Transcript Inborn errors of metabolism

F Ahmadabadi
Child Neurologist
ARUMS
2014
INBORN ERRORS OF
METABOLISM
 Every child with unexplained . . .
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Neurological deterioration
Metabolic acidosis
Hypoglycemia
Inappropriate ketosis
Hypotonia
Cardiomyopathy
Hepatocellular dysfunction
Failure to thrive
. . . should be suspected of having a metabolic disorder
When to suspect an IEM?
Clinical:
 Vomiting
 Lethargy
 FTT
 Seizure
 Respiratory
 Coma
 Cardiomyopathy
 Odor
 Abnormal hair
 Dysmorphology
Labs:
 Metabolic acidosis
 Hypoglycemia
 Hyperammonemia
 Reducing substances
in urine
 Ketonuria
 Pancytopenia
Metabolic
Disorders
High
Normal
Urea cycle
defect
Normal
HAG Acidosis
Organic
acidemia
HAG Acidosis
Organic
acidemia
Normal or N AG
Aminoacidopathy
or Galactosemia
Organic
Acidemia
Ketosis
No No
skin\
manifestation
No Odor
1)MMA
2)PPA
Characteristic odor
1)MSUD
2)IVA
Skin
manifestation
MCD
No Ketosis
1)Glutaric A
2)Acyl CoA deficiency
3)HMG CoA deficiency
Screening
1)Gutherie
2)MS/MS
Perform before discharge or 7th day of birth
Disease
PKU
MSUD
Thyrosinemia
Propionic acidemia
Methyl mallonic
Isovalleric
Biotinidase deficiency
Galactosemia
Urea cycle defect
Test
Age of treatment
Confirming
Guthrie
MS/MS
MS/MS
1st weeks of life
Phenylalanin(p)
AA (p)AA (p)
1st week of life
1st weeks of life
Organic acids(u) profile
OAP (u)- AA (p)
Enzyme assessment
Biotinidase
Enzyme assessment
1st days of life
MS/MS
1st days of life
GALT
AA (p) profile
DNA motations
Treatment in hyprammonemia
1. D/C oral intake temporarily
2. Usually IVF’s with glucose to give 12-15
mg/kg/min glu and at least 60 kcal/kg to prevent
catabolism (may worsen PDH)
3. Bicarb/citrate
4. Carnitine/glycine
5. Na benzoate/arginine/citrulline
6. Dialysis--not exchange transfusion
7. Vitamins--often given in cocktails after labs drawn
before dx is known
Biotin, B6, B12, riboflavin, thiamine, folate
Metabolic Disorders Presenting as
Severe Neonatal Disease
1. Disorders of Carbohydrate Metabolism
• Galactosemia - presents with severe liver disease, gram negative
sepsis, and/or cataracts
 Enz deficiency: Gal-1-phos uridyl transferase, UDP-gal-4epimerase
• Glycogen storage disease type 1a & 1b - presents as
hypoglycemia
 Enz deficiency: Glucose-6 phosphatase
 Lactic Acidosis - presents as lactic acidosis +/- hypoglycemia
 Enz deficiency: Pyruvate carboxylase, Pyr dehydrogenase, etc.
• Fructose intolerance - Needs fructose exposure, hypoglycemia and
acidosis
Metabolic Disorders Presenting as
Severe Neonatal Disease
2.
Amino Acid Disorders
•
Maple syrup urine disease - presents with odor to
urine and CNS problems
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•
Nonketotic hyperglycinemia - presents with CNS
problems
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•
Enz deficiency: Branched chain ketoacid decarboxylase
Enz deficiency: Glycine cleavage system
Tyrosinemia - Severe liver disease, renal tubular
dysfunction
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Enz deficiency: Fumaryl acetate
Transient tyrosinemia of prematurity - progressive coma
following respiratory distress
Metabolic Disorders Presenting as
Severe Neonatal Disease
3. Urea Cycle Defects and Hyperammonemia
4. All present with lethargy, seizures, ketoacidosis,
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neutroenia, and hyperammonemia
Ornithine carbamyl transferase (OTC) deficiency
Carbamyl phosphate synthetase deficiency
Citrullinemia
Arginosuccinic Aciduria
Argininemia
Transient tyrosinemia of prematurity
Metabolic Disorders Presenting as
Severe Neonatal Disease
 All present with lethargy, seizures, ketoacidosis, neutropenia,
hyperammonemia, and/or hyperglycinemia
4. Organic Acid Defects
• Methylmalonic acidemia
• Proprionic acidemia
• Isovaleric acidemia - odor of “sweaty feet”
• Glutaric aciduria type II
• Dicarboxylic aciduria
5. Miscellaneous
• Peroxisomal disorders
• Lysosomal storage disease
• Pyridoxine dependent seizures
Amino acids
metabolism
diorders
Phenyl ketonuria
 AR
 Prevalence 1/10000
 They are normal at birth.
Inheritance
normal
carrier
GSD
“Baby”
Phenylketonuria
Phenylalanin
Phenlketones
Thyrosin
Clinical manifestation
 Normal at birth
 Severe MR(IQ<30)
 Blound appearance
 Odor
 Microcephalia
 Seborroic dermatitis
 Dominant maxilla
Diagnosis
 Ferric chloride test(urin phenyl ketones)
 Guthrie test
 Screening test
 MS/MS
 Phenylalanin>6mg/dlit(360 mic M) 
 Thyrosin (low)
Diagnostic test
Treatment
 Low phenylalanin Regimen (Phenylalanin2-6mg/dlit)
 Treatment must start in first 10 days of life.
 It must be continued till 10-12 yrs old.
 In malignant PKU, Neurotransmitters
are needed.(BH4)
+
 Maternal hyperphenylallanenimiaMR-MicrocephalliaCHD
Carbohydrate
metabolism
disorders
1)Galactosemia
Lactose
Glucose+Galactose
Galactose -1_phosphate
Glucose-1-Phosphate
Clinical findings
Feeding  Hepatic failure (Bil –Coagulopathy -Glu)
Tubulopathy (Acidosis-Glucosuria-A aciduria)
Cataract
E coli sepsis is more than others
In older patients  Learning disorders-Ovarian Failure
Diagnosis:
Screening  Urin reducing substrare
Diagnostic test  RBCs Gal1-P U transferase
Glycogen Storage Diseases
Type 0
Type IV
Type I
Type VII
Type II
GSD Type III
Type III
2)Glycogen storage diseases
1) liver involement &Hypoglycemia (1-6-8)
2) Muscle involvement (5-7)
3) Both of liver and Muscle (3)
4) Without any effect on Glucose & anearobic activities (2-4)
Mucopolysaccharidosis
Disease
Onset
Corneal
involevment
Retinal
involvement
Organomega
ly
CNS
involvement
B/M
Hurler
1Yrs
+
_
++
Severe
Alder-reilly
Hunter
1-2yrs
_
+
++
Mild
Alder-reilly
Sanfilippo
2-6 yrs
_
_
+
Severe
Alder-reilly
Normal
Alder-reilly
Liver
Morquo
2 yrs
+-
_
_
Hurler syndrome
HURLER SYNDROME
LIPIDOSIS
Organome Cherry red
galy
spot
Guacher
disease
Nimenpic
+
_
+
+
Taysachs
_
+
Fabry
+
Farber
+
Onset
1st month
3-6
month
1st 4
Treatment in hyprammonemia
1. D/C oral intake temporarily
2. Usually IVF’s with glucose to give 12-15
mg/kg/min glu and at least 60 kcal/kg to prevent
catabolism (may worsen PDH)
3. Bicarb/citrate
4. Carnitine/glycine
5. Na benzoate/arginine/citrulline
6. Dialysis--not exchange transfusion
7. Vitamins--often given in cocktails after labs drawn
before dx is known
Biotin, B6, B12, riboflavin, thiamine, folate