Neonate iem may 2021

Approach to Inborn Errors
of Metabolism
DR J P SONI
Professor and Head of the Department
Paediatrics
Division of Paediatric Cardiology
DR S N Medical College
Jodhpur
Doc_jpsoni@yahoo.com

Objectives
 What is normal Metabolism?
 What is a metabolic disease?
 what is the Frequency, under lying cause &
Type of IEM.
 How to recognize IEM in a neonate with non-specific signs and
symptoms “ WHY & HOW”.
 To make use of simple lab tests in the diagnosis of IEM
 To know the initial management of life threatening conditions
associated with IEM

catabolism
galactose
Fatty acid
Sucrose
&
starch
Amino acids

PROTEIN GLYCOGEN FAT
AMINO ACIDS
FRUCTOSE
GALACTOSE
FREE FATTY ACIDS
AMMONIA
UREA
UREA CYCLE
ORGANIC ACIDS
GLUCOSE
PYRUVATE
ACETYL CoA
KREBS CYCLE
NADH
KETONES
ATP
LACTATE
An integrated view of the metabolic pathways


?
What happens when normal
metabolism is not occurring
because of “enzyme deficiency”
Answer
Inborn errors of metabolism

Glucose
Fatty acid
glycogen
AA Pool
Hypoglycemia, Acidosis, Ketosis
Failure of conversion

Definition:
Inborn errors of metabolism occur from a
group of rare genetic disorders in which the
body cannot metabolize food components
normally. These disorders are usually caused
by defects in the enzymes involved in the
biochemical pathways that break down food
components.
What is Inborn Error Metabolism ?

IEM also defined as -
A genetically determined biochemical
disorder in which a specific enzyme
defect produces a metabolic block that
may have pathologic consequences at
birth (e.g., phenylketonuria) or in later
life (e.g., diabetes mellitus); Also called
as enzymopathy and genetotrophic
disease.

What Happens in a metabolic
disease?
IEMs are disorders of metabolism in which normal metabolic pathway is blocked
usually due to genetic defect of a specific enzyme.
Garrod’s hypothesis
A B C
substrate excess product deficiency
D toxic metabolite
The chemical or physical changes depends upon the substances in a biological
system for any disease originating in an individual”

Inborn Errors of Metabolism
 An inherited enzyme deficiency leading to the
disruption of normal bodily metabolism of
substrate “A” or “B”.
 Accumulation of a toxic substrate “D”
(compound acted upon by an enzyme in a
chemical reaction).
 Impaired formation of a product “C” normally
produced by the deficient enzyme

defective enzyme
Substrate “A”
“B”(increased)
Product “C”
(decreased)
action
Metabolites “D”
(increased)
Co-factor A Co-factor B
other
enzymes Metabolites
(decreased)
EFFECT ON OTHER METABOLIC ACTIVITY
e.g., activation, inhibition, competition
Theoretical consequences of an enzyme deficiency.

Pathophysiology:
Single gene defects result in bnormalities in the synthesis or
catabolism of proteins, carbohydrates, or fats.
Most are due to a defect in an enzyme or transport
protein, which results in a block in a metabolic pathway.
Effects are due to toxic accumulations of substrates
before the block, intermediates from alternative metabolic
pathways, and/or defects in energy production and utilization
caused by a deficiency of products beyond the block.
Nearly every metabolic disease has several forms that
vary in age of onset, clinical severity and, often, mode of
inheritance.

IEM
 Incidence : 3-4 /1000 live birth in developed
countries.
 In neonate 20% acute illness is because of
IEM.
 Such 300 genetic disorders are known.
 IEM is responsible for 0.5- 3-4% mental
retardation.

Frequency:
In the US : The incidence, collectively, is
estimated to be 1 in 5000 live births. The
frequencies for each individual IEM vary, but most
are very rare. Of term infants who develop
symptoms of sepsis without known risk factors,
as many as 20% may have an IEM.
Internationally: The overall incidence is
similar to that of US. The frequency for individual
diseases varies based on racial and ethnic
composition of the population.

The common thing in IEM is these are
 genetic disorders, mostly autosomal recessive and less
commonly X linked or Mitrochondrial; due to defect in specific
enzyme.
These disorders are progressive.
Early diagnosis enables genetic counseling regarding prognosis
of disease, risk of recurrence of the disease, specific therapy and
prenatal diagnosis by C.V.S., AMNIOCENTESIS and CORD
BLOOD.
The uncommon thing in IEM are
They differ in pathogenesis, clinical presentation and treatment
protocol.
IEM - GENETIC DISORDER

 Metabolic diseases are individually rare, but
as a group are not uncommon.
 There presentations in the neonate are often
non-specific at the outset.
 Many are treatable.
 The most difficult step in diagnosis is
considering the possibility!

Why to pursue a metabolic diagnosis?
 Inborn errors of metabolism are important diseases because
they are severely debilitating.
 Often some of them can be treated effectively if diagnosed
early.
 Diagnosis is difficult because presenting symptoms are
protean, nonspecific and may not be obvious.
 Diagnostic tests for metabolic disorders are not available every
where and need to be sent to specialty laboratories to a very
remote place.

Why pursue a metabolic diagnosis?
 Clinicians sometimes dismiss this category of
diseases as being too rare.
 Because of high mortality and morbidity.
 An understanding of the clinical manifestations of
IEM's provides the basis for knowing when to
consider the diagnosis.
 What is actually important is to "Keep them in mind.

One important feature of
IEM's is that both symptoms
and signs may worsen after
stress which may occur
naturally after "infections"
or produced once "milk
feeding“ is established

Mortality/Morbidity:
IEMs can affect any organ system and usually do affect
multiple organ systems.
Manifestations vary from those of acute life-threatening
disease to subacute progressive degenerative disorder.
Progression may be unrelenting with rapid life-
threatening deterioration over hours, episodic with
intermittent decompensations and asymptomatic
intervals, or insidious with slow degeneration over
decades.

Type of IEM – substrate involved
IEM Disorders may of:
 Amino acids
 Carbohydrates
 Fatty acid
 Organic acids
 Minerals

The Daunting Differential List:
 Transient
Hyperammonemia of
Newborn
 Inborn Errors of Metab:
– Organic Acidemias
– Fatty Acid Oxidation def
– Urea Cycle Defects
– Amino Acidurias
– Non-ketotic Hyperglycinemia
 Molybdenum Cofactor
Deficiency
– Sulfite Oxidase Deficiency
 Metal Storage Disorders:
 Cholesterol Disorders:
 Leukodystrophies, other…
– Krabbe disease
 Mitochondrial Disorders
 Glycogen Storage
Disorders
 Hyperinsulinism
 Carbohydrate Disorders
 Lysosomal Disorders
– Mucopolysaccharidoses (X-
linked Hunter’s, Hurler’s)
– Gaucher disease
– Tay-Sachs Disease
 Peroxisomal Disorders
– Zellwegger’s (Cerebro-
Hepato-renal)
– X-linked
Adrenoleukodystrophy

classification Based on toxin character
Small molecule disease
Carbohydrate
Protein
Lipid
Nucleic Acids
Large molecule
Lysosomes
Peroxisomes
Other Organelle disease
Mitochondrial
Cytoplasm

Clinical presentation of IEM
 Acute encephalopathy
 Chronic encephalopathy
 Myopathy
 Movement disorders
 Delayed motor and mental mile stone
 Psychriatric & behavioral abnormalities

Clinical presentation type of
IEM
Neurological deterioration (lethargy / coma)
IEM WITH METABOLIC ACIDOSIS: MSUD,
ORGANIC ACIDEMIA, FATTY ACID OXIDATION, PRIMARY
ACTIC ACIDOSIS, DEFCT IN PYRUVATE METABOLISM AND
MITROCHONDRIAL RESPIRATORY CHAIN FUNCTION.
IEM WITH HYPOGLYCEMIA : ORGANIC ACIDURIAS,
DEFECTS IN FATTYOXIDATION AND GLUCONEOGENESIS.
IEM with hyperammonemia : UCD, PROPIONIC
ACIDEMIA(PPA), METHYMALONIC ACIDEMIA.

 Acute life threatening illness
– Encephalopathy - lethargy, irritability, coma
– Vomiting
– Respiratory distress
 Seizures, Hypertonia, Apnea
 Rx conditions
 Pyridoxine dependency
 Folinic acid responsive
seizures
 Serine synthesis defect
 Creatinine deficiency
Non ketotic hyperglycinemia NKHG
Sulfite oxidase & xanthine oxidase deficiency
Peroxisomal disorders
Neonatal gluteric aciduris type II
Neuronal migration defect
Urea cycle disorders
Biotin deficiency
Clinical pointer to specific IEM

HYPOTONIA
MENTAL RETARDATION
SKIN PIGMENTATION :
Hypo pigmentation – Albinism, PKU, Gricoli syn
Hyper-pigmentation - CAH
Haemochromatosis

COARSE FACIES: Hypothyrodism, MPS- Hurler & Hunter
GM1- ganglosidosis
Fucosidosis/mannosidosis/sialidosis
Mucolipidosis – I cell disease
Coffin Lowary syndrome
ALOPECIA – Acroderamtitis entropahica,
Biotinidase def. (hair loss and alopecia)
multiple carboxylase defects,
Cong. Erythropoetic porphyria.
HAIR ABNORMALITY – Kinky hair – menke’s disease
Arginosuccemic aciduria,
Multiple carboxylase deficiency.
PKU ( silky golden hair)
lynsinuric protein intolerance

OCULAR ABNORMALITIES –
Cataract - Galactosemia
zellweger
Homocystinuria
Ectopia lentis - Homocystnemia, marfan syn.
Iris heterochromia/retinitis pigmentosa – zellweger
Ptosis - mitochondrial diseases
Opthamoplegia - Kearn – Sayre syh.
Corneal clouding - MPS
Optic atrophy - Neur. Ceroid lipofusc.

CUTANEOUS ABNORMALITY –
Perioral eruption - Multiple carboxylase deficiency.
Increased pigmentation - Adrenoleucodystrophy
Decreased pigmentation- PKU
ANGIOKERATOMAS - Fabry’s diseases, Fucosidosis,
Aspartylglucosaminuria
Failure to thrive
Hydrop fetalis

ABNORMAL URINE ODOR : pungent/ sweet
Musty or Mousy: PKU
Boiled Cabbage Tyrosinemia or hypermethioninemia
Maple Syrup Maple syrup urine disease
Sweaty feet: Isovaleric acidemia or glutaric acidemia type II
Tomcat urine Multiple carboxylase deficiencies (Biotin
deficiency).

LIVER DYSFUNCTION -
CATRACT - Galactosemia
PROFYRIS CRISIS -Tyrosinemia type I
HEPATOMEGALY WITH HYPOGLYCEMIA - GSD,
STEATOSIS - Beta – oxidation def
LIVER FAILURE – Hereditary fructose intolerance,
galactosemia, tyrosinemia type I, fatty oxidation defect &
mitochondrial respiratory chain defect.
CHOLESTTATIC JAUNDICE WITH FAILURE TO THRIVE :
Alpha 1 antitrypsin deficiency, Byler diseases, citrin deficiency,
Nieman pick disease type “C”, inborn errors of bile acid metbolism
& peroxisomal disorders.

CARDIAC DYSFUNCTION - Carintine uptake deficiency,
VLCHAD, C.acylcarnitine translocase deficiency, C.
palmitoyltransferase II deficiency , Trifunctional protein defici.
CARDIAC FAILURE / ARRHYTHMIA - Hypoparathyrodism,
Thymine deficiency-dependent states & fatty acid oxidation
disorders.
CARDIOMYOPATHY - Pompe’s disease
FAOD
Glconeogenesis type III / IV
Respiratory chain disorders

Weaning associated IEMs :
Fructose intolerance
Fructose 1-6 phosphtase deficiency
Urea cycle defects
Lysinuric protein intolerance
HHH syndrome
MSUD , Organic aciduria

 When to suspect IEM in a neonate with
non-specific signs and symptoms ?

New born with
 Acute encephalopathy
 Bacterial sepsis
 Cardiomyopathy
 Death unexpected
 Enlarged liver
 Family history
 G Jaundice
 Hydrops
 Interactable Hiccups

 Rapid deterioration in an otherwise well infant.
 Septic appearing infant or abnormal sepsis such as
E.coli.
 Regression in previously achieved milestones.
 Recurrent emesis or feeding difficulty, alterations in
respirations, abnl urine/body smell, changing
MS/lethargy, jaundice, sz, intractable hiccups.
 Can masquerade like pyloric stenosis.
 Dietary aversion- proteins, carbs.

Suspect IEM if Family History of
 CONSANGUINITY, ethnicity, inbreeding
 Feta loss and Neonatal deaths
 Maternal family history(Pedigree) suggestive of
– males - X-linked disorders
– all - mitochondrial DNA is maternally inherited.
 A positive family history may be helpful!

ABG pH 7.35-7.45, Pao2 70-100, PaCO2 40
HCO3- 22-28
Anion gap 3-13
B. Sugar > 40mg%
S. Ammonia 9 – 33 umol/l (Mg = mmol/ 0.56)
S. and urinary Ketone
S. Lactate 19mgm/dl csf 16mg/dl (mmol = mg X .11)
Haemogram
Investigation protocol

Specific type I
pH 7.4 - No acidosis
Ketone - absent - No ketosis
S. Amonia < 50 - Normal ammonia
S. Lactate < 20 - Normal lactate
Normal blood 60mg% - sugar
Normal Count, normal S. Ca , Mg
DNPH negative
Neurological intoxication type I distress with convulsion &/or
myoclonic jerk
A third gravida was referred for prenatal diagnosis. Her first pregnancy was
Terminated for IUD. Second born at term was appropriate for date. He fed well
Till 4 days of life .he developed seizures. Septic screen was negative. His blood
parameter were-
Which IEM to suspect ?

Suspect
Pyridoxine dependency
Folinic acid responsive seizures
Serine synthesis defect
Molybdenum Co factor defi(SO/XO)
Creatinine deficiency
Dx
Gylcine in blood & csf
Pridoxine – EEG
Sulfite in urine
VLCFA analysis
Non ketotic hyperglycinemia NKHG
Sulfite oxidase & xanthine oxidase
deficiency

CSF amino
acids
Increase
Alanine
threonine
mitrochondriopat
hy
Increase
Glycine
NKHG
Decrease
Serrine
3
phosphoglycerate
Dehydrogenase
def.
Increase
Pipeocolic acid
Glutamic acid
Threonine
Decrease GABA
Pyridoxine
defifiency

Specific type II
pH 7.3 - Mild acidosis
Ketone - + - Mildly elevated
Blood 60mg% - sugar
S. Amonia 50 - Normal
Normal count
DNPH ++++
Neurological intoxication type II - distress with convulsion &/or
myoclonic jerk
A 2500 gm neonate was born term and discharge on 2nd day of life. There were no
adverse perinatal events. On day 5 he was readmitted with history of poor feeding
And lethargy. He developed seizures and dystonic posturing of limbs & progress
To encephalopathy . He developed respiratory distress without significant chest finding
His blood parameter revealed acidosis and ketone in urine -

Suspect
MSUD
burnt sugar like odor –leucine, isoleucine
Elevated valine , methionine
Organic Acidemia- 2OH caproic acid
2 OH methyl valeric acid
2 OH Iso-vleric acid

Specific type III
pH 7.25 - Acidosis
Ketone - +++ - Elevated
Blood 30mg% - Hypogylcemia
S. Amonia 150 - Hyperammonia
Normal count leucopenia,thrombocytopenia
DNPH ++++
myoclonic jerk
A 2500 gm neonate was born term and discharge on 2nd day of life. There were no
adverse perinatal events. On day 5 he was readmitted with history of poor feeding
And lethargy. He developed significat respiratory distress without significant chest finding.
Ther was history of loss of three sibs in past two felames and one male.
His blood parameter revealed severe acidosis and +++ ketones in urine

Suspect
Propionic academia
TMS – increased level of propinyl carnitine,
urine- methylcitrate & 3-Ohpropionate
IVS1+5G>A, IVS3+2T>C
Methyl malonic academia
Iso-valeric academia
Gluteric academia
Biotinidase deficiency

Approach to metabolic acidosis
Increase
Anion
gape
No gape
Diarrhea
RTA
No ketone
Hypoglycemia
FAOD
yes
Ketone in
urine
No
B. sugar Yes
DKA
AA
&
OA
OA
MSUD
MMA
PPA
GA1
MCD
yes
Normal
L/P
ratio
Inc
Mitrochondrial

TMS normal
Carnitine / acylcarnitine C3 elevated
(MMA:PPA:Isolaveric = 3:2:1)
Elevated c3 acylcarnitine
Propionic academia
Methylmalonic academia
Cobalamine defect
B12 deficiency
URINARY GCMS

Specific type IV
Ammonia > 200 - Hyperammonia
pH 7.4 - No acidosis
Ketone - absent - No ketosis
Normal blood 60mg% - sugar
Normal count
DNPH negative
myoclonic jerk
A third gravida was referred for prenatal diagnosis. Her first pregnancy was
Terminated for IUD. Second born at term was appropriate for date. He fed well
Till 4 days of life .he developed seizures. HYPERAMONIMIA. Septic screen was
negative. His blood parameter were-

Suspect
Suspect urea cycle disorder
FAOD- glutric acidemia type II
CPT,CACT,LCAD.LCHAD
Dx
HPCL – citrulline, ornithine, arginine, ASA, Orotic
acid
MS- Acyl carnitine profile

Urea cycle disorder
 No acidosis (respiratory alkalosis)
 No ketones (unlike organic acidemia)
 No hypoglycemia
 But with hyperammonemia

NH3 high
< 24 hours > 24 hours
Preterm
Trasient hyper
Amonia of newborn
(THAN)
Term
Organic acidemia
Fatty acid oxidation
Acidosis
Ketosis
Positive Negative
Urea cycle defect
---------------------------------------------------------------------
-----------------------------

AMMONIA + CO2+ ATP
CARBAMYL PHOSPHATE SYNTHATASE
CARBMOYL PHOSPHTASE
+ORNITHINE
ORNITHINE TRANSCARBMYLASE
CITRULLINE
+ ASPARTiC ACID
ARGINOSUCCINIC ACID SYNTHATASE
ARGINOSUCCINIC ACID
ARGINOSUCCINIC ACID LYASE
ARGININE
ARGINASE
UREA AND ORNITHINE
UREA CYCLE
Low orotate in urine
High orotate in urine
Low Citrulline
High Citrulline
TMS cannot differentiate Aspartic acid and citrulline
orotate

Plasma Citrulline
Absent / trace
Urinary orotate
low
high
Carbamoyl Phosphate
Synthetase deficiency
Ornithin transcarbamylase
deficiency
100-300 m mol
Arginino succinic acid lyase
>1000m mol
Arginosuccinic acid
Synthetase deficiency
-----------------------------------------------------------------------------------

Specific type V
Neurological distress with energy deficiency
Mainly lactic acidosis
Acidosis ++
Amonia normal /mildly elevated +
DNPH negative /+
Ketone negative / +
Blood sugar normal /low
Normal count
A 3 kg male, born to consanguineously married muslim parents.
The child developed poor feeding, lethargy and seizure.
septic screen was negative.
There was hypoglycemia and severe lactic acidosis.

Suspect
Pyruvate carboxylase deficiency
Pyruvate dehydrogenase deficiency
Kreb’s cycle defect
Respiratory chain defect
Multiple carboxylase defects
Mitochondrial defect

Specific type V
Neurological distress with energy deficiency
Mainly lactic acidosis
Acidosis ++
Amonia normal /mildly elevated +
DNPH negative /+
Ketone negative / +
Normal count
A four motn old 3 kg male, born to consanguineously married muslim
parents.The child developed poor feeding, lethargy and seizure.
Baby hair being shaved at one week of life and not regrown after that.
Child also developed macular rashes at the nape of neck.
septic screen was negative. Seizures refractory to three anticonvulsants.
There was hypoglycemia and severe lactic acidosis.

Suspect
Biotinidase deficiency
(Multiple carboxylase defects)

Specific type VI
Mainly hepatic defect
Hepatomegaly / jaundice +++
Liver cell failure +/-
Acidosis +/-
Amonia +/-
DNPH negative /+
Ketone negative / +
Normal count
A 3 kg male, born to consanguineously married muslim parents.
The child developed poor feeding, lethargy,
high color urine, failure to gain weight.
septic screen was negative.

Suspect
Galactosemia
Tyrosinemia
Fructose aldolase deficiency
Fructose 1-6 dehydrogenase deficiency
Neonatal haemochromatosis
Respiratory chain defects
Alpha 1- antitrypsin deficiency

Specific type VII
Extra-pyramidal signs
GA type I
Methyl malonic acidemia
Propionic acidemia
Lesch nyhan syndrome
Wilson’s disease
Segawa’s disease

SEIZURES
HYPOTONIA
MENTAL RETARDATION
SKIN PIGMENTATION :
Hypo pigmentation – Albinism, PKU, Gricoli syn
Hyperpigmentation - CAH
Haemochromatosis

COARSE FACIES: Hypothyroidism, MPS- Hurler & Hunter
GM1- ganglosidosis
Fucosidosis/mannosidosis/sialidosis
Mucolipidosis – I cell disease
Coffin Lowary syndrome
ALOPECIA – Acroderamtitis entropahica,
Biotinidase def. (hair loss and alopecia)
multiple carboxylase defects,
Cong. Erythropoetic porphyria.
HAIR ABNORMALITY – Kinky hair – menke’s disease
Arginosuccemic aciduria,
Multiple carboxylase deficiency.
PKU ( silky golden hair)
lynsinuric protein intolerance

CUTANEOUS ABNORMALITY –
Perioral eruption - Multiple carboxylase deficiency.
Increased pigmentation - Adrenoleucodystrophy
Decreased pigmentation- PKU
ANGIOKERATOMAS - Fabry’s diseases, Fucosidosis,
Aspartylglucosaminuria

ONE SHOULD HAVE HIGH INDEX OF
SUSPICION OF IEM

Signs and Symptoms
Differential Diagnosis of newborn crash
Adrenal insufficiency, Sepsis,
Congenital heart disease, Asphyxia
 􀂄 Amino acid abnormality (MSUD)
 􀂄 Urea cycle abnormality
 􀂄 Organic aciduria (proprionic, ethylmalonic)
 􀂄 Congenital lactic acidosis
 􀂄 Mitochondrial disorder

Large Molecule Disease
The hallmark of large molecule disease is the storage of large
molecules in tissue or body fluids.
These tend to cause dementia, epilepsy, movement disorders,
gradual blindness and spasticity, in the case of leucodystrophies.
large molecules is arbitrary; however in general, the
dysfunctional molecules have a structural, membrane, receptor
or other function in cells but are not directly involved in
intermediary energy metabolism and removal of acid or nitrogen.
Because these disorders produce their symptoms in tandem
with gradual accumulation of the stored material, these
conditions present at varying intervals after birth.

These can be classified as lysosomal, peroxisomal or golgi apparatus
disorders.
The lysosomal storage diseases are a group of which over forty disorders are
currently known that result from defects in lysosomal function.
Lysosomes are cytoplasmic organelles that contain enzymes (specifically, acid
hydrolases) that break macromolecules down to peptides, amino acids,
monosaccharides, nucleic acids and fatty acids.
The lysosomal storage diseases are classified by the nature of the primary
stored material involved, and can be broadly broken into the following:
lipid storage disorders (including Gaucher's and Niemann-Pick diseases);
gangliosidosis (including Tay-Sachs disease);
leukodystrophies;
mucopolysaccharidoses;
glycoprotein storage disorders and
mucolipidoses.

are characterized by dysfunction of the peroxisome. They bridge
the category of small molecule disease and large molecule
disease.
They cause fluid accumulation of unmetabolized long chain fatty
acids in the plasma, but these are not stored in fixed intracellular
concentrations as large molecule disease.
Therefore the most efficient screening test is to measure long and
very long chain fatty acids in the plasma. These diseases tend to
present with signs of central with or without peripheral myelin
dysfunction.
In the neonatal presentations liver, heart and skeletal systems
can be involved. Examples include Zellweger, neonatal Refsum
and Neonatal ALD

Golgi apparatus disorders:
Also represented currently by the congenital
disorders of glycosylation.
These are characterized by defective
glycosylation of proteins in the golgi apparatus.
The proteins are normal but they are
glycosylated insufficiently so that their function,
transport and survival is impaired. A diagnosis
can therefore be obtained by measuring the
"hypoglycosylated forms of serum transferrin".
Examples include
Phosphomannomutase deficiency.

Fates of amino acid carbon skeletons
Carbon skeletons can be glucogenic or ketogenic

Signs and Symptoms
 Respiratory
 Cardiac
 GI
 Neurological
 Infectious disease

Presentation
 Metabolic acidosis
 Hyperammonemia
 Hypoglycemia

Metabolic acidosis
 pH <7.35
 Excess H+
 HCO3 deficit
 Decreased PaCO2 because of compensatory
hyperventilation.
 Calculate anion gap
– Na – (Cl + HCO3)
– Normal is 8-16meq/l

Metabolic Acidosis
 If Chloride is increased- HCO3 wasting
 GI or renal disorders
 If Chloride is Normal and
Anion gap is > = 16--- excess acid
production

Metabolic acidosis
 Approach is to give Na HCO3
 If unresponsive to HCO3-- IEM

Hyperammonemia
 Normal ammonia level- < 50 umol/l
 > 200 -- IEM
 If within 24 hours of life; preterm, RD
THAN
 After 24 hours- IEM

Hypoglycemia
Hypoglycemia
Acidosis
Lactic
acidosis
G-6 pase def
F -1,6 dipase def
Pyuvate
Carboxylase Def.
Keto
acidosis
Ketotic
hypoglycemia
GSD type 0,3,6,9,
GH def.
Cortisol def.
No acidosis
Low Ketone
High
FFA
Fatty acid
oxidation disorder
Low FFA
Hyperinsulinism
Panhypopituritism
SGA

Recognize that Smell:
 Musty or Mousy:
 PKU
 Boiled Cabbage
 Tyrosinemia or hypermethioninemia
 Maple Syrup
 maple syrup urine disease
 Sweaty feet:
 isovaleric acidemia or glutaric acidemia type II
 Cat urine
 multiple carboxylase deficiencies (Biotin deficiency)

STEPS:
 1. Determine if there is metabolic acidosis
 2. Is anion gap >16?
 3. Is there hypoglycemia?
 4. Is there hyperammonemia?
– Within 24 HOL?
– After 24 HOL?

defective enzyme
Substrate
(increased)
Product
(decreased)
action
Metabolites
(increased)
Co-factor A Co-factor B
other
enzymes Metabolites
(decreased)
EFFECT ON OTHER METABOLIC ACTIVITY
e.g., activation, inhibition, competition
Theoretical consequences of an enzyme deficiency.

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-4-
epimerase
• 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

2. Amino Acid Disorders
• Maple syrup urine disease - presents with odor to urine
and CNS problems
 Enz deficiency: Branched chain ketoacid
decarboxylase
• Nonketotic hyperglycinemia - presents with CNS
problems
 Enz deficiency: Glycine cleavage system
• Tyrosinemia - Severe liver disease, renal tubular
dysfunction
 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,
neutroenia, and hyperammonemia
 Ornithine carbamyl transferase (OTC) deficiency
 Carbamyl phosphate synthetase deficiency
 Citrullinemia
 Arginosuccinic Aciduria
 Argininemia
 Transient tyrosinemia of prematurity

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

What to do for the Dying Infant
Suspected of Having an IEM
 Autopsy--pref. performed within 4 hours
of death
 Tissue and body fluid samples
– Blood, URINE, CSF (ventricular tap),
aqueous humour, skin biopsy, muscle
and liver--frozen in liquid nitrogen
 Filter paper discs from newborn screen--
call lab and ask them not to discard

Normal /High
Plasma Ammonia
Blood pH & CO2
Acidosis
No Ketosis
Fatty acid oxidation defects

“Stumbling Blocks” in
Diagnosing Inborn Errors of
Metabolism
 Signs and symptoms are often nonspecific
– Routine childhood illnesses excluded 1st
– Inborn errors considered only secondarily
 Unfamiliarity with biochemical
interrelationships/ diagnostic tests
– Inappropriate sample collection
– Inappropriate sample storage

 Every child with unexplained . . .
– 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
 Infants have only a limited repertoire of symptoms--sxs
non-specific
– Vomiting, lethargy, FTT, sz’s, resp (tachypnea,
hyperpnea, apnea), coma, cardiomyopathy
– Odor, abnormal hair, dysmorphology
 Labs: metabolic acidosis, hypoglycemia,
hyperammonemia, reducing substances in urine,
ketonuria, pancytopenia
 Not all infants with life threatening IEM have either
acidosis or hyperammonemia (i.e. non-ketotic
hyperglycinemia, mild lactate elev).

Laboratory Assessment of Neonates
Suspected of Having an
Inborn Error of Metabolism
Routine Studies Special Studies
Blood lactate and
pyruvate
Complete blood count
and differential Plasma amino acids
Plasma ammonia Plasma carnitine
Plasma glucose Urine amino acids
Plasma electrolytes and
blood pH Urine organic acids
Urine ketones
Urine-reducing
substances

“Waiting until sepsis and other
more common causes of
illness are ruled out before
initiating a specific diagnostic
evaluation is inadvisable, as is
indiscriminate study of all ill
newborns for metabolic
disorders.”

Clinical Symptomatology of Inborn Errors of Metabolism (IEM) in the Neonate or
Infant
Symptoms indicating possibility of an IEM (one or all)
Infant becomes acutely ill after period of normal behavior and feeding;
this may occur within hours or weeks
Neonate or infant with seizures and/or hypotonia, especially if seizures
are intractable
Neonate or infant with an unusual odor
Symptoms indicating strong possibility of an IEM, particularly when coupled
with the above symptoms
Persistent or recurrent vomiting
Failure to thrive (failure to gain weight or weight loss)
Apnea or respiratory distress (tachypnea)
Jaundice or hepatomegaly
Lethargy
Coma (particularly intermittent)
Unexplained hemorrhage
Family history of neonatal deaths, or of similar illness, especially in
siblings
Parental consanguinity
Sepsis (particularly Escherichia coli)

Physical Anomalies Associated With Acute-Onset Inborn Errors of Metabolism (IEM)
Anomaly Possible IEM
Ambiguous genitalia Congentital adrenal hyperplasia
Hair and/or skin problems (alope- Multiple carboxylase deficiency, biotinidase
cia, dermatitis) deficiency, argininosuccinic aciduria
Structural brain abnormalities Pyruvate dehydrogenase deficiency
(agenesis of corpus callosum,
cortical cysts)
Macrocephaly Glutaric aciduria, type I
Renal cysts, facial dysmorphia Glutaric aciduria, type II; Zellweger syndrome
Facial dysmorphia Peroxisomal disorders, (Zellweger syndrome)
Cataract Galactosemia, Lowe syndrome
Retinopathy Peroxisomal disorders
Lens dislocation, seizures Sulfite oxidase deficiency
Molybdenum cofactor deficiency
Facial dysmorphia, congenital heart 3-OH-isobutyric CoA deacylase deficiency
disease, vertebral anomalies

Clinical Manifestations of Inborn Errors Presenting
Neonatally
Neurologic Signs
Poor suck
Lethargy (progressing to coma)
Abnormalities of tone
Loss of reflexes
Seizures
Gastrointestinal Signs
Poor feeding
Vomiting
Diarrhea
Respiratory Signs
Hyperpnea
Respiratory failure
Organomegaly
Liver
Heart

Inborn Errors of Metabolism of Acute Onset: Nonacidotic,
Nonhyperammonemic Features
Neurologic Features Predominant (Seizures, Hypotonia, Optic
Abnormality)
Glycine encephalopathy (nonketotic hyperglycinemia)
Pyridoxine-responsive seizures
Sulfite oxidase/santhine oxidase deficiency
Peroxisomal disorders (Zellweger syndrome, neonatal adrenoleuko-
dystrophy, infantile refsum disease)
Jaundice Prominent
Galactosemia
Hereditary fructose intolerance
Menkes kinky hair syndrome
1-antitrypsin deficiency
Hypoglycemia (Nonketotic): Fatty acid oxidation defects (MCAD, LCAD,
carnitine palmityl transferase, infantile form)
Cardiomegaly
Glycogen storage disease (type II phosphorylase kinase b deficiency18
)
Fatty acid oxidation defects (LCAD)
Hepatomegaly (Fatty): Fatty acid oxidation defects (MCAD, LCAD)
Skeletal Muscle Weakness: Fatty acid oxidation defects (LCAD, SCAD,
multiple acyl-CoA dehydrogenase

Treatment consists of medication and a diet low in tyrosine
and another amino acid called phenylalanine (phe). The low-
tyrosine/phenylalanine diet is made up of a special medical
formula and carefully chosen foods. You must start the
treatment as soon as you know your child has the condition.
The following treatments are often recommended for children
with tyrosinemia 1:
1. Medication
A medication called nitisinone (Orfadin® ), also known as
NTBC, is used to prevent liver and kidney damage. It also
stops the neurologic crises. The medication lessens the risk
for liver cancer. Your child should start taking Nitisinone as
soon as possible. Your doctor will need to write a prescription
for this medication.
Nitisinone will increase the level of tyrosine in your child’s
blood. So, a low-tyrosine diet is a very important part of
treatment.

Vitamin D is sometimes used to treat children who have rickets.
Do not take any medication without talking with your doctor.
2. Medical Formula
The special medical formula gives babies and children the nutrients and protein
they need while helping keep their tyrosine levels within a safe range. Your
metabolic doctor and dietician will tell you what type of formula is best and how
much to use.
3. Low-tyrosine / phenylalanine diet:
The diet is made up of foods that are very low in tyrosine and phenylalanine.
This means your child will need to limit foods such as cow’s milk and regular
formula. He or she will need to avoid meat, eggs and cheese. Regular flour, dried
beans, nuts and peanut butter contain these amino acids and must also be
limited.
Many vegetables and fruits have only small amounts of phenylalanine and
tyrosine and can be eaten regularly in carefully measured amounts.

There are other medical foods such as special flours, pastas, and
rice that are made especially for people with tyrosinemia 1. Some
states offer help with payment, or require private insurance coverage
for formula and other special medical foods.
Your metabolic doctor and dietician will decide on the best food plan
for your child. The exact plan will depend on many things such as
your child’s age, weight, general health, and how well the medication
is working. Your dietician will fine-tune your child’s diet over time.
4. Blood, urine and other tests
Your child will have regular blood and urine tests to check:
•amino acid levels
•the amount of succinylacetone
•nitisinone level
•liver and kidney function

Blood tyrosine concentration greater than 600 mol/L confers risk of precipitation of
tyrosine as bilateral, linear, branching subepithelial corneal opacities [Ahmad et al 2002],
causing photophobia and itchy, sensitive eyes. The crystals resolve once tyrosine levels
are reduced.

Glucose
galactose
Lactose
Sucrose
&
starch
Fructose
Accumulation of toxic metabolites
Hypoglacemia e.i. galactossemia

Glucose
Fatty acid
glycogen
AA Pool
Hypoglycemia, Acidosis, Ketosis
Gylcogen metabolites

Respiratory chain
Glucose
Pyruvate Lactate
Acetyl Co
NADH
NADH
ATP
Mitochondria
Failure of conversion of NADH to ATP
Accumulation of NADH
Lactic acidosis
Hall marker of Mitrochondrial disorder

NEURUMETABOLIC
DISORDERS
SMALL MOLECULAR
DEFECT
ACUTE IN INFANCY INTERMITTENT
ACIDOSIS
HYPOGLYSEMIA
WEAKNESS
ATAXIA
SPATICITY
PROPIONIC ACIDEMIA
METHYL MALONIC
ACIDURIA
MULTIPLE CARBOXYLASE
DEFICIENCY
ISOVALERIC ACIDEMIA
UREA CYCLE DISORDERS
LARGE MOLECULAR
CHORONIC
LATE IN CHILD HOOD
PROGRESSIVE CNS
DEGENERATION
SEIZURES
DEVELOPMENTAL DELAY
MENTAL RETARDATION
FAILURE TO THRIVE
HYPOTONIA
SPATICITY
MUSCULAR WEAKNESS
ORGANOMEGALY
COARSE FEATURES
FUNDUS ABNORMALITY
POOR FEEDING
VOMITING
LETHARGY
CONVULSION
HYPOTONIA
CATARCT
ABNORMAL ODOUR
AMINO ACIDURIA
ORGANIC ACIDS
SIMPLE SUGAR

BIOCHEMICAL APPROACH TO NEUROMETABOLIC
DISORDERS
BLOOD
pH
&
CO2
PLASMA NH₃
HIGH
AMONIA
NORMAL pH
NO KETOSIS
UREA CYCLE
ACIDOSIS
NORMAL
AMONIA
pH & CO2
PKU
NKH
GALACTOSEMIA
PEROXISOMAL -
VLCFA

BIOCHEMICAL APPROACH TO NEUROMETABOLIC
DISORDERS
SPECIFIC AMINOACID
ELEVATION
NO SPECIFIC AMINO
ACID ELEVATION
CITRULLINEMIA
ARGINIEMIA
ARGINOSUCCINIC ACIDEMIA
HYPERAMONEMIA,
HYPERORNITHINEMIA-
HOMOCITRULLINEMIA
URINARY OROTIC
HIGH
ORNITHINE
TRANSCARBAMYLASE
LOW/NORMAL
PLASMA CITRULLINE
LOW
CARBAMYL PHOSPHATE
SYNTHATASE
N –Acetyl-glutamic acid (NAG)
synthatase deficiency
ORGANIC
ACIDEMIAS
PROOIONIC ACIDEMIA
METHYLMSLONIC ACIDOSIS
ISOVALORIC ACIDEMIA
MULTIPLE CARBOXYLASE
DEFICIENCY
FATTY ACID-ACYL Co,A
DEHYDROGENASE DEFICIENCY
HIGH NH3
NORMAL pH
NO KETOSIS
UREA CYCLE
HIGH NH3
ACIDOSIS

ACIDOSIS
KETONE/SKIN
MANIFESTATION
NO SKIN
MANIFESTATION
CLASSICAL ODOR
MAPPLE SYRUP
URINE DISEASE
ISOVALERIC
ACIDURIA
NO ODOR
METHYMALONIC
ACIDEMIA
PROPIONIC ACIDEMIA
KETOTHIOLASE
DEFICIENCY
SKIN
MANIFESTATION
YES
MULTIPLE
CARBOXYLASE
DEFICIENCY
NO KETOSIS / MILD
KETOSIS
3 HYDROXY
3METHYLGLUTERI
C ACIDURIA
ACYL CoA
DEHYDRONASE
DEFICIENCY
HMG Co A
SYNTHATASE
DEFICIENCY

NEURUMETABOLIC
DISORDERS
LARGE MOLECULAR
CHORONIC
LATE IN CHILD HOOD
PROGRESSIVE CNS
DEGENERATION
SEIZURES
DEVELOPMENTAL DELAY
MENTAL RETARDATION
FAILURE TO THRIVE
HYPOTONIA
SPATICITY
MUSCULAR WEAKNESS
ORGANOMEGALY
COARSE FEATURES
FUNDUS ABNORMALITY

EXTRA CNS ABNORMALITY
NO
GRAY METTER
BIOTINADASE
GM2
LEIGHS
MELAS
PYRIDOXINE
WHITE MATTER
“CENTRAL “
ALEXENDER
CANAVAS
X-ADRENO LEUCO DYSTROPHY
GM1/GM2
“CENTRAL AND
PERIPHRAL NERVE”
METACHROMATIC
LEUCODYSTROPHY
KRABBE’S
PEROXISM
YES
MYO PATHY -
MITROCHONDRIAL DISORDER
LIVER, SPLEEN, BONE,
FACIES- MPS
GM1
GAUCHER
ZELLWEGER
SIALIDANS
N P D
SKIN
HOMOCYSTNEMIA
MENKES DISEASE
FUCOSIDOSIS
GALACTOSIALIDOSIS

Goals for this lecture:
 Discuss acute/emergency management of IEMs.
 Review broad categories of IEMs.
 Focus on Board favorite zebras.
 Complete the Board prep. Objectives in most
recent 2006 edition.
 Integrate the “Laughing your way through Boards”
tips.
 Have fun with this usually stressful topic.

What we WON’T DO:
 Memorize metabolic pathways.
 Mention, think of, or utter the enzyme α-
ketoglutarate dehydrogenase
complex.
 Laugh at, throw bagels or coffee at, or
otherwise mock Drew.
 Discuss the adverse sequelae of the Eagle’s
previous decision to recruit T.O.

IEM Board/Prep Goals:
 Inheritance patterns
 Indication for genetics
 Eval of hypoglycemia
 Eval of acidosis
 Vitamin Rx for enzyme
disorders
 Treat Hypoglycemia
 Natural Hx of PKU
 Plan/diet for PKU
 Manage Glycogen storage
diseases- Type 1
 Recognize
– Urea Cycle defects
– Organic acidemias
– S+S of CHO disorders
– S+S of Galactosemia
– S+S of hyperinsulinism
– Glycogen Storage Dz
– Lipoprotein Disorders
– Gaucher + Lipid Storage Dz
– S+S of Tay-Sachs
– S+S of Fatty Acid and
Carnitine metabolism

IEM- Index of Suspicion:
 Rapid deterioration in an otherwise well infant.
 Septic appearing infant or abnl sepsis such as
E.coli.
 Failure to thrive.
 Regression in milestones.
 Recurrent emesis or feeding difficulty, alterations
in respirations, abnl urine/body smell, changing
MS/lethargy, jaundice, sz, intractable hiccups.
 Can masquerade like pyloric stenosis.
 Dietary aversion- proteins, carbs.

Basic Principles:
 Although individually rare, altogether they
are 1:800-5000 incidence.
 Broadly Defined: An inherent deficiency in a
key metabolic pathway resulting in
– Cellular Intoxication
– Energy deprivation
– Mixture of the two

History and Antecedent Events:
 Catabolic state induction
(sepsis,fasting,dehydration)
 Protein intake
 Change or addition of PO proteins, carbs,
etc… in formula
 **Gotta ask- Consanguinity
 FHx of SIDS

Assessment:
 Detailed H+P
– Describe sz
– Fevers
-Milestones
-FHx
-Mom’s GsPs
-NAT questions
 **Dysmorphology does not
r/o IEMs**
 Physical Exam:
– Vitals
– Level of alertness
– Abnl activity/mvmts
– CV- perfusion
– Dysmorphology, hair,
smell, eyes-cornea
– Abdo- HS megaly
– Neuro- DTRs, tone, etc
– Skin- bruise, pigment,
color

Emergency Management:
 Can be life threatening
event requiring rapid
assessment and
management.
 ABC’s
 ABG-acidosis
 BMP, Ca and LFTs
 NH4
 Lactate, Pyruvate
 CBC, Blood Cx if uncertain
 Coags- PT/PTT
 UA-ketones, urine reducing
substances, hold for OA/AAs
 Newborn scrn results
 LP- r/o Meningitis, but send lactate
STAT, AAs, hold tubes for future
 Drug tox screen if indicated.
 **Hold spun blood or urine sample
in fridge for later if possbile.
– **ABG, Lactate are iced STAT
samples
– ** NH4 should be free flowing,
arterial sample

Emergency Management:
 Correct hypotension.
 NPO, reverse
catabolism with D5-
D10 1-1.5 x maint.
 Correct hypoglycemia.
 Correct metabolic
acidosis.
 Dialysis, lactulose if
High/toxic NH4
– (nl is <35µmol/L)
 Search for and treat
precipitants; ie:
Infection, dehydration.
 Low threshold for
Sepsis w/u + ABx if
uncertain.
 Pyridoxine for neonatal
sz. if AED no-response
 Ativan, Versed, AEDs
for status epilepticus.

Some quick supplements:
 Carnitine for elimination of Organic Acid
through creation of carnitine esters.
 Sodium Benzoate, Phenylacetate for
Hyperammonemia elimination.

Patient is stabilized. Now what:
 Broad DDx for IEMs scares people.
 You can group into KEY features.
 Can focus on initial labs = Hyperammonia,
hypoglycemia, metabolic acidosis.
 Can focus on Prominent neurologic features.
 Can focus on Dysmorphic features.
 If these don’t exactly fit, resort back to categories
of IEMs and Neurodegenerative Disorders.

Quick References:
MA:
*metabolic
acidosis
NH4:
Glu:
Dz:
*Non-ketotic
Hyperglycine
*Urea Cycle
defects
*Fatty Acid
Oxs
*OAemia
*OAemia *OAemia *OAemia *Glycogen Strg
dfc
*Amino Aciduris
*Carb
Metabolism dfc

Transient Hyperammonemia of
Newborn:
 Markedly high NH4 in an infant less than 24
HOL, or first 1-2 DOL before protein intake
occurs.
 Often in context of large, premature infant with
symptomatic pulmonary disease.
 Very sick infant.
 Unknown precipitant, unknown etiology (possible
slow delayed urea cycle initiation), with potential
for severe sequelae (20-30% death, 30-40% abnl
devo) if not treated.
 Does not recur after being treated.

Organic Acidemias:
 *Acidotic with high Gap
 *Urine Ketones high
 *High to nl Ammonia
 Often present first 2-7 days of life after dietary
protein introduced.
 Drunk appearance in infant.
 *May have low WBC and Plts.
 Check serum AAs/OAs, Urine AAs/OAs, CSF
OAs/AAs.

Organic Acidemias cont:
 **Multiple Carboxylase Deficiency**
or
Defect in Biotin Utilization
 Biotin is vital cofactor in many pathways, defect results in:
 Severe deterioration, dermatitis, alopecia, immune
deficiency- candidal skin infections.
 High NH4, acidemic, ketotic like the others.
 Dx by enzyme assay.
 Rx with Biotin 10mg/kg/d PO
**Rocky will get this if he consumes too much Avidin, aka,
raw eggs.

Amino Acidurias:
 Maple Syrup Urine Disease
– Sweet smell of body fluid esp Urine.
– Classically develops in 1st week of Life.
– Poor feeding, emesis, lethargy and coma.
– Periods of Hypertonicity.
– Secondary Hypoglycemia.
– Possible Metabolic Acidosis, hyperammonemia
– **Obtain serum/urine AAs/OAs**
– Treatment requires rapid removal of Branched chain
AAs, often through dialysis.

Amino Acidurias:
 Fresh Urine Uric acid and Sulfite Dipstick if
neurologic abnormalities are present, low
uric acid is suggestive for molybdenum
cofactor deficiency and Sulfite Oxidase
Deficiency.
 Don’t forget PKU. Basic on newborn scrn,
but only does good if results followed up.

For the Boards:
 *Sweaty feet smell*
– Isovaleric Acidemia, think ISOTONER shoes smell
 What defect may present with Pulmonary
Embolus?
 Homocystinuria- and thereafter may ask which
supplement to initiate?
 Pyridoxine- due to residual enzyme activity.
 Other names to know:
– Methylmalonic Acidemia- Rx with large dose vitamin
B12
– Propionic Acidemia- RX with Biotin.

Urea Cycle Defects:
 All but one of the disorders is autosomal recessive.
 Symptom free period and then emesis->lethargy-->>COMA
 Key features:
– High Ammonia, low BUN
– Possible Lactic acidosis
– *Absence of ketonuria*
– Nl to mild low Glucose
 **Treat high ammonia, infuse glucose, send plasma
AAs/OAs, urine orotic acid, and plasma citrulline.
 Infusion of 6ml/kg 10% Arginine HCl over 90 min may help.
 Milder forms may show episodic emesis, confusion, ataxia,
and combativeness after high protein meals.

For the Boards:
 Most common Urea cycle defect and also
only X-linked:
 Ornithine Transcarbamylase Deficiency

Fatty Acid Oxidation Defects:
 **Autosomal recessive inheritance**
 Examples are MCAD, LCAD, VLCAD
 Defect in acyl-CoA Dehydrogenase, a mitochondrial duty,
and important in fasting state.
 KEY features:
 Acute attack of life-threatening coma with Hypoglycemia
 Absence of urine ketones, and reducing substances, nl
serum AAs.
 +/- mild acidosis, or hyperammonemia, elevated LFTs, abnl
coags. +/-Hepatomegaly-/+
 Dx with serum Acylcarnitine Profile or fibroblast enzyme
assay

For the Boards:
 Fetal Defect in LCHAD may result in
Prenatal course complicated by :
 Maternal HELLP syndrome

Non-ketotic Hyperglycinemia:
 Unique entity in that Glucose, NH4, pH are all
normal.
 4 types with varying ages of onset, however,
classic form is Neonatal with onset in 1st week of
life.
 Will present just like the other devastating IEMs.
Lethargy, emesis, hypotonia, seizures, etc…
 Uncontrolled hiccups.
 Dx with no urine ketones, and Elevated Glycine.
 No effective Rx. Will require diet restriction.
 Long term is a devastating disease.

Galactosemia:
 First 1-2 wks of Life: Presents with hypoglycemia, jaundice,
emesis.
 Secondary to intolerance of Galactose. Will be in baby’s first
meals of breast milk or lactose containing formulas.
 Also index of suspicion for GramNeg or E.coli sepsis.
 Dx assisted by Non-glucose reducing substances in urine.
 Confirmation by Galactose-1-PO uridyl transferase activity in RBCs.
 Adverse sequelae include Cataracts, MR, persistent liver
disease.

 Which is worse?
– Essential Fructosuria
– Inherited Fructose Intolerance
 Inherited Fructose Intolerance
– Occurs after ingestion of Fructose (sucrose= glucose +
fructose)
– Severe and life threatening intoxication of F-1-PO4.
– Presents with emesis, seizures and profound illness
after ingestion of fructose.
– May also present similar to Galactosemia.
– Life long avoidance of fructose.

Glycogen Storage Disorders:
 Type 1= Von Gierke’s:
– Shortly after birth: Severe lifethreatening Hypoglycemia
– Lactic acidosis –due to isolated glycolysis of G6Po
– Hyper-uricemia, hyper lipidemia
– Increased association with epistaxis
– *Hepatomegaly
– **Adverse response to Glucagon with worsening Lactic acidosis
 Management requires IV glucose, and then as outpt, close
NG corn-starch or glucose solution administration to
achieve close to nl glucose homeostasis.
 Frequent snacks and meals. Continuous nighttime glucose
infusions up to the age of 2.

Glycogen Storage Disorders:
 Type 2- Pompe’s disease:
 Normal Glucose
 Do to an accumulation of glycogen in lysosomes.
 **Ancient city of Pompeii was destroyed by Mt. Vesuvius- 79 AD**
 Manifested by massive Cardiomegaly,
Hepatomegaly, Macroglossia.
 Fatal If results in CHF.
 Limited therapies in Neonatal Variant.
– Attempts at enzyme replacement ongoing.

Mitochondrial Disorders:
 Emerging spectrum of diseases with life-time
variation of presentation.
 Infantile/Neonatal: may present with
encephalopathic picture, regressed milestones,
cerebral cortical atrophy.
 Generally lab findings of:
– Lactic Acidosis
– Nl to low serum pyruvate, incomparison to Lactate
– Nl organic acids.
– *** Important to check CSF values of the above***

Leigh’s Disease
 AKA- Subacute necrosing encephalopathy
 Due to defects in the mitochondrial electron
transport chain.
 May have devastating presentation with significant
developmental regression.
 Unfavorable natural history.
 May respond to host of supplements.
 **Other Mitochondrial disorders for completion
sake**
– MELAS, MERRF, Leber’s HON

Leukodystrophies:
 Krabbe disease:
– Type 1- “Infantile”= irritability, hypertonia,
hyperesthesia, and psychomotor arrest, followed by
rapid deterioration, optic atrophy, and early death
– Type 2- Late infantile
– Type 3- Juvenile
– Type 4- Adult
 A demyelination disorder due to CNS
accumulation of galactosylceramide.
 Diagnosis: supported by cortical atrophy on
CT/MRI, High CSF protein and definite evidence
of deficient GALC assay in WBCs or skin
fibroblasts.

Lysosomal Disorders
Focus on key differences:
 Gaucher Disease:
– Infantile vs chronic
juvenile
– Organomegaly
– Bone pain
– Easy bruisability
– **low Plts,
osteosclerosis, and lytic
bone lesions
– MNEUNOMIC=
“Clumsy Gaucho
cowboy”
 Tay-Sachs Disease:
– Progressive neurologic
degeneration in first
YOL and death by age
4-5 yo
– AR inheritance with
classic Jewish
Ashkenazi relationship.
– Increased startle reflex
– Cherry red macula
– Macrocephaly

Peroxisomal Disorders
 Zellweger Syndrome
 aka: Cerebro-hepato-renal
syndrome
 Typical and easily
recognized dysmorphic
facies.
 Progressive degeneration
of Brain/Liver/Kidney, with
death ~6 mo after onset.
 When screening for PDs.
obtain serum Very Long
Chain Fatty Acids-
VLCFAs

Further Evaluation in IEMs:
 ** Head CT, MRI, Ophtho, Audio, EKG,
EEG**
 Genetics consultation.
 Peds Neuro consultation.

Random Questions for the Boards:
 Amino Acids responsible for MSUD?
 Valine, Leucine, Isoleucine
 Name 1 of the 3 classic Metal Storage disorders?
 Menke’s Kinky Hair Syndrome (X-link recessive)
 Wilson’s Disease
 Neonatal Hemachromatosis
 Lysosomal storage disease associated with Adrenal Gland
calcifications?
 Wolman Disease
– Fatty acid deposits, nl lipid panel
– **Mneumo= Wool Man Disease  white wool deposits.

Recognize that Smell:
 Musty or Mousy:
 PKU
 Boiled Cabbage
 Tyrosinemia or
hypermethioninemia
 Maple Syrup
 maple syrup urine disease
 Sweaty feet:
 isovaleric acidemia or glutaric
acidemia type II
 Cat urine
 multiple carboxylase
deficiencies (Biotin deficiency)

Follow up Questions ?
 Name some classic Mucopolysaccharidosis?
 Hunter’s (X-linked, no corneal clouding)
 Hurler’s (presence of Corneal clouding)
 Morquio Syndrome (nl IQ, short, cloudy cornea) *tattoo on FI
 -How are mucopolysaccharidoses Diagnosed?
 Urine MPSs, definite with Skin Fibroblast Bx
 How to treat Neonatal Hyperinsulinism?
 Diazoxide- inhibits pancreatic B-cell insulin secretion.
 Child Dx with PKU, now diet restricted, but with
progressive neuro deterioration. What else might be
deficient?
 Tetrahydrobiopterin (BH4)

Finally and to wet your appetite for
Sat:
 Name this syndrome and the associated metabolic
defect.
 Smith-Lemli-Opitz Syndrome: due to defect in
cholesterol synthesis.

What are the clinical manifestations of a
child with IEM?
Neurologic manifestations-
Neurologic manifestations may be in the form of unexplained encephalopathy,
seizures, acute ataxia or an acute psychotic episode. Acute metabolic
encephalopathy (Small Molecule Disease) .
Acute encephalopathy -
metabolic disorder usually results from accumulation in the brain,
to a critical level, of a small diffusible metabolite or precursor e.g.
1.ammonia or
2. from deficiency of an essential product (adenosine triphosphate)
3. form a defective transport process e.g. carnitine.
These disorders are therefore also called as “small molecule diseases”.
Most of these metabolites cross the placenta and are cleared by the mother
and thus affected neonates are normal at birth

A pneumonic to be remembered in acute
encephalopathy is GELAK which spells for glucose,
electrolytes, lactate, ammonium and ketones.
It is important to decipher where the hypoglycemia
is ketotic or hypoketotic
Hypoketotic hypoglycemia is due to over utilization of glucose whereas ketotic is
due to underproduction.
Over utilization can be due to hyperinsulism or fatty acid oxidation defects -FAOD.
Hyperinsulism should be suspected with recurrent, severe hypoglycemia occurring after
a short fasting period, or if high concentrations are required (> 12 mg/kg/min).
A clue to the presence of hyperinsulinism is a Free Fatty Acid/3 Hydroxybutryate ratio of
usually less than three, whereas in fatty acid oxidation defects it is more than three.

 The most common defect in fatty acid oxidation is MACD
deficiency.
Upto one quarter of cases first present in the newborn period
with fasting hypoglycemia. a small but important proportion of
sudden infant deaths can also result from defects in fatty acid
oxidation and this group of disorders must be excluded if there is
history of SIDS or near miss SIDS.
When hypocalcaemia is associated with metabolic acidosis, it suggests a defect
in gluconeogenesis or an organic academia (GSD type I or fructose 6
biphosphatase deficiency).
When ketosis is associated with hypoglycemia MSUD should be considered.
The combination of cholestatic jaundice and hypoglycemia should prompt one
to think of pituitary insufficiency or FAOD.

Metabolic encephalopathy may be associated with
elevated blood ammonia and this is a clinical emergency
as ammonia is a potent neurotoxin.
Lactate estimation is fraught with preanalytical errors
and a persistently high lactate>2.0 mmol/L is considered
significant. A rise in CSF lactate is pathognomonic of a
metabolic defect, if meningitis is excluded.
A normal blood and CSF lactate in an acutely sick newborn
effectively excludes a mitochondrial respiratory chain

A rise in CSF lactate is pathognomonic of a metabolic defect,
if meningitis is excluded
Lactic acidosis occurring as a sequel of
hypoxemia gets corrected easily and exists with a
normal Lactate: Pyruvate ratio
Organic Acidosis result from an a defect in an
enzyme that normally degrades an organic acid
and result in accumulation of that anion, often
producing acidosis

The major difference between organic acidemias and
aminoacidopathies is the severe metabolic acidosis.
In addition to encephalopathy, these patients have
moderate to severe hyperammonemia as a result of
secondary inhibition of urea cycle by accumulating
organic acids and hypoglycemia.
Bone marrow suppression with pancytopenia is
commonly observed and hence the association with
sepsis.

These following pointers may help us in diagnosis:
1. Metabolic acidosis may imply the patient has a small
molecule disease.
2. Hypoglycemia without ketones may imply that patient
has a disorder of fatty acid oxidation .
3. Organomegaly with coarse features may imply that
patient has a storage disorder

These following pointers may help us in diagnosis:
1. Organomegaly without coarse features may imply that patient has a storage
or a non-storage disease .
2. Hyperammonemia can also accompany organic acidemias and mitochondrial
disorders due to suppression of the urea cycle by toxic metabolites along with
primary urea cycle defects.
3. Pancytopenias commonly accompany organic acidemias and can predispose
to sepsis and hence may defy the principle of parsimony or the KISS principle
"keep it simple, stupid" suggesting that both can co-exist and frequently do.
However these rules of thumb are only starting
possibilities.
Therefore small molecule diseases may cause
hepatomegaly and large molecule disease can cause
acidosis .

Type 3: Progressive Neurological
Deterioration
 Examples: Tay Sachs disease
Gaucher disease
Metachromatic leukodystrophy
 DNA analysis show: mutations

Chronic encephalopathy or Episodic illness
There should be high threshold for suspicion
of diplegia as in arginase deficiency.
There should be a high threshold for
suspicion of hyperammonemia in patients
whose neurologic status deteriorates for no
apparent cause.

Small molecule diseases
Chronic hyperammonemia in an infant may present with cyclical vomiting, faddy
eating (high protein intolerance), behavioural changes and neurologic deficits
(e.g., spastic diplegia as in arginase deficiency).
There should be a high threshold for suspicion of hyperammonemia in patients
whose neurologic status deteriorates for no apparent cause.
One of the common presentations is the one with "overwhelming metabolic
coma" which is the combination of cerebral and hepatic failure in the presence
of lactic academia with or without hyperammonemia.
This syndrome complex is often called Reye's like illness
(Fulminant hepatoencephalopathy).
.

The disease is often biphasic,
with the first phase consisting of a trivial viral disorder from which the patient
seems to be recover uneventfully.
The second phase that of encephalopathy, is almost always heralded by
persistent, unrelenting vomiting lasting for several hours to 1 day. Progressive
disturbance in the level of consciousness soon follows, reaching varying
degrees of severity in a rostrocaudal fashion. An early stage of lethargy and
confusion in some patients progresses stereotypically to delirium, dystonic
(decorticate/decerebrate) coma, and finally herniation of the brain stem.
In the 1980s, a number of diseases were discovered that could mimic RS
clinically (vomiting and encephalopathy), biochemically (abnormal liver
enzymes and elevated blood ammonia), and pathologically (microvesicular
steatosis of the liver).
The list of diseases that could mimic RS became quite extensive and has been
reported in the setting of several small molecule diseases

If Physical examination of neonates
reveals
 General – Dysmorphisms
(abnormality in shape or size),
 ODOUR - Urine
 H&N - cataracts, retinitis pigmentosa
 CNS - tone, seizures, tense fontanelle
 Resp - Kussmaul’s, tachypnea
 CVS - myocardial dysfunction
 Abdo - HEPATOMEGALY
 Skin - jaundice

Neonate iem may 2021

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