Fact sheets print

1 | P a g e Ist edition by dr.amir abdelazim ahmed
Rapid
Notes
Information for DOCTORS about the
Disorders included in the Kuwait’
Newborn Screening Panel
By
Dr.Amir Abdelazim Ahmed
Clinical pathology specialist
Kuwait newborn screening laboratories

Content :
Subject
1 Panel of newborn screening program in
Kuwait
2 Summary for conditions affect newborn
screening results
3 Table for notes in clinical and therapeutic
principles
4 Amino acid disorders
5 Fatty acid disorders
6 Organic acid disorders
7 Endocrine disorders
8 Galactosemia

Panel of 22 disorders
Amino Acidemias :
Phenylketonuria (PKU)
Maple syrup urine disease (MSUD)
Homocystinuria (Cystathionine synthase def.)
Citrullinemia (ASA synthase deficiency )
Tyrosinemia (Type 1)
Argininosuccinic Aciduria (ASA Lyase deficiency)
Organic Acidemias :
Propionic Acidemia (PA)
Methylmalonic Acidemia (MMA)
Isovaleric Acidemia (IVA)
Glutaric Acidemia Type I (GA-I)
3-methylcrotonyl-CoA Carboxylase deficiency (3MCC)
Beta Ketothiolase deficiency (Mitochondrial Acetoacetyl CoA
Thiolase deficiency)
Multiple CoA Carboxylase deficiency (MCD)
Fatty Acid Oxidation Defect :
Medium Chain Acyl CoA Dehydrogenase Deficiency (MCAD)
Very Long Chain Acyl CoA Dehydrogenase Deficiency (VLCAD)
Long Chain Hydroxy Acyl Dehydrogenase (LCHAD)
Trifunctional Protein Deficiency (TFP)
3-Hydroxy-3-methylglutaryl-CoA Lyase Deficiency (3HMG)
Galactosemia
Biotinidase Deficiency
Endocrine Disorders :
Congenital Hypothyrodism
Congenital Adrenal Hyperplasia

disorders Appearance
of
symptoms
Risk
of
crisis
Screening
time
Factors causing false
positive results
Factors causing false
negative results
Congenital
hypothyroidism
first year of life,
early treatment
prevents mental
retardation,
developmental
delays
12 - 72 hr and
2 - 6 weeks
 TSH surge in first 12-24 hours
 topical iodine on baby or
breastfeeding mother
 maternal hyperthyroidism treated
with propylthiouracil,
 acute illness until recovered
 iodine deficiency
 delayed rise of TSH in affected
 infants, particularly if preterm
(immature
hypothalamicpituitary- thyroid
axis)
 dopamine therapy (suppresses
 TSH)
 steroid treatment (suppresses
TSH & T4)
Congenital
adrenal
hyperplasia
first week of life yes 12 - 48 hr and
2 - 4 weeks
 preterm birth or LBW
 sick or stressed infant
 mother with CAH and elevated
 17-OHP
 early collection (<24 hr of age)
 maternal steroid treatment
steroid (dexamethasone)
treatment in infant
Biotindase 1 week – 10
years of age
(most show
Symptoms
between 3 – 6
months of age)
birth - 72 hr  heat with humidity damage to
specimen
 prematurity
 liver disease
 , jaundice
 transfusion of plasma or other
blood products
Galactosemia first week of life yes birth - 48 hours  heat damage to specimen,
 age of specimen (received by lab
more than 4 – 5 days after
collection)
 red blood cell transfusion
PKU 6 - 8 months of
age
(irreversible brain
damage happens
if
treatment is not
started in first
weeks
of life)
24 - 48 hours  parenteral nutrition
 liver dysfunction or immaturity
 maternal PKU or hyperphe
uncontrolled by diet or medication
 early collection (<24 hours of
age) or collection only a few
hours after transfusion or
discontinuation of ECMO
MSUD first two weeks of
life
yes 24 - 48 hours  parenteral nutrition
 early collection (<24 hours of
age) or collection only a few
hours after transfusion or
discontinuation of extra
corporeal membrane
oxygenation
HCY 3 - 7 days  parenteral nutrition
 early collection, pyridoxine
responsive cases are not
identified by NBS
CIT &
ASA
first two weeks of
life
yes 24 - 48 hours  parenteral nutrition
 early collection or collection
only a few hours after
transfusion ordiscontinuation
of extra corporeal membrane
oxygenation
TYR 1 3 – 4 months of
age
(liver is damaged
by
that time)
more than 1
week of age
FAO
disorders
first few days to
months or years
(more easily
detected during
acute illnesses or
during times of
increased energy
need)
yes birth - 48 hours  carnitine supplementation, MCT
oil
 fatty liver of pregnancy or HELLP
syndrome* can cause elevated
even chain acylcarnitines
MCD,
MMAs,
PA
yes 24 - 48 hours maternal Vitamin B12 deficiency
Organic
acid
disorders
first two weeks of
life
yes 24 - 48 hours parenteral nutrition
IVA first two weeks of
life
yes 24 - 48 hours pivalic acid antibiotic therapy
3MCC yes 24 - 48 hours asymptomatic mother with
3MCC, unaffected infant

Chronic Neurological Diseases Life Threatening Diseases
Phenylketonuria Medium chain acyl-CoA dehydrogenase
deficiency
Glutaric acidemia type 1 Very Long chain acyl-CoA dehydrogenase
deficiency
Biotindase Deficiency 3Methyl 3-hydroxyglutarayl CoA lyase deficiency
Multiple Carboxylase Deficiency Isovaleric Acidemia
Congenital Hypothyroidism Maple Syrup Urine Disease
Multi Organ Diseases Argininosuccinic aciduria
Citrullinemia
Methyl malonic acidemia
Homocystinuria Propionic acidemia
Long Chain 3hydroxy acyl-CoA dehydrogenase
deficiency
B-ketothiolase deficiency
Congenital adrenal hyperplasia
Trifunctional protein deficiency
Liver Diseases
Tyrosinemia type 1
Galactosemia

Abnormal screening results
Retest same filter paper
Confirmatory testing
Consult specialist

Disease Primary
Analyte
Measured
Screening Can
Prevent…
Tretmenat
Argininosuccinic Acidemia
(ASA)
Citrulline …developmental
delay , seizures , coma
, death
Avoid fasting , low
protein diet , medication
Β-Ketothiolase (BKT)
Deficency
C5OH … brain damage ,
developmental delay ,
coma , death
Avoid fasting , low
protein and fat diet ,
medication
Biiotindase Deficency Biotindase … developmental
delay , hypotonia ,
seizures , skin , rash ,
hair loss , death
Biotin (vitamin)
supplementation
Citrullinemia Cirtulline … developmental
delay , seizures , coma
, death
Low protein diet , avoid
fasting , medication
Congenital Adrenal
Hyperplasia (CAH)
17-OH
progesterone
… salt-wasting crises ,
death
Hormone and mineral
replacement
Congenital
Hypothyroidism
Thyroid
hormones
… severe and
irreversible
failure to thrive
Hormone replacement
Galactosemia Galactose -1-
phosphate
uridyl
transferase
(GALT)
… failure to thrive ,
liver damage , sepsis,
death
Galactose restricted diet
Glutaric Acidemia Type I
(GAI)
C5DC … developmental
delay , spasticity ,
encephalopathy ,
coma , death
Avoid fasting , low
Homocystinuria Methionine … developmental
delay , lens
dislocation ,
thrombosis
Low methionine diet ,
medication , dietary
supplementation
3-Hydroxy-3-
methylglutaryl CoA Lyase
Deficiency
C5OH … brain damage ,
death
Avoid fasting , low
protein and fat diet ,
carnitine
supplementation
Isovaleric Acidemia (IVA) C5 … encephalopathy ,
neurological damage,
coma , death
Avoid fasting , low
LCHAD Deficiency C16OH … cardiomyopathy ,
seizures ,
coma , death
Avoid fasting , diet low in
long –chain fats
Maple Syrup Urine
Disease (MSUD)
Leucine
/isoleucine
.. failure to thrive ,
seizures ,
coma , death
fasting ,

MCAD Deficiency C8 … seizures , coma ,
dudden death
Avoid fasting , aggressive
treatment of illness
3-Methylcrotonyl-CoA
Carboxylase Deficiency
C5OH …failure to thrive ,
seizure , coma , death
Avoid fasting ,
medications , low
protein diet ,
supplementation
Methylmalonic Acidemia
(mutase deficiency and
cobalamin defects)
C3 … failure to thrive ,
encephalopathy ,
coma , death
fasting ,, vitamin B12
supplementation
Multiiple Carbosylase
Deficency
C3 , C5OH … failure to thrive ,
encephalopathy ,
coma , death
Biotin supplementation
Phenylketonuria Phenylalanine …severe and
irreversible
developmental delay
Phenylalanine restricted
diet , supplementation
Proprioic Acidemia C3 …encephalopathy ,
developmental delay,
coma, death
Avoid fasting , low
Trifunctional protein
Deficiency
C16OH ..developmental delay
, failure to thrive ,
cardiomyopathy ,
coma , sudden death
Avoid fasting , diet low in
long chain fats
Tyrosinemia Type I Tyrosine and
Succinylacetone
… liver and kidney
damage and sequelae
, failure to thrive ,
cpagulopathy
Special diet , medication
VLCAD Deficiency C14:1 … developmental
delay and failure to
thrive , hepatomegaly
, cardiomyopathy ,
coma , sudden death
Avoid fasting , special
diet
Legand
Organic acid
disorders
Immune deficiencies
Fatty acid
oxidation
disorders
Endocrine disorders
Amion acid
disorders

Amino-acid disorders
HOMOCYSTINURIA
Homocystinuria is an inborn error of the transsulfation pathway which causes an
increase in the levels of homocysteine and methinonine in the blood. It is caused by
cystathionine β-synthase (CBS) deficiency which leads to the inability to convert
homocysteine to cystathionine .
Incidence
Very rare
Clinical Manifestation
Patients affected with homocystinuria may present with ectopia lentis which is found
in 85% of patients , skeletal abnormalities such as genu valgus and “marfanoid
habitus”, mental retardation and thromboembolism.
Pathophysiology
Increased homocysteine levels is found to inhibit linking of collagen and elastic tissues
which predisposes zonule generation of the eye predisposing patients to myopia and
lens dislocation.5 Skeletal abnormalities are thought to result from damage to fibrillin
in patients with cytathionine β-synthase and due to a reduction in collagen
crosslinking6 while the mechanism that contributes to the atherogenic propensity of
hyperhomocystinemia are related to endothelial dysfunction and injury which leads to

platelet aggregation and thrombus formation.7 Chemical abnormalities and the
repeated thromboemolic strokes may contribute to the mental retardation.
Inheritance
autosomal recessive
Screening:
increased methionine on MSMS
Confirmatory Testing
Total homocysteine in plasma. Amino acids in plasma, methylmalonic acid in urine and
enzyme study in fibroblasts may be used to confirm the diagnosis.
Prognosis
Early diagnosis and treatment can prevent thromboembolic events and reduce the
complications brought about by increased levels of homocysteine
Treatment of HCY
Treatment is through the dietary restriction of protein and the supplementation of formula
lacking methionine. Vitamin B6, folic acid and betaine are also given.
Preliminary / Initial Management During Metabolic Crisis
Metabolic crises may be caused by illness, prolonged fasting or stressful situations such as
SURGERY and severe infection.
The goal of treatment is to reverse the catabolic state and prevent essential amino acid
deficiency.

Long Term Management
The aim of treatment is to reduce plasma total homocysteine levels to as close to
normal as possible while maintaining normal growth rate. This can be done in the
following ways:
Supplementation of Vitamins
Pyridoxine (Vitamin B6)- may start with 50-100mg/day. May progress to 500-
1000mg/day guided by plasma homocysteine and methionine monitoring. About half
of patients with CBS deficiency respond often only partially to large doses of
pyridoxine. But since high doses of pyridoxine has been associated with
sensoryneuropathy, it should then be kept at the lowest dose that is able to achieve a
good metabolic control. Doses higher than 250mg/day should be avoided in newborns
and young infants. If patients do not respond to pyridoxine, a low methionine, high
cystine diet must be introduced and continued throughout life.
Folic acid – may start at 5-10 mg/day as response to pyridoxine may also be influenced
by folate depletion Vitamin C supplementation has been shown to ameliorate
endothelial dysfunction in CBS patients suggesting its possible value in reducing the
long term risk of atherothrombotic complications. One may give it at 100mg/ day
Diet
_ Low Methionine Diet- synthetic methionine free amino acid mixtures for infants
_ Supplements of essential fatty acids and carbohydrates are also required
_ After infancy, foods containing proteins low in methionine can be introduced.
What to Do:
If unwell and cannot tolerate oral intake:
a. Nothing per orem
b. Ensure patient’s airway is secure
c. Insert IV access. Collect samples for methionine and homocystine levels (contact the Biochemical Genetic Laboratory NIH). May
request for other investigations (i.e. CBC, Blood gas) as needed. May give fluid boluses if patient requires.
d. Start D12.5% 0.3 NaCl at full maintenance. Assess patient clinically, if there is need to increase fluid, may do so up to 1.2 or 1.5X
the maintenance especially if the patient will undergo surgery.
e. Make sure that the patient is well hydrated. Monitor input and output strictly (q6 hours)
f. Start betaine, folic acid and vitamin B6
If unwell but is able to tolerate oral intake:
a. Insert oro- or nasogastric tube and start continuous feeding with HCY formula to run at maintenance rate
b. Insert IV access. Collect samples for methionine and homocystine level (contact the Biochemical Genetics Laboratory, NIH). May
request for other investigations (i.e. CBC, blood gas) as needed. May give fluid boluses if patient requires.
c. Start D12.5% 0.3 NaCl at 5-10 cc/hr. Make sure that the patient is well hydrated especially if he will undergo surgery. Monitor
input and output strictly (6 hours)
d. Start betaine, folic acid and vitamin B6
*Children should not be protein restricted for longer than necessary (24-48 hours).
* Inform metabolic doctor on call for further guidance regarding on-going management.

Betaine
Betaine is a homocysteine lowering agent (remethylates homocysteine to methionine)
that is especially useful when compliance to the diet is unsatisfactory. One can start at
100mg/kg/day with a maximum dose of 6-9 grams in adults.
Monitoring of plasma homocysteine and methionine levels
Plasma monitoring of methionine, cysteine, cysteine:homocysteine disulfide and
homocysteine should be done every 3 months. The goal is a plasma homocysteine
level of <60umol/L.
Key metabolite : Methionine , elevated
Emergency key : Low
Action : Referral to a metabolic center
Confirmation analysis :
Total homocysteine in plasma
Amino acids in plasma
Organic(mwthylmalonic)acids in urine
Mutation analysis
Therapy :
Diet restricted in methionine
Betaine
Pyridoxine in responsive patients
Vitamene B12
Folic acid
Signs and symptoms :
Mental retardation
Dislocation of the lenses
Marfanoid habitus
Osteoporosis
Thromboembolism
Prognosis : Good
References
1 Schulze A, Matern D, Hoffmann GF. Chapter 2: Newborn screening in Sarafoglou K, Hoffman GF and Roth KS
(eds). Pediatric Endocrinology and Inborn Errors of Metabolism. New York:McGraw Hill, 2009 pp 17-32.
2 Yap S. Homocystinuria due to cystathionine β-synthase deficiency. Orphanet 2005.
http://www.orpha.net/data/photo/GBuk-CbS.pdf Accessed Feb. 16, 2012.
3 Chapter 22 Homocystinuria. Nyhan WL, Barshop BA and Ozand P. Atlas of Metabolic Diseases 2nd ed. Great
Britain:Oxford University Press, 2005 pp 146-151.
4 Cruysburg JR, Boers GHJ, Trijbels FMJ et al. Delay in diagnosis of homocystinuria: retrospective study of
consecutive patients. BMJ 1996;313:1037-1040.
5 Burke JP, O’Keefe M, Bowell R and Naughten ER. Ocular Complications in Homocystinuria – Early and Late
Treated. Br J Ophthalmol. 1989 June; 73 (6):427-431.
6 Mudd SH, Levy HL, Skovby F. Disorders of transsulfuration. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds.
The Metabolic and Molecular Bases of Inherited Disease. 8th ed. Vol 2. New York: McGraw-Hill, 2001:2007-
2056.

MAPLE SYRUP URINE DISEASE [MSUD]
Maple syrup urine disease (MSUD) is due to a defect or deficiency of the branched
chain ketoacid
dehydrogenase (BCKD) enzyme complex leading to the elevated quantities of leucine,
isoleucine, valine and their corresponding oxoacids in body fluids.1 Accumulation of
the latter amino acids will result in life threatening encephalopathy if not adequately
treated.
Incidence
Very rare
There are different classifications of MSUD based on the enzyme activity and these
include: classical, intermediate, intermittent, thiamine responsive and E-3 deficient
MSUD. Classical MSUD (residual enzyme <2%) is the most severe and common form
with symptoms of poor suck, lethargy, hypo and hypertonia, opisthotonic posturing,
seizures and coma developing 4-7 days after birth.1 The characteristic odor of maple
syrup may be detected as soon as neurological symptoms develop. Patients with
intermediate MSUD (residual enzyme 3-30%) have gradual neurologic problems
resulting in mental retardation.1 Intermittent form of MSUD go into metabolic crisis
when there is a stressful situation such as infection or after surgery.
Thiamine-responsive MSUD’s clinical symptomatology and metabolic disturbance is
ameliorated once pharmacologic dose of thiamine has been given. E-3 deficient MSUD
present with symptoms similar to those of intermediate MSUD but they also have
lactic acidosis.
Pathophysiology
Due to mutations in the gene coding for the branched chain keto-acid dehydrogenase
enzyme, the levels of leucine, valine and isoleucine increase in blood. The increase in
leucine may cause competitive inhibition with other precursors of neurotransmitters
causing the neurologic manifestations.
Inheritance:
autosomal recessive
Screening:
leucine + isoleucine, valine, (leucine + isloeucine)/phe ratio
Diagnosis is confirmed by detection of the highly increased branched-chain amino acid
levels via quantitative amino acid analysis and/or by increased urinary excretion of α-

keto and hydroxyl acids and branched chain amino acids using gas chromatography-
mass spectrometry (GC-MS) and quantitative amino acid analysis.2
Prognosis
Patients with MSUD are now expected to survive, they are generally healthy between
episodes of metabolic imbalance and some attend regular school. However, the
average intellectual performance is clearly below those of normal subjects.
Treatment of MSUD
lacking leucine, valine and isoleucine.
surgery and severe infection.
The goal of treatment is to lower down the levels of leucine, isoleucine and valine, reverse
the catabolic state and prevent essential amino acid deficiency.
What to Do:
a. Nothing per orem
c. Insert IV access. Collect samples for leucine level, plasma amino acids, blood glucose and urine
ketones. May request for other investigations (i.e. CBC, blood gas) as needed. May give fluid
boluses if patient requires.
d. Start D12.5% 0.3 NaCl at full maintenance. Assess patient clinically, if there is need to increase
fluid, may do so up to 1.2 or 1.5X the maintenance.
e. Start intralipid at 1g/kg/24 hours.
f. Monitor input and output strictly (q6 hours)
a. Insert oro- or nasogastric tube and start continuous feeding with BCAD formula to run at
maintenance rate
b. May give valine at 50mg/kg/day divided into 6 doses and isoleucine 30mg/kg/day divided into
6 doses
c. Insert IV access. Collect samples for leucine level, plasma amino acids, blood glucose and urine
ketones. May request for other investigations (i.e. CBC, blood gas) as needed. May give fluid
boluses if patient requires.
d. Start D12.5% 0.3 NaCl at 5-10 cc/hr.
e. Monitor input and output strictly (q6 hours)
*If patient does not improve with the initial management (within 12 hours), hemodialysis may be indicated.
Monitor patient clinically, the necessity of hemodialysis will depend on patient’s clinical status.

Long term Management
The aim of life long maintenance therapy is to maintain the branched chain amino acid
levels at near normalconcentrations. Regular evaluation of nutritional status,
metabolic control, growth percentiles as well as developmental progress are
imperative for a good clinical and cognitive outcome.
Diet
The major component of the diet is a special formula that do not contain any leucine,
isoleucine or valine but are otherwise nutritionally complete. They contain all the
necessary vitamins, minerals, calories and the other amino acids needed for growth.
They will also be given a formula supplemented with carefully controlled amounts of
a protein-based formula.
The protein-based formula provides the infant with the limited amount of branched
chain amino acids needed to grow and develop normally.
As children with MSUD grow, they continue taking the special formula. They are
allowed other foods which are weighed or measured in the home to supply the
prescribed amount of leucine each day. Typically the MSUD diet does not include any
high protein foods such as meat, nuts, eggs, and most dairy products. Children
gradually learn to accept the responsibility for controlling their diets and generally
being on low protein at all times.
Frequent determination of leucine levels are likewise encouraged so that proper
dietary adjustments be done for effective management of the condition.
Special supplements
Occasionally, small amounts of free valine and isoleucine must be added to the
amounts provided by the natural protein because the tolerance for leucine is lower
than the other two. Under conditions of high leucine and low valine and isoleucine
levels, a rapid fall of plasma leucine can be achieved only by combining a reduced
leucine intake with a temporary supplement of leucine and isoleucine.
Treatment of intercurrent decompensations
Acute intercurrent episodes are prevented by being aware of those situations that may
induce protein catabolism. These include intercurrent infections, immunizations,
trauma, anesthesia and surgery. Parents must have at their disposal a semi emergency
diet in which natural protein intakes are reduced by half or an emergency diet in which
natural proteins are suppressed. In both, energy supply is reinforced using
carbohydrates and lipids. Solutions containing a mixture of glucose polymer and lipids
can be used. Timely evaluation and intensive treatment of minor illnesses at any age
is essential, as late death attributed to recurrence of metabolic crises with infections
has occurred.

Emergency Protocol for Maple Syrup Urine Disease
Important points to be relayed to the parents over the phone:
1. Avoid delay and bring the child to the hospital at once
2. Bring formula (if known MSUD patient)
3. Bring isoleucine and valine tablets (if known MSUD patient)
4. Ask for child’s current weight
5. Ask about an estimated time of arrival at the ER
Alert Emergency Department of the patient’s arrival
1. Talk to the Admitting Officer and Nursing Team Leader
2. Ask them to do an urgent clinical assessment (history and physical examination)
3. *Prepare 12.5% dextrose (maintenance)
4. *Prepare Intralipid 2g/kg/day
5. Collect blood for **plasma amino acids or on dried blood spot. Check for urine
ketones. Other
examinations as required.
6. Contact the Physician on call once patient arrives at ER
—————————
* Please prescribe for weight before the patient arrives.
** Collect in green top tube. Transport immediately to Biochemical Genetics Laboratory
Principles of Management
Reversion of catabolism
Start IV infusion using 12.5% dextrose -maintenance + %dehydration (add potassium
if serum K is not high). If the patient is encephalopathic, additional sodium may be
required (up to 6 mmols/kg/day). If there is a
concern about cerebral edema (focal neurologic signs or fluctuating level of
consciousness) fluids may need to be restricted.
_ Stop natural protein.
_ Intralipid at 2g/kg/day. This can be infused in the same line peripherally.
_ The patient may also have an enteral emergency sick day regimen, which can be
administered
continuously via a nasogastric feeding tube.
_ Treat underlying cause. Treat dehydration, electrolyte imbalance, infection and
acidosis
_ Consider dialysis if with acute deterioration of cerebral function consider the
following
_ Maintain plasma concentrations of isoleucine and valine more than 200 umol/L

Key metabolite : Leucine + isoleucine , valine , elevated
Emergency key : High
Action : Immediate referral to metabolic
specialist
Organic acid in urine
Enzyme activity in lymphocytes
Mutation analysis
Therapy :
Acute management :
Discontinue natural protein
Provide large amount of calories ,fluids
and electrolytes
Enteral therapy :
Special formula that contains all required
amino acids but is free of leucine , valine
and isoleucine
Progressive encephalopathy
Maple syrup smell of urine
Mental retardation
Prognosis : Moderate , often mild mental
impairment even in well treated children
References
1 Chapter 24 Maple syrup urine disease. Nyhan WL, Barshop BA and Ozand P. Atlas of Metabolic Diseases 2nd
ed. Great Britain:Oxford University Press, 2005 pp 159-164
2 Hoffman GF and Schulze A. Chapter 7: Organic Acidurias in Sarafoglou K, Hoffman GF and Roth KS (eds).
Pediatric Endocrinology and Inborn Errors of Metabolism. New York:McGraw Hill, 2009 pp 93-94.
3 Schulze A, Matern D, Hoffmann GF. Chapter 2: Newborn screening in Sarafoglou K, Hoffman GF and Roth KS
(eds). Pediatric Endocrinology and Inborn Errors of Metabolism. New York:McGraw Hill, 2009 pp 17-32.
4 Wendel U and de Baulny H. branched chain organic acidurias/acidemias. Inborn Metabolic Diseases Chapter
19 4th edition eds Fernandes, Saudubray, van den Berghe, Walter pp246-256

PHENYLKETONURIA [PKU]
Phenylketonuria is a disorder of aromatic amino acid metabolism in which
phenylalanine cannot be converted to tyrosine due to a deficiency or absence of the
enzyme phenylalanine hydroxylase. Phenylalanine hydroxylase requires the co-factor
6-pyruvoyltetrahydropterin or BH4 for activity in the hydroxylation to tyrosine,
absence of this co-factor may present with an increase in plasma phenylalanine similar
to phenylketonuria but is considered a separate disorder.
Incidence
1:15,000 worldwide
Patients affected with PKU appear normal at birth.2,4 The most important and
sometimes the only
manifestation of PKU is mental retardation.2 Patients may present with constitutional,
intellectual and neurologic abnormalities and signs as well as hypopigmentation of the
skin and hair and iris rapidly develop due to impaired metabolism of melanin.4 Seizures
occur in a fourth of patients.
The odor of the phenylketonuric patient is that of phenylacetic acid described as
mousy, barny, or musty.
Pathophysiology
PKU results from a deficiency of activity of a liver enzyme, phenylalanine hydroxylase
leading to increased concentrations of phenylalanine in the blood and other tissues.4
Elevated phenylalanine interfere with myelination, synaptic sprouting and dendritic
pruning; and in addition, it competitively inhibits the uptake of neutral amino acids in
the blood-brain barrier causing reduced tyrosine and tryptophan concentrations
thereby limiting the production of neurotransmitters.4
Inheritance
autosomal recessive
Screening
increased phenylalanine levels on MSMS
The demonstration of decreased enzyme activity is confirmatory. However, in the
presence of increased phenylalanine levels, it is important to differentiate
phenylketonuria from a BH4 deficiency. This is accomplished through administration
of tetrahydrobiopterin (doses of 2mg/kg intravenously and 7.5-20mg/kd orally) which
leads to a prompt decrease to normal in the concentration of phenylalanine. Pterin

metabolites in urine are likewise useful, demonstrating a very low biopterin and high
neopterin levels.
Prognosis
When treatment is started early and performed strictly, motor and intellectual
development can be expected to be near normal.
Tetrahydrobiopterin BH4 Oral Loading Test
Preliminary / Initial Management During Metabolic Crises
The goal of treatment is to reverse the catabolic state and prevent essential amino acid
deficiency.

Diet
Dietary management is the key to treatment. The diet of patients has four
components:
_ complete avoidance of food containing high amounts of phenylalanine;
_ calculated intake of low protein/phenylalanine natural food
_ sufficient intake of fat and carbohydrates to fulfill the energy requirements of the
patient and;
_ calculated intake of phenylalanine free amino acid mixture supplemented with
vitamins, minerals and trace elements as the main source of protein.
In young children
At the start of treatment in infants with blood phenylalanine levels above 1200 umol/L,
a period (usually 24-48 hrs) of phenylalanine free milk brings levels down at a rate of
400 umol/l per day. As levels approach the therapeutic range (120-360umol/L),
phenylalanine is then added (around 1-1.5g/kg/day). Infants with lesser degrees of
phenylalanine accumulation need less rigorous restriction and smooth control is easier
to achieve.
The prescription of phenylalanine is adjusted until serial blood levels have stabilized.
What to Do:
a. Nothing per orem
c. Insert IV access. Collect samples for phenylalnine levels. May request for other
investigations (i.e. CBC, blood gas) as
needed. May give fluid boluses if patient requires.
d. Start D12.5% 0.3 NaCl at full maintenance. Assess patient clinically, if there is need to
increase fluid, may do so up to
1.2 or 1.5X the maintenance.
e. Start Intralipid at 1g/kg/day
a. Insert oro- or nasogastric tube and start continuous feeding with PKU formula to run at
maintenance rate
b. Insert IV access. Collect samples for phenylalanine levels. May request for other
investigations (i.e. CBC, blood gas) as
needed. May give fluid boluses if patient requires.
c. Start D12.5% 0.3 NaCl at 5-10 cc/hr.
d. Monitor input and output strictly (q6 hours)
* Inform metabolic doctor on call for further guidance regarding on-going management

In older children, adolescents and adults
Given the practical difficulties involved in sustaining a strict low phenylalanine diet, a
relaxation of the diet at some point before adolescence is allowed. It is recommended
that older children be offered the opportunity to remain on a diet that keep blood
phenylalanine concentrations ar or below 700umol/L after mid-childhood and into
adulthood.
Phenylalanine levels rise in response to minor events such as intercurrent illness,
decline in energy intake or in growth rate, reduction in the amount of protein
substitute and rise in phenylalanine intake, thus diet should be adjusted as needed.
Managing illness
During illness, children cannot take their prescribed diet. High energy fluids with or
without fat emulsion will help reduce catabolism and are more acceptable to children
during time of illness. As anabolism takes over, it is important to reintroduce
phenylalanine allowance to avoid phenylalanine deficiency as diet is re-established.
Monitoring of phenylalanine levels and growth and development
Regular monitoring of phenylalanine levels (at least monthly or more frequent
depending on the clinical status of patient) should be done religiously. There is
evidence that raising blood phenylalanine concentrations is associated with reversible
impairments in neuropsychological performance, thus assessment of mental
development should likewise be enforced. The risk of maternal phenylketonuria in
adolescent girls and women of reproductive age should also be emphasized as this risk
increases linearly in proportion to maternal phenylalanine concentrations.
Defects of Biopterin Metabolism (i.e. 6 Pyruvoyltetrahydrobiopterin synthase deficiency)
There is no diet restriction in these types of disorders. The following medications
should be given:
_ Tetrahydrobiopterin: 5-10 mg/kg/day
L-Dopa 8-12 mg/kg/day (neonates 1-3mg/kg/day, infants 4-7 mg/kg/day)
_ 5-OH-tryptophan (max 6-9mg/kg/day)
Key metabolite : Phe , elevated
Emergency key : Moderate
Action : Refer to metabolic specialist
Confirmation analysis : Amion acid in plasma
Pterin analysis in urine
DHPR-activity in DBS
Therapy : Phe restricted diet
Signs and symptoms : Severe mental retardation –seizures
Prognosis : Excellent , normal development

References
1Chapter 20: Phenylketonuria. Nyhan WL, Barshop BA and Ozand P. Atlas of Metabolic Diseases 2nd ed. Great
Britain:Oxford University Press, 2005 pp 127-133.
2Chapter 21 Hyperphenylalaninemia and defective metabolism of tetrahydrobiopterin. Nyhan WL, Barshop
BA and Ozand P. Atlas of Metabolic Diseases 2nd ed. Great Britain:Oxford University Press, 2005 pp 136-145
3Burgard P, Lui X, Hoffmann GF. Chapter 13: Phenylketonuria in Sarafoglou K, Hoffman GF and Roth KS (eds).
Pediatric Endocrinology and Inborn Errors of Metabolism. New York:McGraw Hill, 2009 pp 163-168.
4Kaye CI and the Committee on Genetics. Newborn screening fact sheets. Pediatrics 2006;118:934-963.
5 Walter JH, Lee P, Burgard P, Hyperphenylalaninemia. Inborn Metabolic Diseases Chapter 17 4th edition eds
Fernandes, Saudubray, van den Berghe, Walter pp224-226
6 Zschocke J and Hoffman G. Vademecum Metabolicum (Diagnosis and Treatment of Inborn Errors of
Metabolism) 3rd edition pp 153.
Analyte phenylalanine
Method of
measured
Tandem mass spectrophotometer LC.MS/MS - cutoff 120 uM/L
Flurometeric (DELFIA) - cutoff 3.5 ug/dl
Differential
diagnosis
Phenylketonuria (Classical PKU);
non-PKU mild hyperphenylalaninemia; pterin defects;
Transient hyperphenylalaninemia.
False positive Prematurity , weight , nutrituion, health status and treatment at time of specimen
collection
Screen must be 24-48 hr after feeding of protein to decrease false negative
Clinical
presentation
PKU : Asymptomatic in the neonate. If untreated PKU will cause irreversible mental
retardation, hyperactivity, autistic-like features, and seizures and hyperactivity,
eczematoid rash unpleasant odor microcephaly and prominent maxilla. Treatment
will usually prevent these symptoms.
Pterin defects cause early severe neurologic disease (developmental
delay/seizures) and require specific therapy.
Diagnostic
evaluation and
confirmatory
test
 Classic PKU: Plasma amino acid analysis which shows increased phenylalanine
without increased tyrosine (increased phenylalanine:tyrosine ratio). Identification
of phenyl ketones in urine by ferric chloride , Deficiency of BH4 cofactor must be
ruled out
 Urine pterin analysis(neopterin&biopetrin) and red blood cell DHPR assay will
identify pterin defects.plasma , Consider PAH mutation testing. phenylalanine
slight increase and no excretion to phenyl ketones , BH4 loading test :patient with
BH4 deficiency show normalize of phenylalanine level after 4 hrs from the loading
dose of BH4
Causes and
mechanism
In classic PKU the phenylalanine from ingested protein cannot be metabolized to
tyrosine because of deficient liver phenylalanine hydroxylase (PAH). This causes
elevated phenylalanine.
Pterin defects result from deficiency of tetrahydrobiopterin (BH4), the cofactor for
PAH and other hydroxylases. This produces not only increased phenylalanine but
also neurotransmitter deficiencies.
Genetics PKU is caused by a mutation in a gene on chromosome 12
Prenatal diagnosis
Prevalence 1:15000 (turkey has highest rate)
Action for
result
Contact family immediately to evaluate baby and provide basic information about
PKU and dietary management and initiate confirmatory test and refer to
metabolic specialist
Treatment  Phenylalanine – restricted diet (such as meat, chicken, fish, eggs, nuts, cheese,
legumes, milk and other dairy products. Starchy foods, such as potatoes, bread,
pasta, and corn)
 Oral administration of the cofactor tetrahydrobiopterin BH4

TYROSINEMIA
There are 2 clinically recognized types of tyrosinemia.
Type I (hepatorenal) is characterized by liver toxicity from increased concentrations of
tyrosine. There is anssociated renal tubular defects and peripheral neuropathy. There
is also a high risk for hepatocellular carcinoma. The deficient enzyme is
fumarylacetoacetase.
Type II (oculocutaneous) tyrosinemia exhibits with corneal lesions and hyperkeratosis
of palms and soles. It is caused by the deficiency of the enzyme, tyrosine
aminotransferase.
Incidence
Very rare
Tyrosine-I is usually asymptomatic in newborns, but if left untreated it affects liver,
kidney, bone, and peripheral nerves. Two patterns are reported: an acute or chronic
form. The acute form presents with acute hepatic decompensation where infants are
noted to have jaundice, abdominal distention, failure to thrive, ascites and
hepatomegaly, renal disease is also prominent and a “boiled cabbage” odor in urine is
observed; the chronic liver disease feature is that of hepatic cirrhosis.
Tyrosinemia type II is a distinctive oculocutaneous syndrome. Eye findings can be
limited to lacrimation, photophobia, and redness. Cutaneous lesions includepainful
nonpruritic blisters or erosions that crust and become hyperkeratotic. Mental
retardation is also an infrequent finding.
Pathophysiology
In type I, the deficient enzyme, fumarylacetoacetase catalyzed the last step in tyrosine
degradation. The increased concentrations of tyrosine and its metabolites is
postulated to inhibit many transport functions and enzymatic activities.
In type II, deficiency of the rate limiting enzyme tyrosine transaminase in tyrosine
catabolism leads to accumulation of tyrosine, phenolic acids, tyramine in the blood ad
urine.1
Inheritance
autosomal recessive
Screening
increased tyrosine and succinylacetone for type I; increased tyrosine for type II
Confirmation can be done through plasma amino acid levels (increased tyrosine) and
urine metabolic screening (increased succinylacetone).

Prognosis
If untreated, death from liver failure may occur in the first year of life for hepatorenal
tyrosinemia.
Treatment of Tyrosinemia
lacking tyrosine. Patients are also given nitisinone (NTBC) which is an inhibitor of p-
hydroxyphenylpyruvate dioxygenase as maintenance medication.
Metabolic crises may be caused by illness, high consumption of protein, prolonged fasting or
stressful situations such as surgery and severe infection. The goal of treatment is to control
level of tyrosine, correct bleeding parameters, reverse the catabolic state and prevent
essential amino acid deficiency.
What to Do:
a. Nothing per orem except medications
c. Insert IV access. Collect samples for blood glucose, plasma amino acids, liver function
tests, coagulation studies and urine succinylacetone. May request for other investigations
(i.e. CBC, blood gas) as needed. May give fluid boluses if patient requires.
d. Start D12.5% 0.3 NaCl at full maintenance. Assess patient clinically, if there is need to
increase fluid, may do so up to 1.2 or 1.5X the maintenance.
e. Start nitisinone (2mg/kg) per orem.
f. Monitor input and output strictly (6 hours)
a. Insert oro- or nasogastric tube and start continuous feeding with tyrosine free formula
to run at maintenance rate
b. Start nitisinone (2mg/kg) per NGT
c. Insert IV access. Collect samples for blood glucose, plasma amino acids, liver function
tests, coagulation studies and urine succinylacetone. May request for other investigations
(i.e. CBC, blood gas) as needed. May give fluid boluses if patient requires.
d. Start D12.5% 0.3 NaCl at 5-10 cc/hr.
e. Monitor input and output strictly (q6 hours)

Tyrosinemia type I
Treatment options for tyrosinemia I include dietary therapy (restriction of
phenylalanine and tyrosine), liver transplantation and use of the pharmacologic agent
2(2-nitro-4-trifluoro-methylbenzoyl)-1,3-cyclohexanedione or NTBC.
NTBC
The rationale for the use of NTBC is to block tyrosine degradation at an early step so
as to prevent production of toxic down stream metabolites such as
fumarylacetoacetate, maleylacetoacetate and succinylacetone. It is recommended at
an initial dose of 1 mg/kg/day. The risk of hepatocellular carcinoma appears to be
much reduced in patients started early on NTBC treatment (before 6 months of age).
Diet
Dietary restriction of phenylalanine and tyrosine is necessary to prevent the known
adverse effects of hypertyrosinemia. Tyrosine levels are aimed between 200-400
umol/L using a combination of a protein restricted diet and phenylalanine and tyrosine
free amino acid mixtures.
Supportive therapy
In the acutely ill patient, supportive treatment is essential. Clotting factors, albumin,
electrolytes and acid/base balance should be closely monitored and corrected as
necessary. Tyrosine and phenylalanine intake should be kept to a minimum during
acute decompensation. Addition of vitamin D may be required to treat rickets.
Infections should be treated aggressively.
Monitoring of patients on NTBS should include regular blood tests for liver function,
blood counts, clotting studies, alpha feto protein, tests of renal and tubular function,
hepatic imaging and plasma amino acid profile.
Blood levels of phenylalanine and tyrosine should be checked every 3 months and the
diet should be supervised regularly.
Tyrosinemia type II
Diet
Treatment consists of phenylalanine and tyrosine restricted diet and the skin and eye
symptoms resolve within weeks of treatment. In general, skin and eye symptoms do
not occur at tyrosine levels <800umol/L, however, as hypertyrosinemia may be
involved in the pathogenesis of neurodevelopmental symptoms, it may be beneficial
to maintain much lower levels. Growth and nutritional status should be regularly
monitored.

Key metabolite : Tyrosine ( &succinylacetone in TYR I)
Action : Referral to metabolic specialist
Plasma anino acids
Serum alpha-fetoprotein
Succinylacetone in urine
Therapy :
2-nitro-4-trifluoromethylbenzoyl-3-
cyclohexanedione NTBC
Dietary restriction of phenylalanine and
tyrosine
Acute or chronic liver failure
Tubulopathy – peripheral neuropathy
Porphyria like crisis
Vomiting , lethargy , diarrhea
Failure to thrive - rickets
Hepatocellular carcinoma
Prognosis : Good if start treatment early
Note of caution :
- Tyrosine also elevated in liver
diseases , prematurity
,tyrosinemiaII and III and infection
- Tyrosine may be normal in an
appreciable number of tyrosinemia
I causing false negative results
- Humidity and heat and exposure to
EDTA denature the enzyme causing
false positive
References
1Kaye C. Newborn screening fact sheets.2006 Pediatrics 118:3 pp e960-962
2 Chapter 26: Hepatorenal tyrosinemia. Nyhan WL, Barshop BA and Ozand P. Atlas of Metabolic Diseases 2nd
ed. Great Britain:Oxford University Press, 2005 pp 175-179.

Analyte Tyrosine
Method of
measured
Tandem mass spectrophotometer LC.MS/MS - cutoff 229 uM/L
Differential
diagnosis
Tyrosinemia I (hepatorenal);
tyrosinemia II (oculocutaneous , Richer-Hanhart syndrome);
tyrosinemia III;
transient hypertyrosinemia;
liver disease.
False positive In first two weeks infants who receive high protein diets and premature baby due
to delay maturation of 4-HPPD enzyme always show positive screen for PKU
(transient hypertyrosenemia)
Clinical
presentation
Tyrosinemia I is usually asymptomatic in the neonate. If untreated, it will cause
liver
disease and cirrhosis early in infancy, peripheral neuropathy ,renal failure and
mortality 60%
Tyrosinemia II is asymptomatic in the neonate but will cause hyperkeratosis of the
skin, corneal ulcers, and in some cases, mental retardation
Tyrosinemia III show developmental delay ,seizures and no liver or renal
abnormalites
Diagnostic
evaluation and
confirmatory
test
 Plasma amino acid analysis will show increased tyrosine in all of the
tyrosinemias.
 Urine organic acid analysis may reveal increased succinylacetone in tyrosinemia
I.
 Assay tyrosine aminotransferase activity in liver or by DNA analysis for gene
mutation
 Measure plasma level for 4-hydroxyphenylpyruvic acid and urine level for 4-
hydroxyphenylacetic acid and can confirmed by assay activity of 4-HPPD liver
biopsy or mutation of 4-HPPD gene
Causes and
mechanism
Herediary :
 Tyrosinemia I :deficiency of fumarylacetoacetate hydrolase FAH (autosomal
recessive) tyrosine accumulate from ingested protein and phenylalanine
metabolism cannot be metabolized by FAH to fumaric acid and acetoacetic acid.
The resulting fumarylacetoacetate accumulates and is converted to
succinylacetone, the diagnostic metabolite, which is liver toxic and leads to
elevated tyrosine.
 Tyrosinemias II :deficiency of tyrosine aminotransferase (A.R)
 Tyrosinemias III : deficiency of 4-hydroxyphenpyruvate dioxygenase 4-HPPD
(A.R)
Acquired :
 Severe hepatocellular dysfunction
 Scurvy (vitamin c is the cofactor for enzyme 4-HPPD)
 hyperthyroidism
Genetics  FAH has been mapped to chromosome 15q
 Tyrosine aminotransferase mapped to chromosome 16q
 4-HPPD mapped to chromosome 12q24-qter
Prenatal diagnosis DNA analysis can be used to test specific mutation and measure succinylacetone
in amniotic fluid
Prevalence Worldwide : Tyrosinemia I : 1:100,000
Action for
result
Contact family to evaluate baby and provide basic information about tyrosinemia
and initiate confirmatory test and refer to metabolic specialist
Treatment Diet low in phenylananine and tyrosine
Nitisinone which inhibit tyrosine degradation at 4-HPPD
Vitamin c as cofactor for 4-HPPD
Liver transplantation in hepatocellular disease

UREA CYCLE DEFECTS
CITRULLINEMIA
Citrullinemia is an inborn error of metabolism resulting from the deficiency of
argininosuccinate synthetase, an enzyme present in all tissues but the level of which
is highest in the liver where it functions in the urea cycle.
Incidence
Very rare
Following a brief hiatus in which the newborn appears normal, anorexia, vomiting and
lethargy develop followed rapidly by progression to deep coma. The symptoms mimic
that of sepsis and affected newborns present with severe lethargy, poor feeding to
respiratory distress, jitteriness and seizures.
A late onset form may occur as late as 20 years old and present as symptoms such as
slurred speech, irritability, insomnia or delirium.
Pathophysiology
Argininosuccinate synthetase is an enzyme that converts citrulline to
argininosuccinate, the absence of which causes an increase in plasma citrulline and
ammonia levels.3

Inheritance
autosomal recessive
Screening
increased citrulline and low arginine on MSMS
Confirmatory testing may be done through the demonstration of amino acids in
plasma (decreased arginine and high citrulline), presence of orotic acid in urine and
increased levels of ammonia in blood.
Prognosis
Prognosis for intellectual development depends on the nature of the initial
hyperammonemia especially its duration or those of recurrent episodes.
Key metabolite : Citrulline ,elevated
specialist
Blood ammonia
Orotic acid in urine
Mutation analysis
Therapy :
Low protein diet
L-arginine - sodium benzoate
Sodium phenylbutyrate
Hemodialysis or hemofiltration
Liver transplantation
Hyper ventilation
Vomiting - hypothermia
Hyperammonemic encephalopathy
rapidly progressing to coma ,cerebral
edema and death
Prognosis : Poor in neonatal cases unless early liver
transplant is performed
Moderate in intermittent cases
Note of caution : Consider to stop therapy after prolonged
hyperammonemia

ARGININOSUCCINIC ACIDEMIA
Argninosuccinate lyase or argininosuccinase catalyzes the conversion of the
argininosuccinate formed from citrulline and aspartate to fumarate and arginine.5
Incidence
rare
Neonatal onset disease presents with severe hyperammonemic coma within the first
few days of life with an overwhelming illness that rapidly progresses from poor
feeding, vomiting, lethargy or irritability and tachypnea to seizures, coma and
respiratory arrest; late onset disease are less acute and more subtle often precipitated
by stress such as infection and anesthesia.
A unique finding in patients is the presence of trichorrhexis nodosa where hair is very
friable and breaks off easily.
Pathophysiology
Argininosuccinate lyase deficiency causes the accumulation of citrulline and
decreasethe levels of arginine, the last compound of the urea cycle prior to the
splitting off of urea.6 This causes the increased ammonia levels in blood that is
responsible for the signs and symptoms observed.
Inheritance:
autosomal recessive
Screening
elevated citrulline, low arginine on MSMS
Confirmation may be done through amino acids (elevated citrulline, low arginine, high
argininosuccinate) in plasma , increased ammonia in blood, increased orotic acid in
urine and enzyme studies in erythrocytes or fibroblasts.
Prognosis
Prognosis for intellectual development depends on the nature of initial
hyperammonemia, especially its duration or the nature of recurrent episodes.

Key metabolite : Citrulline ,elevated
specialist
Blood ammonia
Orotic acid in urine
Enzyme activity in erythrocytes
Therapy :
Low protein diet
L-arginine (high dose ) - sodium benzoate
Sodium phenylbutyrate
Hemodialysis or hemofiltration
Liver transplantation
Lethargy - hyperventilation
Vomiting - hypothermia
Hyperammonemic encephalopathy
progressing to coma ,cerebral edema and
death
Prognosis : Moderate : hyperammonemia easy to
control but mental retardation will
develop in most cases
Treatment of UCDs
Treatment is through the dietary restriction of protein and the supplementation of a protein
free formula. Sodium benzoate, an ammonia scavenger, is given as well as arginine
supplementation.
Preliminary / Initial Management During Metabolic Crises
Metabolic crises may be caused by an excess intake of protein, illness, prolonged fasting or
stressful situations such as surgery and severe infection. The goal of treatment is to reverse
the catabolic state and prevent essential amino acid deficiency.

Diet
Most patients require a low protein diet. Many suggest severe protein restriction but
in early infancy, patients may need > 2 g/kg/day during phases of rapid growth. The
protein intake usually decreases to approximately 1.2-1.5 g/kg/day during pre-school
years and 0.8-1 g/kg/day in late childhood. After puberty, the quantity of natural
protein may be less than 0.5 g/kg/day. However, it should be emphasized that there is
considerable variation in the needs of individual patients.
Some patients may not take their full protein allowance and some may not achieve
good nutrition with restriction of natural protein, thus replacement with an essential
amino acid mixture, giving up to 0.7 g/kg/day be added to the dietary regimen.
Alternative pathways for nitrogen excretion
The effect of giving the following drugs is that nitrogen will be excreted in compounds
other than urea, thus the load of the urea cycle is reduced.
_ Sodium Benzoate 250-500 mg/kg/day (elimination of 1 mol NH3 per mol of glycine)
_ Phenylbutyrate 250-500 mg/kg/day (elimination of 2 mol NH3 per mol of glutamine)
What to Do:
a. Nothing per orem
c. Insert IV access. Collect samples for serum ammonia. May request for other investigations (i.e. CBC,
blood gas) as needed. May give fluid boluses if patient requires.
d. Start D12.5% 0.3 NaCl at full maintenance. Assess patient clinically, if there is need to increase fluid, may
do so up to 1.2 or 1.5X the maintenance.
e. Start IV sodium benzoate loading dose (250mg/kg) to run for four hours
f. Start IV arginine loading dose (250mg/kg) to run for four hours
g. Monitor input and output strictly (6 hours)
a. Insert oro- or nasogastric tube and start continuous feeding with protein free formula to run at
maintenance rate
b. Insert IV access. Collect samples for serum ammonia. May request for other investigations (i.e. CBC,
blood gas) as needed. May give fluid boluses if patient requires.
c. Start D12.5% 0.3 NaCl at 5-10 cc/hr.
d. Start IV sodium benzoate loading dose (250mg/kg) to run for four hours
e. Start IV arginine loading dose (250mg/kg) to run for four hours
*If patient does not improve with the initial management (within 12 hours), hemodialysis may be indicated.
Monitor patient clinically, the necessity of hemodialysis will depend on patient’s clinical status.

Replacement of deficient nutrients
Arginine is normally a nonessential amino acid, because it is synthesized within the
urea cycle. For this reason, all patients with urea cycle disorders are likely to need a
supplement of arginine to replace what is not synthesized. The aim should be to
maintain plasma arginine concentrations between 50-200 umol/L.
Monitoring
All treatments must be monitored with regular quantitative estimation of plasma
ammonia and amino acids, paying particular attention to the concentration of
glutamine and essential amino acids. The aim is to keep plasma ammonia levels below
80 umol/L and plasma glutamine levels below 800 umol/L. All diets must be
nutritionally complete and must meet requirements for growth and development.
EMERGENCY MANAGEMENT OF INTERCURRENT HYPERAMMONEMIA IN PATIENTS WITH
UREA CYCLE DISORDERS
Early Diagnosis and Therapy
This is the most important aspect of intercurrent hyperammonemia. Delays are disastrous. A
plasma ammonium level should be done as an emergency procedure on any child with these
diseases who exhibits lethargy or vomiting of any degree, and the metabolic on-call physician
should be alerted. Secure IV access needs to be established without delay.
NB Ammonium needs to be collected in a Lithium Heparin tube, min 0.5 mls and transported
IMMEDIATELY to the laboratory on ICE. Inform laboratory that the specimen is coming.
If the ammonium level approaches three times the upper limits of normal, the ammonium
level should be repeated and plasma obtained for electrolytes, blood gas and quantitative
amino acids and urine for metabolic screening tests. Without waiting for the repeat
ammonium value, the regimen described below should be followed as an emergency
procedure.
All dietary and intravenous protein intake should be discontinued. Because reduction of body
protein
breakdown is desirable a high parenteral caloric intake should be provided from 12.5%
glucose and Intralipid.
Intralipid (20%) should be commenced at a dose of 2gm/kg/day, grading up to 3-4gms/kg/day
over the next 24 hours. Other fluids should be calculated to provide maintenance fluid as
indicated by the child’s condition. Do not delay commencing priming infusion whilst
organising maintenance fluids. If there are signs of cerebral edema this needs to be managed
appropriately. Enteral feeding should be recommenced as soon as the patient is able to
tolerate it. This needs to be done in consultation with the metabolic team.
_ Give sodium benzoate up to 500 mg/kg/day-orally or intravenously. If the patient has not
received any medication, give a priming dose of 250 mg/kg in 2-4 hours then 250 mg/kg in
the next 20-24 hours
_ Give L-arginine orally or intravenously:
_ Up to 700 mg/kg/day in citrullinemia na argininosuccinic aciduria
_ Up to 150 mg/kg/day in ornithine transcarbamylase deficiency and carbamoyl phosphate
synthase deficiency

_ Plasma levels of ammonium, electrolytes, blood gas should be measured four hours after
the completion of the priming infusion and every eight hours thereafter until plasma
ammonium levels are normal or near normal, or as otherwise directed by the metabolic
physician. These drugs may cause urine potassium loss; the serum potassium level should be
monitored and treated as needed.
_ The drugs may cause one or two vomiting episodes, usually towards the end of the 2-3 hour
treatment period. Respiratory alkalosis may occur or be exacerbated during therapy with
these drugs.
_ If plasma ammonium level does not decrease within 8 hours urgently discuss the child with
the metabolic
physician. It is likely that the child will need hemodialysis.
_ If intracranial pressure is elevated, conventional osmotherapy with mannitol should begin.
Corticosteroids may be contraindicated because they induce negative nitrogen balance.
_ When the ammonium level is stable at normal or near normal levels oral medication may
be gradually added as the intravenous medication is gradually reduced. This should be done
in consultation with the metabolic physician.
References
1Su TS, Bock HGO, Beaudet AL et al. Molecular analysis of argininosuccinate syntehtase deficiency in human fibroblasts.
J Clin Invest 1982:70:1334-1339.
2Chapter 31: Citrullinemia. Nyhan WL, Barshop BA and Ozand P. Atlas of Metabolic Diseases 2nd ed. Great Britain:Oxford
University Press, 2005 pp 210-
213.
3Wasant P, Viprakasit V, Srisomsap C et al. Argininosuccinate synthetase deficiency: mutation analysis in 3 Thai patients.
Southeast Asian J Trop Med Pub
Health 2005;36(3):757-761.
4 Leonard J. Disorders of the urea cycle and related enzymes. Inborn Metabolic Diseases Chapter 18,4th edition eds
Fernandes, Saudubray, van den
Berghe, Walter pp 269-271
5Chapter 32: Argininosuccinic aciduria. Nyhan WL, Barshop BA and Ozand P. Atlas of Metabolic Diseases 2nd ed. Great
Britain:Oxford University Press,
2005 pp 216-219.
6Chen BC, Ngu LH and Zabedah MY. Argininosuccinic aciduria: clinical and biochemical phenotype findings in Malaysian
children. Malaysian J Pathol
2010;32(2):87-95.
7 Zschocke J and Hoffman G. Vademecum Metabolicum (Diagnosis and Treatment of Inborn Errors of Metabolism) 3rd
edition pp 153.

FATTY ACID DISORDER
MEDIUM-CHAIN ACYL-COA DEHYDROGENASE DEFICIENCY [MCAD]
Medium chain acyl-CoA dehydrogenase (MCAD) deficiency is the most common defect
of fatty acid oxidation.
Incidence
rare
MCAD deficiency has a very wide spectrum of clinical presentations ranging from
benign hypoglycemia to coma
and death. Two presentations have been noted: (1) hypoketotic hypoglycemia or Reye
syndrome which occurs within the first two years of life and (2) the chronic disruption
of muscle function which include cardiomyopathy, weakness, hypotonia and

arrhythmia. In addition, MCAD deficiency has been shown to be associated with
sudden infant death syndrome (SIDS).4 A “metabolic stress” such as prolonged fasting
often in connection with viral infections is usually required to precipitate disease
manifestations but patients are completely asymptomatic between episodes.
Pathophysiology
MCAD catalyzes the initial step in the β-oxidation of C12-C6 straight chain acyl-CoAs
and MCAD deficiency results in a lack of production of energy from β-oxidation of
medium chain fatty acids and hepatic ketogenesis and gluconeogenesis.
Inheritance
autosomal recessive
Screening
increased octanoylcarnitine on MSMS and a high C10/carnitine ratio
Urine organic acid profile will show medium chain dicarboxylic aciduria.4
Measurement of the specific MCAD enzyme activity in disrupted cultures skin
fibroblasts, lymphocytes, or tissue biopsies from muscle can confirm the diagnosis.
Prognosis
Most authors report a mortality rate of 20-25% during the initial decompensation.4
Although the majority of children survive their initial episode, a significant amount of
children who survived and perhaps children who have experienced clinically
unrecognized episodes, suffer from long term sequelae and about 40% are judged to
have developmental delay.2 Long term outcome remains dependent on constant
monitoring for early signs of illness and rapid medical intervention to prevent
complications
Long term management
Avoidance of fasting
It is essential to prevent any period of fasting which would be sufficient to require the
use of fatty acids as fuel.
This can be done by simply ensuring that patients have adequate carbohydrate feeding
at bedtime and do not fast for more than 12 hours overnight. For young babies they
should be fed every 3–4 hours with a late night feed continuing until about 9 months
of age and they should not fast for longer than 6 - 8 hours. During intercurrent illness
(when child has poor appetite, low energy or excessive sleepiness, vomiting, diarrhea,
infection or fever), care should be taken to give extra feedings of carbohydrate during

the night and inform the doctor for the “sick day regimen” which mainly consists of
high energy drink.
In a few patients with severe defects in fatty acid oxidation who had developed
weakness and/or cardiomyopathy, addition of continuous intragastric feedings such
as the use of uncooked cornstarch at bedtime might be considered as a slowly released
form of glucose.
Diet
Dietary fat restriction is not routine in patients with MCAD deficiency.
Emergency management of patients with MCAD deficiency
When patients with fatty acid oxidation disorders become ill, treatment with
intravenous glucose should be given immediately. Delay may result on sudden death
or permanent brain damage. The goal is to provide sufficient glucose to stimulate
insulin secretion to levels that will only suppress fatty acid oxidation in liver and
muscle, but also block adipose tissue lipolysis.
Solutions of 10%dextrose should be used at infusion rates of 10 mg/kg per min or
greater to maintain high to normal levels of plasma glucose, above 100mg/dl. Do not
give intravenous lipids
Key metabolite : C8 (octanoyl carnitine ) , elevated
Action : Contact family to ascertain clinical
condition and referral to metabolic
specialist
Acylcarnitine profile in DBS/plasma
Carnitine status in plasma/serum
Organic acids in urine
Enzyme activity fibroblasts
Mutation analysis
Therapy : Avoid fasting (L-carnitine
supplementation)
Hypoketotic hypoglycemia
Reye-like syndrome
Lethargy , nausea , vomiting, coma,
seizures, cardiac arrest
Prognosis : excellent
Note of caution : Neonatal manifestation in rare cases
References:
1Strauss AW, Andersen BS and Bennett MJ. Chapter 5: Mitochondrial Fatty Acid Oxidation Defects in
Sarafoglou K, Hoffman GF and Roth KS (eds). Pediatric Endocrinology and Inborn Errors of Metabolism. New
York:McGraw Hill, 2009 pp 60-62.
2 Hsu HW, Zytkovicz TH, Comeau AM et al. Spectrum of Medium chain acyl-coA dehydrogenase deficiency
detected by newborn screening. Pediatrics 2008;121:e1108-e1114.

3 Chapter 40: Medium chain acyl-CoA dehydrogenase deficiency. Nyhan WL, Barshop BA and Ozand P. Atlas
of Metabolic Diseases 2nd ed. Great Britain:Oxford University Press, 2005 pp 260-265.
4 Wilson CJ, Champion MP, Collins JE et al. Outcome of medium chain acyl-CoA dehydrogenase deficiency after
diagnosis. Arch Dis Child 1999;80:459-462.
5 Stanley C, Bennett M, Mayatepek E. Disorders of mitochondrial fatty acid oxidation and related metabolic
pathways. Inborn Metabolic Diseases Chapter 23 4th edition eds Fernandes, Saudubray, van den Berghe,
Walter pp 184
Analyte Octanoylcarnitine (C8) (always associated with C6 and C10)
Method of
measured
Tandem mass spectrophotometer LC.MS/MS - cutoff 0.200 uM/L
Differential
diagnosis
Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency.
False
positive
The specificity of MS/MS to identify MCAD deficiency appears to be 100%, with a few
false negative results having been reported as a result of inappropriate cut-off selection
False postive may be as marker “octanoylcarnitine” is not specific for MCAD deficiency
and is expected to be elevated in other disorders (i.e., glutaric acidemia type II, and
possibly medium-chain 3-keto acyl-CoA thiolase deficiency) and in newborns treated with
valproate or fed a diet rich in medium-chain triglycerides
Clinical
presentation
MCAD deficiency is usually asymptomatic in the newborn although it can present acutely in
the neonate with hypoglycemia, metabolic acidosis, hyperammonemia, and hepatomegaly.
MCAD deficiency is associated with high mortality unless treated promptly; milder variants
exist. Hallmark features include vomiting, lethargy, and hypoketotic hypoglycemia. Untreated
MCAD deficiency is a significant cause of sudden death.
Prognosis : 25% sudden death in the first attack of illness
Permanent brain injury occur in some patients during attack
Prognosis for survivors without brain damage more than 60%
Diagnostic
evaluation
and
confirmatory
test
 Plasma acylcarnitine analysis will show increase C8 ,C10 consistent with MCADD.
 Urine organic acid analysis may also show low ketones and high medium chain
dicarboxylic acids (adipic ,suberic and sebacic acids) that derive from microsomal
and perioxisomal omega oxidation of fatty acid
 Increase urinary acylglycines (hexanoyl-,suberyl-,3phenylpropionyl glycines)
 Diagnosis can be confirmed by mutation analysis of the MCAD gene and
determination of fatty acid B-oxidation in fibroblast and measure MCAD enzyme
activity in fibroblast.
 In acute attack show hypoketotic hypoglycemia (no metabolic acidemia)
 Liver function :elevated ALT,AST and prolonged PT , PTT
 Liver biopsy show micro or macro-vesicular steatosis due to triglyceride
accumulation
Causes and
mechanism
MCAD deficiency is a fatty acid oxidation (FAO) disorder. Fatty acid oxidation occurs mainly
during prolonged fasting and/or periods of increased energy demands (fever, stress), when
energy production relies increasingly on fat metabolism. In an FAO disorder, fatty acids and
potentially toxic derivatives accumulate because of a deficiency in one of the mitochondrial
FAO enzymes.
Genetics Diagnosis can be confirmed by finding the common A985G mutation
Second common mutation T199C has been detected in infants with characteristic
acylcarnitines in newborn screening test
Prenatal
diagnosis
Test of sibling of affected patients important to detect asymptomatic family members as
many as 50% of affected patients have never had an episode
Prevalence 1:5000 to 1:17000
Action for
result
Contact family , evaluate baby for poor feeding , lethargy , hypotonia and hepatomegaly ,
start confirmatory investigation, educate family to avoid fasting , refer to metabolic
specialist
Treatment Acute : 10% dextrose to treat hypoglycemia and suppress lipolysis
Chronic: avoid fasting - restricting dietary fat or treatment with carnitine is controversial

LONG-CHAIN L-3-HYDROXYACYL-CoA DEHYDROGENASE [LCHAD]
Long chain L-3 hydroxyacyl-CoA dehydrogenase (LCHAD) is a component of
trifunctional protein. Isolated LCHAD deficiency catalyzes the third step in the fatty
acid oxidation spiral, converting long chain 3-hydroxyacyl- CoA esters into long chain
3-keto-CoA species by using NAD as a cofactor.
Incidence
Very rare
Patients exhibit moderate or severe multiorgan involvement either neonatally or
during the first two years of life.They may present in the first year of life with
hypoketotic hypoglycemia and liver dysfunction, Reye syndrome- like symptoms,
seizures, coma and death.2 By adolescence, ophthalmologic abnormalities including
loss of visual acuity, chorioretinal atrophy, progressive retinitis pigmentosa and
peripheral sensorimotor polyneuropathy may be observed.2,3,4, Up to 40% of
symptomatic patients may have tachycardic arrhythmias, apneic episodes,
cardiopulmonary arrest and unexplained death.2 A strong association has been
demonstrated with heterozygous mothers developing acute fatty liver or pregnancy
or hemolysis, elevated liver enzymes and low
platelet count (HELLP) syndrome when carrying an affected fetus.
Pathophysiology
Since the enzyme LCHAD is part of the fatty acid oxidation, a deficiency causes a
problem in the energy utilization of the body which causes the presentation of signs
and symptoms as listed above.
Inheritance
autosomal recessive
Screening
elevated C16 (palmitoylcarnitine), 3-hydroxypalmitoylcarnitine, C18, 3-hydroxy-C18-
carnitines and C18:1- hydroxycarnitine 2,3
Confirmatory testing is done through enzyme assays performed in cultured cells such
as skin fibroblasts. The common mutation G1528C has been identified in affected
individuals and may be used for confirmation.

Prognosis
Patients with LCHAD deficiency who present symptomatically often die during the
acute episode or suffer from sudden, unexplained death and mortality occurs in
approximately 38%.
Primary goal of treatment is to avoid metabolic stress brought about by infection and
long periods of fasting.
Patients should be given frequent feedings, supplementation with medium chain
triglycerides (MCT formula) and an overnight infusion of cornstarch. Treatment with
L-carnitine remains controversial.
Patients must be ensured to have adequate carbohydrate feeding at bedtime and do
not fast for more than 12 hours overnight. For young babies they should be fed every
3–4 hours with a late night feed continuing until about 9 months of age and they
should not fast for longer than 6 - 8 hours. During intercurrent illness, when appetite
is diminished, care should be taken to give extra feedings of carbohydrate during the
night. A” sick day regimen” containing high glucose drinks should be given.
form of glucose.
Diet
Sometimes a low fat, high carbohydrate diet is recommended. Food plan is
recommended. Carbohydrates give the body may types of sugar that can be used as
energy. In fact, for children needing this treatment, most food in the diet should be
carbohydrates (bread, pasta, fruit, etc.) and protein (lean meat and low-fat dairy
foods).
Any diet changes should be made under the guidance of an experienced dietitian.
People with LCHADD cannot use certain building blocks of fat called “long chain fatty
acids”. The dietitian can help create a food plan low in these fats. Much of the rest of
fat in the diet may be in the form of medium chain fatty acids.
Medium Chain Triglyceride oil (MCT oil) is often used as part of the food plan for
people with LCHADD. This special oil has medium chain fatty acids that can be used in
small amounts for energy.
In addition to the above supplements, some doctors suggest taking DHA
(docosahexanoic acid) which may help prevent loss of eyesight.

Avoid prolonged exercise
Long periods of exercise can also trigger symptoms. Problems occurring during or after
exercise can include:
muscle aches, weakness, cramps and reddish-brown color to the urine.
It is advised to have high carbohydrate intake prior to exercise to prevent lipolysis and
to restrict physical activity to levels that are not likely to precipitate an attack of
rhabdomyolysis.
Intercurrent illness
Advise parents to refer the child to the doctor if he/she has any of the following:
_ poor appetite
_ low energy or excessive sleepiness
_ vomiting
_ diarrhea
_ an infection
_ a fever
_ persistent muscle pain, weakness, or reddish-brown color to the urine
Children with LCHADD need to eat extra starchy food and drink more fluids during any
illness - even if they may not feel hungry – or they could develop hypoglycemia or a
metabolic crisis. When they become sick, children with LCHADD often need to be
treated in the hospital to prevent serious health problems.
Emergency management of patients with LCHAD deficiency
give intravenous lipids!

Key metabolite : C16OH – C18:OH , elevated
specialist
Acylcarnitines in DBS/plasma
CK,liver transamiases
Mutation analysis
Therapy : Diet : restriction of LCT.MCT
Avoid fasting
(careful with L-carnitine
supplementation)
cardiomyopathy
Liver disease
Muscular hypotonia
Neuropathy - retinopathy
Exercise intolerance
Muscle pain rhabdomyolysis
Prognosis : Moderate
Patients with a severe phenotype with
cardiac involvement die in the first weeks
of life despite immediate treatment
Note of caution : Mother of an affected fetus may develop
acute fatty liver of pregnancy of HELLP
syndrome
References
1 Chapter 42: Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency. Nyhan WL, Barshop BA and Ozand P.
Atlas of Metabolic Diseases 2nd ed. Great Britain:Oxford University Press, 2005 pp 272-275.
3Eskelin P and Tyni T. LCHAD and MTP Deficiencies – Two Disorders of Mitochondrial Fatty Acid Beta-Oxidation
with Unusual Features. Cur Ped Rev 2007;3:53-59.
4 Moczulski D, Majak I, Mamczur D. An overview of β-oxidation disorders. Postepy Hig Med Dosw 2009;63:266-
277.
5 Gillingham M, Van Calcar S, Ney D et al. Dietary management of long chain 3-hydroxyacyl-CoA
dehydrogenase deficiency. A Case report and survey. J Inherit Metab Dis 1999;22(2):123-131.
6Stanley C, Bennett M, Mayatepek E. Disorders of mitochondrial fatty acid oxidation and related metabolic
Walter pp 184
7Long chain hydroxyl acyl co-A dehydrogenase deficiency. Available at
http://www.newbornscreening.info/Parents/fattyaciddisorders/LCHADD.html

VERY LONG-CHAIN ACYL-COA DEHYDROGENASE DEFICIENCY
[VLCADD]
Very long-chain acyl-CoA dehydrogenase catalyzes the dehydrogenation of C22-C12
straight chain fatty acids, and because the long chain fatty acids constitute a major
proportion of the fatty acids, VLCAD deficiency is generally a more severe condition
than MCAD or SCAD deficiency and multiple tissues are affected.
Incidence
rare
The clinical presentation of symptomatic VLCAD deficiency is heterogenous with
phenotypes of different severities.
There are three forms described: (1) severe childhood form with neonatal onset and
cardiomyopathy; (2) milder childhood form with delayed onset of symptoms often
triggered by metabolic stress and presents as hypoketotic hypoglycemia and; (3) adult
form which presents with isolated skeletal muscle involvement with recurrent episode
of muscle pain, rhabdomyolysis and myoglobinuria.
Pathophysiology
VLCAD catalyzes the dehydrogenation of acyl CoA esters of 14-20 carbon length in the
first step of mitochondrial fatty acid oxidation.3,4 VLCAD deficiency results in lack of
production of energy from β-oxidation of longchain fatty acids. Because heart and
muscle tissues depend heavily on energy from long chain fatty acid oxidation, a VLCAD
deficiency severely affect these tissues.
Inheritance
autosomal recessive
Screening
elevation of tetradecenoylcarnitine (C14:1) on MSMS
The enzyme defect can be detected through culture skin fibroblasts.1 The gene for
VLCAD has been clone and sequenced successfully and play a role in diagnosis of this
disorder.
Prognosis
Fifty percent of patients die within 2 months of initial symptomatology.4 However,
timely and correct diagnosis leads to dramatic recovery so that early detection could
prevent the onset of arrhythmias, heart failure, metabolic insufficiency and death.

The goal of treatment is to reverse the catabolic state and prevent hypoglycemia.
Treatment of this disorder include avoidance of fasting by frequent feeding, overnight
continuous feeding, reduction of amount of long chain fat in diet while supplying
essential fatty acids in the form of canola, walnut oil or safflower oil and
supplementation with medium chain triglycerides (MCT).
Patients must be ensured to have adequate carbohydrate feeding at bedtime and do
not fast for more than 12 hours overnight. For young babies they should be fed every
3–4 hours with a late night feed continuing until about 9 months of age and they
should not fast for longer than 6 - 8 hours. During intercurrent illness, when appetite
is diminished, care should be taken to give extra feedings of carbohydrate during the
night. A” sick day regimen” containing high glucose drinks should be given.
What to Do:
a. Nothing per orem
c. Insert IV access. Monitor glucose levels. For patients with VLCAD, collect samples for
serum CK. May request for other investigations (i.e. CBC, Blood gas) as needed. May give
fluid boluses if patient requires.
d. Start D10% 0.3 NaCl at full maintenance. Assess patient clinically, if there is need to
increase fluid, may do so up to 1.2 or 1.5X the maintenance.
e. Monitor input and output strictly (q6 hours). Check for the color of urine.
If unwell and is able to tolerate oral intake:
a. Insert oro- or nasogastric tube and start continuous feeding with a high glucose formula
b. Insert IV access. Monitor glucose levels. For patients with VLCAD, collect samples for
serum CK. May request for other investigations (i.e. CBC, Blood gas) as needed. May give
fluid boluses if patient requires.
c. Start D10% 0.3 NaCl at 5-10 cc/hr.
d. Monitor input and output strictly (q6 hours). Check for the color of urine.
*Patients with VLCAD may have rhabdomyolysis. Monitor CK levels and hydrate
adequately. If CK levels continually rise, hemodialysis may be indicated.

form of glucose.
Diet
Sometimes a low fat, high carbohydrate diet is recommended. Food plan is
recommended. Carbohydrates give the body may types of sugar that can be used as
energy. In fact, for children needing this treatment, most food in the diet should be
carbohydrates (bread, pasta, fruit, etc.) and protein (lean meat and low-fat dairy
foods).
Any diet changes should be made under the guidance of an experienced dietitian.
People with VLCADD cannot use certain building blocks of fat called “long chain fatty
acids”. The dietitian can help create a food plan low in these fats. Much of the rest of
fat in the diet may be in the form of medium chain fatty acids.
Medium Chain Triglyceride oil (MCT oil) is often used as part of the food plan for
people with VLCADD. This special oil has medium chain fatty acids that can be used in
small amounts for energy.
Ask your doctor whether your child needs to have any changes in his or her diet.
Avoid prolonged exercise
Long periods of exercise can also trigger symptoms. Problems occurring during or after
exercise can include:
muscle aches, weakness, cramps and reddish-brown color to the urine.
It is advised to have high carbohydrate intake prior to exercise to prevent lipolysis and
to restrict physical activity to levels that are not likely to precipitate an attack of
rhabdomyolysis.
Intercurrent illness
Advise parents to refer the child to the doctor if he/she has any of the following:
_ poor appetite
_ low energy or excessive sleepiness
_ vomiting
_ diarrhea
_ an infection
_ a fever
_persistent muscle pain, weakness, or reddish-brown color to the urine
Children with VLCADD need to eat extra starchy food and drink more fluids during any
illness - even if they may not feel hungry – or they could develop hypoglycemia or a
metabolic crisis. When they become sick, children with VLCADD often need to be
treated in the hospital to prevent serious health problems.

Emergency management of patients with VLCAD deficiency
give intravenous lipids
Key metabolite : C14:1(myrisotoleyl carnitine),elevated
Action : Immediate referral to metabolic center
Acylcarnitine profile in DBS/plasma
Carnitine status in plasma/serum
CK,liver transaminases
Organic acids in urine
Mutation analysis
Therapy : Avoid fasting
In severe cases : dietary restriction of
LCT,MCT
Careful with L-carnitine supplementation
Cardiomayopathy , arrhythmias
Rhabdomyolysis
Liver disease
Prognosis : Generally good(but there are fatal cases)
Note of caution : False negative screening reported world
wide
References
2Liebig M, Schymik I, Mueller M et al. Neonatal screening for very long chain acyl-CoA dehydrogenase
deficiency: enzymatic and molecular evaluation of neonates with elevated C14:1-carnitine levels. Pediatrics
2006;118(3):1064-1069.
3 Chapter 41: Very long chain acyl-CoA dehydrogenase deficiency. Nyhan WL, Barshop BA and Ozand P. Atlas
of Metabolic Diseases 2nd ed. Great Britain: Oxford University Press, 2005 pp 267-270.
4 Wood JC, Mager MJ, Rinaldo P et al. Diagnosis of very long chain acyl-dehydrogenase deficiency from an
infant’s newborn screening card. Pediatrics 2001l108:e19-e21.
5 Stanley C, Bennett M, Mayatepek E. Disorders of mitochondrial fatty acid oxidation and related metabolic
Walter pp 184

Analyte Tetradeccanoylcarnitine (C14:1) always associated with 3-OH stearoylcarnitine ( C18
OH)
Method of
measured
Differential
diagnosis
Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency.
Disorder is sometimes mistaken for Reye syndrome
False
positive
75% from newborn staff effort consumed to catch true cases
Clinical
presentation
More severe and earlier than MCAD
VLCAD deficiency may present acutely in the neonate and is associated with high mortality
unless treated promptly; milder variants exist. Features of severe VLCAD deficiency in
infancy include hepatomegaly, cardiomyopathy during acute attack associated with fasting
and arrhythmias, lethargy, hypoketotic hypoglycemia,muscle weakness , rhabdomyolysis
and failure to thrive. Treatment is available.
Diagnostic
evaluation
and
confirmatory
test
Plasma acylcarnitine profile may show increased C14:1 acylcarnitine (and lesser elevations
of other long chain acylcarnitines).
Urinary organic acid profile show nonketotic dicarboxylic aciduria (increase C6-C12)
Assay of enzyme activity of VLCAD in fibroblast
Diagnosis is confirmed by mutation analysis of VLCAD gene and other biochemical genetic
tests.
Sudden unexpected death can occur in several patients
Causes and
mechanism
VLCAD deficiency is a fatty acid oxidation (FAO) disorder. Fatty acid oxidation occurs during
prolonged fasting and/or periods of increased energy demands (fever, stress), when energy
production relies increasingly on fat metabolism. In a FAO disorder, fatty acids and potentially
toxic derivatives accumulate because of a deficiency in one of the mitochondrial FAO
enzymes.
Genetics ACADVL A gene on chromosome 17p13.1 encodes acyl-Coenzyme A dehydrogenase -
autosomal recessive
Prenatal
diagnosis
Amniocytes from a pregnancy at risk for an unspecified fat oxidation defect produced
increased levels of long-chain acylcarnitines consistent with a deficiency in very-long-chain
acyl-CoA dehydrogenase (VLCAD). Measurements of the enzymatic activity confirmed
VLCAD deficiency in amniocytes
Prevalence affect 1 in 40,000 to 120,000 people
Action for
result
Contact family , evaluate baby for poor feeding , lethargy , hypotonia ,arrhythmia and
hepatomegaly , start confirmatory investigation, educate family to avoid fasting , refer to
metabolic specialist
Treatment Avoiding of fasting for more than 10 hours
Continuous intra gastric feeding is useful in some patients

TRIFUNCTIONAL PROTEIN [TFP] DEFICIENCY
The mitochondrial trifunctional protein (TFP) is a multienzyme complex of the β-
oxidation cycle composed of four α-subunits harbouring long-chain enoyl-CoA
hydratase and long chain L-3-hydroxyacyl-CoA dehydrogenase and four β-subunits
encoding long chain 3-ketoacyl-CoA thoilase.1 General or complete TFP deficiency is
defined and occurs when markedly decreased activity of all three enzymatic
components, LCHAD, long chain 2,3 enoyl CoA drasate and LKAT exist.
Incidence
Very rare
General TFP deficiency has three phenotypes: the lethal phenotype presenting with
lethal cardiac failure or sudden death due to arrhythmias, the hepatic phenotype and
the neuromyopathic phenotype that has lateronset, episodic, recurrent skeletal
myopathy with muscular pain and weakness often induced by exercise or exposure to
cold and peripheral neuropathy.
It is important to note that fetuses with complete TFP deficiency can cause maternal
liver diseases of pregnancy.
Pathophysiology
Mitochondrial fatty acid β-oxidation is a major energy-producing pathway.3 Any defect
in any enzyme may cause the characteristic signs and symptoms which include
hypoketotic hypoglycemia.
Inheritance
autosomal recessive
Screening
increased C16 and C18 on MSMS
Confirmatory testing is through the demonstration of decreased enzyme activity on
cultured fibroblasts.Mutations in the HADHA and HADHB gene may result in
mitochondrial trifunctional protein deficiency4 and mayplay a role in confirmation.
Prognosis
Patients with metabolic crises do well unless the hypoglycemia and seizures are
prolonged and cause developmental delay, older onset patients with rhabdomyolysis
can reduce episodes significantly with dietary management and do well.

Long term and emergency management
Treatment includes avoidance of fasting, reduced long-chain fat intake,
supplementation with medium chain triglycerides, supplementation with fat-soluble
vitamins, and avoidance of other potential stressors such as prolonged exercise.
Emergency management includes administration of intravenous glucose infusions.
References
1Speikerkoetter U, Khuchua Z, Yue Z et al. General Mitochondrial Trifunctional Protein (TFP) Deficiency as a
results of either α or β-subunit mutations exhibits imilar phenotypes because mutation in either subunit alter
TFP complex expression and subunit turnover. Ped Res 2003l55(2):1-7.
2Strauss AW, Andersen BS and Bennett MJ. Chapter 5: Mitochondrial Fatty Acid Oxidation Defects in 14
3 Kamijo T, Wanders RJA, Saudubray JM et al. Mitochondrial Trifunctional Protein Deficiency. J Clin Invest
1994;93:1740-1747.
4Trifunctional protein deficiency. Available at http://ghr.nlm.nih.gov/condition/mitochondrial-trifunctional-
protein-deficiency
5Stanley C, Bennett M, Mayatepek E. Disorders of mitochondrial fatty acid oxidation and related metabolic
Walter pp 184
Analyte C16OH +/- C18
Method of
measured
Differential
diagnosis
Long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency;
Trifunctional protein (TFP) deficiency.
False
positive
Consider that cefotaxime treatment in the baby or mother may alter lab results.
Clinical
presentation
LCHAD and TFP deficiencies may present acutely and are then associated with high
mortality unless treated promptly. Hallmark features include hepatomegaly,
cardiomyopathy, lethargy, hypoketotic hypoglycemia, elevated liver transaminases,
elevated creatine phosphokinase (CPK), lactic acidosis, and failure to thrive.
Rhabdomyolysis (a serious and sometimes fatal complication) may occur. Milder variants
exist.
Diagnostic
evaluation
and
confirmatory
test
Plasma acylcarnitine analysis will show a characteristic pattern consistent with LCHADD or
TFP deficiency.
Urine organic acid analysis may also show an abnormal profile.
Differentiation between both disorders requires further biochemical and molecular genetic
testing
Causes and
mechanism
LCHADD and TFP deficiencies are fatty acid oxidation (FAO) disorders. Fatty acid oxidation
occurs during prolonged fasting and/or periods of increased energy demands (fever, stress)
after glycogen stores become depleted and energy production relies increasingly on fat
metabolism. Fatty acids and potentially toxic derivatives accumulate in FAO disorders which
are caused by deficiency in one of the enzymes involved in FAO.
Genetics COMMOM MUTATION IN THE a SUBUNIT , E474Q IS SEEN IN MORE THAN 60% OF
LCHAD
Treatment Avoiding fasting stress
Dietary supplements with medium-chain triglyceride oil and docosahexaenoic acid DHA

ORGANIC ACID DISORDER
3-METHYLCROTONYL-COA CARBOXYLASE DEFICIENCY [3MCC]
The deficiency of 3-methylcrotonyl CoA carboxylase (3MCC) is a disorder of leucine
metabolism that was first described by Eldjarn et al. in 1970.1 In most instances, it has
been found that neonates who test positive for this condition in expanded newborn
screening do not actually have the condition but instead reflect the increased levels of
the metabolites of their mothers.
Incidence
Very rare

There is a broad spectrum of clinical presentation ranging from no symptoms to failure
to thrive, hypotonia, and cardiomyopathy to severe metabolic decompensation with
metabolic acidosis and hypoglycemia. Some patients may have a late presentation (1-
3 years old) with an acute episode of Reye syndrome, massive ketosis, acidosis,
lethary, coma leading to a fatal outcome.
Pathophysiology
3-methycrotonyl CoA carboxylase is responsible for the carboxylation of 3-
methylcrotonyl-CoA, the fourth step in leucine catabolism; a deficiency of which
causes a disturbance in leucine catabolism.
Inheritance
autosomal recessive
Screening
Increased 3-hydroxyisovaleryl carnitine on MSMS
An increase in 3-hydroxyisovaleric (3 HIVA) and 3-methylcrotonyl glycine (3 MCG) are
found in urine, confirmatory testing is done through the demonstration of decreased
enzyme activity in cultured fibroblasts.
Prognosis
3-MCC is a common, mostly benign condition; whether treatment with a low-protein
diet, carnitine and glycine supplementation has the potential to change the clinical
course in several affected patients remains to be elucidated.
Long term treatment of symptomatic infants based on mildly protein restricted diet
results in general improvement and reduction in the number of exacerbations. It is
effective in lowering the excretion of organic acids which however, never disappears.
Glycine supplementation at 175 mg/kg/day increases the excretion of 3 MCG.
Carnitine supplementation at 100 mg/kg.day corrects the very low plasma carnitine
levels and increases the excretion of 3 HIVA.

Key metabolite : C5OH(3OH isovaleryl-carnitine) ,
elevated
Emergency key : Low
Action : Referral to metabolic specialist
Acylcarnitine profile
Carnitine status in plasma /serum
Enzyme activity
Mutation anmalysis
Therapy : Possibly carnitine supplementation
Benign disorder under risk of
decompensation
Prognosis : Good
Note of caution : NBS may detect affected mothers
C5OH not specific to 3MCC deficiency but
also in MCD – Biotindase def. – 3HMG-
BKTD
References
1Leonard JV, Seakins JWT, Bartlett K et al. Inherited disorders of 3-methylcrotonyl CoA carboxylation. Arch Dis
Child 1981;56:52-59.
2 Chapter 9: 3-methylcrotonyl carboxylase deficiency/3-methylcrtotonyl glycinuria. Nyhan WL, Barshop BA
and Ozand P. Atlas of Metabolic Diseases 2nd
ed. Great Brita 3Hoffman GF and Schulze A. Chapter 7: Organic
Acidurias in Sarafoglou K, Hoffman GF and Roth KS (eds). Pediatric Endocrinology and Inborn Errors of
Metabolism. New York:McGraw Hill, 2009 pp 93-94.
4 Ficicioglu MD and Payan I. 3-Methylcrotonyl-CoA carboxylase deficiency: metabolic decompensation in a
noncompliant child detected through newborn screening. Pediatrics 2006;118:2555-2556.
5Wendel U, de Baulny HO. Branched chain organic acidurias/acidemias. Inborn Metabolic Diseases Chapter 19
4th edition eds Fernandes, Saudubray, van den Berghe, Walter pp 257 in:Oxford University Press, 2005 pp 66-
68.

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