Newborn Screening Panel of Disorders: Management Protocol

Newborn Screening
Panel of Disorders
Management Protocol
NEWBORN SCREENING REFERENCE CENTER 1

Table of Contents
AMINO ACID DISORDER
Homocystinuria 3
Maple Syrup Urine Disease 5
Phenylketonuria 8
Tyrosinemia 12
UREA CYCLE DEFECT
Citrullinemia 14
Arginininosuccinic Acidemia 15
FATTY ACID DISORDER
Carnitine Uptake Defect 19
Medium Chain Acyl—CoA Dehydrogenase Deficiency 20
Long Chain Acyl—CoA Dehydrogenase Deficiency 22
Very Long Chain Acyl—CoA Dehydrogenase Deficiency 25
Tri Functional Protein Deficiency 28
ORGANIC ACID DISORDER
3-Methylcrotonyl CoA Carboxylase Deficiency 30
B—Ketothiolase Deficiency 32
Biotinidase Deficiency 33
Glutaric Aciduria Type 1 34
Isovaleric Acidemia 37
Methylmalonic Acidemia 38
Multiple Carboxylase Deficiency 39
Propionic Acidemia 40
ENDOCRINE DISORDER
Congenital Adrenal Hyperplasia 44
Congenital Hypothyroidism 48
CYSTIC FIBROSIS 51
AMINO ACID DISORDER
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 .1
Incidence
1:344,0002
Clinical Manifestation
Patients affected with homocystinuria may present with ectopia lentis which is found in 85% of patients3 ,
skeletal abnormalities such as genu valgus and “marfanoid habitus”, mental retardation and
thromboembolism.3,4
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.7
Inheritance
autosomal recessive2
Screening:
increased methionine on MSMS2
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.2
Prognosis
Early diagnosis and treatment can prevent thromboembolic events and reduce the complications brought
about by increased levels of homocysteine.3
Long Term Management 8,9,10

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 sensory

AMINO ACID DISORDER
...HOMOCYSTINURIA
neuropathy, 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.
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.
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.
7
Boushey CJ, Beresford SA, Omenn GS, Motulsky AG. A Quantitative Assessment of Plasma Homocysteine as a Risk Factor for Vascular Disease: Probably
Benefits of Increasing Folic Acid Intakes. JAMA 1995l 274:1049-1057.
8
Ueland PM. Homocysteine Species as Components of Plasma Redox Thiol Status. Clin Chem 1995; 41:340-342.
9
Andria G, Fowler B, Sebastio G. Disorders of Sulfur Amino Acid Metabolism. Chapter 22, Inborn Metabolic Diseases 4th edition eds fernandes,
Saudubray, van den Berghe, Walter pp277-278
10
Zschocke J and Hoffman G. Vademecum Metabolicum (Diagnosis and Treatment of Inborn Errors of Metabolism) 3rd edition pp71.

AMINO ACID DISORDER
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
1 in 200,000 live births 2. It is the most common inborn error of metabolism that has so far been reported in
the Phlippines. To date, over 100 cases have been detected over the last 2 decades.
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.3 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.1,3
Thiamine-responsive MSUD’s clinical symptomatology and metabolic disturbance is ameliorated once
pharmacologic dose of thiamine has been given.2 E-3 deficient MSUD present with symptoms similar to those
of intermediate MSUD but they also have lactic acidosis.1,2
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.3
Inheritance:
autosomal recessive 2,3
Screening:
leucine + isoleucine, valine, (leucine + isloeucine)/phe ratio 2
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. 2
Long term Management 4

The aim of life long maintenance therapy is to maintain the branched chain amino acid levels at near normal

AMINO ACID DISORDER
...MAPLE SYRUP URINE DISEASE [MSUD]
concentrations. 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
AMINO ACID DISORDER
...MAPLE SYRUP URINE DISEASE [MSUD]
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 on ice .
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.
Also consider the following
∴ Maintain plasma concentrations of isoleucine and valine more than 200 umol/L
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

AMINO ACID DISORDER
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.1 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.2
Incidence
1:10,000 worldwide 3
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.2
The odor of the phenylketonuric patient is that of phenylacetic acid described as mousy, barny, or musty.2
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 2,4
Screening
increased phenylalanine levels on MSMS4
The demonstration of decreased enzyme activity is confirmatory.4 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.3
Prognosis
When treatment is started early and performed strictly, motor and intellectual development can be expected
to be near normal.4

AMINO ACID DISORDER
...PHENYLKETONURIA
Tetrahydrobiopterin BH4 Oral Loading Test

Name: Date performed:
Birth date: Performed by:
Weight:
Height:
Time Procedure Result

-12 hours Collect urine, frozen and protect Urine pterins
from light (in dark bottle). Submit to
Biochemical Genetics laboratory the
following day
- 3 hours Stop feeding the baby 3 hours before
the start of BH4 load to ensure that
he/she will get the entire amount of
BH4 by making him/her hungry
0 hours (day of BH4 load) Just before oral loading, collect Phe level
blood on filter card (2). Submit 1 to
NBS laboratory and the other one to
Biochemical Genetics laboratory.
Feed the baby with BH4 tablets at 20
mg/kg. Dissolve in 20 ml distilled
water just before feeding, rinse bot-
tle with 10 ml distilled water and
feed the patient
0.5 hours May resume feeding the baby with
regular infant formula or breast milk
1 hour Collect blood on filter card by heel Phe level
prick. Submit to NBS laboratory
4 hours Collect blood on filter card by heel Phe level
8 hours Collect blood on filter card by heel Phe level
Collect urine, frozen and protect Urine pterins
24 hours (day 2) Collect blood on filter card (2). Sub- Phe level
mit 1 to NBS laboratory and the
other one to Biochemical Genetics
laboratory.
Collect urine, frozen and protect Urine pterins
Note: All blood and urine samples submitted to Biochemical Genetics laboratory will be sent to Dr. Hsiao’s laboratory in Taiwan

AMINO ACID DISORDER
...PHENYLKETONURIA
Long Term Management 5
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.
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)6
There is no diet restriction in these types of disorders. The following medications should be given:
∴ Tetrahydrobiopterin: 5-10 mg/kg/day

AMINO ACID DISORDER
...PHENYLKETONURIA [PKU]
∴ 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)
References
1
Chapter 20: Phenylketonuria. Nyhan WL, Barshop BA and Ozand P. Atlas of Metabolic Diseases 2nd ed. Great Britain:Oxford University Press, 2005 pp
127-133.
2
Chapter 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
3
Burgard 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.
4
Kaye 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.

AMINO ACID DISORDER
TYROSINEMIA
There are 2 clinically recognized types of tyrosinemia.
∴
Type I (hepatorenal) is characterized by liver toxicity from increased concentrations of tyrosine. There is an
ssociated 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. 1
Incidence
1:100,000 for tyrosinemia type I. Incidence for type II has not been established yet.1
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.2
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.2
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 2
Screening
increased tyrosine and succinylacetone for type I; increased tyrosine for type II2
Confirmation can be done through plasma amino acid levels (increased tyrosine) and urine metabolic screening
(increased succinylacetone).2
Prognosis
If untreated, death from liver failure may occur in the first year of life for hepatorenal tyrosinemia.1

AMINO ACID DISORDER
...TYROSINEMIA
Long Term Management 3
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.
References
1
Kaye 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.
3
Chakrapani A, Holme E. Disorders of tyrosine metabolism. Inborn Metabolic Diseases Chapter 18,4th edition eds Fernandes, Saudubray, van den Berghe,
Walter pp237-239

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.1
Incidence
1:~50,0002
Following a brief hiatus in which the newborn appears normal, anorexia, vomiting and lethargy develop
followed rapidly by progression to deep coma.2 The symptoms mimic that of sepsis and affected newborns
present with severe lethargy, poor feeding to respiratory distress, jitteriness and seizures.3
A late onset form may occur as late as 20 years old and present as symptoms such as slurred speech, irritability,
insomnia or delirium.3
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
Screening
increased citrulline and low arginine on MSMS 4
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.4
Prognosis
Prognosis for intellectual development depends on the nature of the initial hyperammonemia especially its
duration or those of recurrent episodes.3

UREA CYCLE DEFECTS
ARGININOSUCCINIC ACIDEMIA
Argninosuccinate lyase or argininosuccinase catalyzes the conversion of the argininosuccinate formed from
citrulline and aspartate to fumarate and arginine.5
Incidence
1:70,000 6
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.6
A unique finding in patients is the presence of trichorrhexis nodosa where hair is very friable and breaks off
easily.6
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 MSMS4
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.4
Prognosis
Prognosis for intellectual development depends on the nature of initial hyperammonemia, especially its
duration or the nature of recurrent episodes.6
Long Term Management 4,7
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

UREA CYCLE DEFECTS
...ARGININOSUCCINIC ACIDEMIA
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)
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.

UREA CYCLE DEFECTS
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.

UREA CYCLE DEFECTS
References
1
Su TS, Bock HGO, Beaudet AL et al. Molecular analysis of argininosuccinate syntehtase deficiency in human fibroblasts. J Clin Invest 1982:70:1334-1339.
2
Chapter 31: Citrullinemia. Nyhan WL, Barshop BA and Ozand P. Atlas of Metabolic Diseases 2nd ed. Great Britain:Oxford University Press, 2005 pp 210-
213.
3
Wasant 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
5
Chapter 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.
6
Chen 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
CARNITINE UPTAKE DEFECT [CUD]
Carnitine uptake defect is also known as carnitine transporter deficiency. It is due to an abnormality in the
transport that facilitates carnitine’s entry into certain cells.1
Incidence
current prevalence is unknown 2
Patients may present with hypoketotic hypoglycemia, modest hepatomegaly and Reye-like syndrome, progres-
sive heart failure and muscle weakness.2 Most patients present with a progressive cardiomyopathy associated
with skeletal myopathy.3
Pathophysiology
Carnitine is necessary for transport of long-chain fatty acids into mitochondria to enter the β-oxidation cycle.2
Genetic defects of the carnitine trasporter results in failure of tissues of the cardiac and skeletal muscle and in
the renal tubules to concentrate intracellular levels of carnitine, thus reducing available cofactor for the car-
nitine cycle.3
Inheritance
Screening
decreased free and esterified carnitines 2
Confirmation of the diagnosis can be made biochemically by monitoring the uptake of carnitine by skin fibro-
blasts in culture.3
Prognosis
Patients on long term therapy report normal skeletal muscles tone, no episodes of metabolic decompensation,
and essentially normal intellect.3
Long term management 4

Treatment with carnitine improves cardiac and skeletal function to nearly normal within a few months. It also
corrects any impairment in hepatic ketogenesis which may be present. With oral carnitine at doses of 100 mg/
kg/day, plasma carnitine levels can be maintained in the low to normal range and liver carnitine levels may be
normal.
References
1
Chapter 37: Carnitine transporter deficiency. Nyhan WL, Barshop BA and Ozand P. Atlas of Metabolic Diseases 2nd ed. Great Britain:Oxford University
Press, 2005 pp 246-250.
2
Wilcken B. Disorders of Carnitine Cycle and Detection by Newborn Screening. Ann Acad Med 2008;37(12):71-73.
3
Strauss AW, Andersen BS and Bennett MJ. Chapter 5: Mitochondrial Fatty Acid Oxidation Defects in Sarafoglou K, Hoffman GF and Roth KS (eds). Pedi-
atric Endocrinology and Inborn Errors of Metabolism. New York:McGraw Hill, 2009 pp 60-62.
4
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

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.1
Incidence
1~1:15,0002
MCAD deficiency has a very wide spectrum of clinical presentations ranging from benign hypoglycemia to coma
and death.27 Two presentations have been noted: (1) hypoketotic hypoglycemia or Reye syndrome which oc-
curs within the first two years of life and (2) the chronic disruption of muscle function which include cardio-
myopathy, weakness, hypotonia and arrhythmia.2,3 In addition, MCAD deficiency has been shown to be associ-
ated with sudden infant death syndrome (SIDS).4 A “metabolic stress” such as prolonged fasting often in con-
nection with viral infections is usually required to precipitate disease manifestations but patients are com-
pletely asymptomatic between episodes.2
Pathophysiology
MCAD catalyzes the initial step in the β-oxidation of C12-C6 straight chain acyl-CoAs and MCAD deficiency re-
sults in a lack of production of energy from β-oxidation of medium chain fatty acids and hepatic ketogenesis
and gluconeogenesis.2
Inheritance
Screening
increased octanoylcarnitine on MSMS3 and a high C10/carnitine ratio2
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.2
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 complications3
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 inter-

FATTY ACID DISORDER
...MEDIUM-CHAIN ACYL-COA DEHYDROGENASE DEFICIENCY [MCAD]
current 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 cardiomyopa-
thy, 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 5
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 suf-
ficient 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!
References:
1
Strauss 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

FATTY ACID DISORDER
LONG-CHAIN L-3-HYDROXYACYL-CoA DEHYDROGENASE [LCHAD]
Long chain L-3 hydroxyacyl-CoA dehydrogenase (LCHAD) is a component of trifunctional protein.1 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.2
Incidence
1:100,000 to 1:200,0002
Patients exhibit moderate or severe multiorgan involvement either neonatally or during the first two years of
life.3 They may present in the first year of life with hypoketotic hypoglycemia and liver dysfunction, Reye syn-
drome-like symptoms, seizures, coma and death.2 By adolescence, ophthalmologic abnormalities including loss
of visual acuity, chorioretinal atrophy, progressive retinitis pigmentosa and peripheral sensorimotor polyneuro-
pathy may be observed.2,3,4, Up to 40% of symptomatic patients may have tachycardic arrhythmias, apneic epi-
sodes, cardiopulmonary arrest and unexplained death.2 A strong association has been demonstrated with het-
erozygous mothers developing acute fatty liver or pregnancy or hemolysis, elevated liver enzymes and low
platelet count (HELLP) syndrome when carrying an affected fetus.5
Pathophysiology
Since the enzyme LCHAD is part of the fatty acid oxidation, a deficiency causes a problem in the energy utiliza-
tion of the body which causes the presentation of signs and symptoms as listed above.
Inheritance
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.2 The
common mutation G1528C has been identified in affected individuals and may be used for confirmation.3
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%.2
Long term management 2,5,6,7

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

FATTY ACID DISORDER
...LONG-CHAIN L-3-HYDROXYACYL-COA DEHYDROGENASE [LCHAD]
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.
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 activ-
ity 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.

FATTY ACID DISORDER
...LONG-CHAIN L-3-HYDROXYACYL-COA DEHYDROGENASE [LCHAD]
Emergency management of patients with LCHAD deficiency 5
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.
21
3
Eskelin 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.
6
Stanley C, Bennett M, Mayatepek E. Disorders of mitochondrial fatty acid oxidation and related metabolic pathways. Inborn Metabolic Diseases Chap-
ter 23 4th edition eds Fernandes, Saudubray, van den Berghe, Walter pp 184
7
Long chain hydroxyl acyl co-A dehydrogenase deficiency. Available at http://www.newbornscreening.info/Parents/fattyaciddisorders/LCHADD.html

FATTY ACID DISORDER
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 gen-
erally a more severe condition than MCAD or SCAD deficiency and multiple tissues are affected.1
Incidence
1:50,000 to 1:120,0002
The clinical presentation of symptomatic VLCAD deficiency is heterogenous with phenotypes of different sever-
ities.3 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.1,3
Pathophysiology
VLCAD catalyzes the dehydrogenation of acyl CoA esters of 14-20 carbon length in the first step of mitochon-
drial fatty acid oxidation.3,4 VLCAD deficiency results in lack of production of energy from β-oxidation of long-
chain fatty acids. Because heart and muscle tissues depend heavily on energy from long chain fatty acid oxida-
tion, a VLCAD deficiency severely affect these tissues.1
Inheritance
Screening
elevation of tetradecenoylcarnitine (C14:1) on MSMS1,3
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.4
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, meta-
bolic insufficiency and death.4
Long term management 1,4,5,6

Treatment of this disorder include avoidance of fasting by frequent feeding, overnight continuous feeding, re-
duction 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).27,32
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

FATTY ACID DISORDER
...VERY LONG-CHAIN ACYL-COA DEHYDROGENASE DEFICIENCY [VLCADD]
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.
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 activ-
ity 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 5


FATTY ACID DISORDER
...VERY LONG-CHAIN ACYL-COA DEHYDROGENASE DEFICIENCY [VLCADD]
References
1
2
Liebig 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 Brit-
ain: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 pathways. Inborn Metabolic Diseases Chap-
ter 23 4th edition eds Fernandes, Saudubray, van den Berghe, Walter pp 184
6
Very long chain acyl co-A dehydrogenase deficiency. Available at http://www.newbornscreening.info/Parents/fattyaciddisorders/VLCADD.html

FATTY ACID DISORDER
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 dehydro-
genase 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.2
Incidence
about 20 patients have been described3
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 later-
onset, episodic, recurrent skeletal myopathy with muscular pain and weakness often induced by exercise or
exposure to cold and peripheral neuropathy.2,3
It is important to note that fetuses with complete TFP deficiency can cause maternal liver diseases of preg-
nancy.2
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.2
Inheritance
Screening
increased C16 and C18 on MSMS2
Confirmatory testing is through the demonstration of decreased enzyme activity on cultured fibroblasts.2 Mu-
tations in the HADHA and HADHB gene may result in mitochondrial trifunctional protein deficiency4 and may
play a role in confirmation.
Prognosis
Patients with metabolic crises do well unless the hypoglycemia and seizures are prolonged and cause develop-
mental delay, older onset patients with rhabdomyolysis can reduce episodes significantly with dietary manage-
ment and do well.2
Long term and emergency management 5

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.

FATTY ACID DISORDER
...TRIFUNCTIONAL PROTEIN [TFP] DEFICIENCY
References
1
Speikerkoetter 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.
2
Strauss 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.
4
Trifunctional protein deficiency. Available at http://ghr.nlm.nih.gov/condition/mitochondrial-trifunctional-protein-deficiency
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

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 in-
creased levels of the metabolites of their mothers.2
Incidence
1:120,000 in Australia3
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.4 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.4
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.5
Inheritance
Screening
increased 3-hydroxyisovaleryl carnitine on MSMS3
An increase in 3-hydroxyisovaleric (3 HIVA) and 3-methylcrotonyl glycine (3 MCG) are found in urine, confirma-
tory testing is done through the demonstration of decreased enzyme activity in cultured fibroblasts.4
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 elu-
cidated.3

Long term treatment of symptomatic infants based on mildly protein restricted diet results in general improve-
ment 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.
References
1
Leonard 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 Britain:Oxford University Press, 2005 pp 66-68.

...3-METHYLCROTONYL-COA CARBOXYLASE DEFICIENCY [3MCC]
3
4
Ficicioglu MD and Payan I. 3-Methylcrotonyl-CoA carboxylase deficiency: metabolic decompensation in a noncompliant child detected through new-
born screening. Pediatrics 2006;118:2555-2556.
5
Wendel 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

B-KETOTHIOLASE DEFICIENCY
Beta ketothiolase deficiency is a defect of mitochondrial acetoacetyl-CoA thiolase involving ketone body me-
tabolism and isoleucine catabolism.1
Incidence
> 30 patients have been reported2
This rare disorder is characterized by normal early development followed by progressive loss of mental and
motor skills, it is clinically characterized by intermittent ketoacidotic episodes with no clinical symptoms in be-
tween.2 Some patients may present with vomiting, hypotonia, lethargy, coma, hyperventilation and dehydra-
tion.3 Ketoacidotic crises may occur following a bout of infection or mild illness.2
Pathophysiology
Mitochondrial acetoacetyl CoA thiolase is responsible for the cleavage of 2-methylacetoacetyl CoA in isoleu-
cine metabolism, acetoacetyl CoA formation in ketogenesis and acetoacetyl CoA cleavage is ketolysis.2
Inheritance
autosomal recessive2,3
Screening
increased tiglycarnitine and 2-methylhydroxybutylcarnitine on MSMS3
An increased excretion of 2-methyl 3-hydroxybutyric and 2-methylacetoacetic acid in urine is observed but de-
finitive diagnosis is established by demonstrating decreased enzyme activity in cultured fibroblasts.3
Prognosis
The frequency of ketoacidotic attacks decreases with age.3 Clinical consequences can be avoided by early diag-
nosis and appropriate management of ketoacidosis.2

These patients can decompensate rapidly in early childhood. To prevent this, fasting must be avoided and a
high carbohydrate intake must be maintained during any metabolic stress, such surgery or infection. Drinks
containing carbohydrate should be started at the first sign of illness. Hospital admission is needed if these are
not tolerated or if patient develops moderate to heavy ketonuria. In hospital, patients require intravenous
infusion of glucose. A moderate protein restriction is also recommended because this enzyme is also involved
in isoleucine catabolism. A low fat has also been recommended. Protein and fat should certainly be avoided
during illness.
References
1
Fukao T. Beta kethothiolase deficiency. Orphanet 2001 http://www.orpha.net/data/patho/GB/uk-T2.pdf Accessed Feb 15, 2012.
2
Chapter 17: Mitochondrial acetoacetyl CoA thiolase (3-oxothiolase) deficiency. Nyhan WL, Barshop BA and Ozand P. Atlas of Metabolic Diseases 2nd ed.
Great Britain:Oxford University Press, 2005 pp 102-106.
3
4
Morris A. Disorders of ketogenesis and ketolysis. Inborn Metabolic Diseases Chapter 14 4th edition eds Fernandes, Saudubray, van den Berghe, Walter
pp 195
BIOTINIDASE DEFICIENCY
Biotinidase deficiency is a form of multiple carboxylase deficiency in which the fundamental defect is an inabil-
ity to cleave biocytin for biotin recycling.1 Biotin is a water-soluble vitamin of the B complex that acts as a co-
enzyme in each of 4 carboxylases in humans (pyruvate carboxylase, propionyl-coenzyme A carboxylase, β-
methylcrotonyl CoA caorboxylase and acetyl-CoA carboxylase).1
Incidence
1 in 110,000 1
Biotinidase deficiency presents with a median age of 3 months or as late as 10 years of age, symptoms include
dermatologic affectation appearing as patchy desquamation and neurological manifestations such as seizures
in 70% of patients and ataxia that can interfere with walking. Some patients may also have optic atrophy and
hearing loss.1,2
Individuals with partial biotinidase deficiency can present with skin manifestations and no neurologic symp-
toms.1,2
Pathophysiology
Biotinidase deficiency results in an inability to recycle endogenous biotin which means the brain is unable to
recycle biotin adequately leading to decreased pyruvate carboxylase activity in the brain and accumulation of
lactate which in turn causes the neurologic symptoms.1
Inheritance
Screening
biotinidase in MSMS and presence of 3-hydroxy-isovaleric, 3-methylcrotonic, 3-hydroxypropionic, methylcitric,
3-hydroxybutyric acids, and acetoacetate in urine organic acid 3
Confirmatory studies are performed by determining biotinidase activity in serum.2
Prognosis
Once therapy is instituted, cutaneous symptoms resolve quickly as do seizures and ataxia, however other
symptoms such as hearing loss and optic atrophy are less reversible.2

Biotin at 5-10 mg/day should be given.
References
1
Chapter6: multiple carboxylase deficiency/biotinidase deficiency. Nyhan WL, Barshop BA and Ozand P. Atlas of Metabolic Diseases 2nd ed. Great Brit-
ain:Oxford University Press, 2005 pp 42-48.
2
Baumgartner M, Suormala T. Biotin-responsive disorders. Inborn Metabolic Diseases Chapter 23 4th edition eds Fernandes, Saudubray, van den Berghe,
Walter pp 333-337.
3
Seashore M. The Organic Acidemias: An Overview. Gene Reviews,1993. http://www.ncbi.nlm.nih.gov/books/NBK1134/ Accessed April 30, 2012.

GLUTARIC ACIDURIA TYPE 1 [GA 1]
Glutaric Aciduria 1 (GA1) was first described by Goodman and colleagues in 1975.1 It is caused by a deficiency
of glutaryl-CoA dehydrogenase which catalyzes the oxidative decarboxylation of glutaryl-CoA, an intermediate
in the degradation of the amino acids lysine and tryptophan.2 This causes an increase in glutaric, 3-
hydroxyglutaric, glutaconic and glutarylcarnitine.1
Incidence
1 in 100,000 newborns 3
Two subsets of patients are characterized based on the levels of glutaric acid excreted in the urine: the low
(<100 mmol/mmol creatinine) and high excretors (>100 mmol/mmol creatinine).4 However, the risk of devel-
oping striatal injury resulting in neurologic dysfunction is the same regardless of excretion status.
Patients with GA1 may present with hypotonia, head lag, feeding difficulties, irritability.1 Macrocephaly is seen
in about 75% of infants, but this is non-specific.2 If left untreated, 90% of patients develop neurologic disease
presenting as dystonic-dyskinetic posturing, athetoid movements, opisthotonus, spastic, rigidity, clenched fists,
tongue thrust and profuse sweating.1,2 The encephalopathic crises precipitated by immunization, infection,
surgery and fasting results in the affectation of the basal ganglia and exaggerates the neurologic manifesta-
tions which occur frequently until the 4th year of life.1
Patients may also be observed to have retinal hemorrhages and on MRI present with subdural hemorrhages
and be mistaken to be victims of child abuse.1
Pathophysiology
It was found that 3-hydroxglutaric and glutaric acid share structural similarities with glutamate which causes
excitatory cell damage; futher, the accumulation of these metabolites modulate glutamatergic and GABAergic
neurotransmission resulting in an imbalance of excitatory and inhibitory neurotransmitters.1
Inheritance
Screening
increased glutarylcarnitine on MSMS2
Confirmatory Test
Glutaric acid and 3-hydroxyglutaric acid is increased in urine organic acid analysis.1 Confirmatory testing is
achieved through the demonstration of a decrease in enzyme activity in skin fibroblasts.1,3
Prognosis
The early diagnosis and treatment intervention in patients with GA1 prevents striatal degeneration in 80-90%
of infants.1 However, study by Beauchamp et al. (2009) showed that despite early treatment, patients with
GA1 may have mild fine motor and articulation problems and raise the question of prenatal damage or subtle
post-natal ongoing neurotoxic effects of glutaric and hydroxyglutaric acids or both.5

...GLUTARIC ACIDURIA TYPE 1 [GA 1]
Long term management 1,2,3,4,6
Diet
Most patient with glutaric aciduria type I are treated by restriction of natural protein in general or of lysine in
particular, supplemented with a lysine free amino acid mixture. The intake of tryptophan should only be re-
duced.
Oral supplementation with carnitine and riboflavin
Carnitine should be supplemented lifelong at 50-100mg/kg/day. If riboflavin is tried, responsiveness should be

investigated by giving riboflavin in increasing doses from 50-300 mg and monitoring total glutaric acid in 24
hour urine samples.
Neuropharmacologic agents
Baclofen 1-2mg/kg/day or benzodiazepines at 0.1-1 mg/kg/day reduce involuntary movements and improve
motor function, probably mostly through muscle relaxation. In patients with residual motor function, anticho-
linergics, such as trihexyphenidyl, may improve choreoathetosis. Valproic acid is contraindicated as it effec-
tively competes with glutaric acid for esterification with L carnitine and may promote disturbances in the mito-
chondrial acetyl CoA-CoA ratio.
Supportive treatment
Despite the severe motor handicap in some patients, intellectual functions are preserved. Affected patients
require a multidisciplinary specialist institution. The social integration of patients can be greatly improved by
language computers. As involuntary movements become severe, feeding difficulties can become a major
problem. Increased muscular tension and sweating require a high intake of calories and water. Percutaneous
gastrostomy can lead to a dramatic improvement in nutritional status, marked decrease in psychological ten-
sion associated with feeding, reduction in the burden of care for families and even a reduction in dystonia/
dyskinesia. Neurosurgical intervention of subdural hygromas/hematomas should be avoided. Acute encepha-
lopathic crises can be precipitated by common febrile diseases, vaccinations or surgical interventions during
infancy and early childhood. If untreated, the majority of these patients manifest such crises with potentially
devastating neurological sequelae.
Emergency Protocol for Glutaric Aciduria type I


2. Bring carnitine (if known to have GAI)
3. Bring formula (Lysine free and tryptophan reduced formula)

...GLUTARIC ACIDURIA TYPE 1 [GA 1]
5. *Prepare IV carnitine (100 mg/kg/day)
6. Collect blood for blood gas, electrolytes, and glucose. Other examinations as required.
Contact the Metabolic Physician ll once patient arrives at ER
—————
Principles of Management:
∴ 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.
∴ Cease natural protein
∴ Intralipid at 2g/kg/day. .
∴ The patient may also have an enteral sick day regimen, which can be administered continuously via a na-
sogastric feeding tube.
Specific therapy
∴ IV Carnitine 100 mg/kg/day (Dilute to suitable volume with NSS and infuse over 1 hour)
∴ Treat underlying cause. Treat dehydration, electrolyte imbalance and acidosis. Treat neurologic symptoms
appropriately.
References
1
Metabolism. New York:McGraw Hill, 2009 pp 93-94
2
Keyser B, Muhlhause C, Dickmanns A et al. Disease-causing missense mutations affect enzymatic activity, stability and oligomerization of glutaryl-CoA
dehydrogenase (GCDH). Hum Mol Gen 2008;17(24):3854-3863.
3
Kolker S, Christensen E and Leonard JV. Diagnosis and management of glutaric aciduria type I – revised recommendations. J Inherit Metab Dis
2011;34:677-694.
4
Kolker S, Christensen E and Leonard JV. Guideline for the diagnosis and management of glutaryl-CoA dehydrogenase deficiency. J Inherit Metab Dis
2007;30:5-22
5
Beauchamp MH, Boneh A and Anderson V. Cognitive, behavioural and adaptive profiles of children with glutaric aciduria type I detected through new-
born screening. J Inherit Metab Dis 2009;169:1-7.
6
Hoffman G. Cerebral organic acid disorders and other disorders of lysine catabolism. Inborn Metabolic Diseases Chapter 23 4th edition eds Fernandes,
Saudubray, van den Berghe, Walter pp 301-302

ISOVALERIC ACIDURIA [IVA]
Isovaleric acidemia (IVA) was the first organic acidemia to be described. It is caused by a deficiency of is-
ovaleryl-CoA dehydrogenase, an enzyme located proximally in the catabolic pathway of the essential
branched-chain amino acid leucine.1
Incidence
1:75,000 (US, worldwide)2
The clinical manifestation of IVA may be acute or chronic. An acute or neonatal presentation is characterized
by non-specific findings of vomiting, lethargy, poor feeding, seizures that may progress to a comatose state.3 A
characteristic odor in the urine described as “sweaty feet” or “dirty socks” has been reported among patients
with IVA.1,3 It has also been found that in bone marrow cultures, isovaleric acid is an inhibitor of granulopoietic
progenitor cell proliferation which accounts for the pancytopenia or thrombocytopenia found in patients.1 A
chronic form may present with developmental delay or mental retardation.1,3 Both acute or chronic patients
may suffer from metabolic crisis and are sometimes misdiagnosed as suffering from diabetic ketoacidosis be-
cause of the similarity in presentation: acidosis, hyperglycemia and ketosis.1
Pathophysiology
At present, the specific pathophysiology of IVA is unclear. It is surmised that accumulating CoA derivative se-
questers CoA, thereby disturbing the mitochondrial energy metabolism.1
Inheritance
Screening
increased C5 acylcarnitine on MSMS1
Confirmatory Test:
There is note of increased isovalerylcarnitine and isovalerylglycine in plasma or urine. Enzymatic assay on cul-
tured fibroblasts or mutation analysis may also be done.1,3
Prognosis
In a study by Grunert et al. (2012)4, among patients with IVA, the mortality rate is high in association with early
neonatal presentation. Neurocognitive outcome is better with early diagnosis and management. The age of
diagnosis but not the number of catabolic episodes contribute to the neurocognitive outcome.4

METHYLMALONIC ACIDEMIA [MMA]
Methylmalonic academia (MMA) is due to a defect in methylmalonyl CoA mutase or a defect in the enzyme’s
vitamin B12 derived co-factor 5’-deoxyadenosylcobalamin.5 Among patients with a defect of methylmalonyl
CoA mutase, two subgroups exist: Mut0 patients have no enzyme activity while Mut- patients have a spectrum
of residual activity.1
Incidence
1 in 100,000 Caucasians1
Clinical Manifestation:
Patients present with severe metabolic crisis in the first months of life, progressive failure to thrive, feeding
problems, recurrent vomiting, dehydration, hepatomegaly, lethargy, seizures and developmental delay.1 Some
affected children may also have failure of linear growth, anorexia and developmental failure.5 Patients may
have metabolic decompensations following bouts of acute illness or minor infections.1,5 They are prone to epi-
sodes of metabolic strokes that primarily affect the basal ganglia.5
Neonates affected with MMA share similar physical characteristics such as high forehead, broad nasal bridge,
epicanthal folds, long smooth philtrum and triangular mouth.5 Unique to this disorder is the development of
chronic renal failure in the second decade in 20-60% of patients.1
Pathophysiology
Methylmalonyl CoA-mutase catalyzes the conversion of methylmalonyl CoA to succinyl CoA which can enter
the tricarboxylic acid cycle.5 This causes the accumulation of methylmalonate in the body which may be toxic
to the brain and the kidneys.6
Inheritance
Screening
increase in propionylcarnitine on MSMS1,7
Urine metabolic screening reveal elevated methylmalonic acid, propionylglycine, 3-hydroxypropionic acid and
methylcitrate; plasma amino acids show elevated glycine, alanine and methionine.1 Definitive testing is the
demonstration of decreased enzyme activity through cultured fibroblasts.5
Prognosis
The long-term outcome of in MMA is influenced by the underlying defect.6 Mut0 patients have the worst prog-
nosis, most of the patients may have very early onset signs and symptoms that occur even before the results of
NBS are available, and die immediately or survive with significant neurodevelopmental disability.7 Vitamin B12
responsive methylmalonic acidurias have a reasonable outcome.1

MULTIPLE CARBOXYLASE DEFICIENCY [MCD]
Mutliple carboxylase deficiency, also known as holocarboxylase synthase leads to a failure of synthesis of all
carboxylases.1
Incidence
30-40 patients are known so far1
Most patients present acutely in the first few hours of life. Patients may have dehydration, go into deep coma
leading to death, ketosis, high anion gap metabolic acidosis, failure to thrive, alopecia and a characteristic ery-
thematous eruption on the skin that can be bright, red, scaly or desquamative. 1,2
Pathophysiology
Holocarboxylase synthase binds biotin, an essential cofactor in gluconeogenesis, fatty acid synthesis and the
catabolism of several amino acids.1,2 This in turn, leads to a failure of the synthesis of the active holocarboxy-
lases which is the body’s main source of biotin.
Inheritance
Screening
increased priopionyl carnitine and 3-hydroxyisovaleryl carnitine1
An increased methylcrotonylglycine and 3-hydroxyisovaleric acid in blood and urine with lactic acidosis can be
observed but definitive testing is done through measurement of enzyme activity in fibroblasts.1
Prognosis
Prognosis is good if treatment is initiated immediately and the clinical course is followed carefully by close
monitoring of biochemical abnormalities.1
Long term management2

Treatment is through giving biotin 10-20mg/day. The clinical response to treatment is dramatic, ketosis and
acidosis disappear along with hyperammonemia, lethargy, hypotonia and ataxia. The dermatological effects of
the disorder are likewise reversed.
References
1
Chapter 5: Multiple carboxylase deficiency/holocarboxylase deficiency. Nyhan WL, Barshop BA and Ozand P. Atlas of Metabolic Diseases 2nd ed. Great
Britain:Oxford University Press, 2005 pp 36-39.
2
Baumgartner M, Suormala T. Biotin-responsive disorders. Inborn Metabolic Diseases Chapter 23 4th edition eds Fernandes, Saudubray, van den Berghe,
Walter pp 333-337.

PROPIONIC ACIDEMIC [PA]
Propionic acidemia (PA) is an organic acidopathy also known was propionic aciduria and ketotic hyperglycine-
mia.8 It is due to the defective activity of propionyl CoA which is the first step in the pathway of propionate
metabolism in which propionyl CoA, the product of the metabolism of isoleucine, valine, theronine and me-
thionine is converted to methylmalonyl CoA then to succinyl CoA which undergoes oxidation in the citric acid
cycle.9
Incidence
1 in 100,0009
Patients usually are healthy at birth but quickly develop overwhelming disease, which may be misinterpreted
as sepsis or ventricular hemorrhage.1 Additional symptoms include vomiting, acidosis, dehydration, lethargy to
coma, recurrent ketotic episodes, hypotonia, seizures and hyperammonemia.10 Some patients may have
acute-onset neurological symptoms described as metabolic strokes, arrhythmias, cardiomyopathy and an exfo-
liative rash.1
Patients may also present with similar dysmorphic characteristics such as frontal bossing, widened nasal
bridge, wide set eyes, epicanthal folds, long philtrum and upward curvature of the lips.10
Pathophysiology
Due to an increase in propionic acid, abnormal ketogenesis occurs because propionic acid is an inhibitor of mi-
tochondrial oxidation and succinic and alpha-ketoglutaric acid.10 Inhibition of glycine cleavage enzyme leads to
hyperglycinemia and the inhibition of N-acetylglutamate synthase, an enzyme of the urea cycle, causes hy-
perammonemia.1
Inheritance
Screening
elevated propionylcarnitine in MSMS1
The predominant compound found in blood and urine is 3-hydroxypropionic acid; others may include tiglic
acid, tiglyglycine, butanone and propionylglycine.10 Highly elevated levels of glycine in plasma and urine can be
observed but confirmatory testing is through the demonstration of low levels of enzyme on cultured fibro-
blasts.1,10
Prognosis
Despite early diagnosis and treatment, the neonatal onset form of PA is still complicated by early death in in-
fancy or childhood while late onset forms reach adulthood but often are handicapped by severe extrapyrami-
dal movement disorders and mental retardation; however, progress has been achieved in survival and preven-
tion of neurologic sequelae in affected children with early diagnosis and treatment.1
Long term management for IVA, MMA and PA 11

The goal of treatment is to reduce the production of isovaleric, methylmalonic anc propionic acid by means of:
...PROPIONIC ACIDEMIC [PA]
Diet
Patients with IVA, MMA and PA should be maintained on a low protein diet (about 1-1.5 g/kg/day). To im-
prove the quality of this diet, it may be supplemented with a relatively small amount of synthetic amino acids
free from the precursor amino acids( ie formula free of methionine, threonin, valine and isoleucine for MMA
and PA).
The diet must be nutritionally complete with adequate energy intake and sufficient vitamins and minerals. In
children with severe forms of MMA and PA, anorexia and feeding problems can be addressed by nasogastric
tube or gastrostomy tube placement.
Vitamin therapy
Every patient with MMA should be tested for responsiveness to vitamin B12. Parenteral hydroxocobalamin at
1000-2000 ug/day should be tried for about 10 days during a stable metabolic condition. During this period, a
24 hour urine samples must be collected for urine oganic acid analysis. Vitamin B12 responsiveness leads to a
prompt and sustained decrease of propionyl CoA by products or a drop in the urinary MMA level by more than
50%.
Most B12 responsive patients need only mild protein restriction or none at all. Vitamin B12 is given orally or
once per day or is administred once a week (1000-2000 ug IM).
Carnitine/glycine therapy
For MMA and PA, chronic oral administration of L carnitine at 100 mg/kg/day is effective in not only preventing
carnitine depletion but also in allowing urinary propionylcarnitine excretion, thus reducing propionate toxicity.
For IVA, supplemental therapy with L-carnitine 50-100 mg/kgor glycine at 150-300 mg/kg/day can be used.
Metronidazole therapy
For MMA and PA, microbial propionate production can be suppressed by antibiotics. Metronidazole, an antini-
otic that inhibits anaerobic colonic flora has been found to be specifically effective in reducing urinary excre-
tion of propionate metabolites by 405 in MMA and PA patients. A dose of 10-20 mg/kg/day for ten consecu-
tive days each month may be of significant benefit.
Growth hormone
There is a place for recombinant human GH treatment as an adjuvant therapy in patients with MMA and PA,
mainly in those with reduced linear growth.
Biochemical Monitoring
During the course of decompensation plasma ammonia, blood gases, lactate, glucose, uric acid and ketones
should bemonitored. Regular amino acid analysis is important. For MMA, levels of MMA in the plasma or
urine should be controlled . The measurement of carnitine/acylcarnitine in blood may also be useful.
Emergency Protocol for Propionic Aciduria/Methymalonic Aciduria


2. Bring formula ( if known patient with MMA/PA)
3. Bring carnitine, vitamin B12 (if known patient with MMA/PA)

5. *Prepare IV carnitine (100 mg/kg/day)
6. Collect blood for CBC, electrolytes, blood gas, lactate, glucose plasma methylmalonate (for MMA),
plasma carnitine profile and ammonia**. Collect urine for urine organic acid c screening. Check for
urine ketones. Other examinations as required.
7. Contact the Metabolic Physician once patient arrives at ER
—————
** Collect in green top tube. Must be on ice. Transport to lab immediately
Principles of Management:
∴ 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.
∴ Cease natural protein
∴ Intralipid at 2g/kg/day.
∴ The patient may also have an enteral sick day regimen, which can be administered continuously via a
nasogastric feeding tube.
Specific therapy
∴ IV Carnitine 100 mg/kg/day (Dilute to suitable volume with NS or G5W and infuse over 1 hour)
∴ Hydroxocobalamin 1mg/ IM ( for B12 responsive MMA only)
∴ Treat underlying cause. Treat infection, dehydration, electrolyte imbalance and acidosis
∴ Consider hemodialysis if with acute deterioration of cerebral function or if with intractable metabolic aci-
dosis/hyperammonemia.
Also consider the following

∴ Check for amylase and lipase if suspecting pancreatitis. Be alert for signs and symptoms of cardiomyopa-
thy
∴ If the patient has hyperammonemia, may give Sodium benzoate.
References
1
2
Fingerhut R and Olgemöller B. Newborn screening for inborn errors of metabolism and endocrinopathies: an update. Anal Bioanal Chem. 2009;
393:1481-1497
3
Vockley J and Ensenauer R. Isovaleric academia: new aspects of genetic and phenotypic heterogeneity. Am J Med Genet C Semin Med Genet
2006;142C(2):95-103.
4
Gurnert SC, Wendel U, Linder M et al. Clinical and neurocognitive outcome in symptomatic isovaleric academia. Orphanet J Rar Dis 2012;7:9
5
Chapter 3: Methylmalonic Acidemia. Nyhan WL, Barshop BA and Ozand P. Atlas of Metabolic Diseases 2nd ed. Great Britain:Oxford University Press,
2005 pp 18-26.
6
http://www.e-imd.org/rc/e-imd/htm/Article/2011/e-imd-20110728-195831-072/src/htm_fullText/fr/MethylmalonicAciduria.pdf Accessed Feb 25,
2012.
7
Cheng KH, Lie MY, Kao CH et al. Newborn screening for methylmalonic aciduria by tandem mass spectrometry: 7 years’ experience from two centers in
Taiwan. J Chin Med Assoc 2010;73(6)314-319.
8
Chapman KA and Summar ML. Propionic academia consensus conference summary. Mol Gen Metab 2011 article in press.
9
Chapter 2: Propionic academia. Nyhan WL, Barshop BA and Ozand P. Atlas of Metabolic Diseases 2nd ed. Great Britain:Oxford University Press, 2005 pp
8-15.
10
Pena L, Franks J, Chapman KA et al. Natural history of propionic academia. Mol Gen Metab 2011: article under press
11 Wendel U, de Baulny O. Branched chain organic acidurias/acidemias. Inborn Metabolic Diseases Chapter 19 4th edition eds Fernandes, Saudubray, van
den Berghe, Walter pp 254-255

ENDOCRINE DISORDER
CONGENITAL ADRENAL HYPERPLASIA [CAH]
CAH is a group of autosomal recessive disorders characterized by impaired cortisol synthesis. The most com-
mon form of CAH is caused by mutations in CYP21A2, the gene encoding the adrenal steroid 21-hydroxylase
enzyme (P450c21) that accounts for approximately 95%of CAH.
A cardinal feature of classic or severe virilizing CAH in newborn females is genital ambiguity. About 75% of
classic CAH patients have aldosterone deficiency manifesting with salt wasting, failure to thrive, and potentially
fatal hypovolemia and shock. Mild non-classic forms of CAH patients show variable degrees of postnatal andro-
gen excess and may be asymptomatic.
Fig 1. Steroid Biosynthetic Pathway

Source: Speizer, PW et al. Congenital Adrenal Hyperplasia due to Steroid 21 Hydroxylase Deficiency: An Endocrine Society Clinical
Practice Guideline. JCEM 95:4133-4160, 2010.
Newborn Screening
The screening method in the Philippines uses blood spot 17OHP levels by immunoassay. Figure 1 illustrates the
steroidogenic pathway to demonstrate that plasma 17-OHP will elevate in CAH due to 21-hydroxylase defi-
ciency (P450c21).
Results of NBS for CAH

The Attending Physician (AP) and NBS coordinator (NSF) should recall the baby within 24 hours notification of a
positive CAH screen from the NSC long-term follow-up nurse.
Recommended Confirmatory Tests for CAH

Serum 17-OHP (RIA) in accredited laboratories only
Ancillary tests:
Serum sodium and potassium
Random blood glucose

ENDOCRINE DISORDER
...CONGENITAL ADRENAL HYPERPLASIA [CAH]
Chromosomal Analysis for those with ambiguous genitalia
Pelvic Ultrasound for those with ambiguous genitalia
Recommended Monitoring Schedule and tests

(See appendix: Summary of Clinical and Biochemical Monitoring in CAH)
17-OHP
Serum sodium and potassium
Plasma rennin (if available)
Recommended Treatment for CAH
A. Medical
Acute adrenal crisis: Admit to pediatric intensive care setting (PICU or NICU) and co-manage with a pediatric
endocrinologist.
1. Collect blood for confirmatory tests

2. Assess hydration and give IVF accordingly (D5 Normal Saline).
3. Monitor BP, blood glucose, plasma sodium, potassium and chloride.
4. Start IV stress dose of hydrocortisone.
Neonates and infants 25 mg every 6 hours
Children 50 mg every 6 hours
If not in adrenal crisis, start oral medications as follows:

Hydrocortisone 10-15 mg/BSA in 2-3 divided doses
Fludrocortisone 0.05- 0.1mg/day
NaCl tablet: 1-2 gms/day (up to 4 gms/day)
B. Surgical consultation is recommended for babies with ambiguous genitalia.
C. Psychological support is recommended for affected patients and their families.
Duties of the Medical Persons Involved
Attending Physician or Pediatrician
This doctor is in charge of the over-all care of the patient. He is responsible for the confirmation of CAH. He
coordinates with the Pediatric endocrinologist, to ensure optimal care of the patient’s CAH.
During the first patient visit (clinic or home visit), he should take the anthropometric measurements (weight,
length, head circumference) and plot these on the WHO growth charts. It is important for him to assess if pa-
tient is in acute adrenal crisis (dehydrated, failing to thrive, hypotensive, low blood sugar, weak looking). If in
acute crisis, admit and manage the immediate medical needs of the patient and refer to pediatric endocrinolo-
ENDOCRINE DISORDER
gist for co-management.
He should also obtain a complete history and PE. If there is any deviation from normal parameters of growth
and development, further evaluation is warranted. All data should be recorded in the patient’s chart.
Once the patient is stable, he schedules subsequent clinic or home visits as recommended below:
0-6 months: monthly
7-12 months: every 2 months
after 3 years old: every 4-6 months
It is the responsibility of the AP to make the necessary referrals to the pediatric endocrinologist and other spe-
cialists.
Pediatric Endocrinologist
Oversees the comprehensive management (further diagnostics and prescriptions) of any patient referred for
CAH. Interprets the confirmatory test results and makes the recommendations for treatment.
Should evaluate the patient’s physical and biochemical parameters at the onset (diagnosis), and as follows:
0 -12 months: Every 3 months
13 months and onwards: Every 4-6 months
Treatment of CAH (Algorithm)

Confirmed CAH
Start Hydrocortisone and Fludrocorti-
Clinical Parameters* Laboratory Parameters

Length or Height
Serum 17-OHP, Na, K (q3-4 months for 1
Weight
year; every 6 months thereafter)
Blood Pressure
Pigmentation of areola, armpit, inguinal Bone age: every 2-3 years
regions
External Genitalia
*stunting, inappropriate weight

changes
Hypertension Monitor patient
Progressive Pigmentation Review dose
Progressive virilization Check compliance
Cushingoid features Counseling
Low back pains
Fig 2. Treatment Algorithm in CAH

ENDOCRINE DISORDER
Appendix
Table 1. Clinical and Biochemical Monitoring in CAH
Clinical evaluation
Laboratory evaluation Other Referrals
Attending Physician/ Specialist
Pediatrician
Baseline within one month of age Endocrinologist: Baseline: At Diagnosis
Weight Co-management from confir- 17-OHP (for patients with am-
Length mation of CAH RBS, Na, K biguous genitalia):
Head Circumference Cortisol
Include phallus length, signs of PRA ** Genetic counseling, sur-
early puberty, rapid physical Chromosomes if with gical evaluation and psy-
growth ambiguous genitalia chological support
During Clinic Visits Endocrinologist: Once 17OHP is within
At Puberty
Plot anthropometrics on WHO 0-12 months normal range, every 3
Psychological support
growth charts Every 3 months for titration months; (17OHP, Na, K)
Developmental screening * of medications
Check hyper-pigmentation of Optional, cortisol and
areola, armpits, inguinal 13 months onwards PRA
area, labio-scrotal folds Every 4-6 months
Genital exam Other labs as per medical
specialist
Females ≥ 8 years Appropriate clinical and lab Bone age at 12months
Note for onset of menses; evaluation and yearly thereafter
Tanner staging
Males ≥ 9 years Gender Identity issues and
Monitor pubertal development concerns can be addressed/
Tanner staging referral to appropriate spe-
cialist if needed.
References
1. Speizer PW., Azziz R., Baskin LS., et al. Congenital Adrenal Hyperplasia due to Steroid 21 Hydroxylase Deficiency: An Endocrine Society Clinical Practice
Guideline. JCEM 95:4133-4160, 2010.
2. Philippine Society of Pediatric Metabolism and Endocrinology (PSPME)’s Guidelines for the Management of Congenital Adrenal Hyperplasia drafted
Nov 6, 2013 (unpublished).

ENDOCRINE DISORDER
CONGENITAL HYPOTHYROIDISM [CH]
Congenital Hypothyroidism (CH) occurs in1:3500-1:4000 screened newborns. The mental deficiency and poor
physical growth in untreated CH are well recognized and this is precisely why newborn screening has been
adopted to identify babies at risk for CH and to facilitate treatment before 2 weeks in order to prevent undesir-
able consequences.
One parameter of a successful newborn screening program for CH is the mental outcome and functionality of
the babies identified and treated. Hence, these recommendations were drafted as guidelines to help general
practitioners ensure the comprehensive and optimal management of patients with CH.
Newborn Screening
In the Philippines, primary TSH detection is the screening method.
Newborn screening is best done on the 48th to 72nd hour. Before 48 hours, there is a risk of a falsely positive
NBS due to the physiologic TSH surge.
For premature babies, newborn screening should be done on day 7 of life or earlier if blood transfusion or ex-
change transfusion will be done.
For term babies who require blood transfusion or exchange transfusion, newborn screening should be done
before the procedure.
Proper documentation of newborn screening and transport of the dried blood spot to the Newborn Screening
Center (NSC) should be followed according to instructions in the National NBS Manual of Operations.
Results of NBS for CH

The Attending Physician (AP) and NBS coordinator (at the NSF) should recall the baby within 24 hours notifica-
tion of a positive CH screen from the NSC long-term follow – up nurse.
Recommended confirmatory tests for CH:

Blood FT4 or T4, TSH (in accredited labs only )
Thyroid imaging: Tc 99 scan or ultrasound
X-ray (AP) of the left knee and ankle for bone aging (optional)
Recommended monitoring tests (biochemical parameters):

Blood FT4 (preferred) or T4 and TSH
Bone aging, if warranted
Recommended treatment:
L-thyroxine 10-15 mcg/kg/day
Dose adjustments needed for the very low birth weights and premature. Please call Pediatric Endocrinologist
Duties of the Medical Persons Involved
Attending Physician or Pediatrician
This doctor is in charge of the over-all care of the patient. He is responsible for the confirmation of CH.
He coordinates with the Pediatric endocrinologist, to ensure optimal care of the patient’s hypothyroidism. Dur-

ENDOCRINE DISORDER
...CONGENITAL HYPOTHYROIDISM [CH]
ing the first patient visit (clinic or home visit), he should take the anthropometric measurements (weight,
length, head circumference) and plot these on the WHO growth charts. He should measure the length and
width anterior fontanel. He should also obtain a complete history and PE. Any deviation deserves further
evaluation.
All data should be recorded in the patient’s chart.
He schedules subsequent clinic or home visits as recommended below:
0-6 months: monthly
after 3 years old: every 6 months
It is the responsibility of the AP to make the necessary referrals to the pediatric endocrinologist and other spe-
cialists.
Pediatric Endocrinologist
Oversees the comprehensive management (further diagnostics and prescriptions to include hearing evaluation
at pre-school age) of any patient referred for CH. Interprets the confirmatory thyroid function results and
makes the recommendations for treatment
Should evaluate the patient’s physical and biochemical parameters at the onset or diagnosis (before 2 weeks),
and as follows:
0 -12 months: Every 3-4 months
13-36 months: Every 6 months
36th month: Schedule re-evaluation of thyroid status.
Yearly thereafter if permanent hypothyroidism is confirmed.
Treatment (decision algorithms)

ENDOCRINE DISORDER
...CONGENITAL HYPOTHYROIDISM [CH]
A. Normal FT4 and Normal TSH:
No CH, No treatment
B. Normal FT4 and High TSH:
No treatment; Repeat FT4 and TSH after 2 weeks; correlate with clinical findings
If repeat TSH elevated > 10 mU/L, treat with L-thyroxine; evaluation of thyroid function recom-
mended at 3 years of age.
If repeat TSH 6-10 mU/L, consult with Pediatric Endocrinologist.
(Reference TSH at 2-6 weeks of age is 1.7-9.1 mU/L as per D. Fisher in Sperling, 2002)
C. Low FT4 and High TSH:
Primary CH confirmed. Treat with L-thyroxine
D. Low FT4 and Normal TSH:
Treat with L-thyroxine.
Preterm baby and very sick neonates may also have this picture. The decision to treat will need a more exten-
sive evaluation by the pediatric endocrinologist.
E. Low FT4 and delayed elevation in TSH: Please work with a Pediatric Endocrinologist.
F. Transient elevation in TSH: Treat if clinically indicated. Pediatric endocrinology consult recommended.
Appendix
List of Accredited labs for confirmatory FT4 and TSH (c/o DOH/NSRC)
Clinical Clues to CH.
1. Neonate: Mottled, dry skin, lethargy, poor cry, prolonged jaundice, umbilical hernia, constipation,
hypothermia
2. Infant: Macroglossia, prominent forehead, posterior fontanel still open beyond 6 weeks, consti-
pation, feeding difficulties, hoarse cry, developmental delay, delayed tooth eruption, subopti-
mal linear growth
3. Child: short stature, constipation, pseudo-muscular hypertrophy, dry skin, coarse hair, edematous
References
1. Liz Smith. “Updated AAP Guidelines on Newborn Screening and Therapy for Congenital Hypothyroidism” Am Fam Physician 2007 Aug 1; 76 (3) 439-
444.
2. Balhara B, et al. “Clinical Monitoring Guidelines for Congenital Hypothyroidism: Laboratory Outcome Data in the First Year of Life”. J Pediatr 2011;
158:532-7.
3. Philippine Society of Pediatric Metabolism and Endocrinology (PSPME) ’s Guidelines for the Management of CH created Nov 6, 2012 (unpublished).
4. Australasian Pediatric Endocrine Group: Guidelines for Management of Congenital Hypothyroidism from www.apeg.org.au/
PositionStatementManagementGuideline/tabid/87/Default.aspx Downloaded April 15, 2013

CYSTIC FIBROSIS (CF)
Cystic Fibrosis is an inherited condition caused by build-up of sticky and thick mucus that can damage the
body’s organs. It occurs when a particular cell protein called “cystic fibrosis transmembrane conductance regu-
lator” (CFTR) is either missing or not working well.
Incidence
Occurs in 1:2,500-3,000 Caucasian newborns
CF is variable and causes minimal effects in some people and more serious health problems in others. Symp-
toms usually start in early childhood. In fact, most children with CF show effects before one year of age. There
are some people who do not find out they have CF until adulthood.
The first things parents often notice when a child has CF are:
Salty sweat; many parents notice a salty taste when kissing their child
Poor weight gain and growth, even when a baby or child eats a lot. This is sometimes called ‘failure to
thrive (FTT)’
Constant coughing or wheezing
Thick mucus and phlegm
Many lung and sinus infections (pneumonias and bronchitis)
Greasy, smelly stools that are bulky and pale colored

Intestinal problems (diarrhea or constipation, pain, gas)
Polyps in the nose
About 15-20% of newborns with CF have a blockage of their intestines called meconium ileus. This is caused by
thick stool that gets stuck in the intestines.
About 15% of children with CF have lung effects but do not have problems with digestion. About 85% of chil-
dren have problems with both lungs and digestion. There are also some people who have been diagnosed with
CF because of genetic test results, but who have very few symptoms of CF.
Over time, people with CF can have chronic health issues such as:
Repeated bouts of bronchitis or pneumonias leading to permanent lung damage
Collapsed lung, bleeding from the lungs, or lung failure
Poor growth and poor weight gain due to malnutrition
Chronic diarrhea

ENDOCRINE DISORDER
...CYSTIC FIBROSIS (CF)
Fatigue and anemia
Males are usually sterile due to blocked or absent vas deferens (the tubes carrying the sperm from the tes-
tes to the penis). There are now techniques which allow some men with CF to father their own chil-
dren.
A small number of people with CF develop high blood sugar and may need insulin
therapy
Some people with CF have bouts of pancreatitis, a painful inflammation of the pancreas
Some people with CF develop liver disease over time
Bone thinning, which can lead to osteoporosis, is seen in some people with CF
Lung infection or permanent damage to the lungs is the main cause of death in people with CF
Pathophysiology
Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene provides instructions for making a
channel that transports chloride ions into and out of the cells. Mutations in CFTR cause disruptions in
the flow of chloride ions and water across cell membranes. Cells that line passageways of lungs, pan-
creas, etc produce unusually sticky and thick mucus.
Inheritance
Autosomal recessive
Screening
Increase in Immunoreactive trypsinogen (IRT) on MSMS
Sweat chloride test (greater than 60 mEq/L)
Transepithelial nasal potential difference (NPD) - absence of functional CFTR at the apical surface with re-
sultant alterations in chloride efflux and sodium transport produces an abnormal electrical potential
difference across epithelial surfaces
Ideally, mutation testing
Prognosis

If treated appropriately, CF does not affect intelligence or the ability to learn. People with CF can attend
regular school and should be able to achieve the same level of education as people who do not have
CF. If left untreated, CF can cause serious chronic health effects that could lead to early death. Many
of the symptoms of CF can be controlled with proper medication and treatment.
Long-Term Management
The main goal of treatment is to keep the lungs clear of thick mucus and to provide with the correct
amount of calories and nutrients to keep the patient healthy. Certain treatments may be advised for
some children but not others. When necessary, treatment is usually needed throughout life.
Respiratory – antibiotics, bronchodilators, mucolytics, chest physiotherapy, steroids, heart/lung transplan-
tation
Gastrointestinal – nutritional therapy, oral pancreatic enzymes
Prevention of complications – biliary sludging, diabetes, exercise, immunization, chronic airway infection
Diet
Vitamin supplements: People with CF have trouble absorbing some vitamins, especially fat-soluble vita-
mins such as vitamin A, D, E and K. Specific supplements may be suggested.
A higher-calorie diet: Many babies and children with CF need more food than typical in order to stay
healthy. Some children with CF need up to twice the normal number of calories to grow appropriately.
A dietitian who has experience with CF can help come up with a good nutrition plan for the patient.
Extra fluid: The patient may need to drink more water and liquids in order to help loosen the thick mucus
and to prevent dehydration. Children with CF lose more salt than others, especially during exercise or
in hot weather.
Other important considerations
Have the child vaccinated according to the regular childhood schedule. Children with CF need all the usual
childhood vaccinations. It is especially important to have a measles vaccine. In addition, the primary
physician may suggest that the child have vaccinations against influenza and pneumonia on a yearly
basis. Children with CF should also be protected against RSV, a respiratory illness that can be severe,
and sometimes life-threatening, in children with chronic lung disease.
Keep the child away from all forms of smoke, especially cigarette smoke. It can add to lung damage.
Teach good hand washing habits to prevent infection.
If the child has a respiratory infection and is too sick to eat or follow regular health habits, call your doctor
right away. During some illnesses, your child may need to be seen in the hospital for treatment.
ENDOCRINE DISORDER
Encourage your child to get plenty of exercise. This will help maintain your child’s lung function and im-
prove overall health.
References:
Chiong, MAD. (2013). Cystic Fibrosis [powerpoint presentation]. Retrieved from lecture notes during Orientation-Workshop on Hemoglobinopathies.
http://newbornscreening.info/Parents/otherdisorders/CF.htm. Accessed on 7 November 2014.


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Newborn Screening

NEWBORN SCREENING REFERENCE CENTER 1

Maple Syrup Urine Disease 5

UREA CYCLE DEFECT

FATTY ACID DISORDER

Carnitine Uptake Defect 19

Medium Chain Acyl—CoA Dehydrogenase Deficiency 20

Long Chain Acyl—CoA Dehydrogenase Deficiency 22

Very Long Chain Acyl—CoA Dehydrogenase Deficiency 25

Tri Functional Protein Deficiency 28

ORGANIC ACID DISORDER

3-Methylcrotonyl CoA Carboxylase Deficiency 30

Glutaric Aciduria Type 1 34

Multiple Carboxylase Deficiency 39

Congenital Adrenal Hyperplasia 44

Long Term Management 8,9,10

NEWBORN SCREENING REFERENCE CENTER 3

Monitoring of plasma homocysteine and methionine levels

NEWBORN SCREENING REFERENCE CENTER 4

Long term Management 4

NEWBORN SCREENING REFERENCE CENTER 5

Treatment of intercurrent decompensations

Emergency Protocol for Maple Syrup Urine Disease

1. Avoid delay and bring the child to the hospital at once

NEWBORN SCREENING REFERENCE CENTER 7

NEWBORN SCREENING REFERENCE CENTER 8

Tetrahydrobiopterin BH4 Oral Loading Test

Time Procedure Result

NEWBORN SCREENING REFERENCE CENTER 9

In older children, adolescents and adults

Monitoring of phenylalanine levels and growth and development

Defects of Biopterin Metabolism (i.e. 6 Pyruvoyltetrahydrobiopterin synthase deficiency)6

NEWBORN SCREENING REFERENCE CENTER 10

NEWBORN SCREENING REFERENCE CENTER 11

NEWBORN SCREENING REFERENCE CENTER 12

NEWBORN SCREENING REFERENCE CENTER 13

NEWBORN SCREENING REFERENCE CENTER 14

Long Term Management 4,7

NEWBORN SCREENING REFERENCE CENTER 15

Alternative pathways for nitrogen excretion

Replacement of deficient nutrients

NEWBORN SCREENING REFERENCE CENTER 16

EMERGENCY MANAGEMENT OF INTERCURRENT HYPERAMMONEMIA IN PATIENTS WITH

Early Diagnosis and Therapy

NEWBORN SCREENING REFERENCE CENTER 17

NEWBORN SCREENING REFERENCE CENTER 18

Long term management 4

NEWBORN SCREENING REFERENCE CENTER 19

Long term management 5

NEWBORN SCREENING REFERENCE CENTER 20

Dietary fat restriction is not routine in patients with MCAD deficiency.

Emergency management of patients with MCAD deficiency 5

NEWBORN SCREENING REFERENCE CENTER 21

Long term management 2,5,6,7

NEWBORN SCREENING REFERENCE CENTER 22

Avoid prolonged exercise

NEWBORN SCREENING REFERENCE CENTER 23

NEWBORN SCREENING REFERENCE CENTER 24