PEDIATRICS

TOPIC 06.2: INBORN ERROR OF METABOLISM

Dr. Ailyn Agdeppa
October 1, 2019

OUTLINE OF THE TOPIC

I. APPROACH TO INBORN ERROR OF METABLISM
II. NEONATAL PERIOD
III. LABORATORY STUDIES
IV. CHILDREN AFTER NEEONATAL PERIOD
V. NEWBORN SCREENING
VI. METABOLIC DISORDERS

**Note: According to Doc Agdeppa the quiz and exam will be taken
from her slides ONLY.

INBORN ERROR OF METABOLISM

An approach to Inborn Errors of Metabolism
● Many childhood conditions are caused by gene mutations that encode
specific proteins.
• These mutations can result in the alteration of primary protein structure
or the amount of protein synthesized.
• The functional ability of protein, whether it is an enzyme, receptor,
transport vehicle, membrane, or structural element, may be relatively or
seriously compromised.
• These hereditary biochemical disorders are collectively termed
inborn errors of metabolism.
• Some mutations produce disease states that range from very mild
to lethal.
● Severe forms of inborn error of metabolism usually present in the
**Familiarize this table above.
newborn period or shortly thereafter
● It is both technologically and economically possible to screen for a large
INBORN ERROR OF METABOLISM URINE ODOR
number of metabolic conditions in the 1st few days of life, before any
clinical manifestations of the disease become apparent Glutaric academia (type II) Sweet feet, acrid
● Children w/ IEM may present w/ one or more of large variety of signs and Hawkinsinuria Swimming pool
symptoms. Isovaleric acidemia Sweet feet, acrid
● These may include metabolic acidosis, persistent vomiting, failure Maple syrup urine disease Maple syrup
to thrive, developmental delay, hypoglycemia, elevated blood or Hypermethioninemia Boiled cabbage
urinary levels, of a particular metabolite (an amino acid, organic Multiple carboxylase deficiency Tomcat urine
acid, ammonia), a peculiar odor (Table84.3), or physical changes
Oasthouse urine disease Hops-like
such as hepatomegaly).
Phenylketonuria Mousey or musty
Trimethylaminuria Rotting fish
Tyrosinemia Boiled cabbage, rancid butter

NEONATAL PERIOD
● Inborn errors of metabolism causing clinical manifestations in the
neonatal period are usually severe and are often lethal if proper therapy
is not initiated promptly. Clinical findings are usually nonspecific and
similar to those seen in infants with sepsis. An inborn error of metabolism
should be considered in the differential diagnosis of a severely ill neonatal
infant, and special studies should be undertaken if the index of suspicion
is high.
● Infant with metabolic disorders are usually normal at birth, sign and
symptoms such as lethargy, poor feeding, convulsions, and vomiting may
develop as early as a few hours after birth.
● A history of clinical deterioration in a previously normal neonate should
suggest an inborn error of metabolism.
● Lethargy, poor feeding, convulsions, and coma may also be seen in
infants with hypoglycemia or hypocalcemia.
● Measurements of blood concentrations of glucose and calcium
and response to intravenous injection of glucose or calcium

“Don’t pray for an easy life. Pray for the strength to endure difficult one”. -Bruce Lee
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 PEDIATRICS
usually establish these diagnoses. o Bilirubin level, transaminases levels, prothrombin time, and
activated partial thromboplastin time to evaluate hepatic function.
● Because most inborn errors of metabolism are inherited as
autosomal recessive traits, a history of consanguinity and/or death SECONDARY STUDIES
in the neonatal period should increase suspicion of this diagnosis. ● If initial tests results are outside the reference range, consider
● Some of these disorders have a high incidence in specific consultation with an IEM specialist to determine which test are
population groups. appropriate, how specimens are to be collected and stored, and where
● Tyrosinemia type 1 is more common among French-Canadians of they should be sent.
Quebec than in the general population. o Plasma quantitative amino acids and acylcarnitines (1-2 mL in
ethylenediaminetetraacetic acid [EDTA] or heparin tube, on ice).
● Therefore, knowledge of the ethnic background of the patient may
o Urine organic acids, acylglycine, and/or orotic acid (5-10 mL, freeze
be helpful in diagnosis immediately)
● Physical examination usually reveals nonspecific findings, with o Serum lactate and pyruvate levels (these may be helpful but are
most signs related to the central nervous system often difficult to interpret in the critically ill child because of multiple
● Hepatomegaly is a common finding in a variety of inborn errors of factors that may contribute to lactic acidosis).
metabolism o Cerebrospinal fluid (CSF) lactate, pyruvate, organic acids,
● Occasionally, a peculiar odor may offer an invaluable aid neurotransmitters, and/or disease-specific metabolites collected at
the same time as plasma (1-2 mL).
to the diagnosis
o EEG, nerve conduction studies, evoked potential studies, and/or
● A physician caring for a sick infant should smell the patient and electromyelography may be valuable but are rarely indicated in the
his or her excretions; for example, patients with maple syrup urine emergency department.
diseases have the unmistakable odor of maple syrup in their urine ● When blood ammonia, pH, and bicarbonate values are normal, other
and on their bodies. aminoacidopathies (such as hyperglycemia) or galactosemia should be
considered; galactosemic infants may also manifest cataracts,
LABORATORY STUDIES hepatomegaly, ascites, and jaundice.
● Most inborn errors of metabolism presenting in the neonatal period are
EMERGENT EVALUATION
lethal if specific treatment is not initiated immediately.
● Make sure every effort to collect specimens for definitive diagnosis while
the child is acutely ill (particularly samples for biochemical analysis, since o Specific diagnosis, even in an infant in whom death seems
biochemical abnormalities may be transient). inevitable, is of great importance for genetic counselling of the
● Laboratory abnormalities can be transient; therefore values within the family.
reference range do not rule out an inborn error or metabolism (IEM). o Every effort should be made to determine the diagnosis while the
● Studies may need to be repeated during other episodes of illness. infant is alive; post-mortem examination is not always helpful.
● Most IEMs with acute life-threatening presentation can be categorized o A specific diagnosis may be established by measurement of
based on findings of initial laboratory evaluations with the presence of at abnormal metabolites in body fluids, by assay of the specific
least 1 of the following (see table 1 below): enzyme activity, or by identification of the mutant gene.
● METABOLIC ACIDOSIS:
▪ Metabolic acidosis usually with elevated anion gap occurs with
many IEMs and is a hallmark or organic acidemias.
● HYPOGLYCEMIA:
▪ A prospective study revealed that in the ED, hypoglycemia
(plasma glucose level <50 mg/dL) is rare in children (0.44% of
those tested), even during periods of poor enteral intake in a
study of 40 children with hypoglycemia, 32 had a metabolic
workup performed on initial samples, and 28% of those had a
previously undiagnosed fatty acid oxidation defect or endocrine
disorder.
● HYPERAMMONEMIA:
▪ Early manifestations include anorexia, abdominal pain,
headache, irritability, fatigue, late tachypnea, vomiting, lethargy,
seizures, coma, and death. Ammonia level greater than 100
mcg/dL in the neonate and greater than 60 mcg/dL beyond in the
neonatal period is considered elevated. Ammonia is highest in
the urine cycle defects often exceeding 1000 mcg/dL and
causing primary respiratory alkalosis sometimes with
compensatory metabolic acidosis. Ammonia in organic
acidemias, if elevated, rarely exceeds 500 mcg/dL and in fatty
acid oxidation defects are usually less than 250 mcg/dL.
INITIAL LABORATORY EVALUATION
● Obtain the following tests:
o Complete blood count (CBC) to screen for neutropenia, anemia
and thrombocytopenia.
o Serum electrolytes, bicarbonate, and blood gases levels to detect
electrolyte imbalance and to evaluate anion gap (usually elevated)
and acid/base status.
o Blood urea nitrogen and creatinine levels to evaluate renal function. *Anion Gap = Sodium – (Chloride + Bicarbonate)
“Don’t pray for an easy life. Pray for the strength to endure difficult one”. -Bruce Lee
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CHILDREN AFTER NEONATAL PERIOD the heel-prick method but the laboratory testing methods applied
● Most inborn errors of metabolism that cause symptoms in the 1 st few days are different.
of life exhibit milder variant forms that have a more insidious onset. • What are the additional disorders tested by expanded
o These forms may escape detection during the neonatal period, and newborn screening?
the diagnosis may be delayed for months or even years. o Aside from six conditions in the present panel – Congenital
o Early clinical manifestations in children with these forms are hyperthyroidism, Congenital Adrenal Hyperplasia, Galactosemia,
commonly nonspecific and may be attributed to perinatal insults. phenylketonuria, Maple Syrup Urine Disease and Glucose-6-
• Clinical manifestations such as mental retardations, motor deficits, Phosphate Dehydrogenase Deficiency – expanded newborn
developmental regression, convulsions, myopathy, recurrent emesis, and screening will screen for additional disorders falling under various
cardiomyopathy are the common findings in older children groups of conditions namely: hemoglobinopathies, disorders of
amino acid and organic acid metabolism, disorders of fatty acid
• There may be an episodic or intermittent pattern, with episodes of acute
oxidation, disorders of carbohydrate metabolism, disorders of
clinical manifestations separated by periods of seemingly disease-free
biotin metabolism and cystic fibrosis.
states.
● How much is the fee for newborn screening?
• The episodes are usually triggered by stress or a nonspecific catabolic o Expanded newborn screening will be offered to you as an option
insult such as an infection. in all newborn screening facilities. The first option is screening for
• The child may die during one of these acute attacks. the six disorders at Php 550, which is included in the newborn care
• An inborn error of metabolism should be considered in any child with one package for PhilHealth members and the second option is
or more of the following manifestations: screening for the full complement of disorders at Php1500.
o Unexplained mental retardation, ● Is expanded screening covered by PhilHealth?
o Developmental delay or regression, or motor deficit or convulsions; o Currently, only P550 is covered by PhilHealth. If you are a
o Unusual odor, particularly during an acute illness; PhilHealth member, and opt to have your baby undergo expanded
o Intermittent episodes of unexplained vomiting, acidosis, mental newborn screening, you will pay the remaining cost which is P950.
deterioration, or coma ● Where is newborn screening available?
o Hepatomegaly; o Newborn screening is available in Hospitals, Lying-ins, Rural
o Renal stones; Health Unit, Health Centers and some private clinics. If babies are
o Or muscle weakness delivered at home, babies may be brought to the nearest institution
o Or cardiomyopathy offering newborn screening.
• When are newborn screening results available?
BASIC INFORMATION ABOUT NEWBORN SCREENING o Results can be claimed from the health facility where NBS was
● What is newborn screening? availed. Normal NBS results are available by 7-14 working days
o Newborn screening (NBS) is a simple procedure to find out if your from the time samples are received at the NSC.
baby has a congenital metabolic disorder that may lead to mental o Positive NBS results are relayed to the parents immediately by the
retardation or even death if left untreated health facility. Please ensure that the address and phone number
• Why is it important to have newborn screening? you will provide to the health facility are correct.
o Most babies with metabolic disorders look “normal” at birth. By ● A NEGATIVE SCREEN MEANS THAT THE NBS RESULT IS NORMAL
doing NBS, metabolic disorders may be detected even before ● A positive screen means that the newborn must be brought back to
clinical signs and symptoms are present. And as a result of this, his/her health practitioner for further testing.
treatment can be given early to prevent consequences of untreated
● What should be done when a baby is tested a positive NBS result?
conditions.
o Babies with positive results must be referred at once to a specialist
• When is newborn screening done? for confirmatory testing and further management. Should there be
o Newborn screening is ideally done immediately after 24 hours from no specialist in the area, the NBS secretariat office will assist its
birth. attending physician.
• How is newborn screening done? FAMILIARIZE THIS TABLE.
o A few drops of blood are taken from the baby’s heel, blotted on a DISORDER EFFECT IF NOT EFFECT IF
special absorbent filter card and then sent to Newborn Screening
SCREENED SCRRENED AND
Center
TREATED
● Who will collect the sample for newborn screening?
o The blood sample for NBS may be collected b any of the following: CH (Congenital Severe growth and Normal
physician, nurse, medical technologist or trained midwife. Hypothyroidism) Mental Retardation
• What is expanded newborn screening? CAH (Congenital Death Alive and Normal
o The expanded newborn screening program will increase the Adrenal Hyperplasia)
screening panel of disorders from six (6) to twenty-eight (28). This GAL (Galactosemia) Death and Alive and Normal
will provide opportunities to significantly improve the quality of life Cataracts
of affected newborns through facilitating early diagnosis and early PKU Severe Mental Normal
treatment. (Phenylketonuria) Retardation
● What is the difference between newborn screening and expanded
G6PD Deficiency Severe Anemia Normal
newborn screening?
o The difference is the number of disorders each of them can detect. Kernicterus
Both tests are performed by collecting a few drops of blood through 9MSUD (Maple Syrup Death and Mental Alive and Normal
Urine Disease) Retardation

“Don’t pray for an easy life. Pray for the strength to endure difficult one”. -Bruce Lee
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EXPANDED NEWBRON SCREENING 3-METHYLCROTNYL CoA CARBOXYLASE DEFICIENCY (3-MCC)
● WHAT IS 3-MCC?
o The deficiency of 3-methylcrotonyl CoA carboxylase (3MCC) is a
disorder of leucine metabolism that was first described by Eldjarn
et al. in 1970
o In most instances, it has been found that neonates who test
positive for this condition in expanded newborn screening do not
actually have the condition but instead reflect the increased levels
of the metabolites of their mothers.
● CLINICAL MANIFESTATION
o 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.
o Some patients may have a late presentation (1-3 years old) with
an acute episode of Reye syndrome, massive ketosis, acidosis,
lethargy, come leading to a fatal outcome.
● PATHOPHYSIOLOGY
o 3-methylcrotonyl 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.
o Inheritance: autosomal recessive
● CONFIRMATORY TESTING
o An increase in 3-hydroxyisovaleric and 3- methylcrotonyl glycine
EXPANDED NEWBRON SCREENING PANEL are found in urine, confirmatory testing is done through the
demonstration of decreased enzyme activity in cultured fibroblasts
● OVERVIEW OF DISEASE MANAGEMENT
o Treatment strategies include the restriction of natural protein
intake and giving of carnitine supplementation (100mg/kg).
● PROGNOSIS
o 3-MCC is a common, mostly benign condition; whether treatment
with a low-protein diet, carnitine and glycine supplementation has
the potential to change the clinical course in several affected
patients remains to be elucidated.

BETA-KETOTHIOLASE DEFICIENCY
● WHAT IS BETA-KETOTHIOLASE DEFICIENCY?
o Beta ketothiolase deficiency is a defect of mitochondrial
acetoacetyl-CoA thiolase involving ketone body metabolism and
isoleucine catabolism.
● CLINICAL MANIFESTATION
o This rare disorder is characterized by normal early development
followed by progressive loss of mental and motor skills, it is
clinically characterized by intermittent ketoacidoacidotic episodes
with no clinical symptoms in between.
o Some patients may present with vomiting, hypotonia, lethargy,
coma, hyperventilation and dehydration.
o Ketoacidoacidotic crises may occur following a bout of infection or
mild illness.
● PATHOPHYSIOLOGY
o Mitochondrial acetoacetyl CoA thiolase is responsible for the
cleavage of 2-methylacetoacetyl CoA in isoleucine metabolism,
acetoacetyl CoA formation in ketogenesis and acetoacetyl CoA
cleavage in ketolysis.
o Inheritance: autosomal recessive
● CONFIRMATORY TESTING
o An increased excretion of 2-methyl 3- hydroxybutyric and 2-
methylacetoacetic acid in urine is observed but definitive
diagnosis is established by demonstrating decreased enzyme
ORGANIC ACID DISORDERS
activity in cultured fibroblasts.

“Don’t pray for an easy life. Pray for the strength to endure difficult one”. -Bruce Lee
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● OVERVIEW OF DISEASE MANAGEMENT
o Due to the heterogeneity in the severity of clinical presentation,
there should be individual treatment programs, general guidelines
for treatment include dietary isoleucine restriction and to avoid
fasting
● PROGNOSIS
o The frequency of ketoacidotic attacks decreases with age
o Clinical consequences can be avoided by early diagnosis and
appropriate management of ketoacidosis.
FATTY ACID DISORDERS
CARNITINE UPTAKE DEFECT (CUD)
● WHAT IS CUD?
o Carnitine uptake defects is also known as carnitine transporter
deficiency.
o In some instances, it is has been found that neonates who test
positive for this condition do not actually have the condition but
instead reflect the decreased levels of their mothers.
● CLINICAL MANIFESTATION
o Patients may present with hypoketotic hypoglycemia, modest
hepatomegaly and Reye-like syndrome, progressive heart failure
and muscle weakness.
o Most patients present with a progressive cardiomyopathy
associated with skeletal myopathy.
● PATHOPHYSIOLOGY
o Carnitine is necessary for transport of long-chain fatty acids into
mitochondria to enter the β- oxidation cycle.
o Genetic defects of the carnitine transport 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 carnitine cycle.
o Inheritance: autosomal recessive
● CONFIRMATORY TESTING
o Confirmation of the diagnosis can be made biochemically by
monitoring the uptake of carnitine by skin fibroblasts in culture.
● OVERVIEW OF DISEASE MANAGEMENT
o Oral carnitine therapy at 100mg/kg/day into four divided doses is
recommended.
● PROGNOSIS
o Patients on long term therapy report normal skeletal muscles tone,
no episodes of metabolic decompensation, and essentially normal
intellect
ENDOCRINE DISORDERS
CONGENITAL ADRENAL HYPERPLASIA
● WHAT IS CONGENITAL ADRENAL HYPERPLASIA (CAH)?
o Congenital Adrenal Hyperplasia (CAH) is a group of disorders
resulting from enzymatic defects in the biosynthesis of steroids.
o There are many enzymes involved in the synthesis of adrenal
hormones but in about 90% of CAH, it is due to 21-hydroxylase
deficiency.
o Others due to cholesterol desmolase 11β- hydroxylase deficiency,
17β-hydroxylase deficiency and 3β-hydroxysteroid
dehydrogenase.
o All forms of CAH are inherited in an autosomal recessive pattern.
o The Philippine NBS data as of December 2013 reports that 1 out
of 13 350 screened newborns have CAH.
● PATHOPHYSIOLOGY
o 21-Hydroxylase deficiency results in decreased cortisol and
aldosterone production which in turn causes increased
adrenocorticotropic hormone (ACTH) secretion.
“Don’t pray for an easy life. Pray for the strength to endure difficult one”. -Bruce Lee
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PEDIATRICS
o High ACTH levels result in hyperplasia of the adrenal cortex.
o The precursor steroids behind the block are diverted to the
androgen biosynthetic pathway, resulting in excess production of
androgens that causes virilization in females and precocious
puberty in males.
o The decrease in the production of aldosterone in CAH results in
salt and water imbalance.
● CLINICAL FEATURES
o Salt-wasting
o Simple virilizing
o Late onset
▪ Neonates with the salt-wasting (SW) form manifest adrenal
crisis in the first 2-4 weeks of life characterized as poor
feeding, vomiting, loose stools or diarrhea, weak cry, failure
to thrive, dehydration and lethargy.
▪ If untreated, the affected newborn will die in a severe salt-
losing crisis with hypoglycemia and hypotension.
▪ The baby who survives may have brain damage.
▪ Affected females usually present with ambiguous genitalia.
● DIAGNOSIS
o Newborn Screening for 21-hydroxylase deficiency is done by
measuring the 17-OHP level on dried blood spot.
o Infants with normal birth weight and a mild elevation of 17-OHP
undergo repeat dried blood spot collection.
o Infants with moderate to severe elevation of 17- OHP and those
who are low birth weight with mild elevation are referred to a
pediatric endocrinologist for evaluation.
● TREATMENT AND MONITORING
o The mainstay of treatment in CAH is glucocorticoid and
mineralocorticoid replacement therapy which corrects the cortisol
deficiency and reverses the abnormal hormonal patterns.
o Patients with deficiencies of mineralocorticoids require the
appropriate replacement hormones
▪ Glucocorticoid replacement must be increased during periods
of stress.
▪ The majority of female patients with prenatal virilization
require surgical repair.
▪ Regular endocrine clinic visits for monitoring of physical
growth and development as well as biochemical 17-OHP
and/or cortisol measurements are recommended for optimal
management.
▪ Genetic counseling is recommended
● PROGNOSIS
o Newborn screening makes early diagnosis and early treatment
possible.
o Early treatment to prevent adrenal crisis is lifesaving in cases of
salt wasting CAH.
o Early diagnosis prevents inappropriate sex assignment for
affected females of the simple virilizing (SV) form.
CONGENITAL HYPOTHYROIDISM
● WHAT IS CONGENITAL HYPOTHYROIDISM (CH)?
o Congenital hypothyroidism (CH) is one of the most common
preventable causes of mental retardation in children.
o According to the Philippine NBS data, (December 2013) 1 out of
2, 733 screened newborns has CH. The most common etiology of
CH is thyroid dysgenesis (TD): absent thyroid, ectopic or
hypoplastic thyroid.
o In rare cases, CH results form mutations in the genes that control
thyroid gland development, including thyroid transcription factor
(TTF-2) and paired box-8 protein (PAX-8).
o Rapid detection by newborn screening, prompt confirmatory
testing and Levothyroxine administration can prevent severe
mental retardation and impaired growth due to CH.
 PEDIATRICS
● PATHOPHYSIOLOGY ▪ The ablest should be crushed, mixed with a few milliliters of
o Normal thyroid hormone levels in the body are maintained by a water, and fed to the infant directly into the mouth
feedback mechanism involving the hypothalamus, pituitary and ▪ It is not recommended that Levothyroxine be mixed with
thyroid gland. soy formula or with formula containing iron, as these
o The hypothalamus senses low circulating levels of thyroid interfere with absorption of the medication.
hormone (T3 and T4) and responds by releasing thyrotropin o Thyroid hormone replacement and medical monitoring are
releasing hormone (TRH). required for life.
o TRH stimulates the anterior pituitary to produce thyroid stimulating o Children with congenital hypothyroidism should be monitored
hormone (TSH). clinically and biochemically.
o TSH, in turn, stimulates the thyroid gland to produce thyroid o Clinical parameters should include linear growth, weight gain,
hormone until levels in blood return to normal. head circumference, developmental progression, and overall well-
o Normal thyroid hormone levels exert a negative feedback to the being.
hypothalamus and the anterior pituitary, thus controlling the o Serum T4 or FT4 and TSH should be monitored at regular
release of both TRH from hypothalamus and TSH from anterior intervals.
pituitary gland.
● PROGNOSIS
o When the thyroid gland does not produce enough T4 and T3, the
o Early diagnosis and optimal treatment of congenital
pituitary gland compensates y producing high levels of TSH.
hypothyroidism prevents severe mental retardation, neurologic
o This biochemical profile of low T4 level and high TSH is a pattern
complications and physical delays.
consistent with Primary CH.
o Even with early treatment, some children may demonstrate mild
o Having the correct level of thyroid hormone in the body is
delays in areas such as reading comprehension and arithmetic.
important, especially in the first two years of life, because it
o Although continued improvement in IQ has been documented in
ensures normal growth and normal development of the brain,
treated patients through adolescence, some cognitive problems
bones and nervous system.
may persist.
● CLINICAL FEATURES ▪ These may include problems in visuospatial, language, and
Signs and Symptoms of hypothyroidism: fine motor function.
o Decreased activity ▪ Defects in memory and attention have been reported..
o Large anterior fontanelle
o Poor feeding FATTY ACID OXIDATION DISORDERS (FAOD)
o Poor weight gain
o Small stature or poor growth ● FAOD includes:
o Prolonged Jaundice o Medium chain acyl co-A dehydrogenase deficiency (MCAD)
o Decreased stooling or constipation o Very long acyl Co-A dehydrogenase deficiency (VLCAD)
o Hypotonia o Long chain hydroxyacyl co-A dehydrogenase deficiency (LHCAD)
o Hoarse cry or weak cry o Trifunctional protein deficiency (TFI).
o Developmental delay ● WHAT ARE FAOD?
Some physical signs of hypothyroidism that may or may not be present o FAOD are group of autosomal recessive disorders caused by the
at birth: deficiency or absence of any of the enzyme needed for beta-
o Coarse facial features oxidation.
o Macroglossia o Children born with this condition appear normal at birth but
o Large fontanelles intreated patients may present with low blood sugar which can
o Umbilical hernia lead to seizures, coma and death.
o Mottled, cool, and dry skin o One type of FAOD, VLCAD (or very long chain acyl-CoA
o Pallor dehydrogenase deficiency) may present with cardiomyopathy and
o Myxedema increased creatine kinase (CK) levels.
o Goiter
● TREATMENT OF FAOD
● DIAGNOSIS o Treatment is through the dietary restriction of fat, VLCAD patients
o Newborn screening for primary CH is done by determining the are treated with a special milk formula containing medium chain
thyroid stimulating hormone (TSH) level on a dried blood spot. triglycerides.
o If the TSH is significantly elevated, this signifies that the baby is at
risk for CH and therefore needs confirmatory thyroid tests. GALACTOSEMIA
o An elevated serum TSH and a low serum FT4 confirms
hypothyroidism. ● WHAT IS GALACTOSEMIA?
o Thyroid imaging (thyroid scan or ultrasound) is recommended to o Galactosemia is a rare genetic metabolic disorder that is inherited
document etiology of CH. in an autosomal recessive manner
o It is an inborn error of carbohydrate metabolism characterized by
● TREATMENT AND MONITORING elevated level of galactose and its metabolites due to enzyme
o Immediate diagnosis and treatment of congenital hypothyroidism deficiencies involved in its metabolism
in the neonatal period is critical to normal brain development and o Galactose is the sugar found mainly in milk and dairy products;
physical growth. produced by the body.
o Treatment started within the first two weeks of life usually prevents o Milk contains a sugar called lactose and during digestion, lactose
neurodevelopment delays. is broken down into sugars glucose and galactose.
o Recommended treatment is the lifetime daily administration of o Glucose can immediately be used as a source of energy by the
Levothyroxine. body, but galactose needs to be further broken down before it can
o Only the tablet form of Levothyroxine is currently approved for be utilized.
therapeutic use.
o Birth incidence of classic galactosemia: 1 per 47,000 in Caucasian
population
“Don’t pray for an easy life. Pray for the strength to endure difficult one”. -Bruce Lee
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 PEDIATRICS
o Philippine NBS data as of Dec 2013 prevalence of 1:33 645. o According to the Philippine NBS data Dec2013, 1 out of 55
screened newborns have G6PD deficiency
● PATHOPHYSIOLOGY
o G6PD-deficiency is an X-linked disorder found in both sexes but
o Children with galactosemia have very little or entirely lack an more males are affected. Female carriers are asymptomatic.
enzyme that helps the body break down galactose.
o There are three different enzyme problems that can lead to ● PATHOPHYSIOLOGY
galactosemia. o G6PD is an enzyme that is present in all cells, but is much valued
o In the first type or classic galactosemia, the enzyme that is in red blood cells (RBCs)
reduced or missing is called galactose-1-phosphate uridyl o G6PD is needed for the first step in Hexose Monophosphate
transferase (GALT). Pathway (HMP). The pathways produces the reduced
o The GALT enzyme enables body to break down galactose into nicotinamide adenine dinucleotide phosphate (NADPH) that
functions as an electron donor in maintaining glutathione in its
glucose reduced form (GSH).
o The second type of galactosemia is due to deficiency in uridine o GSH serves as antioxidant that protects cell against oxidative
diphosphate galactose 4-epimerase (GALE). Its severe type damage.
clinically resembles classic galactosemia.
o The third type, is due to a deficiency in galactokinase (GALK) o The HMP is the only source of NADPH in RBCs, thus the
and presents primarily as cataracts in untreated patients. deleterious effect of G6PD deficiency in RBCs exposed to
oxidative stress
● CLINICAL FEATURES o Such oxidative stress is brought about by food products, drugs,
o Patients can present with feeding problems, failure to thrive, chemical compounds, and infection.
hepatocellular damage, bleeding and sepsis in untreated infants. o A short list of these agents is available on the succeeding slide.
o In approximately 10% of individuals, cataracts are present.
o Failure to thrive is the most common initial clinical symptom of
classic galactosemia
o Vomiting or diarrhea usually begins within few days of milk
ingestion
o Jaundice of intrinsic liver disease may be accentuated by the
severe hemolysis occurring in some patients
o Cataracts have been observed within few days of birth
o There appears to be high frequency of neonatal deaths due to
E.coli sepsis in patient with classic galactosemia
o The association of jaundice and hemorrhagic diathesis in the first
2 weeks of life is clinical presentation in which galactosemia must
be considered.
o Coagulopathy may also be present in galactosemia with little
evidence of liver disease
o Galactosemia also causes learning and language problems in
children, bone mineral density problems and ovarian failure in
girls.
● TREATMENT AND MONITORING
o Dietary elimination on milk and milk products containing lactose is
the treatment for all types of galactosemia
o There is no chemical or drug substitute for the missing enzyme at
this time.
o An infant diagnosed with galactosemia will have to be on soy-
based formula.
o Dietary management under the close supervision of a metabolic
dietician and a metabolic doctor is a must.
o Regular monitoring of blood galactose levels and regular
evaluation by the genetic metabolism team is important for optimal ● CLINICAL FEATURES
treatment. o The most common clinical manifestation of G6PD is hemolytic
induced by various oxidative stresses.
● PROGNOSIS o The patient presets sudden onset of tea-colored urine, jaundice
o Despite an early galactose-free diet, long term complications have and pallor.
been noted in older children and adults with classic galactosemia o Hereditary nonspherocytic hemolytic anemia may also occur in
because of endogenous galactose production patients with severe G6PD deficiency.
▪ These include speech problems, poor intellectual function, o In neonates, G6PD deficiency may present with prolonged
neurologic deficits (predominantly extrapyramidal findings jaundice which is attributed to impaired liver function as supposed
with ataxia), and ovarian failure in females. to hemolysis.
▪ Thus, the need for regular monitoring and evaluation is ▪ The dreaded effect of neonatal jaundice is kernicterus or
important the deposition of bilirubin (product of hemoglobin
catabolism) which causes permanent damage to the brain
GLUCOSE-6-PHOSPHATE DEHYROGENASE (G6PD) DEFICIENCY or death.
● WHAT IS G6PD? o Other associated disorder to G6PD deficiency are decreased RBC
o G6PD deficiency is an enzyme defect affecting around 400 million lifespan and cataract formation.
people worldwide o Although there is a high prevalence of G6PD deficiency, there are
only few severe cases of hemolysis that has been documented
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and most of them are foreign reports.
● DIAGNOSIS
o The currently used method in the diagnosis of G6PD deficiency is
the spot fluorescence test as part of newborn screening panel
o Screening positive patient should immediately undergo
confirmatory testing based on estimation of enzyme activity by
quantitative analysis of the rate of NADPH production from NADP.
● MANAGEMENT
o There is no cure for G6PD deficiency, but the main goal in the
management is avoidance of oxidative insults and blood
transfusions for acute hemolytic crisis.
o Confirmed cases may also be referred to specialist in Pediatric
Hematology for assessment and advice
● PROGNOSIS
o Most G6PD-deficient patients live a normal life without the clinical
features as indicated above
o Since there is no way of telling who will develop hemolytic crisis,
avoidance of oxidative stress and physician consult are advised if
with febrile illness.
● PATIENT EDUCATION
o Parents should be educated regarding their child’s disorder,
specifically the drugs and food that cause oxidative stress, and
thus should be avoided.
o It is also important to emphasize that infection is a common cause
of hemolytic crisis in G6PD deficient patients, hence all affected
patients should see their doctor during febrile illness for
management.
o Parents are also advised to mention to their physicians that the
patient have G6PD deficiency during consults
o As this is an inheritable disease, X-linked, genetic counseling
should be done.
AMINO ACID DISORDERS
HOMOCYSTINURIA (HCY)
● WHAT IS HCY?
o Homocystinuria (HCY) is caused by cystathionine B-synthase
deficiency is an inborn error of the transsulfation pathway which
causes an increase in levels of homocysteine and methionine in
blood.
● CLINICAL MANIFESTATION
o Patients affected with homocystinuria may present with:
1. Ectopia lentis which is found in 85% of patients
2. Skeletal abnormalities are prominent especially genu valgus
and patients are often described to have a “marfanoid
habitus”
3. Mental retardation is common but not invariable and;
4. Thromboembolism
● PATHOPHYSIOLOGY
o Increased homocysteine levels is found to inhibit linking of
collagen and elastic tissue which predisposes zonule generation
of the eye predisposing patients to myopia and lens dislocation
o Skeletal abnormalities are thought to result from damage to fibrillin
in patients with cytathionine B- synthase and due to a reduction in
collagen crosslinking
o The mechanism that contributes to the atherogenic propensity of
hyperhomocystinemia are r/t endothelial dysfunction and injury
which leads to platelet aggregation and thrombus formation
o Finally, chemical abnormalities and the repeated thromboembolic
strokes may contribute to the mental retardation
o Inheritance: autosomal recessive
“Don’t pray for an easy life. Pray for the strength to endure difficult one”. -Bruce Lee
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PEDIATRICS
● CONFIRMATORY TESTING
o Total homocysteine in plasma. Amino acids in plasma,
methylmalonic acid in urine and enzyme study in fibroblasts may
be used to confirm the diagnosis.
● OVERVIEW OF DISEASE MANAGEMENT
o The aim of treatment is to reduce the plasma total homocysteine
through the following approaches:
▪ (1) Large doses of pyridoxine have been effective in
reducing biochemical abnormalities in patients with
cystathionine B-synthase deficiency where about half
respond partially
▪ (2) Folic acid may be given along with betaine that lowers
homocysteine levels by remethylation dietary modification
by giving a low-methionine/high-cystine diet.
● PROGNOSIS
o Early diagnosis and treatment can prevent thromboembolic
events and reduce the complications brought about by increased
levels of homocysteine.
MAPLE SYRUP URINE DISEASE (MSUD)
● WHAT IS MSUD?
o Maple syrup urine disease (MSUD) is due to a defect or deficiency
of the branched chain ketoacid dehydrogenase complex in which
elevated quantities of leucine, isoleucine, valine and their
corresponding oxoacids accumulate in body fluids.
● CLINICAL MANIFESTATION
o Infants with MSUD appear normal at birth
o There are different classifications of MSUD based on the enzyme
activity and these include: classical, intermediate, intermittent,
thiamine response and E-3 deficient MSUD.
o Classical MSUD (residual enzyme <2%) is the most severe and
common form with symptom of poor suck, lethargy, hypo and
hypertonia, opisthotonic posturing, seizures, and coma
developing 4-7 days after birth.
o The characteristic odor of maple syrup may be detected as soon
as neurological symptoms develop.
o Intermediate MSUD (residual enzyme 3-30%) have gradual
neurologic problems resulting in mental retardation
o Intermittent form of MSUD go into metabolic crisis when
stressful situation such as an infection or after surgery happens
o Thiamine response MSUD’s- clinical symptomatology and
metabolic disturbance is ameliorated once pharmacologic dose of
thiamine has been given
o E-3 deficient MSUD- present with symptom similar to those with
intermediate MSUD but also have lactic acidosis
● PATHOPHYSIOLOGY
o Due to a mutation of the branched chain keto-acid dehydrogenase
enzyme, the levels of leucine, valine and isoleucine increase in
blood.
o The increase in leucine may cause competitive inhibition with
other precursors of neurotransmitters causing the neurologic
manifestations
o Inheritance: autosomal recessive
● CONFIRMATORY TESTING
o Diagnosis is confirmed by detection of the highly increased
branched-chain amino acids levels via quantitative amino acid
analysis and or by increased urinary excretion of a-keto and
hydroxyl acids and branched chain amino acids using GC-MS and
quantitative amino acid analysis
● OVERVIEW OF DISEASE MANAGEMENT
o Long term treatment of MSUD is based on dietary restriction of
branched-chain amino acids and supplementation of thiamine if
proven beneficia; valine and isoleucine supplementation is also

recommended
o Frequent determination of leucine levels are likewise encouraged
so that proper dietary adjustments be done for effective
management of the condition
● PROGNOSIS
Children with the classical form of MSUD have only a satisfactory
prognosis if they are diagnosed and treated early.
ORGANIC ACIDURIAS
● WHAT ARE ORGANIC ACIDURIAS?
o Organic acidurias are a group of autosomal recessive disorder
caused by the deficiency or absence of any of the enzymes
needed for the breakdown of some proteins.
o They derive their names from the substrate that accumulates
proximal to the block in the pathway
o They are the following:
▪ Propionic aciduria (PA)- due to a deficiency of propionyl-
CoA carboxylase
▪ Methylmalonic aciduria (MMA)- due to deficiency of
methymalonyl-CoA mutase
▪ Isovaleric aciduria (IVA)- due to a deficiency of isovaleryl-
CoA dehydrogenase
o Untreated children with this condition may present with vomiting,
irritability, drowsiness, rapid breathing, and coma.
o Patients with propionic aciduria and isovaleric aciduria may also
have hyperammonemia. As a result, untreated children may have
encephalopathy, mental retardation or death.
● TREATMENT OF ORGANIC ACIDURIAS
o Treatment is through the dietary restriction of protein.
o Children may be given a special milk formula that is protein free.
o Carnitine and/or glycine are also prescribed.
PHENYLKETUNURIA
● WHAT IS PKU?
o Phenylketonuria(PKU) 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.
o Phenylalanine hydroxylase requires the co- factor 6-
pyruvoyitetrahydropterin 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.
● CLINICAL MANIFESTATION
o Patients affected with PKU appear normal at birth.
o The most important and sometimes the only manifestation is
mental retardation.
o 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.
o Seizures occur in a fourth of patients.
o The odor of the phenylketonuric patient is that of phenylacetic acid
described as mousy, barny, or musty.
● PATHOPHYSIOLOGY
o PKU results from a deficiency of a liver enzyme, phenylalanine
hydroxylase leading to increased concentrations of phenylalanine
in the blood and other tissues.
“Don’t pray for an easy life. Pray for the strength to endure difficult one”. -Bruce Lee
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TRANSCRIBERS: CUDYAM ǀCUSTODIO ǀDE LUNA
PEDIATRICS
o Elevated phenylalanine interfere with myelination, synaptic
sprouting and dendritic pruning; and in addition, it completely
inhibits the uptake of neural amino acids in the blood- brain-barrier
causing reduced tyrosine and tryptophan concentrations thereby
limiting the production of neurotransmitters
o Inheritance: autosomal recessive.
● CONFIRMATORY TESTING
o The demonstration of decreased enzyme activity is confirmatory.
o 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/kg orally) which leads to a prompt decrease to
normal in the concentration of phenylalanine.
● OVERVIEW OF DISEASE MANAGEMENT
o Dietary management is key to treatment.
o The diet of patients has four components:
▪ (1) complete avoidance of food containing high amounts of
phenylalanine;
▪ (2) calculated intake of low protein/phenylalanine natural
food;
▪ (3) sufficient intake of fat and carbohydrates to fulfill the
energy requirements of the patient and;
▪ (4) calculated intake of phenylalanine free amino acid
mixture supplemented with vitamins, minerals and trace
elements as the main source of protein.
● PROGNOSIS
o When treatment is started early and performed strictly, motor and
intellectual development can be expected to be near normal
TYROSINEMIA TYPE 1
● WHAT IS TYROSINEMIA TYPE 1 (HEPATORENAL TYROSINEMIA)?
o Tyrosinemia is also known as hepatorenal tyrosinemia type 1,
tyrosinosis or hereditary tyrosinemia.1
o The deficient enzyme is fumarylacetoacetase.
● CLINICAL MANIFESTATION
o Tyrosine-1 is usually asymptomatic in newborns, but if left
untreated it affects liver, kidney, bone, and peripheral nerves.
o 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.
● PATHOPHYSIOLOGY
o The deficient enzyme, fumarylacetoacetase catalyzed the last
step in tyrosine degradation.
o The increased concentrations of tyrosine and its metabolites is
postulated to inhibit many transport functions and enzymatic
activities.
o Inheritance: autosomal recessive.
● CONFIRMATORY TESTING
o Confirmation can be done through plasma amino acid levels
(increased tyrosine) and urine metabolic screening (increased
succinylacetone)

● OVERVIEW OF DISEASE MANAGEMENT
o Treatment options for tyrosinemia 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(1mg/kg).
● PROGNOSIS
o If untreated, death from liver failure may occur in the first year of
life
PEDIATRICS
● Some IEM can be easily treated
● Some IEM are fatal if not detected and treated early
● High index of suspicion, importance of NBS, parent/patient
education, referral to appropriate specialists and counselling
---------------------END------------------------

UREA CYCLE DEFECTS REFERENCES:

Agdeppa, A. (2019). Inborn Error of Metabolism. Retrieved
● WHAT IS UCDs? form University of Northern Philippines, College of
o The urea cycle is the main pathway of the body to dispose of Medicine.
excess nitrogen.
o It allows for the conversion of ammonia into urea that can be
excreted into the urine.
o Citrullinemia and Argininosuccinic Aciduria are inherited in an
autosomal recessive manner.
o Citrullinemia occurs as a result of argininosuccinic synthase
deficiency while argininosuccinic aciduria is due to a deficiency of
argininosuccinic lyase
o Both conditions may manifest with tachypnea, lethargy, vomiting,
irritability, seizures, coma and ultimately death if left untreated.
o The increased levels of ammonia may cause brain damage.
o Due to blocks in the urea cycle owing to the enzyme deficiency,
patients with UCD have low levels of arginine.
▪ This makes arginine as essential amino acid among
patients with UCD.
● TREATMENT OF UCD’s
o The treatment is through the dietary restriction of protein and the
supplementation of a protein free formula.
o Sodium benzoate, an ammonia scavenger, is given as well as
arginine supplementation.

WHAT ARE THALASSEMIAS AND HEMOGLOBINOPATHIES?

THALASSEMIAS
o Are characterize by a decrease production in the either the α or β globin
chains.
o They are grouped into a α and β thalassemias
o The imbalance in the production of globin chains results in a hemolytic
anemia or precipitation of the red cells in the bone marrow or a process
known as ineffective erythropoiesis.

HEMOGLOBINOPATHIES
o Structural abnormalities and are usually due to a single amino acid
substitution
o Both disorders exhibit unique geographical distribution.
o HbS, HbSC, HbS/β thalassemia or sickle cell disease is typically
common in Africa, Saudi Arabia, India and in the Americas.
o HbE is almost exclusively from South East Asia.

CONCLUSION
INBORN ERRORS OF METABOLISM (IEM)
● Usually caused by:
o Partial or full enzyme deficiencies or
o Transport defects that result in either:
▪ Accumulation of toxic products or
▪ Lack of an important end product
● The manifesting symptoms depend on the particular metabolic
pathway that is affected.

“Don’t pray for an easy life. Pray for the strength to endure difficult one”. -Bruce Lee
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