INBORN ERRORS OF

METABOLISM (IEM)
IEM
• Conditions caused by the genetic errors related to synthesis, metabolism,
transport or storage of biochemical compounds.
• Hereditary diseases that disrupt normal biochemical processes are termed inborn
errors of metabolism or inherited metabolic diseases
• Over 500 human diseases due to IEM are now recognized and a signifiant number
of them are amenable to treatment.
• IEM may present as
• Acute metabolic emergency
• Chronic problems involving either single or multiple organ, either recurrent or
progressive, or permanent
Approach to IEM
• Neonates (may develop as early as a few hours after birth)
• Unexpected deterioration
• Non specific and unexplained features:
• Poor feeding
• Lethargy
• Vomiting
• Hypotonia
• FTT
• Respiratory abnormalities, apnea, bradycardia
• Hypothermia
• Hypoglycemia: Lethargy, poor feeding, seizures, and coma
Approach to IEM
• Children
• Sudden rapid illness precipitated by fever, infection and fasting
• Acute encephalopathy
• Recurrent coma, stroke, ataxia, cramps
• Worsening with intercurrent febrile illness
• History of aversion to sweets, high protein
• Developmental regression
• Facial dysmorphism, structural anomalies of brain, cataract, retinopathy, deafness,
cardiomyopathy, hepatomegaly, myopathy
• Peculiar odor
• Persistant/recurrent hypoglycemia, intractable metabolic acidosis, hyperammonemia,
hyperkalemia
• Reye syndrome like illness
• E. coli sepsis
Approach to IEM
• Others
• Family history of similar illness
• Unexplained siblings deaths due to sepsis or SIDS
• Unexplained disorders in other family member (progressive neurological
disease, HELLP syndrome)
• Parental consanguinity: autosomal recessive
Acute Presentation
• Normal at birth since the small intermediary metabolites are eliminated by
placenta during fetal life
• Important clue for diagnosis → unexpected deterioration after normal period in a
full-term baby
• Symptom free period may be prolonged; intercurrent illnesses, ↑ protein intake,
exercise, fasting and drug intake may precipitate symptoms
• Disorders of glucose, protein and fat breakdown usually present early
• Premature neonates with transient hyperammonemia of newborn (THAN) and
term babies with glutaric acidemia type II or pyruvate carboxylase deficiency may
present on the first day of life
Investigation
Investigation
• HPLC
• Tandem mass spectrometry (TMS)
• Gas chromatography and mass spectrometry (GCMS)
• Useful in specific case
• CSF study
• CXR
• Echocardiography
• USG abdomen
• CT head/MRI brain
• EEG
Principle of management
1) Eliminate dietary or parenteral intake of potentially toxic agent
2) Provide adequate calories (0.2% saline in 10% dextrose IV)
3) Correct metabolic acidosis, dehydration and electrolyte imbalance. Treat
intercurrent illness, if any.
4) Enhance excretion of toxic metabolites. IV phenylacetate and sodium
benzoate with L-arginine (uric cycle defect). Initiate dialysis if plasma
ammonia levels >500- 600 µg/dL, or if do not fall within 2 hours after
initiation of IV treatment
5) Empiric cofactor or coenzyme therapy may be administered
6) If clinical improvement is observed and a final diagnosis is not yet established,
some amino acid intake is provided after 2-3 days of complete protein
restriction (begin at 0.5 g/kg/day, increased to 1-1.5 g/kg/day until diagnostic
evaluation is complete)
Chronic Presentation
• Variable but insidious onset from birth to adulthood
• Unexplained developmental delay with/without:
• Seizures
• Organomegaly
• Coarse facies
• Cataract
• Dislocated lens
• Chronic skin lesions
• Abnormal hair
• Abnormal urine colour
• FTT
• Divided into subgroups depend upon system involvement
 NEUROLOGIC
DD or progressive global
psychomotor retardation
Severe irritability, impulsivity,
aggressiveness, hyperactivity,
behavioral patterns
Complex partial or myoclonic seizures
(early) and often resistance to
therapy
Other CNS symptoms – seizures,
ataxia, spasticity, variable hearing and
visual impairment, and EPS
MUSCULAR
Usually present with myopathy due to
defects in energy metabolism
Progressive myopathy (GSD type II &
III)
Exercise intolerance with cramps &
myoglobinuria (GSD V & VI)
Multisystem disease (mitochondrial
myopathies)
HEPATIC
Presence of conjugated &
unconjugated jaundice,
hypoglycemia, hepatomegaly
Abnormal lipid profile (GSD types I
and III)
Hepatosplenomegaly (lysosomal
storage disorders)
Hepatocellular dysfunction
(galactosemia, GSD III and IV)
Cirrhosis – tyrosinemia, galactosemia,
Wilson disease, hereditary fructose
intolerance
 CARDIAC
FA oxidation defects
Mitochondrial defects
GSD type II
Familial hypercholesterolemia
RENAL OCULAR
Cystinosis (can lead to progressive Cataract in galactosemia, Wilson
failure) disease, Lowe syndrome
Galactosemia Corneal abnormalities in
Tyrosinemia mucopolysaccharidoses, Wilson
disease
Hereditary fructose intolerance
Lens dislocation – homocystinuria
GSD 1 – enlarged kidneys
Cherry red spots – LSD
Investigation
- Complete blood count
- Liver function test
- Electrolyte
- Renal function test
- Bone marrow aspiration
Principle of management
1) Supportive care involving mutidisciplinary team
2) Supply deficient enzyme (enzyme replacement)
3) Organ transplantation, enzyme enhancement through cofactor and
megavitamin
4) Substrate reduction
5) Prenatal diagnosis by enzyme assays or mutation testing on fetal
DNA obtained through amniotic fluid or chorionic villus
biopsy(mostly autosomal recessive)
References
• OP GHAI
• NELSON TEXTBOOK
• PEADIATRIC PROTOCOL MALAYSIA
• Inborn Metabolic Diseases: Diagnosis and Treatment edited by John
Fernandes, Jean-Marie Saudubray, Georges van den Berghe, John H.
Walter
GLYCOGEN STORAGE
DISEASES
 WHAT IS GLYCOGEN?

• The stored form of glucose

• Formed during periods of dietary carbohydrate loading and broken down when glucose demand is
high or dietary availability is low

• Most abundant in the liver and muscle

• In liver, its main role is to maintain glucose homeostasis in which the liver stores glucose for release
to tissues that are unable to synthesize significant amounts during fasting

• In muscle, glycogen serves as source of energy for high-intensity muscle activity where it will
breakdown to provide substrates for generation of ATP
GLYCOGENESIS & GLYOGENOLYSIS
GLYCOGEN STORAGE DISEASES
A group of inherited genetic disorders caused by an enzyme deficiency
affecting carbohydrate metabolism
 CLASSIFICATION

LIVER MUSCLE
• Type 1 (Glucose-6-phospatase) • Type II (Acid maltase)
• Type III (Glycogen debrancher) • Type V (Muscle
• Type IV (glycogen branching phosphorylase)
enzyme) • Type VII
• Type VI and IX (Liver (Phosphofructokinase)
phosphorylase and
phosphorylase b kinase)
METABOLIC Pathways
 CLINICAL MANIFESTATION

• Main role of glycogen in the liver is to store glucose for release to tissues that are
01 unable to synthesize significant amounts during fasting

• Patients with a disorder of hepatic glycogen metabolism cannot breakdown

glycogen to form glucose (hypoglycaemia) and excess glycogen in the liver will later
LIVER cause hepatomegaly

• There will be lactic acidaemia, hyperlipidaemia, hyperuricemia (type I)

• Symptoms improve with eating or glucose administration

• They also may have poor weight gain but developmentally normal
 CLINICAL MANIFESTATION

• Glycogen is the primary source of energy for high-intensity muscle activity by

02 providing substrates for generation of ATP

• Deficiency of enzyme in glycogenolysis will cause exercise intolerance with muscle

pain, cramps, rhabdomyolysis and myoglobinuria
MUSCLE
• Defects in glycogenesis will cause progressive weakness involving trunk and
extremity muscles
 DIAGNOSIS

1. History taking and physical examination

2. Blood tests

3. Urinalysis

4. DNA testing (to confirm the diagnosis)

5. Enzyme assay

6. Liver/Muscle biopsy for histologic studies

(rare)
 TREATMENT
• Glycogen storage disease treatment will depend on the type
of disease and the symptoms

• Main goal is to maintain normal blood glucose levels

 LIVER – I, III, IV, VI

• A nasogastric infusion of glucose in infants and children under age two

• Dietary changes, including:

- In children over age two, frequent small carbohydrate feedings are given throughout the day. E.g.,
uncooked corn starch.

- Elimination of foods that are high in fructose or lactose (type I only)

- Allopurinol (Aloprim, Zyloprim) may be prescribed to reduce uric acid levels in the blood. This is
done to prevent gout and kidney stones

• Liver transplantation in type IV

 MUSCLE – II, V, VII

• Regulating or limiting strenuous exercise to avoid fatigue symptoms

• Improving exercise tolerance by oral intake of glucose or fructose (fructose must be avoided in
people with type I), or an injection of glucagon

• Eating a high protein diet

 Thanks!
Reference:
Illustrated Textbook of Pediatrics 5th Edition

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