INBORN ERROR OF

METABOLISM
IVY NYDIA YUWONO
01071170101
Definition of Metabolism
Metabolism → is the sum of reactions that occur throughout the body within each cell and that provide the body
with energy.

● energy gets used for vital processes and the synthesis of new organic material.
● organism uses its environment to survive by taking nutrients and substances that act as building blocks for
movement, growth, development, and reproduction. All of these are mediated by enzymes, which are proteins with
specialized functions in anabolism and catabolism.
● rate of energy production is called the basal metabolic rate and is affected by factors such as sex, race, exercise,
diet, age, and diseases such as sepsis or cancer.

IEM  Inborn errors of metabolism (IEMs) are a group of disorders which results from deficiency activity of a single
enzyme in a metabolic pathway
Inborn Errors of Metabolism (IEM)
● Inherited disorders that result from a defect in an enzyme or transport protein → resulting in blocking of metabolic
pathway.
● Involve failure of metabolic pathway that will involved in carbohydrates metabolism, fatty acids oxidation, glycogen
storage and protein metabolism.
● 1 in 2500 births.
● Results in:
○ Hypoglycemia (errors of metabolizing and breaking down food)
○ Intoxication ex. hyperammonemia (intervention in excretion of metabolites)
○ Acidosis & hypoglycemia (Fatty acid oxidation intervention)
Clinical Features of IEM
Clinically can be indistinguishable from septic Common presentation in children with IEM:
neonates:
● Neurologic abnormalities (80%)
● Hypoglycemia
● Brady/tachydysrhythmias ○ Developmental delay
● Hypothermia/hyperpyrexia ○ Loss of milestones
● Seizures ○ Poor tone
○ Seizure
● Poor tone
● Gastrointestinal symptoms:
If the problem is in excreting pathways:
○ Vomiting
● Lethargy ○ Hepatomegaly
● Altered mental status ○ Food Intolerance
● Seizure ○ Diarrhea
● Vomiting ○ Dehydration
Specific IEM diagnostic tests
● Organic acid analysis of urine samples by GC/MS
○ Organic acid disorders (MMA, PA, IVA, GA1)
○ One Urea Cycle disorders (OTC)
○ Some Fatty acid oxidation disorders (MCAD, LCHAD)
○ Some amino acid disorders (Tyr1, MSUD)
● Amino acid analysis of serum samples by HPLC, MS/MS
○ Amino acid disorders (PKU, Tyr, MSUD)
○ Urea cycle disorders (ASA, CITN, ARG)
● Acylcarnitine analysis of serum samples by Tandem MS
○ Some organic acid disorders (MMA, PA, IVA)
○ Fatty acid oxidation disorders (MCAD, CPT2, VLCAD)
Diagnosing IEM
● NBS follow-up testing
○ Important to know what was abnormal about the newborn screen
● Disorder may be picked up by only one of these tests
● Many disorders are picked up by more than one of these assays
● Combination of tests may confirm diagnosis
○ MSUD, Tyr type 1 – amino acid, confirmed by organic
○ PKU – amino acid – can be picked up on organic
○ MMA, PA – picked up elevated C3-carnitine on acylcarnitine analysis, differentiated by organic acid analysis
CLASSIFICATION OF IEM (SSIEM SYLLABUS)
Disorders of amino acid and peptide metabolism Congenital disorders of glycosylation and other
disorders of protein modification
Disorders of carbohydrate metabolism
Lysosomal disorders
Disorders of fatty acid and ketone body
metabolism Peroxisomal disorders

Disorders of energy metabolism Disorders of neurotransmitter metabolism

Disorders in the metabolism of purines , Disorders in the metabolism of vitamins and

pyrimidines and nucleotides (non-protein) cofactors

Disorders of the metabolism of sterols Disorders in the metabolism of trace elements

and metals
Disorders of porphyrin and haem metabolism
Disorders and variants in the metabolism of
Disorders of lipid and lipoprotein metabolism xenobiotics
PATHOGENESIS IN PHENYLKETONURIA
- Lack of phenylalanine
hydroxilase blocks the
transformation of
phenylalanine to tyrosine.
- Phenylpyruvic acid into
blood and then out in
sweat and urine (Mousy
odor)
PATHOGENESIS IN PHENYLKETONURIA
- PKU is caused by mutated gene for PAH enzyme (Phenylalanine hydroxilase), caused by defect in the
biosynthesis of cofactor tetrahydrobioptin (BH4).
- PAH gene is located on chromosome 12 & autosomal recessive gene.

Normal blood phenilalanine level is about 1 mg/dl

In Classic PKU, level may range from 6 to 80 mg/dl

PATHOGENESIS IN PHENYLKETONURIA
Other symptoms may include:
● Delayed mental and social skills
● Head size much smaller than normal
● Hyperactivity
● Jerking movements of the arms or legs
● Mental disability / retardation
● Seizures
● Skin rashes
● Tremors
● light skin
LYSOSOMAL STORAGE DISEASE
- The group of lysosomal storage disorders is usually caused by the lack of a hydrolase, its activator or a transporter causing
accumulation of specific substrates in the lysosomes for each disorder type
- defects of the vesicular transport in the endosomal/lysosomal system have been reported to cause phenotypes similar to
lysosomal storage disorders, for example mucolipidosis type IV
- deficiencies includes the neuronal ceroid lipofuscinoses and a growing number of pigmentary disorders, and the elucidation of
the function of these proteins will in a fundamental way increase our understanding on how the vesicular trafficking in the cell is
regulated.
- storage diseases are inherited in an autosomal-recessive fashion, except Fabry disease, Hunter disease (MPS II) and Danon
disease that are all X-linked recessive
- The severity of a lysosomal storage disorder type will depend partially on the type of accumulating waste product

The lysosomal storage disorders were divided into the following 5 groups:

Defects in glycan degradation ,Defects in lipid degradation, Defects in protein degradation, Defects in lysosomal transporters, Defects
in lysosomal traffickin
 HYPOGLYCEMIA IN GLYCOGEN STORAGE DISEASE
TYPE 1
- Glycogen storage disease type 1 → Von Gierke Disease
- inherited disease caused by deficiensies of specific enzyme in glycogen metabolism pathway.
- GSD 1a → deficiency of Glucose 6 Phosphatase, mutation in G6PC gene
- GSD 1b → deficiency of Glucose 6 Phosphate translocase, mutation in SCL37A4 gene
- genetic testing to confirm the diagnosis
- G6Pase & G6PT play role on glycogenolysis & gluconeogenesis
- so, deficiency of G6Pase & G6PT → hypoglycaemia
- symptoms → hypoglycaemia appears with increased intervals between feeds, enlarged liver, metabolic acidosis, FTT with
delayed motor development, can also be asymptomatic
- if left untreated, would develop appearance similar to Cushing syndrome (short, round face, full cheeks)
- treatment → dietary and lifestyle changes, avoid fasting, monitor blood glucose
PATHOGENESIS OF HYPERURICEMIA,
HYPERTRIGLYCERIDEMIA, HYPERLACTEMIA IN GSD
Hyperuricemia: Increased degradation of the adenine nucleotide to uric acid, which is associated with intrahepatic
phosphate concentrations and ATP depletion. Decreased clearance due to competitive inhibition of uric acid excretion by
lactate.

Hypertriglyceridemia: increase in triglyceride and cholesterol concentrations shows an increase in the number of vldl and ldl
particles while the hdl has decreased. Increase in excess synthesis, both of acetyl coA from malonyl coA and decreased
serum lipid clearance. an increase in liver G6P may play a role in the activation of transcription of lipogenesis genes.
Decreased plasma clearance is the result of uptake disorders and lipolysis disorders of circulating lipoproteins.

Hyperlactatemia: As a consequence because of excess G6P that cannot be hydrolyzed into glucose, then it will be
metabolized by the glycolysis pathway which later will produce pyruvate and lactate.
IEM WITH HYPERAMMONEMIA
The urea cycle disorders (UCD)
are a group of inherited
biochemical diseases caused by a
complete or partial deficiency of
any one of the enzymes or
transport proteins required to
convert toxic ammonia into urea
and to produce arginine and
citrulline. The clinical
manifestations of these disorders
are mostly the result of acute or
chronic hyperammonemia, which
affects the central nervous
system.

UREA CYCLE →
Enzyme defects in urea cycle that are associated with
hyperammonemia
● N-acetylglutamate synthetase (NAGS) deficiency → an activator of carbomyl phosphate
synthetase. autosomal recessive.
● Carbamoyl phosphate synthetase I (CPS I ) def → autosomal recessive. affect chromosome
2
● Ornithine transcarbamoylase (OTC) def → most common urea cycle defect. X-linked trait.
OTC is also found in mitochondria, and it presence is to combine with carbamoyl phosphate
to form citrulline and then transported out of mitochondria. If OTC is absence = carbamoyl
phosphate accumulates - enter cytosol and participates in pyrimidine synthesis with CPS II
● Argininosuccinic acid synthetase (AS) def → autosomal recessive. chromosome 9
● Argininosuccinic lyase (AL) def → lack of this enzyme cause argininosuccinic aciduria.
Second most common urea cycle disorder. Autosomal recessive. chromosome 7
● Arginase def → enzyme that is involved in final step of urea cycle = def of this enzyme cause
argininemia. (least frequent UCD). affects chromosome band 6q23. Hyperammonemia is not
severe and the probable cause of neurotoxicity is arginine → leads to progressive spastic
diplegia/quadriplegia, intellectual impairment, vomiting, delayed growth, seizures
REFERENCE
● NA, Summer. (2020). Inborn Errors of Metabolism with Hyperammonemia: Urea Cycle Defects and Related Disorders. - PubMed
- NCBI. Retrieved 5 February 2020, from https://www.ncbi.nlm.nih.gov/m/pubmed/29502911/
● Mew, N., Simpson, K., Gropman, A., Lanpher, B., Chapman, K., & Summar, M. (2020). Urea Cycle Disorders Overview. Retrieved
5 February 2020, from https://www.ncbi.nlm.nih.gov/books/NBK1217/
● https://www.ncbi.nlm.nih.gov/books/NBK534196/
● Jones, P. Newborn Screening & Methods for Diagnosing Inborn Errors of Metabolism. UT Southwest Med Cent Dallas, Texas
[Internet]. Available from: https://www.aacc.org/~/media/files/meetings-and-events/resources-from-past-
events/conferences/2015/profprac/slides-and-handouts/newborn_screening_slides_jones.pdf?la=en
● Zschocke, J. (2014). SSIEM Classification of Inborn Errors of Metabolism. Physician’s Guide to the Diagnosis, Treatment, and
Follow-Up of Inherited Metabolic Diseases, 817–830. doi:10.1007/978-3-642-40337-8_55
● Jeanmonod R, Jeanmonod D. Inborn Errors Of Metabolism. [Updated 2020 Jan 9]. In: StatPearls [Internet]. Treasure Island (FL):
StatPearls Publishing; 2020 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK459183/