Inborn errors of metabolism

Inborn
Errors of
m etabolism
Inborn Errors of metabolism Can Disrupt Amino Acid Degradatio

Noor Aldin Nabil
Saad Salih Mahdi
Preparation and design
of the seminar
Iminoglycinuria

Inborn errors of metabolism (IEM) are a group of inherited metabolic disorders leading to enzymatic
defects in the hum an m etabolism . As its nam e im plies, inborn errors m eans birth defects in newborn
infants which passed down from fam ily and affecting m etabolism . Hence, it is called Inborn errors of
m etabolism or inherited m etabolic disorders. IEM can appear at birth or later in life such as
phenylketonuria, albinism , lactose intolerance, Gaucher disease, Fabry disease etc. IEM refers a condition
where in body’s m etabolism is affected due to genetic disorders. The cause of IEM is m utations in a gene
that code for an enzym e leading to synthesis of defective enzym e activity or deficiency of an enzym e that
affects the norm al function of a m etabolic pathway. The m ain indication of IEM is an excess storage or
accum ulation of specific m etabolites in tissues, organs and blood which further m anifest to health
diseases. In last decades, several hundreds of different IEM have been identified. Most IEM are rare but
som e are life threatening. Although, m ost people do not know what inherited m etabolic disorders are
and m ay never have heard of them .
Therefore, in this presentation you are going to study the basic concept, genetic basis and m etabolic
consequences of inborn errors of m etabolism .
Contents of This presentation

01
Th e Disease
General info about
Disease
02
Diagnosis
Talk about how can
diagnosis
03
Symptoms
Talk about common
symptoms
04
Causes
Talk about causes of
Each disease
05
Treatment
Talk about how can
Treat the disease
06
Chemistry
Talk about chemistry
Correlations

Introduction
Inborn errors of amino acid
metabolism are metabolic disorders
which impair the synthesis and
degradation of amino acids.

Phenylketonuria
01
(PKU) is an inborn error of metabolism that
results in decreased metabolism of the
amino acid phenylalanine.

Figure 1.3 Inherited enzyme defects in catabolic pathway of phenylalanine and Tyrosine and the defective enzyme in indicated by
red summing junctions and the metabolic diseases shaded in the Yellow color (Taken from Principle of Biochemistry, Nelson & Cox,
2004).

Alkaptonuria
02
Alkaptonuria is the first inborn errors of
metabolism discovered by Garrod. Estimated
incident of alkaptonuria is about 2-5 per
million live births.

Alkaptonuria
C low
low proteins diet are
recommended to control
of the ochronosis
reducing
by reducing the level of
hom ogentisic acid in
tissues
Newborn
Newborn
screening and oral
nitisinone therapy
m ay also helpful
for the treatm ent
of this disease
Treatment
Vitam in C

Tyrosinemia
03
Tyrosinemia is also metabolic genetic disorders of
phenylalanine catabolism, occur usually in newborns.
This disorder results due to the absence or deficiency of
enzymes involved in the multiple steps of phenylalanine
and tyrosine catabolism . Untreated tyrosinemia can be
fatal for life .

● Diarrhea
● vom iting
● renal tubular dysfunction
● vitam in D-resistant rickets
● acute interm ittent porphyria
● abdom inal pain
● neuropsychiatric findings
● sensitive to light
● hypertension
● Progressive liver
● renal failure.
● Accum ulation of tyrosine can affect
on eyes, skin
● m ental developm ent
● Persistent keratitis
● hyperkeratosis occur on the fingers,
palm s of hands and soles of feet
● m oderate m ental retardation.
Clinical symptoms
Tyrosinemia I Tyrosinemia II

Albinism
04
Albinism is another congenital hereditary disorder of
amino acid metabolism in which biosynthesis of melanin
is defective. Melanin is a color pigment absent in certain
parts of the body such as eyes, patches of skin and
areas of hair. Normally, melanin is polymers of the
amino acid tyrosine which gives color to skin, hair and
eyes

Causes
 Albinism is caused by the mutation in a
gene coding tyrosine hydroxylase enzyme.
 This enzyme converts tyrosine to 3,4-
dihydroxy phenylalanine (DOPA) .
 Deficient activity of this enzyme leads to
albinism in which melanin formation is
missing. This condition is referred to
hypomelanosis .

Symptoms of the Disease
 Albinism can affect eye and skin in infants or people
 This condition refers to oculocutaneous albinism (OCA) resulting in
hypopigmentation of the hair, skin and eyes
 this disease leads to extremely pale skin, poor vision and white hair

About the Disease
Treatm en t
There is no treatment
for albinism
Treatment Diagnosis
Diagnosis is based on
biochemical finding of
hypopigmentation of the
skin and hair. Molecular
genetic testing of OCA
gene is available for the
albinism diagnosis.
require visual rehabilitation
such as wear prescription
lenses for correction of
refractive errors, use hats with
brims and dark glasses or
transition lenses to reduce
discomfort from bright light and
wear protective clothing to
protect skin from sun exposure

A Picture Is
Worth a
Th ousan d
Words

Urea cycle defects
05
This is an autosomal recessive inherited
genetic disorder that affecting the urea
cycle.

About disease
This is an autosomal recessive inherited
genetic disorder that affecting the urea cycle.
The liver is a vital organ which plays a
promising role in detoxification of
nitrogenous wastes by forming the compound
urea through the urea cycle. Urea is a major
disposal byproduct of amino acids. The
disturbance in the normal urea cycle leads to
accumulation of urea causing cellular toxicity .
The estimated incidence of urea cycle defects
is about 1 in 8,000 live births and generally
occurs in the first few days of life.

Urea cycle defects
The urea cycle disorders
(UCDs) are caused by
defective or total absence of
catalytic activity of the first five
enzymes involved in the urea
cycle . Errors in this cycle, body
unable to detoxify nitrogen
content leads to abnormal
accumulation of ammonia and
other precursor metabolites.
These enzymes are:
defect in the arginase enzyme resulting argenimia while absence of argininosuccinase and
carbamoyl phosphate synthase-I may also cause argininosuccinic acidemia and carbamoyl
phosphate I deficiency respectively.

Treatment
Nutritional modification with
low protein diet may help in
controlling the level of
ammonia in the body
Sodium phenylbutyrate is the primary
medication used to treat urea cycle
disorders. This drug allows an
alternative pathway to disposal of
nitrogen from the body.
If medicine and nutritional
treatment failed, liver
transplantation becomes an
option for UCD’s patient.

Urea cycle defects
Clinical symptoms
 hyperammonemia condition
resulting in neurologic damage
 cerebral edema
 lethargy
 anorexia, hyper- or hypoventilation
 Hypothermia
 seizures, neurologic posturing
 long term hyperammonemia is toxic
to human beings resulting in mental
retardation
Measurement the elevated level of
ammonia, arginine, arginosuccinate in
plasma and orotic acids in urine are
used to diagnosis of urea cycle
disorders
Diagnosis

Homocystinuria
06
Homocystinuria is a rare inherited disorder
of metabolism of the methionine

Homocystinuria
 High level of homocysteine
in cells causing lipid
peroxidation
 fibrosis
 atherogenesis and affecting
muscles cardiovascular
system and nervous
system
Estimation of the level of homocysteine,
total homocysteine, homocysteine-
cysteine mixed disulfide, and methioninein
plasma.
Diagnosis :
Vitamin B6 (Pyridoxine) therapy, betaine, folate and
vitamin B12 supplementation are used to control the
biochemical abnormalities , especially to management
Treatment :
the plasma homocysteine and homocysteine
concentrations and prevent thrombosis.

 The most common form of
homocystinuria affects at least 1 in
200,000 to 335,000 people
worldwide.
 The disorder appears to be more
common in some countries, such
as Ireland (1 in 65,000)
 Germany (1 in 17,800)
 Norway (1 in 6,400)
 Qatar (1 in 1,800)
 The rarer forms of homocystinuria
each have a small number of
cases reported in the scientific
literature.
*We have searched about the incidence
of this and other diseases in Iraq, and we
have not found official rates.
Frequency
Homocystinuria

Maple syrup urine
disease (MSUD)
07
is an inherited disorder of branched chain
amino acids. Affected people with MSUD
have a defective gene inherited from their
family.

Hyperprolinemia
08
is a condition which occurs when the amino acid proline
is not broken down properly by the enzymes proline
oxidase or pyrroline -5-carboxylate dehydrogenase,
causing a buildup of proline in the body

Hyperprolinemia
Hyperprolinemia can also occur with other conditions, such as
malnutrition or liver disease. In particular, individuals with
conditions that cause elevated levels of lactic acid in the blood,
such as lactic acidemia, are likely to have elevated proline levels,
because lactic acid inhibits the breakdown of proline
proline

NKH
09
Nonketotic hyperglycinemia (NKH) is a genetic condition
that can lead to serious neurological problems, coma,
and death. “Hyperglycinemia ” refers to abnormally high
levels of a molecule, glycine. The word “nonketotic ”
distinguishes NKH from certain other health conditions
that can cause increased glycine.

Hyperoxaluria
10
Hyperoxaluria occurs when you have too much oxalate in your
urine. Oxalate is a natural chemical in your body, and it's also
found in certain types of food. But too much oxalate in your urine
can cause serious problems.
Hyperoxaluria can be caused by inherited (genetic) disorders, an
intestinal disease or eating too many oxalate -rich foods. The long -
term health of your kidneys depends on early diagnosis and
prompt treatment of hyperoxaluria.

Hyperoxaluria
Symptoms
 Severe or sudden back pain
 Pain in the area below the
ribs on the back (flank) that
doesn't go away
 Blood in the urine
 Frequent urge to urinate
 Pain when urinating
 Chills or fever
type
 Primary hyperoxaluria.
 Oxalosis
 Enteric hyperoxaluria
 Hyperoxaluria related to
eating high-oxalate foods

Glycinuria
1‫דּ‬
Glycinuria , is an autosomal recessive disorder of renal tubular
transport affecting reabsorption of the amino acid glycine, and
the amino acids proline and hydroxyproline. This results in excess
urinary excretion of all three acids ( -uria denotes "in the urine")
Iminoglycinuria is a rare and complex disorder, associated with a
number of genetic mutations that cause defects in both renal and
intestinal transport systems of glycine and amino acids.

Glycinuria
 Poor appetite
 Sleeping longer or more
often
 Tiredness
 Irritability
 Fever
 Vomiting
 Weak muscle tone (also
known as hypotonia)
 Delayed growth
Clinical symptoms

A Picture Always
Rein forces th e
Con cept

“ Th e greatest disease in th e West
today is n ot TB or leprosy; it is
bein g un wan ted, un loved, an d
un cared for. We can cure ph ysical
diseases with m edicin e, but th e
on ly cure for lon elin ess, despair,
an d h opelessn ess is love.”

1. Garrod. Inborn Errors of Metabolism. Oxford University Press. 1923.
2. Martins A. M. Inborn errors of m etabolism : a clinical overview Sao
Paulo Med J/Rev Paul Med. 1999; 117(6):251-65.
3. Gardner, E.J., Sim m ons, M.J., Snustad, D.P. Principles of Genetics. VIII
Edition. Wiley India 2008.
4. Snustad, D.P., Sim m ons, M.J. Principles of Genetics. VEdition. John.
2009.
5. Sim on S. Cross. Underwood’s pathology: A clinical approach 6th
edition Elsevier Health Sciences. 2013.
References

6. Roberta A Pagon, Editor-in-chief, Margaret P Adam , Holly H Ardinger, Stephanie E
Wallace, et al., Editors. Gene Reviews® Seattle (WA): University of Washington, Seattle;
1993-2017.
7. Debra S Regier and Carol LGreene. Phenylalanine Hydroxylase Deficiency. In: Gene
Reviews®[Internet]. Seattle (WA): 2000-2017; University of Washington, Seattle; Wiley and
Sons Inc.
8. Nelson D.L. and Cox M.M. Lehninger, Principles of Biochem istry, 4th Edition. 2008.
9. Braconi D, Bernardini G, Paffetti A, Millucci L, Gem iniani M, et al. A Com parative
proteomics in alkaptonuria provides insights into inflam m ation and oxidative stress Int J
Biochem Cell Biol. 2016; 81:271-280.
10. Millucci L, Braconi D, Bernardini G, Lupetti P, Rovensky J, Ranganath L, Santucci A.
Am yloidosis in alkaptonuria. JInherit Metab Dis. Sep; 2015; 38(5):797-805.
References

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College of Medicine Al Nahrain University
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Inborn errors of metabolism

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